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Classifications

Harrison's Part

Occupational Disease

◆

Subtypes

2

Acute Cadmium Poisoning (Inhalation)

Acute cadmium poisoning from inhalation of cadmium fumes or dust, typically occurring in occupational settings (welding, smelting, silver jewelry manufacturing). Presents with acute lung injury, chemical pneumonitis, pulmonary edema, and potentially fatal respiratory failure. Symptoms may be delayed 12-36 hours after exposure.

Show evidence (2 references)

PMID:16933734 SUPPORT Human Clinical

"Heavy metal inhalation is a rare cause of acute lung injury. Among the various heavy metals, cadmium is more commonly known to cause acute lung injury."

Confirms acute cadmium inhalation as a cause of acute lung injury.

PMID:41000307 SUPPORT Human Clinical

"For patients with concurrent lung and kidney involvement, mechanical ventilation and continuous renal replacement therapy (CRRT) may be required."

Systematic review confirms severe acute presentations requiring ventilatory support.

Chronic Cadmium Poisoning (Itai-itai Disease)

Chronic cadmium toxicity from prolonged low-level exposure via contaminated food, water, or occupational sources. Characterized by progressive renal tubular dysfunction, Fanconi syndrome, hypophosphataemic osteomalacia, osteoporosis, and pathologic fractures. Itai-itai disease represents the most severe form, endemic in cadmium-polluted areas of Japan.

Show evidence (2 references)

PMID:39111871 SUPPORT Human Clinical

"Itai-itai disease is the most severe case of chronic cadmium (Cd) toxicity, which was endemic in Cd-polluted areas in the Jinzu River basin in Toyama prefecture, Japan."

Describes itai-itai disease as the most severe form of chronic cadmium toxicity.

PMID:23800513 SUPPORT Human Clinical

"He was finally diagnosed with chronic cadmium toxicity resulting from long-term occupational exposure."

Case report confirming chronic cadmium toxicity from occupational exposure with renal and skeletal manifestations.

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Discussions and Knowledge Gaps

1

Does cadmium impair osteoblast function and promote osteoclastic resorption directly, independently of the renal phosphate wasting that drives cadmium osteomalacia?

KNOWLEDGE GAP OPEN gap_cadmium_direct_osteoblast_toxicity

Attached to

pathophysiology#Proposed Direct Bone-Cell Toxicity

Cadmium-exposed patients who develop bone disease characteristically also have proximal tubular injury with phosphate wasting, so clinical observations of reduced bone density cannot separate a direct bone-cell effect from the established renal route. No osteoblast-culture or animal skeletal evidence is currently curated in this entry, so the direct arm is recorded as an unresolved mechanism rather than an asserted one.

Proposed experiments

Osteoblast and osteoclast culture under cadmium exposure

exp_cadmium_osteoblast_direct_toxicity

Expose primary or iPSC-derived osteoblasts and osteoclasts to cadmium at concentrations achievable in bone, reading out osteoblast differentiation markers, alkaline phosphatase activity, mineralization, and RANKL/OPG balance, to establish whether cadmium acts on bone cells directly.

Skeletal outcomes with and without renal phosphate wasting

exp_cadmium_bone_loss_independent_of_renal_route

Compare skeletal outcomes in cadmium-exposed animals with and without established renal tubular phosphate wasting, testing whether bone loss still occurs when the renal route is absent or corrected. This is the experiment that would settle the independence claim.

Show evidence (1 reference)

PMID:18072106 SUPPORT Human Clinical

"We will present a case of cadmium induced peripheral neuropathy, nephropathy, and decreased bone density."

The available human observation couples reduced bone density with nephropathy in the same patient, which is exactly why the question of a direct-versus-renal route remains open.

⚙

Pathophysiology

16

Cadmium Absorption and Systemic Distribution

Cadmium enters the body via inhalation of fumes/dust or gastrointestinal absorption from contaminated food and water. Inhaled cadmium is absorbed considerably more efficiently than ingested cadmium, and gastrointestinal uptake is enhanced by iron deficiency via the shared divalent metal transporter 1 (DMT1). Once absorbed, cadmium distributes via the bloodstream bound to albumin and accumulates in liver, kidney, and bone with a biological half-life of 10-30 years.

cellular response to cadmium ion GO:0071276

Downstream

Hepatic Metallothionein Binding Absorbed cadmium is transported to the liver for initial processing

NF-kB/MAPK Inflammatory Signaling Cadmium ions directly activate inflammatory signaling cascades

Proposed Direct Bone-Cell Toxicity Circulating cadmium may have direct toxic effects on bone cells, but independence from renal phosphate wasting remains unresolved.

Hepatic Oxidative Stress Cadmium causes oxidative stress in hepatocytes

Zinc-Finger Displacement and DNA Repair Inhibition Cadmium delivered to tissues enters cells and, as free intracellular Cd(2+), competes for the structural Zn(II) of zinc-finger domains - the entry point of the genotoxic/carcinogenic arm.

Cadmium-Induced Vascular Cholesterol Dysregulation Circulating cadmium disrupts vascular cholesterol homeostasis via miRNA modulation

Show evidence (5 references)

PMID:23800513 SUPPORT Human Clinical

"Cadmium has a long biological half-life and there is no effective treatment for people who are exposed to it."

Confirms cadmium's long biological half-life contributing to progressive systemic accumulation.

PMID:22349354 SUPPORT Human Clinical

"In both cases, multiple organ damage was observed, involving brain, lung, liver, kidney, red blood cells, and platelets"

Autopsy findings confirm systemic cadmium distribution to multiple organs.

PMID:41000307 SUPPORT Human Clinical

"The study also found that low iron stores exacerbate cadmium poisoning."

Confirms that iron deficiency enhances cadmium absorption via shared transport mechanisms.

+ 2 more references

Hepatic Metallothionein Binding

The liver is the primary site of initial cadmium detoxification. Hepatocytes synthesize metallothionein (MT), a cysteine-rich protein that binds cadmium with high affinity. The cadmium-metallothionein (Cd-MT) complex is slowly released into the bloodstream over time. While MT binding initially protects against free cadmium toxicity, the Cd-MT complex is filtered at the glomerulus and taken up by renal tubular cells, effectively transferring the cadmium burden to the kidney.

hepatocyte CL:0000182

detoxification of inorganic compound GO:0061687

liver UBERON:0002107

Downstream

Renal Proximal Tubular Cadmium Uptake Cd-MT complex released from liver is filtered by glomerulus and reabsorbed by proximal tubule

Show evidence (2 references)

PMID:25042840 SUPPORT Model Organism

"This half-life is partly as a result of metallothioneins (MTs), metal-binding proteins with a high affinity for Cd."

Confirms metallothionein as the primary cadmium-binding protein responsible for cadmium's long biological half-life.

PMID:20354761 SUPPORT Other

"The kidney is the main organ affected by chronic Cd exposure and toxicity. Cd accumulates in the kidney as a result of its preferential uptake by receptor-mediated endocytosis of freely filtered and metallothionein bound Cd (Cd-MT) in the renal proximal tubule."

Review confirms that hepatically-produced Cd-MT is filtered and taken up by the kidney, establishing the liver-to-kidney transfer pathway.

Renal Proximal Tubular Cadmium Uptake

The cadmium-metallothionein (Cd-MT) complex is freely filtered at the glomerulus because of its low molecular weight. Proximal tubular epithelial cells reabsorb Cd-MT via receptor-mediated endocytosis through the megalin/cubilin receptor complex. Once internalized, Cd-MT is degraded in lysosomes, releasing free cadmium ions intracellularly. This mechanism explains the kidney's particular vulnerability to cadmium accumulation.

proximal tubule cell CL:0002306

receptor-mediated endocytosis GO:0006898

proximal tubule UBERON:0004134

Downstream

Proximal Tubular Cell Injury Accumulated free cadmium exceeds intracellular metallothionein binding capacity

Show evidence (4 references)

PMID:20204475 SUPPORT In Vitro

"the multiligand endocytic receptors megalin and cubilin take up cadmium-metallothionein complexes via receptor-mediated endocytosis."

Demonstrates that megalin and cubilin receptors mediate the endocytic uptake of Cd-MT complexes in proximal tubule.

PMID:34298880 SUPPORT Model Organism

"Cd2+ complexed to metallothionein (MT) (CdMT) is taken up through receptor-mediated endocytosis (RME) via the PT receptor megalin:cubilin, which is the predominant pathway for reuptake of filtered proteins in the kidney."

Confirms megalin:cubilin as the predominant receptor for Cd-MT uptake in proximal tubule.

PMID:20354761 SUPPORT Other

"Cd accumulates in the kidney as a result of its preferential uptake by receptor-mediated endocytosis of freely filtered and metallothionein bound Cd (Cd-MT) in the renal proximal tubule. Internalised Cd-MT is degraded in endosomes and lysosomes, releasing free Cd(2+) into the cytosol"

Review details the full Cd-MT uptake pathway: glomerular filtration, receptor-mediated endocytosis, lysosomal degradation, and free Cd2+ release.

+ 1 more reference

Proximal Tubular Cell Injury

When intracellular cadmium exceeds the metallothionein binding capacity of proximal tubular cells, free cadmium ions cause oxidative stress, mitochondrial dysfunction, and activation of apoptotic pathways. Cadmium displaces zinc from zinc-finger proteins and disrupts calcium signaling, leading to tubular cell death.

proximal tubule cell CL:0002306

apoptotic process GO:0006915 ↑ INCREASED

proximal tubule UBERON:0004134

Downstream

Impaired Tubular Reabsorption Tubular cell injury and death cause loss of reabsorptive function

Chronic Kidney Disease Progression Sustained tubular injury leads to tubulointerstitial fibrosis

Show evidence (2 references)

PMID:39111871 SUPPORT Human Clinical

"She had chronic renal failure with a high Cd exposure level and advanced renal tubular dysfunction."

Documents advanced renal tubular dysfunction resulting from proximal tubular cell injury in chronic cadmium exposure.

PMID:20354761 SUPPORT Other

"Internalised Cd-MT is degraded in endosomes and lysosomes, releasing free Cd(2+) into the cytosol, where it can generate reactive oxygen species (ROS) and activate cell death pathways."

Review details the mechanism of tubular cell injury: lysosomal release of free Cd2+ generates ROS and activates apoptosis.

Impaired Tubular Reabsorption

Injury to proximal tubular cells causes Fanconi syndrome, characterized by impaired reabsorption of low-molecular-weight proteins (beta-2-microglobulin, retinol-binding protein), glucose, amino acids, uric acid, and phosphate. This is the earliest and most sensitive clinical indicator of chronic cadmium nephrotoxicity, detectable before decline in GFR.

proximal tubule cell CL:0002306

renal tubular reabsorption GO:0070295 ↓ DECREASED

kidney UBERON:0002113

Downstream

Renal Phosphate Wasting Impaired proximal tubular phosphate reabsorption causes phosphaturia

Renal Tubular Dysfunction Loss of proximal tubular reabsorptive function manifests as Fanconi syndrome (renal tubular dysfunction).

Low-Molecular-Weight Proteinuria Impaired receptor-mediated reabsorption of low-molecular-weight proteins (beta-2-microglobulin, retinol-binding protein) produces tubular proteinuria.

Show evidence (4 references)

PMID:23800513 SUPPORT Human Clinical

"We report the case of a 48-year-old man who presented with severe osteoporosis, impaired renal function and acquired Fanconi syndrome."

Case report confirming cadmium-induced acquired Fanconi syndrome with impaired tubular reabsorption.

PMID:20576581 SUPPORT In Vitro

"Cd reduced the transcriptional expression of megalin and ClC5 and, at the same time, increased the degradation of megalin and ClC5 proteins via the lysosomal pathway in an in vitro model of renal proximal tubular cells."

Demonstrates the molecular mechanism: cadmium downregulates megalin and ClC5, the key receptors for protein reabsorption, explaining Fanconi syndrome.

PMID:32244724 SUPPORT In Vitro

"The exposure of S1 and S2 cells to Cd at 1 and 3 µM for 3 days resulted in significant decreases in the uptakes of β2-MG and metallothionein but not in those of albumin or transferrin."

In vitro study directly demonstrates cadmium impairs endocytic uptake of low-molecular-weight proteins at nonlethal concentrations.

+ 1 more reference

Renal Phosphate Wasting

Impaired proximal tubular phosphate reabsorption leads to chronic phosphaturia and hypophosphataemia. The sustained phosphate loss is the primary metabolic driver of cadmium-induced osteomalacia, as phosphate is essential for hydroxyapatite crystal formation in bone.

phosphate ion transport GO:0006817 ⚠ ABNORMAL

proximal tubule UBERON:0004134

Downstream

Hypophosphataemia Sustained renal phosphate loss lowers serum phosphate, producing hypophosphataemia.

Defective Bone Mineralization Chronic hypophosphataemia impairs hydroxyapatite deposition in bone matrix

Show evidence (1 reference)

PMID:31974582 SUPPORT Human Clinical

"Three silversmiths presented similarly with clinical, biochemical and radiological evidence of hypophosphataemic osteomalacia."

Confirms hypophosphataemia from renal phosphate wasting as the driver of cadmium-induced osteomalacia.

Chronic Kidney Disease Progression

Sustained proximal tubular injury from cadmium accumulation leads to tubulointerstitial inflammation, fibrosis, and progressive nephron loss. Glomerular filtration rate declines as tubulointerstitial nephritis advances, ultimately resulting in chronic kidney disease.

kidney UBERON:0002113

Downstream

Chronic Kidney Disease Progressive tubulointerstitial nephritis and nephron loss reduce GFR, producing chronic kidney disease.

Show evidence (2 references)

PMID:39111871 SUPPORT Human Clinical

"She had chronic renal failure with a high Cd exposure level and advanced renal tubular dysfunction."

Documents progression to chronic renal failure from sustained cadmium-induced tubular damage.

PMID:20354761 SUPPORT Other

"Continued and heavy Cd exposure can progress to the clinical renal Fanconi syndrome, and ultimately to renal failure."

Review confirms the progressive nature of cadmium nephrotoxicity from tubular dysfunction to renal failure.

Defective Bone Mineralization

Chronic hypophosphataemia from renal phosphate wasting impairs hydroxyapatite crystal deposition in osteoid, causing osteomalacia. Bone becomes soft and prone to deformation and pathologic fractures. In itai-itai disease, severe demineralization causes fractures from minimal trauma, height loss, and skeletal deformities.

bone mineralization GO:0030282 ↓ DECREASED

bone UBERON:0002481

Downstream

Osteomalacia Impaired hydroxyapatite deposition in osteoid produces osteomalacia (soft, undermineralized bone).

Bone Pain Osteomalacia and resulting pathologic fractures produce the severe bone pain characteristic of itai-itai disease.

Show evidence (2 references)

PMID:31974582 SUPPORT Human Clinical

"Three silversmiths presented similarly with clinical, biochemical and radiological evidence of hypophosphataemic osteomalacia."

Confirms defective bone mineralization causing osteomalacia in cadmium-exposed workers.

PMID:39111871 SUPPORT Human Clinical

"The shortening of height, bone deformities and fractures, abnormal bone metabolism suggesting osteomalacia, and renal anemia were also noted."

Documents skeletal consequences of defective mineralization in itai-itai disease.

Proposed Direct Bone-Cell Toxicity

A direct skeletal arm of cadmium toxicity is proposed alongside the renal phosphate-wasting route: cadmium is held to act on bone cells themselves, reducing osteoblast function and favouring osteoclastic resorption. The evidence currently curated here does NOT establish that arm — the only human observation available is reduced bone density in an occupationally exposed patient who also had nephropathy, so the renal route is not excluded and the claim of independence from phosphate wasting is not supported. Cell-level (osteoblast culture or animal) evidence is needed before this node asserts a direct mechanism; see the attached knowledge gap.

osteoblast CL:0000062

bone UBERON:0002481

Downstream

Defective Bone Mineralization A direct bone-cell contribution could compound the established mineralization defect from phosphate wasting, but is not yet demonstrated by the curated evidence.

Osteoporosis A direct bone-cell contribution to reduced bone density is proposed but cannot be separated from nephropathy in the currently curated human evidence.

Show evidence (1 reference)

PMID:18072106 SUPPORT Human Clinical

"We will present a case of cadmium induced peripheral neuropathy, nephropathy, and decreased bone density."

Documents reduced bone density in a cadmium-exposed patient. Marked PARTIAL: the same patient had nephropathy, so this single clinical observation cannot separate a direct bone-cell effect from the renal phosphate-wasting route, and cannot support the independence claim.

Hepatic Oxidative Stress

Cadmium disrupts the hepatic redox balance: animal studies show reduced activity of the antioxidant enzymes SOD, GSH-Px, and CAT together with increased lipid peroxidation (elevated MDA). Note the evidence curated here measures antioxidant ENZYME activity rather than glutathione stores themselves, and one study reports cadmium triggering a hepatic antioxidant RESPONSE - so "depletion" is the interpretation placed on these readouts, not a directly measured finding. The claim that cadmium alters cytochrome P450 drug metabolism is not evidenced in this entry.

hepatocyte CL:0000182

glutathione metabolic process GO:0006749 ⚠ ABNORMAL

liver UBERON:0002107

Downstream

Hepatocyte Apoptosis Oxidative stress from glutathione depletion triggers apoptotic cell death

Show evidence (3 references)

PMID:39381600 SUPPORT Model Organism

"liver SOD, GSH-Px, T-AOC and CAT levels were decreased, and MDA level was increased in Cd-treated goats, and 630 DEPs (up 326, down 304) in the livers of Cd-treated goats."

Proteomic study in goats confirms cadmium-induced hepatic antioxidant depletion.

PMID:40164036 SUPPORT Model Organism

"exercise significantly decreased blood ALT and AST levels, alleviating oxidative stress in the liver by reducing MDA synthesis and enhancing SOD and GSH-PX activities."

Mouse model demonstrates cadmium-induced hepatic oxidative stress with depleted antioxidant enzymes.

PMID:41188353 SUPPORT Model Organism

"Cd exposure altered hepatic lipid homeostasis via the perturbation of steatosis gene expression and lipid species abundances. Additionally, Cd exposure triggered a hepatic antioxidant response"

Mouse model demonstrates cadmium triggers hepatic antioxidant response and disrupts lipid homeostasis, consistent with oxidative stress-driven liver injury.

Hepatocyte Apoptosis

Sustained oxidative stress from glutathione depletion triggers hepatocyte apoptosis via mitochondrial pathways. Cadmium causes release of pro-apoptotic proteins (cytochrome c, caspase-3, Bax) and nuclear damage, leading to progressive hepatocellular loss and liver injury.

hepatocyte CL:0000182

apoptotic process GO:0006915 ↑ INCREASED

liver UBERON:0002107

Show evidence (1 reference)

PMID:40164036 SUPPORT Model Organism

"Exercise inhibited nuclear damage and hepatocyte apoptosis caused by Cd by increasing Bcl-2 protein expression and preventing the release of pro-apoptotic proteins such as caspase-3, Cytc, Bax, caspase-8and cleaved-caspase-3."

Mouse model demonstrates cadmium-induced hepatocyte apoptosis via pro-apoptotic protein release.

NF-kB/MAPK Inflammatory Signaling

Cadmium activates pro-inflammatory signaling cascades including the NF-kB and MAPK/JNK pathways, leading to increased secretion of pro-inflammatory cytokines (IL-1beta, IL-6, TNF-alpha, IL-8, CCL2) and upregulation of COX-2. This chronic inflammatory state exacerbates organ-specific injury in kidney, liver, and intestine.

inflammatory response GO:0006954 ↑ INCREASED

Downstream

Proximal Tubular Cell Injury Inflammatory cytokines exacerbate tubular cell damage

Hepatic Oxidative Stress Inflammatory mediators compound hepatic oxidative stress

Show evidence (2 references)

PMID:40191670 SUPPORT In Vitro

"the environmental pollutant cadmium is known to increase the secretion of pro-inflammatory cytokines, including interleukin (IL)-6, IL-8, and chemokine (C-C motif) ligand 2 (CCL2) by activating the mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) pathways."

In vitro study demonstrates cadmium activation of MAPK and NF-kB inflammatory pathways with cytokine secretion.

PMID:40164036 SUPPORT Model Organism

"exercise, both before and during Cd exposure, can reduce Cd caused pathological damages in the liver and duodenum of mice, suppressing the expression levels of the IL-1β, IL-6 and TNF-α genes."

Mouse model confirms cadmium-induced expression of pro-inflammatory cytokines IL-1β, IL-6, and TNF-α.

Cadmium-Induced Vascular Cholesterol Dysregulation

Cadmium disrupts cholesterol homeostasis in the vascular wall, promoting atherosclerosis through miRNA-mediated dysregulation of cholesterol uptake (CD36), efflux (ABCA1), and hydrolysis (NCEH1). Cadmium upregulates miR-30d-5p and downregulates miR-504-3p, promoting foam cell formation and intracellular lipid accumulation in macrophages. This pathway links cadmium exposure to increased cardiovascular risk, particularly ischemic stroke.

cholesterol homeostasis GO:0042632 ⚠ ABNORMAL

Show evidence (3 references)

PMID:41297938 SUPPORT Model Organism

"Cd exposure, even at a relatively low dosage (4 mg/L), significantly facilitates the progression of atherosclerosis in apolipoprotein E-deficient mice fed a high-fat diet. This pro-atherogenic effect was accompanied by comprehensive disturbances in systemic and vascular cholesterol homeostasis"

Mouse model demonstrates cadmium promotes atherosclerosis through disruption of systemic and vascular cholesterol homeostasis, even at low doses.

PMID:41297938 SUPPORT Model Organism

"we identified miR-30d-5p and miR-504-3p as novel epigenetic regulators mediating Cd-induced foam cell formation. Specifically, Cd treatment upregulated miR-30d-5p and downregulated miR-504-3p, which directly targeted NCEH1 and CD36, respectively, thereby promoting intracellular lipid accumulation."

Identifies the molecular mechanism: cadmium modulates specific miRNAs that regulate cholesterol handling genes, driving foam cell formation and atherosclerotic plaque development.

PMID:41297938 SUPPORT Human Clinical

"plasma miR-30d-5p levels were positively associated with Cd exposure and partially mediated the Cd-stroke association, accounting for 16.4% of the total effect."

Human case-control study (494 ischemic stroke patients vs 494 controls) validates miR-30d-5p as a mediator of cadmium-induced stroke risk.

Acute Pulmonary Injury

Inhalation of cadmium fumes causes acute chemical pneumonitis with diffuse alveolar damage, pulmonary edema, and potentially fatal respiratory failure. Cadmium oxide fumes are particularly hazardous, causing delayed-onset (12-36 hours) acute lung injury that may progress to ARDS.

type II pneumocyte CL:0002063

inflammatory response GO:0006954 ↑ INCREASED

lung UBERON:0002048

Downstream

Acute Respiratory Distress Syndrome Diffuse alveolar damage and pulmonary edema from cadmium fume inhalation progress to acute respiratory distress syndrome.

Show evidence (2 references)

PMID:16933734 SUPPORT Human Clinical

"Heavy metal inhalation is a rare cause of acute lung injury. Among the various heavy metals, cadmium is more commonly known to cause acute lung injury."

Case report of acute lung injury from cadmium fume inhalation.

PMID:22349354 SUPPORT Human Clinical

"In both cases, multiple organ damage was observed, involving brain, lung, liver, kidney, red blood cells, and platelets"

Fatal cadmium poisoning cases with pulmonary involvement among multi-organ damage.

Zinc-Finger Displacement and DNA Repair Inhibition

Cadmium is a weak direct mutagen; its genotoxicity is largely indirect and runs through the zinc-finger fold. Cd(2+) substitutes for the structural Zn(II) held tetrahedrally by cysteine thiolates and histidine imidazoles in zinc-finger domains, and cadmium-driven oxidative stress independently oxidises those thiolate donors. Because several DNA-repair proteins (nucleotide-excision and mismatch-repair components) are zinc-finger proteins, the displacement inhibits repair without altering the underlying gene sequence - a loss-of-function-like lesion imposed on the proteome rather than encoded in the genome. This node is the mechanistic bridge from the systemic cadmium burden to the carcinogenic arm, and is why cadmium behaves as a co-mutagen and repair inhibitor rather than as a classical DNA-adduct-forming carcinogen.

DNA repair GO:0006281 ↓ DECREASED

zinc ion binding GO:0008270 ⚠ ABNORMAL

Downstream

Cadmium-Associated Carcinogenesis Impaired repair fidelity allows damage from cadmium-driven oxidative stress and from co-exposures to persist and accumulate, the substrate for malignant transformation.

Show evidence (3 references)

PMID:16310985 SUPPORT In Vitro

"soluble compounds of definite carcinogenic metals and metalloids, such as arsenic, cadmium and nickel, and putative carcinogens, including cobalt and lead, inhibit zinc finger containing DNA repair proteins"

Cell-culture and ex vivo work showing cadmium inhibits zinc-finger-containing DNA repair proteins, the molecular lesion this node models.

PMID:16310985 SUPPORT In Vitro

"Zinc fingers can thus be compromised by a substitution of Zn(II) with another metal ion"

States the substitution mechanism - a competing divalent cation replacing the structural Zn(II) - that makes cadmium a zinc-finger poison.

PMID:38922068 SUPPORT Other

"The epigenetic effects of Cd, including DNA methylation and histone modifications, are also explored to explain its long-term impact on gene expression and disease manifestation"

Review situating cadmium's epigenetic dysregulation alongside the genotoxic arm as a second route to long-term altered gene expression. Evidence source is OTHER because this is a review article.

Cadmium-Associated Carcinogenesis

Cadmium and its compounds have been classified by IARC as carcinogenic to humans (Group 1) since 1993, on the strength of excess lung cancer in occupationally exposed cohorts together with animal tumour data. The contemporary evidence base, reviewed across biological-sample studies, supports a causal role at the lung, pancreas and bladder, with total cancer risk and mortality correlating with measured cadmium body burden. Site attribution is deliberately not curated uniformly: the prostate association was not confirmed on cohort update, and breast and prostate evidence remains weak or inconclusive. Latency is that of chemical carcinogenesis - years to decades - which is why this arm is a feature of chronic rather than acute cadmium poisoning.

lung UBERON:0002048 pancreas UBERON:0001264 urinary bladder UBERON:0001255

Downstream

Cadmium-Associated Lung Neoplasm The site on which the IARC Group 1 designation principally rests, evidenced in occupationally exposed worker cohorts.

Cadmium-Associated Pancreatic Neoplasm One of the three sites for which the contemporary biological-sample evidence base supports a causal role.

Cadmium-Associated Bladder Neoplasm One of the three sites for which the contemporary biological-sample evidence base supports a causal role.

Show evidence (3 references)

PMID:12746140 SUPPORT Human Clinical

"Cadmium (Cd) and its compounds were classified as "carcinogenic to humans (Group 1)" by IARC in 1993"

Establishes the IARC Group 1 classification and its basis in cadmium-exposed worker cohorts.

PMID:38480109 SUPPORT Human Clinical

"Current data consistently suggest a causal role of exposure to cadmium in pancreas, lung, and bladder carcinogenesis."

Systematic review of 9 meta-analyses and 57 original articles giving the sites where a causal role is currently supported.

PMID:12746140 SUPPORT Human Clinical

"The association between cadmium exposure and prostate cancer was not confirmed in the latest available updates."

Carried as a qualification, not a refutation of the node: the same review that establishes the Group 1 classification withdraws support for the prostate site specifically, which is why site attribution here is not uniform.

✶

Histopathology

5

Diffuse Alveolar Damage

Acute cadmium inhalation produces acute lung injury, and the lung is a confirmed target organ at autopsy in fatal poisoning. Diffuse alveolar damage is the expected histological correlate of the clinical acute respiratory distress syndrome, but the specific microscopic features often attributed to it here (hyaline membranes, alveolar edema, type II pneumocyte hyperplasia) are NOT documented in the sources curated for this entry; they are stated as the general ARDS pattern, not as an observed cadmium finding.

Show evidence (2 references)

PMID:22349354 SUPPORT Human Clinical

"In both cases, multiple organ damage was observed, involving brain, lung, liver, kidney, red blood cells, and platelets"

Autopsy of two fatal cadmium poisoning cases confirms the lung as a target organ. Marked PARTIAL: the report describes organ involvement, not the alveolar histology asserted in the node description.

PMID:16933734 SUPPORT Human Clinical

"Heavy metal inhalation is a rare cause of acute lung injury. Among the various heavy metals, cadmium is more commonly known to cause acute lung injury."

Supports cadmium inhalation as a cause of acute lung injury. Marked PARTIAL: this is the clinical syndrome, not a histological description.

Renal Tubulointerstitial Disease and Fibrosis

The kidneys show proximal tubular cell necrosis with loss of brush border, tubulointerstitial inflammatory infiltrates, and progressive fibrosis. Cadmium accumulates in the renal cortex. Both cadmium and lead nephropathies are characterized by tubulointerstitial disease and fibrosis, though only early lead nephropathy shows nuclear inclusion bodies.

Show evidence (2 references)

PMID:22349354 SUPPORT Human Clinical

"In both cases, multiple organ damage was observed, involving brain, lung, liver, kidney, red blood cells, and platelets"

Autopsy confirms the kidney as a target organ. Marked PARTIAL: the report does not describe the tubulointerstitial fibrosis asserted here, which rests on the second citation.

PMID:19106433 SUPPORT Other

"both entities are characterized by tubulointerstitial disease and fibrosis, but only early lead nephropathy is characterized by the presence of proximal tubule nuclear inclusion bodies, due to the combination of lead with a lead binding-protein."

Review confirms tubulointerstitial disease and fibrosis as the characteristic renal histopathology of cadmium nephropathy, and distinguishes it from lead nephropathy by the absence of nuclear inclusion bodies.

Hepatocellular Degeneration

The liver is a confirmed cadmium target organ: postmortem and biopsy analysis shows gross cadmium excess in hepatic tissue, and human epidemiological data link cadmium exposure to hepatic fibrosis. Cadmium accumulates in hepatocytes bound to metallothionein, and when that binding capacity is overwhelmed free cadmium causes oxidative damage and cell death. Note that frank hepatocellular degeneration and necrosis is the expected consequence of that mechanism rather than a microscopic finding documented in the sources curated here — the human evidence in this entry establishes cadmium accumulation and fibrosis, not necrosis histology.

Show evidence (3 references)

PMID:22349354 SUPPORT Human Clinical

"In both cases, multiple organ damage was observed, involving brain, lung, liver, kidney, red blood cells, and platelets"

Autopsy confirms the liver as a target organ. Marked PARTIAL: the report does not describe hepatocellular degeneration or necrosis on microscopy.

PMID:7426480 SUPPORT Human Clinical

"Examination of the liver both in life and after death showed a gross excess of cadmium. This was also found in the kidneys after death."

Liver biopsy and postmortem analysis confirmed gross cadmium accumulation in hepatic tissue.

PMID:41412331 SUPPORT Human Clinical

"Cadmium exposure affects liver health by inhibiting steatosis and promoting fibrosis, with renal and lipid metabolism factors acting as mediators, and diet influencing the outcomes."

NHANES cross-sectional study in adolescents demonstrates cadmium exposure promotes hepatic fibrosis, providing human epidemiological evidence for cadmium-induced hepatocellular damage.

Osteomalacic Bone Changes

Bone biopsy shows widened osteoid seams with defective mineralization, consistent with osteomalacia. In severe cases (itai-itai disease), vertebral bodies show structural changes from gross deformity. Bone biopsies are essential for confirming the diagnosis of osteomalacia in cadmium-exposed patients.

Show evidence (2 references)

PMID:7426480 SUPPORT Human Clinical

"Several bone biopsies and detailed metabolic studies showed typical severe osteomalacia"

Multiple bone biopsies in a cadmium-exposed worker confirmed typical severe osteomalacia on histological examination.

PMID:7426480 SUPPORT Human Clinical

"Previously unreported changes were present in the bones, especially the lumbar vertebrae which were probably more the result of gross bone deformity than cadmium deposition."

Histopathological examination revealed novel structural changes in vertebral bone, attributed to mechanical deformity from osteomalacia rather than direct cadmium deposition.

Intracellular Dense Lysosomal Particles

Transmission electron microscopy reveals a large number of dense lysosomal and phagocytic particles in the cytoplasm near the nucleus. This ultrastructural finding is observed across multiple organs and suggests intracellular cadmium sequestration in lysosomes, with potential genotoxic implications from proximity to the nucleus.

Show evidence (1 reference)

PMID:22349354 SUPPORT Human Clinical

"transmission electron microscopy revealed a large number of dense lysosomal and phagocytic particles in the cytoplasm near the nucleus, indicating the need for a genotoxic study of cadmium."

Ultrastructural finding on TEM showing characteristic perinuclear lysosomal cadmium accumulation, a distinctive histopathological marker of cadmium toxicity.

⬡

Pathograph

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●

Phenotypes

12

Digestive 1

Cadmium-Associated Pancreatic Neoplasm Neoplasm of the pancreas HP:0002894

Show evidence (2 references)

PMID:38480109 SUPPORT Human Clinical

"Current data consistently suggest a causal role of exposure to cadmium in pancreas, lung, and bladder carcinogenesis."

Names this site among the three for which a causal role of cadmium exposure is currently supported.

PMID:38480109 SUPPORT Human Clinical

"The evidence is weak or inconclusive for the remaining cancer sites (including breast and prostate)"

Carried on each site entry as the boundary of the claim, so no single one is read as licensing a uniform cadmium-cancer association across all sites.

Genitourinary 4

Renal Tubular Dysfunction HP:0000124

Show evidence (2 references)

PMID:39111871 SUPPORT Human Clinical

"She had chronic renal failure with a high Cd exposure level and advanced renal tubular dysfunction."

Documents renal tubular dysfunction as a key manifestation of chronic cadmium exposure.

PMID:23800513 SUPPORT Human Clinical

"We report the case of a 48-year-old man who presented with severe osteoporosis, impaired renal function and acquired Fanconi syndrome."

Confirms acquired Fanconi syndrome from chronic cadmium toxicity.

Low-Molecular-Weight Proteinuria HP:0000093

Show evidence (2 references)

PMID:20354761 SUPPORT Other

"An early and sensitive manifestation of chronic Cd renal toxicity, which can be useful in individual and population screening, is impaired reabsorption of low molecular weight proteins (LMWP) (also a receptor-mediated process in the proximal tubule) such as retinol binding protein (RBP). This..."

Review identifies LMW proteinuria as the earliest and most sensitive marker of cadmium nephrotoxicity, suitable for population screening.

PMID:19106433 SUPPORT Other

"Cadmium nephrotoxicity is heralded by increased excretion of beta2-microglobulin, retinol binding protein and alpha1-microglobulin, indicative of decreased proximal tubule function."

Confirms the specific LMW proteins excreted in cadmium nephrotoxicity: beta-2-microglobulin, retinol binding protein, and alpha-1-microglobulin.

Chronic Kidney Disease HP:0012622

Show evidence (1 reference)

PMID:39111871 SUPPORT Human Clinical

"She had chronic renal failure with a high Cd exposure level and advanced renal tubular dysfunction."

Documents chronic renal failure from cadmium exposure.

Cadmium-Associated Bladder Neoplasm HP:0009725

Show evidence (2 references)

PMID:38480109 SUPPORT Human Clinical

"Current data consistently suggest a causal role of exposure to cadmium in pancreas, lung, and bladder carcinogenesis."

Names this site among the three for which a causal role of cadmium exposure is currently supported.

PMID:38480109 SUPPORT Human Clinical

"The evidence is weak or inconclusive for the remaining cancer sites (including breast and prostate)"

Carried on each site entry as the boundary of the claim, so no single one is read as licensing a uniform cadmium-cancer association across all sites.

Metabolism 1

Hypophosphataemia Hypophosphatemia HP:0002148

Show evidence (1 reference)

PMID:31974582 SUPPORT Human Clinical

"Three silversmiths presented similarly with clinical, biochemical and radiological evidence of hypophosphataemic osteomalacia."

Confirms hypophosphataemia as the metabolic derangement underlying cadmium-induced osteomalacia.

Musculoskeletal 2

Osteomalacia HP:0002749

Show evidence (2 references)

PMID:31974582 SUPPORT Human Clinical

"Three silversmiths presented similarly with clinical, biochemical and radiological evidence of hypophosphataemic osteomalacia."

Confirms hypophosphataemic osteomalacia from occupational cadmium exposure.

PMID:39111871 SUPPORT Human Clinical

"The shortening of height, bone deformities and fractures, abnormal bone metabolism suggesting osteomalacia, and renal anemia were also noted."

Documents osteomalacia with bone deformities and fractures in itai-itai disease.

Osteoporosis HP:0000939

Show evidence (2 references)

PMID:23800513 SUPPORT Human Clinical

"We report the case of a 48-year-old man who presented with severe osteoporosis, impaired renal function and acquired Fanconi syndrome."

Case report of severe osteoporosis from chronic cadmium toxicity.

PMID:18072106 SUPPORT Human Clinical

"We will present a case of cadmium induced peripheral neuropathy, nephropathy, and decreased bone density."

Confirms decreased bone density (osteoporosis) from cadmium exposure.

Nervous System 1

Peripheral Neuropathy HP:0009830

Show evidence (2 references)

PMID:18072106 SUPPORT Human Clinical

"Cadmium is a neurotoxic and nephrotoxic heavy metal"

Identifies cadmium as a neurotoxic heavy metal causing peripheral neuropathy.

PMID:41453694 SUPPORT Other

"lead (Pb), cadmium (Cd), and arsenic (As) are pervasive environmental toxicants capable of entering the human body via multiple exposure routes, leading to profound neurotoxic effects."

Review of heavy metal neurotoxicity confirms cadmium produces profound neurotoxic effects through multiple exposure routes.

Respiratory 1

Acute Respiratory Distress Syndrome HP:0033677

Primarily in acute inhalation exposure

Show evidence (2 references)

PMID:16933734 SUPPORT Human Clinical

"Heavy metal inhalation is a rare cause of acute lung injury. Among the various heavy metals, cadmium is more commonly known to cause acute lung injury."

Confirms cadmium as a cause of acute lung injury from inhalation.

PMID:41000307 SUPPORT Human Clinical

"For patients with concurrent lung and kidney involvement, mechanical ventilation and continuous renal replacement therapy (CRRT) may be required."

Systematic review confirms severe pulmonary involvement requiring mechanical ventilation.

Constitutional 1

Bone Pain HP:0002653

Show evidence (2 references)

PMID:19341754 SUPPORT Human Clinical

"a bone disease with fractures and severe pain, the itai-itai disease, a form of Cd-induced renal osteomalacia, was identified in Japan."

Historical review identifies severe bone pain as the defining symptom of itai-itai disease, the archetypal chronic cadmium poisoning syndrome.

PMID:7426480 SUPPORT Human Clinical

"during the last 12 years of his life the patient had suffered increasing disability from gross bone disease. Several bone biopsies and detailed metabolic studies showed typical severe osteomalacia"

Case report documents 12 years of progressive bone pain and disability from cadmium-induced osteomalacia in an occupationally exposed worker.

Neoplasm 1

Cadmium-Associated Lung Neoplasm Neoplasm of the lung HP:0100526

Show evidence (4 references)

PMID:38480109 SUPPORT Human Clinical

"Current data consistently suggest a causal role of exposure to cadmium in pancreas, lung, and bladder carcinogenesis."

Names this site among the three for which a causal role of cadmium exposure is currently supported.

PMID:38480109 SUPPORT Human Clinical

"The evidence is weak or inconclusive for the remaining cancer sites (including breast and prostate)"

Carried on each site entry as the boundary of the claim, so no single one is read as licensing a uniform cadmium-cancer association across all sites.

PMID:38480109 SUPPORT Human Clinical

"Total cancer risk and mortality are also positively correlated with Cd levels in biological samples"

Supports the dose-related nature of the association, measured as cadmium in blood, urine, nails or hair rather than as modelled exposure.

+ 1 more reference

🧬

Genetic Associations

5

SLC39A8 (ZIP8, a zinc/bicarbonate symporter expressed in the S3 segment of the renal proximal tubule, is one of the apical transporters through which cadmium enters tubular cells. It is a toxicokinetic determinant of how much filtered cadmium is reabsorbed rather than excreted, not a cause of the disease.)

Gene: SLC39A8 hgnc:20862 relationship_type: SUSCEPTIBILITY

Show evidence (3 references)

PMID:22534978 SUPPORT In Vitro

"The knockdown of ZIP8, ZIP14 or DMT1 by siRNA transfection significantly reduced the uptake of Cd(2+) and Mn(2+) from the apical membrane."

siRNA knockdown establishes ZIP8 as a functional route of apical cadmium uptake in proximal tubule cells; no single transporter dominates.

PMID:22534978 SUPPORT In Vitro

"ZIP8 and ZIP14 expressed in the S3 segment of proximal tubules play significant roles in the absorption of Cd(2+) and Mn(2+) in the kidney"

Localises the transporter to the S3 segment, the nephron site where cadmium accumulates and where the proximal tubular injury of this disease begins.

PMID:35784893 SUPPORT In Vitro

"the single-nucleotide polymorphism (SNP) variant A391T (rs13107325) is associated with numerous human traits"

Establishes that a common functional variant of this transporter exists and is phenotypically consequential. PARTIAL because the traits studied are blood pressure and insulin resistance, not cadmium handling - the link to cadmium susceptibility is inferred from the transporter's role, not measured.

SLC39A14 (ZIP14 acts alongside ZIP8 in the S3 segment of the proximal tubule as a route of apical cadmium uptake, contributing to renal cadmium accumulation.)

Gene: SLC39A14 hgnc:20858 relationship_type: SUSCEPTIBILITY

Show evidence (1 reference)

PMID:22534978 SUPPORT In Vitro

"ZIP8 and ZIP14 expressed in the S3 segment of proximal tubules play significant roles in the absorption of Cd(2+) and Mn(2+) in the kidney"

Directly assigns ZIP14 a significant role in renal cadmium absorption at the segment where cadmium concentrates.

SLC11A2 (DMT1 is the iron-cadmium shared divalent metal transporter. It is the molecular basis of the best-documented gene-environment interaction in this disease: intestinal DMT1 is upregulated in iron deficiency, so iron-deplete individuals absorb more cadmium from an identical dietary dose. It also contributes to apical cadmium uptake in the renal proximal tubule.)

Gene: SLC11A2 hgnc:10908 relationship_type: SUSCEPTIBILITY

Show evidence (2 references)

PMID:22534978 SUPPORT In Vitro

"The knockdown of ZIP8, ZIP14 or DMT1 by siRNA transfection significantly reduced the uptake of Cd(2+) and Mn(2+) from the apical membrane."

Establishes DMT1 as a functional cadmium uptake route in proximal tubule cells, complementing its better-known intestinal role.

PMID:20204475 SUPPORT In Vitro

"uptake of free Cd(2+) has been demonstrated for the Fe(2+)/H(+) cotransporter divalent metal transporter 1."

Identifies DMT1 as the iron cotransporter that also carries free cadmium, the shared-route mechanism behind the iron-deficiency interaction.

MT1A (Metallothionein sequesters cadmium as the relatively inert Cd-metallothionein complex and is the body's principal endogenous defence against free Cd(2+). Individual differences in inducible metallothionein capacity set where the balance falls between safe storage and free-ion toxicity at a given body burden.)

Gene: MT1A hgnc:7393 relationship_type: MODIFIER

Show evidence (2 references)

PMID:19834257 SUPPORT Human Clinical

"Cadmium accumulates in the renal cortex by the long-term exposure along with increased concentrations of metallothionein, an important protein for protection from cadmium toxicity."

States metallothionein's protective role and its co-accumulation with cadmium in the renal cortex, the target organ of chronic toxicity.

PMID:19834257 SUPPORT Human Clinical

"some individuals have lower metallothionein levels despite increased cadmium accumulation in the kidneys"

Documents the inter-individual variation in metallothionein response that makes this a susceptibility modifier rather than a uniform protective factor.

MT2A (MT2A encodes the other major inducible metallothionein isoform binding cadmium in liver and kidney; the same individual-capacity argument applies as for MT1A.)

Gene: MT2A hgnc:7406 relationship_type: MODIFIER

Show evidence (1 reference)

PMID:19834257 SUPPORT Human Clinical

"some individuals have lower metallothionein levels despite increased cadmium accumulation in the kidneys"

Same inter-individual metallothionein variation applies to the MT2A isoform; the cited work does not resolve the isoforms separately.

💊

Medical Actions

5

Chelation Therapy

Action: chelation therapy Ontology label: Pharmacotherapy NCIT:C15986

Agent: Edetic Acid NCIT:C61742 succimer CHEBI:63623 2,3-disulfanylpropane-1-sulfonic acid CHEBI:888

Chelating agents (CaNa2-EDTA, DMSA, DMPS) are used to bind and promote urinary excretion of cadmium. Effectiveness is limited due to cadmium's tight binding to metallothionein and intracellular sequestration. BAL (dimercaprol) is generally avoided: in rat experiments BAL given shortly after cadmium exposure increased renal cadmium deposition, redistributing the metal toward the critical target organ. The same work shows the effect is timing-dependent — BAL given 24 hours after exposure, once metallothionein has been induced, mobilized hepatic cadmium into bile without raising renal cadmium — so this is an animal-derived caution about early administration rather than a demonstrated clinical contraindication in humans.

Show evidence (4 references)

PMID:41000307 SUPPORT Human Clinical

"The treatment plan includes the use of chelating agents to reduce cadmium levels in the body and antibiotics to maintain the patient's condition."

Systematic review confirms chelating agents as part of standard cadmium poisoning treatment.

PMID:41453694 SUPPORT Other

"Conventional chelation therapy, when used long-term, can lead to renal and gastrointestinal diseases."

Review highlights significant limitations of conventional chelation therapy, noting long-term use can itself cause renal and gastrointestinal toxicity.

PMID:6734559 SUPPORT Model Organism

"The renal deposition of Cd increased on BAL (2,3-dimercaptopropanol) treatment a short time (1/2 hr) after Cd exposure."

Rat data are the basis for avoiding early BAL in cadmium exposure; marked PARTIAL because this is an animal redistribution finding, not a clinical outcome study.

+ 1 more reference

Phosphate Supplementation

Action: Pharmacotherapy NCIT:C15986

Agent: phosphate CHEBI:26020

Neutral phosphate supplements to correct hypophosphataemia from renal phosphate wasting. Phosphate replacement is essential for treating the underlying metabolic defect driving cadmium-induced osteomalacia and results in significant symptom improvement when combined with calcitriol.

Show evidence (1 reference)

PMID:31974582 SUPPORT Human Clinical

"They were initiated on neutral phosphate and calcitriol. On follow-up, they reported significant reduction in severity of symptoms."

Demonstrates effectiveness of phosphate supplementation (combined with calcitriol) for cadmium-induced osteomalacia.

Vitamin D and Calcium Supplementation

Action: vitamin D supplementation Ontology label: Nutritional Supplementation NCIT:C15425

Calcitriol (active vitamin D) supplementation to treat osteomalacia, bypassing the impaired renal 1-alpha-hydroxylation caused by cadmium nephrotoxicity. Calcium supplementation may also be required to address secondary hyperparathyroidism and calcium malabsorption.

Show evidence (3 references)

PMID:31974582 SUPPORT Human Clinical

"They were initiated on neutral phosphate and calcitriol. On follow-up, they reported significant reduction in severity of symptoms."

Demonstrates effectiveness of calcitriol for cadmium-induced osteomalacia.

PMID:41000307 SUPPORT Human Clinical

"for patients with osteochondropathy, supplementation with calcium and vitamin D is recommended."

Systematic review recommends calcium and vitamin D supplementation for skeletal complications.

PMID:7426480 SUPPORT Human Clinical

"typical severe osteomalacia, which responded well initially to calcium and vitamin D treatment."

Case report confirms initial good response to calcium and vitamin D in cadmium-induced osteomalacia.

Supportive ICU Care

Action: supportive care Ontology label: Supportive Care NCIT:C15747

For acute cadmium inhalation with pulmonary involvement, intensive care including mechanical ventilation for ARDS and continuous renal replacement therapy (CRRT) for concurrent renal failure may be required.

Show evidence (1 reference)

PMID:41000307 SUPPORT Human Clinical

"For patients with concurrent lung and kidney involvement, mechanical ventilation and continuous renal replacement therapy (CRRT) may be required."

Systematic review confirms need for ICU-level care in severe acute cadmium poisoning.

Exposure Cessation and Prevention

Removal from cadmium exposure source is essential. Occupational hygiene measures include adequate ventilation, personal protective equipment, and workplace monitoring. Public health interventions include environmental remediation of contaminated soil and water, and regulatory limits on cadmium in food and consumer products.

Show evidence (2 references)

PMID:23800513 SUPPORT Human Clinical

"Therefore, an early diagnosis and prevention of further exposure are important."

Emphasizes the importance of preventing further cadmium exposure given lack of effective treatment.

PMID:31974582 SUPPORT Human Clinical

"regulatory agencies and policy makers ought to survey the silver industry and ensure that the metals used are within permissible safe limits of exposure."

Calls for occupational regulation to prevent cadmium exposure in the silver industry.

🌍

Environmental Factors

4

Occupational Cadmium Exposure

Hazard type: CHEMICAL

Route: INHALATION

Duration: CHRONIC ACUTE

IARC group: GROUP 1

GHS hazard class: CARCINOGENICITY STOT REPEATED EXPOSURE

Exposome domain: SPECIFIC EXTERNAL

Occupational exposure occurs in silver jewelry manufacturing, zinc smelting, battery production, cadmium plating, welding of cadmium-containing alloys, and pigment manufacturing. Workers inhale cadmium fumes and dust, with the silver cottage industry in developing countries being particularly hazardous due to lack of protective measures.

Show evidence (3 references)

PMID:18072106 SUPPORT Human Clinical

"Silver is mixed with cadmium and then used to make silver jewelry. During this process there is a formation of cadmium fumes, and the workers inhale the fumes."

Describes the mechanism of occupational cadmium exposure in the silver jewelry industry.

PMID:31974582 SUPPORT Human Clinical

"We highlight the occurrence of hypophosphataemic osteomalacia due to chronic cadmium exposure in the silver industry in India."

Confirms the silver industry as a source of chronic cadmium exposure.

PMID:41000307 SUPPORT Human Clinical

"cadmium poisoning primarily affects adult males and is often associated with occupational exposure."

Systematic review confirms occupational exposure as the primary route of cadmium poisoning.

Mechanism Target:

TRIGGERS Cadmium Absorption and Systemic Distribution — Industrial processes generate cadmium fume and dust that workers inhale, and inhaled cadmium is the higher-bioavailability route into the body at this node.

Show evidence (1 reference)

PMID:18072106 SUPPORT Human Clinical

"Silver is mixed with cadmium and then used to make silver jewelry. During this process there is a formation of cadmium fumes, and the workers inhale the fumes."

Documents cadmium fume formation during silver jewelry manufacture and its inhalation by workers, the occupational inhalational route into the body.

TRIGGERS Acute Pulmonary Injury — High-dose fume inhalation injures the alveolar epithelium directly at the portal of entry, without requiring the systemic accumulation that drives the chronic renal and skeletal arms. This is why acute cadmium poisoning presents as a lung disease while chronic poisoning does not.

Show evidence (1 reference)

PMID:16933734 SUPPORT Human Clinical

"Heavy metal inhalation is a rare cause of acute lung injury. Among the various heavy metals, cadmium is more commonly known to cause acute lung injury."

Directly attributes acute lung injury to inhaled cadmium, the edge from the inhalational exposure to the pulmonary node.

Environmental Cadmium Contamination

Hazard type: CHEMICAL

Route: ORAL

Duration: LIFETIME

IARC group: GROUP 1

GHS hazard class: CARCINOGENICITY STOT REPEATED EXPOSURE

Exposome domain: GENERAL EXTERNAL

Environmental exposure through contaminated food (rice, vegetables grown in cadmium-polluted soil), drinking water, and ambient air near industrial sources. Mining and smelting operations contaminate local waterways and agricultural land, as in the Jinzu River basin in Japan.

Show evidence (1 reference)

PMID:39111871 SUPPORT Human Clinical

"An elderly female farmer with Cd nephropathy residing in a Cd-polluted area in the northern part of the Akita prefecture was identified through hospital-based screening"

Documents environmental cadmium exposure in an agricultural area with contaminated soil.

Mechanism Target:

TRIGGERS Cadmium Absorption and Systemic Distribution — Cadmium-polluted soil and water enter the food chain, so residents of contaminated areas take cadmium in orally over years. Oral bioavailability is lower than inhalational, but the exposure is continuous.

Show evidence (1 reference)

PMID:39111871 SUPPORT Human Clinical

"An elderly female farmer with Cd nephropathy residing in a Cd-polluted area in the northern part of the Akita prefecture was identified through hospital-based screening"

Documents cadmium nephropathy in a farmer living in a cadmium-polluted area, linking residence in a contaminated environment to systemic cadmium disease.

Tobacco Smoke Exposure

Tobacco smoke is a significant non-occupational source of cadmium: tobacco plants accumulate cadmium from soil, and smoking is a recognised risk factor for cadmium poisoning. Per-cigarette cadmium content and the smoker/non-smoker blood cadmium ratio are not asserted here because the curated sources do not quantify them.

Show evidence (1 reference)

PMID:41000307 SUPPORT Human Clinical

"Common risk factors include smoking and alcohol consumption."

Systematic review identifies smoking as a common risk factor for cadmium poisoning.

Mechanism Target:

TRIGGERS Cadmium Absorption and Systemic Distribution — Tobacco plants concentrate cadmium from soil, so smoking is an inhalational cadmium source and the dominant non-occupational one. Note the cited sentence establishes smoking as a recognized risk factor for cadmium poisoning; it does not itself measure the absorbed dose.

Show evidence (1 reference)

PMID:41000307 SUPPORT Human Clinical

"Common risk factors include smoking and alcohol consumption."

Lists smoking among the common risk factors for cadmium poisoning. It supports smoking as a recognized route of exposure, not a quantified absorption step.

Iron Deficiency as Risk Modifier

Low iron stores increase gastrointestinal cadmium absorption via shared divalent metal transporter 1 (DMT1). Iron-deficient individuals, often women and children, are at higher risk of cadmium accumulation from dietary sources.

Show evidence (1 reference)

PMID:41000307 SUPPORT Human Clinical

"The study also found that low iron stores exacerbate cadmium poisoning."

Systematic review confirms that iron deficiency exacerbates cadmium toxicity.

Mechanism Target:

EXACERBATES Cadmium Absorption and Systemic Distribution — Low iron stores upregulate the shared divalent metal transporter DMT1, so more of an identical dietary cadmium intake is absorbed. This amplifies absorption rather than providing a source of cadmium, which is why it is a modifier and not a route.

Show evidence (1 reference)

PMID:41000307 SUPPORT Human Clinical

"The study also found that low iron stores exacerbate cadmium poisoning."

States that low iron stores exacerbate cadmium poisoning, an amplification of the absorption this node describes rather than an independent exposure.

🔬

Biochemical Markers

5

Blood Cadmium Level (INCREASED)

Show evidence (1 reference)

PMID:41000307 SUPPORT Human Clinical

"Diagnosis relies on a combination of clinical diagnostic tests, blood and urine tests, chest X-rays, kidney ultrasounds, bone density measurements, and skeletal imaging."

Systematic review confirms blood cadmium testing as a key diagnostic tool.

Urinary Cadmium Level (INCREASED)

Show evidence (1 reference)

PMID:41000307 SUPPORT Human Clinical

"Diagnosis relies on a combination of clinical diagnostic tests, blood and urine tests, chest X-rays, kidney ultrasounds, bone density measurements, and skeletal imaging."

Systematic review of reported human cases places urine cadmium testing within the standard diagnostic workup.

Urinary Beta-2-Microglobulin (INCREASED)

Show evidence (1 reference)

PMID:19106433 SUPPORT Other

"Cadmium nephrotoxicity is heralded by increased excretion of beta2-microglobulin, retinol binding protein and alpha1-microglobulin, indicative of decreased proximal tubule function."

Identifies beta-2-microglobulin excretion as a herald of cadmium nephrotoxicity.

Serum Phosphate (DECREASED)

Show evidence (1 reference)

PMID:31974582 SUPPORT Human Clinical

"Three silversmiths presented similarly with clinical, biochemical and radiological evidence of hypophosphataemic osteomalacia."

Confirms hypophosphataemia as a biochemical finding in cadmium-induced osteomalacia.

Hepatic Transaminases (ALT/AST) (INCREASED)

Show evidence (1 reference)

PMID:40164036 SUPPORT Model Organism

"exercise significantly decreased blood ALT and AST levels, alleviating oxidative stress in the liver by reducing MDA synthesis and enhancing SOD and GSH-PX activities."

Mouse readout, and an indirect one: the quoted result is the effect of the exercise intervention arm, from which cadmium's transaminase-raising effect is inferred rather than directly stated. No human transaminase data are curated for this marker.

🔬

Diagnosis

6

Blood Cadmium Level

Blood cadmium reflects recent exposure and is the initial test in suspected acute or occupational exposure. Interpretive cut-offs are laboratory- and population-specific and are deliberately not asserted here, as no source in the curated set supports a single numeric threshold.

blood chemistry measurement NCIT:C47868

Show evidence (1 reference)

PMID:41000307 SUPPORT Human Clinical

"Diagnosis relies on a combination of clinical diagnostic tests, blood and urine tests, chest X-rays, kidney ultrasounds, bone density measurements, and skeletal imaging."

Systematic review confirms blood testing as part of the diagnostic workup.

Urine Cadmium Level

Unstimulated urinary cadmium reflects chronic exposure and accumulated body burden, and is measured alongside blood cadmium in the diagnostic workup. Paired low-molecular-weight proteinuria (retinol-binding protein, beta-2-microglobulin) is the sensitive indicator of whether that burden has produced proximal tubular injury, and is the measure suited to screening exposed populations. Provoked/post-chelation "challenge" urine testing is deliberately not recommended here — it is not accepted mainstream clinical toxicology practice and has no validated interpretive thresholds.

urine chemistry measurement NCIT:C61044

Show evidence (2 references)

PMID:20354761 SUPPORT Other

"An early and sensitive manifestation of chronic Cd renal toxicity, which can be useful in individual and population screening, is impaired reabsorption of low molecular weight proteins (LMWP)"

Review supports paired low-molecular-weight proteinuria, rather than provoked urine metal testing, as the sensitive screening measure in cadmium-exposed individuals and populations.

PMID:41000307 SUPPORT Human Clinical

"Diagnosis relies on a combination of clinical diagnostic tests, blood and urine tests, chest X-rays, kidney ultrasounds, bone density measurements, and skeletal imaging."

Systematic review confirms urine testing as part of the diagnostic workup.

Urinary Beta-2-Microglobulin

Urinary beta-2-microglobulin is used to detect cadmium-related proximal tubular dysfunction, complementing blood and urine cadmium measurements.

urine chemistry measurement NCIT:C61044

Markers: beta-2-microglobulin

Results: Increased urinary beta-2-microglobulin indicates proximal tubular injury.

Show evidence (1 reference)

PMID:19106433 SUPPORT Other

"Cadmium nephrotoxicity is heralded by increased excretion of beta2-microglobulin, retinol binding protein and alpha1-microglobulin, indicative of decreased proximal tubule function."

This supports urinary beta-2-microglobulin as a renal tubular injury marker in cadmium toxicity.

Skeletal Imaging

Bone density measurements (DEXA scan) reveal osteoporosis and osteomalacia. Skeletal radiographs may show pseudofractures (Looser zones) characteristic of osteomalacia. Essential for evaluating the skeletal complications of chronic cadmium exposure.

radiograph imaging procedure NCIT:C38101

Show evidence (1 reference)

PMID:41000307 SUPPORT Human Clinical

"Diagnosis relies on a combination of clinical diagnostic tests, blood and urine tests, chest X-rays, kidney ultrasounds, bone density measurements, and skeletal imaging."

Systematic review confirms bone density measurements and skeletal imaging as part of diagnostic evaluation.

Renal Imaging

Kidney ultrasound assesses renal parenchymal damage, cortical thinning, and structural changes from chronic cadmium nephrotoxicity. Useful for monitoring disease progression in chronically exposed individuals.

renal ultrasonography NCIT:C159885

Show evidence (1 reference)

PMID:41000307 SUPPORT Human Clinical

"Diagnosis relies on a combination of clinical diagnostic tests, blood and urine tests, chest X-rays, kidney ultrasounds, bone density measurements, and skeletal imaging."

Systematic review confirms kidney ultrasound as part of the diagnostic workup.

Chest Imaging

Chest X-ray is important for evaluating acute pulmonary injury from cadmium fume inhalation, showing diffuse bilateral infiltrates consistent with chemical pneumonitis or ARDS.

chest radiograph procedure NCIT:C38103

Show evidence (1 reference)

PMID:41000307 SUPPORT Human Clinical

"Diagnosis relies on a combination of clinical diagnostic tests, blood and urine tests, chest X-rays, kidney ultrasounds, bone density measurements, and skeletal imaging."

Systematic review confirms chest X-ray as part of the diagnostic evaluation.

📊

Prevalence

1

Global

Cadmium poisoning is rare in the general population but occurs in occupational settings (silver industry, smelting, battery manufacturing) and in regions with environmental contamination. Itai-itai disease is endemic in cadmium-polluted areas of Japan. The condition primarily affects adult males through occupational exposure.

Show evidence (1 reference)

PMID:41000307 SUPPORT Human Clinical

"This review emphasizes that cadmium poisoning is rare and complex, with non- specific symptoms and a tendency to cause organ damage."

Systematic review confirms cadmium poisoning is rare overall.

🔀

Differential Diagnoses

5

Conditions with similar clinical presentations that must be differentiated from Cadmium Poisoning:

Lead Poisoning MONDO:0018019

Overlapping Features Lead poisoning shares features with cadmium toxicity including renal tubular dysfunction, peripheral neuropathy, and occupational exposure in metalworking industries. However, lead poisoning characteristically produces basophilic stippling of erythrocytes, a lead line on gingiva, wrist/foot drop, and abdominal colic, which are not features of cadmium toxicity.

Distinguishing Features

Basophilic stippling of erythrocytes on blood smear
Lead line on gingiva (Burton line)
Wrist drop and foot drop from motor neuropathy (cadmium causes sensory neuropathy)
Abdominal colic (lead colic) is characteristic
Elevated blood lead levels rather than blood cadmium
Osteomalacia and severe phosphate wasting are not typical of lead poisoning

Show evidence (2 references)

PMID:19106433 SUPPORT Other

"Cadmium in sufficient cumulative dosage leads to the production of the Fanconi syndrome, a generalized proximal tubular reabsorptive defect thought to be related to inhibition of both ATP production and Na-K-ATPase activity. On the other hand, lead accumulation in the proximal tubule leads to..."

Directly contrasts cadmium vs lead nephrotoxicity, showing both settle in proximal tubule but produce different clinical manifestations.

PMID:19106433 SUPPORT Other

"Beta2-microglobulinuria is not found in lead nephropathy."

Key distinguishing feature: beta-2-microglobulinuria is a hallmark of cadmium nephrotoxicity but absent in lead nephropathy.

Other Causes of Acquired Fanconi Syndrome Not Yet Curated MONDO:0060779

Overlapping Features Acquired Fanconi syndrome can result from multiple causes beyond cadmium, including medications (tenofovir, ifosfamide, cisplatin, valproic acid), multiple myeloma with light chain deposition, and Wilson disease. The clinical presentation of proximal tubular dysfunction with LMW proteinuria, glucosuria, and aminoaciduria is identical regardless of cause.

Distinguishing Features

Medication history (tenofovir, cisplatin, ifosfamide) may explain tubular dysfunction
Multiple myeloma presents with monoclonal protein on serum/urine electrophoresis
Wilson disease shows low ceruloplasmin, elevated urine copper, and Kayser-Fleischer rings
Cadmium toxicity is distinguished by elevated blood/urine cadmium levels and occupational or environmental exposure history

Show evidence (1 reference)

PMID:23800513 SUPPORT Human Clinical

"He was finally diagnosed with chronic cadmium toxicity resulting from long-term occupational exposure."

Case illustrates how Fanconi syndrome presentation required occupational history and cadmium testing to distinguish from other causes.

Vitamin D Deficiency Osteomalacia Not Yet Curated MONDO:0100471

Overlapping Features Nutritional vitamin D deficiency causes osteomalacia with bone pain, proximal myopathy, and pathologic fractures that closely mimic cadmium-induced osteomalacia. Both conditions present with low serum phosphate and elevated alkaline phosphatase.

Distinguishing Features

Low serum 25-hydroxyvitamin D level (< 20 ng/mL)
No renal tubular dysfunction or LMW proteinuria
Normal urinary cadmium levels
Responds to vitamin D supplementation alone without phosphate replacement
No occupational heavy metal exposure history

Show evidence (2 references)

PMID:31974582 SUPPORT Human Clinical

"It is essential to maintain a high index of suspicion in diagnosing this condition. A thorough knowledge of the occupational background of patients, as well as ambient conditions at the workplace is of utmost importance in contemplating the possibility of such rare occurrences."

Emphasizes the need for occupational history to distinguish cadmium-induced osteomalacia from more common nutritional causes.

PMID:7426480 SUPPORT Human Clinical

"The mechanism of development of the severe acquired Fanconi syndrome was thought to be a combination of dietary calcium and vitamin D deficiency and impaired calcium absorption from abnormal vitamin D synthesis, related to the cadmium deposition in the renal tubules"

Demonstrates that cadmium-induced osteomalacia involves impaired renal vitamin D synthesis, making it difficult to distinguish from pure nutritional vitamin D deficiency without cadmium testing.

Metal Fume Fever

Overlapping Features Metal fume fever, typically caused by zinc oxide fume inhalation, presents with flu-like symptoms (fever, myalgias, metallic taste) hours after welding or metalworking. It mimics early acute cadmium inhalation but is self-limiting within 24-48 hours and does not progress to ARDS.

Distinguishing Features

Self-limiting course resolving within 24-48 hours
Does not progress to ARDS or respiratory failure
Typically caused by zinc rather than cadmium fumes
No renal or skeletal toxicity
Cadmium fume exposure causes delayed-onset (12-36 hours) progressive respiratory failure

Show evidence (1 reference)

PMID:16933734 SUPPORT Human Clinical

"Heavy metal inhalation is a rare cause of acute lung injury. Among the various heavy metals, cadmium is more commonly known to cause acute lung injury."

Cadmium fume inhalation causes true acute lung injury, unlike the benign self-limiting course of metal fume fever.

X-linked Hypophosphatemia MONDO:0020720

Overlapping Features X-linked hypophosphatemia (XLH) is an inherited disorder of renal phosphate wasting caused by PHEX gene mutations, leading to excess FGF23 and hypophosphataemic rickets/osteomalacia. It presents with similar phosphate wasting and skeletal findings but occurs from childhood without heavy metal exposure.

Distinguishing Features

Childhood onset with rickets, short stature, and bowing of lower limbs
Family history consistent with X-linked dominant inheritance
Elevated FGF23 levels
No LMW proteinuria or generalized Fanconi syndrome
Normal cadmium levels
No occupational or environmental exposure history

Show evidence (1 reference)

PMID:31974582 SUPPORT Human Clinical

"Three silversmiths presented similarly with clinical, biochemical and radiological evidence of hypophosphataemic osteomalacia."

Adult-onset hypophosphataemic osteomalacia from cadmium exposure contrasts with XLH, which presents in childhood; cadmium-induced phosphate wasting is acquired and accompanied by Fanconi syndrome.

📊

Related Datasets

1

The protease DDI2 regulates NRF1-metallothionein pathway in response to Cadmium toxicity in the liver geo:GSE198150

RNA-seq profiling of liver tissue from liver-specific Ddi2 knockout and wild-type mice, investigating how the protease DDI2 regulates the NRF1-metallothionein pathway in response to cadmium toxicity. Identifies DDI2-mediated metallothionein activation as a protective mechanism against cadmium-induced hepatotoxicity.

mouse BULK RNA SEQ n=4 Illumina HiSeq 2500

liver tissue UBERON:0002107

Conditions: Ddi2 liver-specific knockout wild-type control

PMID:36248746

2 replicates per condition (WT vs Ddi2-KO). Demonstrates that DDI2 cleaves and activates NRF1 to drive metallothionein expression in response to cadmium, linking proteasome homeostasis to heavy metal detoxification.

🔬

Clinical Trials

4

NCT05908383 PHASE_I COMPLETED

Phase I, randomized, double-blind, single-center, single-dose escalation trial evaluating the safety, tolerability, and pharmacokinetic characteristics of injectable GMDTC (a novel cadmium chelation agent) in healthy subjects. This is the foundational safety study for the GMDTC cadmium chelation program.

Show evidence (1 reference)

clinicaltrials:NCT05908383 SUPPORT Human Clinical

"This trial is a randomized, double-blind, single-center, single-dose escalating Phase I clinical trial designed to evaluate the safety, tolerability, and pharmacokinetic characteristics of injectable GMDTC in healthy subjects"

First-in-human safety trial for GMDTC, a novel chelation agent being developed specifically for cadmium poisoning.

NCT06199349 PHASE_I COMPLETED

Phase Ib trial evaluating the safety, tolerability, and pharmacokinetic characteristics of repeated-dose GMDTC injection in people with excessive cadmium levels. This trial extends the Phase I safety profile from healthy volunteers to the target population of cadmium-exposed individuals across three dose cohorts.

Target Phenotypes: Chronic kidney disease HP:0012622

Show evidence (1 reference)

clinicaltrials:NCT06199349 SUPPORT Human Clinical

"This trial is a randomized, double-blind, single-center, single-dose escalating Phase I clinical trial designed to evaluate the safety, tolerability, and pharmacokinetic characteristics of GMDTC for injection after repeated administration in people with excessive cadmium levels."

First trial of GMDTC chelation directly in cadmium-exposed individuals, establishing repeated-dose safety and pharmacokinetics in the target population.

NCT07057414 PHASE_II RECRUITING

Phase IIa, randomized, double-blind, placebo-controlled trial evaluating the safety and efficacy of GMDTC injection in subjects with elevated cadmium levels. This is the first controlled efficacy trial of a chelation agent specifically developed for cadmium poisoning.

Target Phenotypes: Chronic kidney disease HP:0012622

Show evidence (1 reference)

clinicaltrials:NCT07057414 SUPPORT Human Clinical

"This is a randomized, double-blind, placebo-controlled, single-center Phase IIa clinical study."

First placebo-controlled efficacy trial for cadmium-specific chelation therapy, representing a significant advance given that no approved treatment exists for cadmium poisoning.

NCT00376987 PHASE_II COMPLETED

Clinical trial evaluating whether dietary zinc supplements can reduce serum cadmium levels in current cigarette smokers. Leverages the known competitive interaction between zinc and cadmium at shared divalent metal transporters (DMT1) to potentially reduce cadmium body burden through a simple dietary intervention.

Target Phenotypes: Proteinuria HP:0000093

Show evidence (1 reference)

clinicaltrials:NCT00376987 SUPPORT Human Clinical

"Zinc supplements may lower cadmium levels in smokers and may help prevent DNA damage."

Evaluates a non-chelation approach to reducing cadmium burden by exploiting zinc-cadmium competition at shared intestinal transporters.

{ }

Source YAML

click to show

name: Cadmium Poisoning
creation_date: '2026-02-10T22:52:02Z'
description: >-
  Cadmium poisoning is a toxic condition resulting from acute or chronic exposure
  to cadmium, a heavy metal encountered primarily through occupational sources
  (silver jewelry industry, zinc smelting, battery manufacturing), contaminated
  food and water, and tobacco smoke. Acute inhalation of cadmium fumes causes
  severe pneumonitis and acute lung injury. Chronic exposure leads to progressive
  renal tubular dysfunction (Fanconi syndrome), hypophosphataemic osteomalacia,
  osteoporosis, and peripheral neuropathy. The most severe form of chronic cadmium
  toxicity is itai-itai disease, endemic in cadmium-polluted regions of Japan,
  characterized by severe bone pain, fractures, and renal failure. Cadmium has a
  long biological half-life (10-30 years) and there is no effective antidote;
  management centers on exposure cessation, chelation therapy, and supportive care.
category: Environmental
disease_term:
  preferred_term: cadmium poisoning
  term:
    id: MONDO:0043523
    label: cadmium poisoning
parents:
- heavy metal poisoning
has_subtypes:
- name: Acute
  display_name: Acute Cadmium Poisoning (Inhalation)
  description: >-
    Acute cadmium poisoning from inhalation of cadmium fumes or dust, typically
    occurring in occupational settings (welding, smelting, silver jewelry
    manufacturing). Presents with acute lung injury, chemical pneumonitis,
    pulmonary edema, and potentially fatal respiratory failure. Symptoms may be
    delayed 12-36 hours after exposure.
  evidence:
  - reference: PMID:16933734
    reference_title: "Acute lung injury due to cadmium inhalation--a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Heavy metal inhalation is a rare cause of acute lung injury. Among the various heavy metals, cadmium is more commonly known to cause acute lung injury."
    explanation: "Confirms acute cadmium inhalation as a cause of acute lung injury."
  - reference: PMID:41000307
    reference_title: "Clinical characteristics, management, and outcomes of cadmium poisoning: a systematic review of case reports and case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "For patients with concurrent lung and kidney involvement, mechanical ventilation and continuous renal replacement therapy (CRRT) may be required."
    explanation: "Systematic review confirms severe acute presentations requiring ventilatory support."
- name: Chronic
  display_name: Chronic Cadmium Poisoning (Itai-itai Disease)
  description: >-
    Chronic cadmium toxicity from prolonged low-level exposure via contaminated
    food, water, or occupational sources. Characterized by progressive renal
    tubular dysfunction, Fanconi syndrome, hypophosphataemic osteomalacia,
    osteoporosis, and pathologic fractures. Itai-itai disease represents the
    most severe form, endemic in cadmium-polluted areas of Japan.
  evidence:
  - reference: PMID:39111871
    reference_title: "A suspected case of \"itai-itai disease\" in a cadmium-polluted area in Akita prefecture, Japan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Itai-itai disease is the most severe case of chronic cadmium (Cd) toxicity, which was endemic in Cd-polluted areas in the Jinzu River basin in Toyama prefecture, Japan."
    explanation: "Describes itai-itai disease as the most severe form of chronic cadmium toxicity."
  - reference: PMID:23800513
    reference_title: "Ailing bones and failing kidneys: a case of chronic cadmium toxicity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He was finally diagnosed with chronic cadmium toxicity resulting from long-term occupational exposure."
    explanation: "Case report confirming chronic cadmium toxicity from occupational exposure with renal and skeletal manifestations."
pathophysiology:
- name: Cadmium Absorption and Systemic Distribution
  description: >-
    Cadmium enters the body via inhalation of fumes/dust or gastrointestinal
    absorption from contaminated food and water. Inhaled cadmium is absorbed
    considerably more efficiently than ingested cadmium, and gastrointestinal
    uptake is enhanced by iron deficiency via the shared divalent metal
    transporter 1 (DMT1). Once absorbed,
    cadmium distributes via the bloodstream bound to albumin and accumulates
    in liver, kidney, and bone with a biological half-life of 10-30 years.
  biological_processes:
  - preferred_term: cellular response to cadmium ion
    term:
      id: GO:0071276
      label: cellular response to cadmium ion
  evidence:
  - reference: PMID:23800513
    reference_title: "Ailing bones and failing kidneys: a case of chronic cadmium toxicity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cadmium has a long biological half-life and there is no effective treatment for people who are exposed to it."
    explanation: "Confirms cadmium's long biological half-life contributing to progressive systemic accumulation."
  - reference: PMID:22349354
    reference_title: "An investigation and pathological analysis of two fatal cases of cadmium poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In both cases, multiple organ damage was observed, involving brain, lung, liver, kidney, red blood cells, and platelets"
    explanation: "Autopsy findings confirm systemic cadmium distribution to multiple organs."
  - reference: PMID:41000307
    reference_title: "Clinical characteristics, management, and outcomes of cadmium poisoning: a systematic review of case reports and case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The study also found that low iron stores exacerbate cadmium poisoning."
    explanation: "Confirms that iron deficiency enhances cadmium absorption via shared transport mechanisms."
  - reference: PMID:20204475
    reference_title: "Catch me if you can! Novel aspects of cadmium transport in mammalian cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "uptake of free Cd(2+) has been demonstrated for the Fe(2+)/H(+) cotransporter divalent metal transporter 1."
    explanation: "Demonstrates that cadmium enters cells via DMT1, the shared iron transporter explaining iron-deficiency enhanced absorption."
  - reference: PMID:31704329
    reference_title: "Cadmium-binding proteins in human blood plasma."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "this is the first study to reveal cadmium-binding proteins in real human blood plasma, which is extremely critical to our understanding of cadmium transportation and accumulation in human blood."
    explanation: "First identification of cadmium-binding proteins (apolipoprotein A-I) in human plasma, elucidating blood transport mechanisms."
  downstream:
  - target: Hepatic Metallothionein Binding
    description: Absorbed cadmium is transported to the liver for initial processing
  - target: NF-kB/MAPK Inflammatory Signaling
    description: Cadmium ions directly activate inflammatory signaling cascades
  - target: Proposed Direct Bone-Cell Toxicity
    description: Circulating cadmium may have direct toxic effects on bone cells, but independence from renal phosphate wasting remains unresolved.
  - target: Hepatic Oxidative Stress
    description: Cadmium causes oxidative stress in hepatocytes
  - target: Zinc-Finger Displacement and DNA Repair Inhibition
    description: >-
      Cadmium delivered to tissues enters cells and, as free intracellular
      Cd(2+), competes for the structural Zn(II) of zinc-finger domains - the
      entry point of the genotoxic/carcinogenic arm.
    evidence:
    - reference: PMID:38922068
      reference_title: "Cadmium Exposure: Mechanisms and Pathways of Toxicity and Implications for Human Health."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "By detailing the absorption, distribution, metabolism, and excretion (ADME) of Cd, alongside its interactions with cellular components such as mitochondria and DNA, this paper highlights the extensive damage caused by Cd2+ at the cellular and tissue levels."
      explanation: >-
        Draws exactly this edge - from cadmium's absorption and distribution to
        its interaction with DNA and the resulting cellular damage. Evidence
        source is OTHER because this is a review article.
  - target: Cadmium-Induced Vascular Cholesterol Dysregulation
    description: Circulating cadmium disrupts vascular cholesterol homeostasis via miRNA modulation
- name: Hepatic Metallothionein Binding
  description: >-
    The liver is the primary site of initial cadmium detoxification.
    Hepatocytes synthesize metallothionein (MT), a cysteine-rich protein that
    binds cadmium with high affinity. The cadmium-metallothionein (Cd-MT)
    complex is slowly released into the bloodstream over time. While MT
    binding initially protects against free cadmium toxicity, the Cd-MT
    complex is filtered at the glomerulus and taken up by renal tubular cells,
    effectively transferring the cadmium burden to the kidney.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  biological_processes:
  - preferred_term: detoxification of inorganic compound
    term:
      id: GO:0061687
      label: detoxification of inorganic compound
  evidence:
  - reference: PMID:25042840
    reference_title: "Renal cells exposed to cadmium in vitro and in vivo: normalizing gene expression data."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "This half-life is partly as a result of metallothioneins (MTs), metal-binding proteins with a high affinity for Cd."
    explanation: "Confirms metallothionein as the primary cadmium-binding protein responsible for cadmium's long biological half-life."
  - reference: PMID:20354761
    reference_title: "Heavy metal poisoning: the effects of cadmium on the kidney."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The kidney is the main organ affected by chronic Cd exposure and toxicity. Cd accumulates in the kidney as a result of its preferential uptake by receptor-mediated endocytosis of freely filtered and metallothionein bound Cd (Cd-MT) in the renal proximal tubule."
    explanation: "Review confirms that hepatically-produced Cd-MT is filtered and taken up by the kidney, establishing the liver-to-kidney transfer pathway."
  downstream:
  - target: Renal Proximal Tubular Cadmium Uptake
    description: Cd-MT complex released from liver is filtered by glomerulus and reabsorbed by proximal tubule
- name: Renal Proximal Tubular Cadmium Uptake
  description: >-
    The cadmium-metallothionein (Cd-MT) complex is freely filtered at the
    glomerulus because of its low molecular weight. Proximal tubular
    epithelial cells reabsorb Cd-MT via receptor-mediated endocytosis through
    the megalin/cubilin receptor complex. Once internalized, Cd-MT is degraded
    in lysosomes, releasing free cadmium ions intracellularly. This mechanism
    explains the kidney's particular vulnerability to cadmium accumulation.
  cell_types:
  - preferred_term: proximal tubule cell
    term:
      id: CL:0002306
      label: epithelial cell of proximal tubule
  locations:
  - preferred_term: proximal tubule
    term:
      id: UBERON:0004134
      label: proximal tubule
  biological_processes:
  - preferred_term: receptor-mediated endocytosis
    term:
      id: GO:0006898
      label: receptor-mediated endocytosis
  evidence:
  - reference: PMID:20204475
    reference_title: "Catch me if you can! Novel aspects of cadmium transport in mammalian cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "the multiligand endocytic receptors megalin and cubilin take up cadmium-metallothionein complexes via receptor-mediated endocytosis."
    explanation: "Demonstrates that megalin and cubilin receptors mediate the endocytic uptake of Cd-MT complexes in proximal tubule."
  - reference: PMID:34298880
    reference_title: "Increased Endocytosis of Cadmium-Metallothionein through the 24p3 Receptor in an In Vivo Model with Reduced Proximal Tubular Activity."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Cd2+ complexed to metallothionein (MT) (CdMT) is taken up through receptor-mediated endocytosis (RME) via the PT receptor megalin:cubilin, which is the predominant pathway for reuptake of filtered proteins in the kidney."
    explanation: "Confirms megalin:cubilin as the predominant receptor for Cd-MT uptake in proximal tubule."
  - reference: PMID:20354761
    reference_title: "Heavy metal poisoning: the effects of cadmium on the kidney."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Cd accumulates in the kidney as a result of its preferential uptake by receptor-mediated endocytosis of freely filtered and metallothionein bound Cd (Cd-MT) in the renal proximal tubule. Internalised Cd-MT is degraded in endosomes and lysosomes, releasing free Cd(2+) into the cytosol"
    explanation: "Review details the full Cd-MT uptake pathway: glomerular filtration, receptor-mediated endocytosis, lysosomal degradation, and free Cd2+ release."
  - reference: PMID:25042840
    reference_title: "Renal cells exposed to cadmium in vitro and in vivo: normalizing gene expression data."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The high retention properties of the kidneys reside in proximal tubular cells that possess transport mechanisms for Cd-MT uptake, ultimately leading to more Cd accumulation."
    explanation: "Confirms proximal tubular cells possess specific transport mechanisms for Cd-MT uptake."
  downstream:
  - target: Proximal Tubular Cell Injury
    description: Accumulated free cadmium exceeds intracellular metallothionein binding capacity
- name: Proximal Tubular Cell Injury
  description: >-
    When intracellular cadmium exceeds the metallothionein binding capacity
    of proximal tubular cells, free cadmium ions cause oxidative stress, mitochondrial
    dysfunction, and activation of apoptotic pathways. Cadmium displaces
    zinc from zinc-finger proteins and disrupts calcium signaling, leading
    to tubular cell death.
  cell_types:
  - preferred_term: proximal tubule cell
    term:
      id: CL:0002306
      label: epithelial cell of proximal tubule
  locations:
  - preferred_term: proximal tubule
    term:
      id: UBERON:0004134
      label: proximal tubule
  biological_processes:
  - preferred_term: apoptotic process
    modifier: INCREASED
    term:
      id: GO:0006915
      label: apoptotic process
  evidence:
  - reference: PMID:39111871
    reference_title: "A suspected case of \"itai-itai disease\" in a cadmium-polluted area in Akita prefecture, Japan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She had chronic renal failure with a high Cd exposure level and advanced renal tubular dysfunction."
    explanation: "Documents advanced renal tubular dysfunction resulting from proximal tubular cell injury in chronic cadmium exposure."
  - reference: PMID:20354761
    reference_title: "Heavy metal poisoning: the effects of cadmium on the kidney."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Internalised Cd-MT is degraded in endosomes and lysosomes, releasing free Cd(2+) into the cytosol, where it can generate reactive oxygen species (ROS) and activate cell death pathways."
    explanation: "Review details the mechanism of tubular cell injury: lysosomal release of free Cd2+ generates ROS and activates apoptosis."
  downstream:
  - target: Impaired Tubular Reabsorption
    description: Tubular cell injury and death cause loss of reabsorptive function
  - target: Chronic Kidney Disease Progression
    description: Sustained tubular injury leads to tubulointerstitial fibrosis
- name: Impaired Tubular Reabsorption
  description: >-
    Injury to proximal tubular cells causes Fanconi syndrome, characterized
    by impaired reabsorption of low-molecular-weight proteins (beta-2-microglobulin,
    retinol-binding protein), glucose, amino acids, uric acid,
    and phosphate. This is the earliest and most sensitive clinical indicator
    of chronic cadmium nephrotoxicity, detectable before decline in GFR.
  cell_types:
  - preferred_term: proximal tubule cell
    term:
      id: CL:0002306
      label: epithelial cell of proximal tubule
  locations:
  - preferred_term: kidney
    term:
      id: UBERON:0002113
      label: kidney
  biological_processes:
  - preferred_term: renal tubular reabsorption
    modifier: DECREASED
    term:
      id: GO:0070295
      label: renal water absorption
  evidence:
  - reference: PMID:23800513
    reference_title: "Ailing bones and failing kidneys: a case of chronic cadmium toxicity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report the case of a 48-year-old man who presented with severe osteoporosis, impaired renal function and acquired Fanconi syndrome."
    explanation: "Case report confirming cadmium-induced acquired Fanconi syndrome with impaired tubular reabsorption."
  - reference: PMID:20576581
    reference_title: "Cadmium impairs albumin reabsorption by down-regulating megalin and ClC5 channels in renal proximal tubule cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Cd reduced the transcriptional expression of megalin and ClC5 and, at the same time, increased the degradation of megalin and ClC5 proteins via the lysosomal pathway in an in vitro model of renal proximal tubular cells."
    explanation: "Demonstrates the molecular mechanism: cadmium downregulates megalin and ClC5, the key receptors for protein reabsorption, explaining Fanconi syndrome."
  - reference: PMID:32244724
    reference_title: "In vitro Evaluation of The Effects of Cadmium on Endocytic Uptakes of Proteins into Cultured Proximal Tubule Epithelial Cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The exposure of S1 and S2 cells to Cd at 1 and 3 µM for 3 days resulted in significant decreases in the uptakes of β2-MG and metallothionein but not in those of albumin or transferrin."
    explanation: "In vitro study directly demonstrates cadmium impairs endocytic uptake of low-molecular-weight proteins at nonlethal concentrations."
  - reference: PMID:20354761
    reference_title: "Heavy metal poisoning: the effects of cadmium on the kidney."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "An early and sensitive manifestation of chronic Cd renal toxicity, which can be useful in individual and population screening, is impaired reabsorption of low molecular weight proteins (LMWP)"
    explanation: "Review confirms impaired LMWP reabsorption as the earliest and most sensitive indicator of cadmium nephrotoxicity."
  downstream:
  - target: Renal Phosphate Wasting
    description: Impaired proximal tubular phosphate reabsorption causes phosphaturia
  - target: Renal Tubular Dysfunction
    description: Loss of proximal tubular reabsorptive function manifests as Fanconi syndrome (renal tubular dysfunction).
  - target: Low-Molecular-Weight Proteinuria
    description: Impaired receptor-mediated reabsorption of low-molecular-weight proteins (beta-2-microglobulin, retinol-binding protein) produces tubular proteinuria.
- name: Renal Phosphate Wasting
  conforms_to: "defective_skeletal_mineralization#Phosphopenic Substrate Deficiency"
  notes: >-
    Conformance is to the phosphopenic and not the calciopenic arm because the
    lesion is a direct proximal tubular transport defect - the module names
    Fanconi syndrome among its phosphopenic substitutions. One caveat a curator
    should keep in view: the module distinguishes its two arms partly at the
    bedside on parathyroid hormone being normal in the phosphopenic arm, and
    that discriminator degrades in cadmium poisoning once tubular injury has
    progressed to chronic kidney disease, where secondary hyperparathyroidism
    may supervene. The conformance is asserted on the mechanism (tubular
    phosphate loss), not on the PTH profile.
  description: >-
    Impaired proximal tubular phosphate reabsorption leads to chronic
    phosphaturia and hypophosphataemia. The sustained phosphate loss is the
    primary metabolic driver of cadmium-induced osteomalacia, as phosphate
    is essential for hydroxyapatite crystal formation in bone.
  locations:
  - preferred_term: proximal tubule
    term:
      id: UBERON:0004134
      label: proximal tubule
  biological_processes:
  - preferred_term: phosphate ion transport
    modifier: ABNORMAL
    term:
      id: GO:0006817
      label: phosphate ion transport
  evidence:
  - reference: PMID:31974582
    reference_title: "Hypophosphataemic osteomalacia due to cadmium exposure in the silver industry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three silversmiths presented similarly with clinical, biochemical and radiological evidence of hypophosphataemic osteomalacia."
    explanation: "Confirms hypophosphataemia from renal phosphate wasting as the driver of cadmium-induced osteomalacia."
  downstream:
  - target: Hypophosphataemia
    description: Sustained renal phosphate loss lowers serum phosphate, producing hypophosphataemia.
  - target: Defective Bone Mineralization
    description: Chronic hypophosphataemia impairs hydroxyapatite deposition in bone matrix
- name: Chronic Kidney Disease Progression
  description: >-
    Sustained proximal tubular injury from cadmium accumulation leads to
    tubulointerstitial inflammation, fibrosis, and progressive nephron loss.
    Glomerular filtration rate declines as tubulointerstitial nephritis
    advances, ultimately resulting in chronic kidney disease.
  locations:
  - preferred_term: kidney
    term:
      id: UBERON:0002113
      label: kidney
  evidence:
  - reference: PMID:39111871
    reference_title: "A suspected case of \"itai-itai disease\" in a cadmium-polluted area in Akita prefecture, Japan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She had chronic renal failure with a high Cd exposure level and advanced renal tubular dysfunction."
    explanation: "Documents progression to chronic renal failure from sustained cadmium-induced tubular damage."
  - reference: PMID:20354761
    reference_title: "Heavy metal poisoning: the effects of cadmium on the kidney."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Continued and heavy Cd exposure can progress to the clinical renal Fanconi syndrome, and ultimately to renal failure."
    explanation: "Review confirms the progressive nature of cadmium nephrotoxicity from tubular dysfunction to renal failure."
  downstream:
  - target: Chronic Kidney Disease
    description: Progressive tubulointerstitial nephritis and nephron loss reduce GFR, producing chronic kidney disease.
- name: Defective Bone Mineralization
  conforms_to: "defective_skeletal_mineralization#Impaired Hydroxyapatite Deposition at the Mineralization Front"
  description: >-
    Chronic hypophosphataemia from renal phosphate wasting impairs
    hydroxyapatite crystal deposition in osteoid, causing osteomalacia.
    Bone becomes soft and prone to deformation and pathologic fractures.
    In itai-itai disease, severe demineralization causes fractures from
    minimal trauma, height loss, and skeletal deformities.
  locations:
  - preferred_term: bone
    term:
      id: UBERON:0002481
      label: bone tissue
  biological_processes:
  - preferred_term: bone mineralization
    modifier: DECREASED
    term:
      id: GO:0030282
      label: bone mineralization
  evidence:
  - reference: PMID:31974582
    reference_title: "Hypophosphataemic osteomalacia due to cadmium exposure in the silver industry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three silversmiths presented similarly with clinical, biochemical and radiological evidence of hypophosphataemic osteomalacia."
    explanation: "Confirms defective bone mineralization causing osteomalacia in cadmium-exposed workers."
  - reference: PMID:39111871
    reference_title: "A suspected case of \"itai-itai disease\" in a cadmium-polluted area in Akita prefecture, Japan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The shortening of height, bone deformities and fractures, abnormal bone metabolism suggesting osteomalacia, and renal anemia were also noted."
    explanation: "Documents skeletal consequences of defective mineralization in itai-itai disease."
  downstream:
  - target: Osteomalacia
    description: Impaired hydroxyapatite deposition in osteoid produces osteomalacia (soft, undermineralized bone).
  - target: Bone Pain
    description: Osteomalacia and resulting pathologic fractures produce the severe bone pain characteristic of itai-itai disease.
- name: Proposed Direct Bone-Cell Toxicity
  description: >-
    A direct skeletal arm of cadmium toxicity is proposed alongside the
    renal phosphate-wasting route: cadmium is held to act on bone cells
    themselves, reducing osteoblast function and favouring osteoclastic
    resorption. The evidence currently curated here does NOT establish that
    arm — the only human observation available is reduced bone density in an
    occupationally exposed patient who also had nephropathy, so the renal
    route is not excluded and the claim of independence from phosphate
    wasting is not supported. Cell-level (osteoblast culture or animal)
    evidence is needed before this node asserts a direct mechanism; see the
    attached knowledge gap.
  cell_types:
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  locations:
  - preferred_term: bone
    term:
      id: UBERON:0002481
      label: bone tissue
  evidence:
  - reference: PMID:18072106
    reference_title: "Cadmium exposure: health hazards of silver cottage industry in developing countries."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We will present a case of cadmium induced peripheral neuropathy, nephropathy, and decreased bone density."
    explanation: "Documents reduced bone density in a cadmium-exposed patient. Marked PARTIAL: the same patient had nephropathy, so this single clinical observation cannot separate a direct bone-cell effect from the renal phosphate-wasting route, and cannot support the independence claim."
  downstream:
  - target: Defective Bone Mineralization
    description: A direct bone-cell contribution could compound the established mineralization defect from phosphate wasting, but is not yet demonstrated by the curated evidence.
  - target: Osteoporosis
    description: A direct bone-cell contribution to reduced bone density is proposed but cannot be separated from nephropathy in the currently curated human evidence.
- name: Hepatic Oxidative Stress
  description: >-
    Cadmium disrupts the hepatic redox balance: animal studies show reduced
    activity of the antioxidant enzymes SOD, GSH-Px, and CAT together with
    increased lipid peroxidation (elevated MDA). Note the evidence curated here
    measures antioxidant ENZYME activity rather than glutathione stores
    themselves, and one study reports cadmium triggering a hepatic antioxidant
    RESPONSE - so "depletion" is the interpretation placed on these readouts,
    not a directly measured finding. The claim that cadmium alters cytochrome
    P450 drug metabolism is not evidenced in this entry.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  biological_processes:
  - preferred_term: glutathione metabolic process
    modifier: ABNORMAL
    term:
      id: GO:0006749
      label: glutathione metabolic process
  evidence:
  - reference: PMID:39381600
    reference_title: "Proteomic analysis of toxic effects of short-term cadmium exposure on goat livers."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "liver SOD, GSH-Px, T-AOC and CAT levels were decreased, and MDA level was increased in Cd-treated goats, and 630 DEPs (up 326, down 304) in the livers of Cd-treated goats."
    explanation: "Proteomic study in goats confirms cadmium-induced hepatic antioxidant depletion."
  - reference: PMID:40164036
    reference_title: "Exercise antagonizes cadmium-caused liver and intestinal injury in mice via Nrf2 and TLR2/NF-κB signalling pathway."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "exercise significantly decreased blood ALT and AST levels, alleviating oxidative stress in the liver by reducing MDA synthesis and enhancing SOD and GSH-PX activities."
    explanation: "Mouse model demonstrates cadmium-induced hepatic oxidative stress with depleted antioxidant enzymes."
  - reference: PMID:41188353
    reference_title: "Cadmium exposure during adolescence and young adulthood induces signatures of metabolic dysfunction-associated steatotic liver disease."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Cd exposure altered hepatic lipid homeostasis via the perturbation of steatosis gene expression and lipid species abundances. Additionally, Cd exposure triggered a hepatic antioxidant response"
    explanation: "Mouse model demonstrates cadmium triggers hepatic antioxidant response and disrupts lipid homeostasis, consistent with oxidative stress-driven liver injury."
  downstream:
  - target: Hepatocyte Apoptosis
    description: Oxidative stress from glutathione depletion triggers apoptotic cell death
- name: Hepatocyte Apoptosis
  description: >-
    Sustained oxidative stress from glutathione depletion triggers hepatocyte
    apoptosis via mitochondrial pathways. Cadmium causes release of pro-apoptotic
    proteins (cytochrome c, caspase-3, Bax) and nuclear damage,
    leading to progressive hepatocellular loss and liver injury.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  biological_processes:
  - preferred_term: apoptotic process
    modifier: INCREASED
    term:
      id: GO:0006915
      label: apoptotic process
  evidence:
  - reference: PMID:40164036
    reference_title: "Exercise antagonizes cadmium-caused liver and intestinal injury in mice via Nrf2 and TLR2/NF-κB signalling pathway."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Exercise inhibited nuclear damage and hepatocyte apoptosis caused by Cd by increasing Bcl-2 protein expression and preventing the release of pro-apoptotic proteins such as caspase-3, Cytc, Bax, caspase-8and cleaved-caspase-3."
    explanation: "Mouse model demonstrates cadmium-induced hepatocyte apoptosis via pro-apoptotic protein release."
- name: NF-kB/MAPK Inflammatory Signaling
  description: >-
    Cadmium activates pro-inflammatory signaling cascades including the NF-kB
    and MAPK/JNK pathways, leading to increased secretion of pro-inflammatory
    cytokines (IL-1beta, IL-6, TNF-alpha, IL-8, CCL2) and upregulation of
    COX-2. This chronic inflammatory state exacerbates organ-specific injury
    in kidney, liver, and intestine.
  biological_processes:
  - preferred_term: inflammatory response
    modifier: INCREASED
    term:
      id: GO:0006954
      label: inflammatory response
  evidence:
  - reference: PMID:40191670
    reference_title: "Andrographolide Reduces Cytokine Release and Cyclooxygenase-2 Expression by Inhibiting the JNK and NF-κB Pathways in Glioblastoma Cells Exposed to Cadmium."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "the environmental pollutant cadmium is known to increase the secretion of pro-inflammatory cytokines, including interleukin (IL)-6, IL-8, and chemokine (C-C motif) ligand 2 (CCL2) by activating the mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) pathways."
    explanation: "In vitro study demonstrates cadmium activation of MAPK and NF-kB inflammatory pathways with cytokine secretion."
  - reference: PMID:40164036
    reference_title: "Exercise antagonizes cadmium-caused liver and intestinal injury in mice via Nrf2 and TLR2/NF-κB signalling pathway."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "exercise, both before and during Cd exposure, can reduce Cd caused pathological damages in the liver and duodenum of mice, suppressing the expression levels of the IL-1β, IL-6 and TNF-α genes."
    explanation: "Mouse model confirms cadmium-induced expression of pro-inflammatory cytokines IL-1β, IL-6, and TNF-α."
  downstream:
  - target: Proximal Tubular Cell Injury
    description: Inflammatory cytokines exacerbate tubular cell damage
  - target: Hepatic Oxidative Stress
    description: Inflammatory mediators compound hepatic oxidative stress
- name: Cadmium-Induced Vascular Cholesterol Dysregulation
  description: >-
    Cadmium disrupts cholesterol homeostasis in the vascular wall, promoting
    atherosclerosis through miRNA-mediated dysregulation of cholesterol uptake
    (CD36), efflux (ABCA1), and hydrolysis (NCEH1). Cadmium upregulates
    miR-30d-5p and downregulates miR-504-3p, promoting foam cell formation
    and intracellular lipid accumulation in macrophages. This pathway links
    cadmium exposure to increased cardiovascular risk, particularly ischemic
    stroke.
  biological_processes:
  - preferred_term: cholesterol homeostasis
    modifier: ABNORMAL
    term:
      id: GO:0042632
      label: cholesterol homeostasis
  evidence:
  - reference: PMID:41297938
    reference_title: "Cadmium Exposure Promotes Atherosclerosis by Disrupting Cholesterol Homeostasis via miR-30d-5p Regulation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Cd exposure, even at a relatively low dosage (4 mg/L), significantly facilitates the progression of atherosclerosis in apolipoprotein E-deficient mice fed a high-fat diet. This pro-atherogenic effect was accompanied by comprehensive disturbances in systemic and vascular cholesterol homeostasis"
    explanation: "Mouse model demonstrates cadmium promotes atherosclerosis through disruption of systemic and vascular cholesterol homeostasis, even at low doses."
  - reference: PMID:41297938
    reference_title: "Cadmium Exposure Promotes Atherosclerosis by Disrupting Cholesterol Homeostasis via miR-30d-5p Regulation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "we identified miR-30d-5p and miR-504-3p as novel epigenetic regulators mediating Cd-induced foam cell formation. Specifically, Cd treatment upregulated miR-30d-5p and downregulated miR-504-3p, which directly targeted NCEH1 and CD36, respectively, thereby promoting intracellular lipid accumulation."
    explanation: "Identifies the molecular mechanism: cadmium modulates specific miRNAs that regulate cholesterol handling genes, driving foam cell formation and atherosclerotic plaque development."
  - reference: PMID:41297938
    reference_title: "Cadmium Exposure Promotes Atherosclerosis by Disrupting Cholesterol Homeostasis via miR-30d-5p Regulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "plasma miR-30d-5p levels were positively associated with Cd exposure and partially mediated the Cd-stroke association, accounting for 16.4% of the total effect."
    explanation: "Human case-control study (494 ischemic stroke patients vs 494 controls) validates miR-30d-5p as a mediator of cadmium-induced stroke risk."
- name: Acute Pulmonary Injury
  description: >-
    Inhalation of cadmium fumes causes acute chemical pneumonitis with diffuse
    alveolar damage, pulmonary edema, and potentially fatal respiratory failure.
    Cadmium oxide fumes are particularly hazardous, causing delayed-onset (12-36
    hours) acute lung injury that may progress to ARDS.
  cell_types:
  - preferred_term: type II pneumocyte
    term:
      id: CL:0002063
      label: pulmonary alveolar type 2 cell
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  biological_processes:
  - preferred_term: inflammatory response
    modifier: INCREASED
    term:
      id: GO:0006954
      label: inflammatory response
  evidence:
  - reference: PMID:16933734
    reference_title: "Acute lung injury due to cadmium inhalation--a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Heavy metal inhalation is a rare cause of acute lung injury. Among the various heavy metals, cadmium is more commonly known to cause acute lung injury."
    explanation: "Case report of acute lung injury from cadmium fume inhalation."
  - reference: PMID:22349354
    reference_title: "An investigation and pathological analysis of two fatal cases of cadmium poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In both cases, multiple organ damage was observed, involving brain, lung, liver, kidney, red blood cells, and platelets"
    explanation: "Fatal cadmium poisoning cases with pulmonary involvement among multi-organ damage."
  downstream:
  - target: Acute Respiratory Distress Syndrome
    description: Diffuse alveolar damage and pulmonary edema from cadmium fume inhalation progress to acute respiratory distress syndrome.
- name: Zinc-Finger Displacement and DNA Repair Inhibition
  description: >-
    Cadmium is a weak direct mutagen; its genotoxicity is largely indirect and
    runs through the zinc-finger fold. Cd(2+) substitutes for the structural
    Zn(II) held tetrahedrally by cysteine thiolates and histidine imidazoles in
    zinc-finger domains, and cadmium-driven oxidative stress independently
    oxidises those thiolate donors. Because several DNA-repair proteins
    (nucleotide-excision and mismatch-repair components) are zinc-finger
    proteins, the displacement inhibits repair without altering the underlying
    gene sequence - a loss-of-function-like lesion imposed on the proteome
    rather than encoded in the genome. This node is the mechanistic bridge from
    the systemic cadmium burden to the carcinogenic arm, and is why cadmium
    behaves as a co-mutagen and repair inhibitor rather than as a classical
    DNA-adduct-forming carcinogen.
  conforms_to: "genome_instability_mutation#Failure of DNA Damage Surveillance and Repair"
  biological_scale: MOLECULAR
  molecular_functions:
  - preferred_term: zinc ion binding
    modifier: ABNORMAL
    term:
      id: GO:0008270
      label: zinc ion binding
  biological_processes:
  - preferred_term: DNA repair
    modifier: DECREASED
    term:
      id: GO:0006281
      label: DNA repair
  evidence:
  - reference: PMID:16310985
    reference_title: "Damage of zinc fingers in DNA repair proteins, a novel molecular mechanism in carcinogenesis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "soluble compounds of definite carcinogenic metals and metalloids, such as arsenic, cadmium and nickel, and putative carcinogens, including cobalt and lead, inhibit zinc finger containing DNA repair proteins"
    explanation: >-
      Cell-culture and ex vivo work showing cadmium inhibits zinc-finger-containing
      DNA repair proteins, the molecular lesion this node models.
  - reference: PMID:16310985
    reference_title: "Damage of zinc fingers in DNA repair proteins, a novel molecular mechanism in carcinogenesis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Zinc fingers can thus be compromised by a substitution of Zn(II) with another metal ion"
    explanation: >-
      States the substitution mechanism - a competing divalent cation replacing the
      structural Zn(II) - that makes cadmium a zinc-finger poison.
  - reference: PMID:38922068
    reference_title: "Cadmium Exposure: Mechanisms and Pathways of Toxicity and Implications for Human Health."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The epigenetic effects of Cd, including DNA methylation and histone modifications, are also explored to explain its long-term impact on gene expression and disease manifestation"
    explanation: >-
      Review situating cadmium's epigenetic dysregulation alongside the genotoxic
      arm as a second route to long-term altered gene expression. Evidence source
      is OTHER because this is a review article.
  downstream:
  - target: Cadmium-Associated Carcinogenesis
    description: >-
      Impaired repair fidelity allows damage from cadmium-driven oxidative stress
      and from co-exposures to persist and accumulate, the substrate for malignant
      transformation.
    evidence:
    - reference: PMID:16310985
      reference_title: "Damage of zinc fingers in DNA repair proteins, a novel molecular mechanism in carcinogenesis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "This reactivity can therefore be regarded as a novel molecular mechanism in carcinogenesis."
      explanation: >-
        The cited work draws exactly this edge: zinc-finger damage in DNA repair
        proteins as a mechanism of carcinogenesis.
- name: Cadmium-Associated Carcinogenesis
  description: >-
    Cadmium and its compounds have been classified by IARC as carcinogenic to
    humans (Group 1) since 1993, on the strength of excess lung cancer in
    occupationally exposed cohorts together with animal tumour data. The
    contemporary evidence base, reviewed across biological-sample studies,
    supports a causal role at the lung, pancreas and bladder, with total cancer
    risk and mortality correlating with measured cadmium body burden. Site
    attribution is deliberately not curated uniformly: the prostate association
    was not confirmed on cohort update, and breast and prostate evidence remains
    weak or inconclusive. Latency is that of chemical carcinogenesis - years to
    decades - which is why this arm is a feature of chronic rather than acute
    cadmium poisoning.
  biological_scale: ORGANISM
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  - preferred_term: pancreas
    term:
      id: UBERON:0001264
      label: pancreas
  - preferred_term: urinary bladder
    term:
      id: UBERON:0001255
      label: urinary bladder
  evidence:
  - reference: PMID:12746140
    reference_title: "Cadmium, lung and prostate cancer: a systematic review of recent epidemiological data."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cadmium (Cd) and its compounds were classified as \"carcinogenic to humans (Group 1)\" by IARC in 1993"
    explanation: >-
      Establishes the IARC Group 1 classification and its basis in cadmium-exposed
      worker cohorts.
  - reference: PMID:38480109
    reference_title: "Cadmium in biological samples and site-specific cancer risk and mortality: A systematic review of original articles and meta-analyses."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Current data consistently suggest a causal role of exposure to cadmium in pancreas, lung, and bladder carcinogenesis."
    explanation: >-
      Systematic review of 9 meta-analyses and 57 original articles giving the
      sites where a causal role is currently supported.
  - reference: PMID:12746140
    reference_title: "Cadmium, lung and prostate cancer: a systematic review of recent epidemiological data."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The association between cadmium exposure and prostate cancer was not confirmed in the latest available updates."
    explanation: >-
      Carried as a qualification, not a refutation of the node: the same review that
      establishes the Group 1 classification withdraws support for the prostate site
      specifically, which is why site attribution here is not uniform.
  downstream:
  - target: Cadmium-Associated Lung Neoplasm
    description: >-
      The site on which the IARC Group 1 designation principally rests, evidenced
      in occupationally exposed worker cohorts.
    evidence:
    - reference: PMID:38480109
      reference_title: "Cadmium in biological samples and site-specific cancer risk and mortality: A systematic review of original articles and meta-analyses."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Exposure to cadmium poses a risk for increased cancer incidence and mortality."
      explanation: >-
        States the exposure-to-malignancy step this edge asserts, at the level of
        incidence and mortality.
  - target: Cadmium-Associated Pancreatic Neoplasm
    description: >-
      One of the three sites for which the contemporary biological-sample
      evidence base supports a causal role.
    evidence:
    - reference: PMID:38480109
      reference_title: "Cadmium in biological samples and site-specific cancer risk and mortality: A systematic review of original articles and meta-analyses."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Current data consistently suggest a causal role of exposure to cadmium in pancreas, lung, and bladder carcinogenesis."
      explanation: Names the pancreas among the sites with a supported causal role.
  - target: Cadmium-Associated Bladder Neoplasm
    description: >-
      One of the three sites for which the contemporary biological-sample
      evidence base supports a causal role.
    evidence:
    - reference: PMID:38480109
      reference_title: "Cadmium in biological samples and site-specific cancer risk and mortality: A systematic review of original articles and meta-analyses."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Current data consistently suggest a causal role of exposure to cadmium in pancreas, lung, and bladder carcinogenesis."
      explanation: Names the bladder among the sites with a supported causal role.
phenotypes:
- category: Renal
  name: Renal Tubular Dysfunction
  diagnostic: true
  description: >-
    Proximal renal tubular dysfunction manifesting as Fanconi syndrome with
    low-molecular-weight proteinuria (beta-2-microglobulinuria), glucosuria,
    aminoaciduria, and phosphaturia. The earliest and most sensitive indicator
    of chronic cadmium nephrotoxicity.
  evidence:
  - reference: PMID:39111871
    reference_title: "A suspected case of \"itai-itai disease\" in a cadmium-polluted area in Akita prefecture, Japan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She had chronic renal failure with a high Cd exposure level and advanced renal tubular dysfunction."
    explanation: "Documents renal tubular dysfunction as a key manifestation of chronic cadmium exposure."
  - reference: PMID:23800513
    reference_title: "Ailing bones and failing kidneys: a case of chronic cadmium toxicity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report the case of a 48-year-old man who presented with severe osteoporosis, impaired renal function and acquired Fanconi syndrome."
    explanation: "Confirms acquired Fanconi syndrome from chronic cadmium toxicity."
  phenotype_term:
    preferred_term: Renal tubular dysfunction
    term:
      id: HP:0000124
      label: Renal tubular dysfunction
- category: Renal
  name: Low-Molecular-Weight Proteinuria
  diagnostic: true
  description: >-
    Increased urinary excretion of low-molecular-weight proteins (beta-2-microglobulin,
    retinol-binding protein, alpha-1-microglobulin) reflecting
    impaired proximal tubular reabsorption. A hallmark biomarker of cadmium
    nephrotoxicity used for screening in exposed populations.
  evidence:
  - reference: PMID:20354761
    reference_title: "Heavy metal poisoning: the effects of cadmium on the kidney."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "An early and sensitive manifestation of chronic Cd renal toxicity, which can be useful in individual and population screening, is impaired reabsorption of low molecular weight proteins (LMWP) (also a receptor-mediated process in the proximal tubule) such as retinol binding protein (RBP). This so-called 'tubular proteinuria' is a good index of proximal tubular damage"
    explanation: "Review identifies LMW proteinuria as the earliest and most sensitive marker of cadmium nephrotoxicity, suitable for population screening."
  - reference: PMID:19106433
    reference_title: "Nephrotoxicity of cadmium & lead."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Cadmium nephrotoxicity is heralded by increased excretion of beta2-microglobulin, retinol binding protein and alpha1-microglobulin, indicative of decreased proximal tubule function."
    explanation: "Confirms the specific LMW proteins excreted in cadmium nephrotoxicity: beta-2-microglobulin, retinol binding protein, and alpha-1-microglobulin."
  phenotype_term:
    preferred_term: Proteinuria
    term:
      id: HP:0000093
      label: Proteinuria
- category: Musculoskeletal
  name: Osteomalacia
  description: >-
    Defective bone mineralization caused by cadmium-induced renal phosphate
    wasting, leading to hypophosphataemia. Presents with bone pain, proximal
    muscle weakness, waddling gait, and pathologic fractures.
  evidence:
  - reference: PMID:31974582
    reference_title: "Hypophosphataemic osteomalacia due to cadmium exposure in the silver industry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three silversmiths presented similarly with clinical, biochemical and radiological evidence of hypophosphataemic osteomalacia."
    explanation: "Confirms hypophosphataemic osteomalacia from occupational cadmium exposure."
  - reference: PMID:39111871
    reference_title: "A suspected case of \"itai-itai disease\" in a cadmium-polluted area in Akita prefecture, Japan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The shortening of height, bone deformities and fractures, abnormal bone metabolism suggesting osteomalacia, and renal anemia were also noted."
    explanation: "Documents osteomalacia with bone deformities and fractures in itai-itai disease."
  phenotype_term:
    preferred_term: Osteomalacia
    term:
      id: HP:0002749
      label: Osteomalacia
- category: Musculoskeletal
  name: Osteoporosis
  description: >-
    Decreased bone mineral density from combined effects of renal phosphate and
    calcium wasting, direct cadmium toxicity to osteoblasts, and secondary
    hyperparathyroidism. Contributes to pathologic fractures, particularly in
    chronic exposure.
  evidence:
  - reference: PMID:23800513
    reference_title: "Ailing bones and failing kidneys: a case of chronic cadmium toxicity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report the case of a 48-year-old man who presented with severe osteoporosis, impaired renal function and acquired Fanconi syndrome."
    explanation: "Case report of severe osteoporosis from chronic cadmium toxicity."
  - reference: PMID:18072106
    reference_title: "Cadmium exposure: health hazards of silver cottage industry in developing countries."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We will present a case of cadmium induced peripheral neuropathy, nephropathy, and decreased bone density."
    explanation: "Confirms decreased bone density (osteoporosis) from cadmium exposure."
  phenotype_term:
    preferred_term: Osteoporosis
    term:
      id: HP:0000939
      label: Osteoporosis
- category: Musculoskeletal
  name: Bone Pain
  description: >-
    Severe bone pain, particularly in the legs, pelvis, and spine. The hallmark
    symptom of itai-itai disease (literally "it hurts, it hurts" disease).
    Results from osteomalacia and pathologic fractures.
  evidence:
  - reference: PMID:19341754
    reference_title: "Historical perspectives on cadmium toxicology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a bone disease with fractures and severe pain, the itai-itai disease, a form of Cd-induced renal osteomalacia, was identified in Japan."
    explanation: "Historical review identifies severe bone pain as the defining symptom of itai-itai disease, the archetypal chronic cadmium poisoning syndrome."
  - reference: PMID:7426480
    reference_title: "Cadmium-induced osteomalacia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "during the last 12 years of his life the patient had suffered increasing disability from gross bone disease. Several bone biopsies and detailed metabolic studies showed typical severe osteomalacia"
    explanation: "Case report documents 12 years of progressive bone pain and disability from cadmium-induced osteomalacia in an occupationally exposed worker."
  phenotype_term:
    preferred_term: Bone pain
    term:
      id: HP:0002653
      label: Bone pain
- category: Metabolic
  name: Hypophosphataemia
  description: >-
    Low serum phosphate levels resulting from impaired proximal tubular phosphate
    reabsorption. A key driver of cadmium-induced osteomalacia and a diagnostic
    clue when found with renal tubular dysfunction.
  evidence:
  - reference: PMID:31974582
    reference_title: "Hypophosphataemic osteomalacia due to cadmium exposure in the silver industry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three silversmiths presented similarly with clinical, biochemical and radiological evidence of hypophosphataemic osteomalacia."
    explanation: "Confirms hypophosphataemia as the metabolic derangement underlying cadmium-induced osteomalacia."
  phenotype_term:
    preferred_term: Hypophosphatemia
    term:
      id: HP:0002148
      label: Hypophosphatemia
- category: Renal
  name: Chronic Kidney Disease
  description: >-
    Progressive decline in renal function from chronic cadmium accumulation.
    Glomerular filtration rate declines as tubular damage progresses to
    tubulointerstitial nephritis.
  evidence:
  - reference: PMID:39111871
    reference_title: "A suspected case of \"itai-itai disease\" in a cadmium-polluted area in Akita prefecture, Japan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She had chronic renal failure with a high Cd exposure level and advanced renal tubular dysfunction."
    explanation: "Documents chronic renal failure from cadmium exposure."
  phenotype_term:
    preferred_term: Chronic kidney disease
    term:
      id: HP:0012622
      label: Chronic kidney disease
- category: Neurological
  name: Peripheral Neuropathy
  description: >-
    Cadmium-induced peripheral neuropathy, reflecting cadmium's neurotoxic
    properties. Reported in occupationally exposed workers in the silver
    jewelry industry.
  evidence:
  - reference: PMID:18072106
    reference_title: "Cadmium exposure: health hazards of silver cottage industry in developing countries."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cadmium is a neurotoxic and nephrotoxic heavy metal"
    explanation: "Identifies cadmium as a neurotoxic heavy metal causing peripheral neuropathy."
  - reference: PMID:41453694
    reference_title: "Advances in understanding the neurotoxicity of lead, cadmium, arsenic, and therapeutic strategies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "lead (Pb), cadmium (Cd), and arsenic (As) are pervasive environmental toxicants capable of entering the human body via multiple exposure routes, leading to profound neurotoxic effects."
    explanation: "Review of heavy metal neurotoxicity confirms cadmium produces profound neurotoxic effects through multiple exposure routes."
  phenotype_term:
    preferred_term: Peripheral neuropathy
    term:
      id: HP:0009830
      label: Peripheral neuropathy
- category: Pulmonary
  name: Acute Respiratory Distress Syndrome
  notes: Primarily in acute inhalation exposure
  description: >-
    Acute respiratory distress syndrome from cadmium fume inhalation. May be
    fatal and often presents with delayed onset after initial asymptomatic period.
    Requires mechanical ventilation and intensive care support.
  evidence:
  - reference: PMID:16933734
    reference_title: "Acute lung injury due to cadmium inhalation--a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Heavy metal inhalation is a rare cause of acute lung injury. Among the various heavy metals, cadmium is more commonly known to cause acute lung injury."
    explanation: "Confirms cadmium as a cause of acute lung injury from inhalation."
  - reference: PMID:41000307
    reference_title: "Clinical characteristics, management, and outcomes of cadmium poisoning: a systematic review of case reports and case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "For patients with concurrent lung and kidney involvement, mechanical ventilation and continuous renal replacement therapy (CRRT) may be required."
    explanation: "Systematic review confirms severe pulmonary involvement requiring mechanical ventilation."
  phenotype_term:
    preferred_term: Acute respiratory distress syndrome
    term:
      id: HP:0033677
      label: Acute respiratory distress syndrome
- category: Oncologic
  name: Cadmium-Associated Lung Neoplasm
  description: >-
    Excess lung cancer incidence and mortality in populations with elevated
    cadmium body burden. This is the site on which the IARC Group 1 designation
    principally rests, evidenced most strongly in occupationally exposed cohorts.
    Site attribution is deliberately split across three entries rather than
    asserted as one undifferentiated malignancy phenotype, because the evidence
    is site-specific: lung, pancreas and bladder are supported while breast and
    prostate explicitly are not. Onset follows the years-to-decades latency of
    chemical carcinogenesis, so this is a manifestation of chronic rather than
    acute cadmium poisoning. `frequency:` is omitted throughout: the underlying
    evidence is exposure-response association across heterogeneous cohorts, not a
    per-patient manifestation rate, so no FrequencyEnum band is justified.
  phenotype_term:
    preferred_term: Neoplasm of the lung
    term:
      id: HP:0100526
      label: Neoplasm of the lung
  evidence:
  - reference: PMID:38480109
    reference_title: "Cadmium in biological samples and site-specific cancer risk and mortality: A systematic review of original articles and meta-analyses."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Current data consistently suggest a causal role of exposure to cadmium in pancreas, lung, and bladder carcinogenesis."
    explanation: >-
      Names this site among the three for which a causal role of cadmium exposure
      is currently supported.
  - reference: PMID:38480109
    reference_title: "Cadmium in biological samples and site-specific cancer risk and mortality: A systematic review of original articles and meta-analyses."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The evidence is weak or inconclusive for the remaining cancer sites (including breast and prostate)"
    explanation: >-
      Carried on each site entry as the boundary of the claim, so no single one is
      read as licensing a uniform cadmium-cancer association across all sites.
  - reference: PMID:38480109
    reference_title: "Cadmium in biological samples and site-specific cancer risk and mortality: A systematic review of original articles and meta-analyses."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Total cancer risk and mortality are also positively correlated with Cd levels in biological samples"
    explanation: >-
      Supports the dose-related nature of the association, measured as cadmium in
      blood, urine, nails or hair rather than as modelled exposure.
  - reference: PMID:12746140
    reference_title: "Cadmium, lung and prostate cancer: a systematic review of recent epidemiological data."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cadmium (Cd) and its compounds were classified as \"carcinogenic to humans (Group 1)\" by IARC in 1993"
    explanation: >-
      The Group 1 classification rests substantially on excess lung cancer in
      cadmium-exposed worker cohorts, which is why it is cited on this site.
- category: Oncologic
  name: Cadmium-Associated Pancreatic Neoplasm
  description: >-
    Excess pancreatic cancer incidence in populations with elevated cadmium body
    burden. Named alongside lung and bladder as a site where the contemporary
    biological-sample evidence base supports a causal role.
    Site attribution is deliberately split across three entries rather than
    asserted as one undifferentiated malignancy phenotype, because the evidence
    is site-specific: lung, pancreas and bladder are supported while breast and
    prostate explicitly are not. Onset follows the years-to-decades latency of
    chemical carcinogenesis, so this is a manifestation of chronic rather than
    acute cadmium poisoning. `frequency:` is omitted throughout: the underlying
    evidence is exposure-response association across heterogeneous cohorts, not a
    per-patient manifestation rate, so no FrequencyEnum band is justified.
  phenotype_term:
    preferred_term: Neoplasm of the pancreas
    term:
      id: HP:0002894
      label: Neoplasm of the pancreas
  evidence:
  - reference: PMID:38480109
    reference_title: "Cadmium in biological samples and site-specific cancer risk and mortality: A systematic review of original articles and meta-analyses."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Current data consistently suggest a causal role of exposure to cadmium in pancreas, lung, and bladder carcinogenesis."
    explanation: >-
      Names this site among the three for which a causal role of cadmium exposure
      is currently supported.
  - reference: PMID:38480109
    reference_title: "Cadmium in biological samples and site-specific cancer risk and mortality: A systematic review of original articles and meta-analyses."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The evidence is weak or inconclusive for the remaining cancer sites (including breast and prostate)"
    explanation: >-
      Carried on each site entry as the boundary of the claim, so no single one is
      read as licensing a uniform cadmium-cancer association across all sites.
- category: Oncologic
  name: Cadmium-Associated Bladder Neoplasm
  description: >-
    Excess bladder cancer incidence in populations with elevated cadmium body
    burden. Named alongside lung and pancreas as a site where the contemporary
    biological-sample evidence base supports a causal role.
    Site attribution is deliberately split across three entries rather than
    asserted as one undifferentiated malignancy phenotype, because the evidence
    is site-specific: lung, pancreas and bladder are supported while breast and
    prostate explicitly are not. Onset follows the years-to-decades latency of
    chemical carcinogenesis, so this is a manifestation of chronic rather than
    acute cadmium poisoning. `frequency:` is omitted throughout: the underlying
    evidence is exposure-response association across heterogeneous cohorts, not a
    per-patient manifestation rate, so no FrequencyEnum band is justified.
  phenotype_term:
    preferred_term: Bladder neoplasm
    term:
      id: HP:0009725
      label: Bladder neoplasm
  evidence:
  - reference: PMID:38480109
    reference_title: "Cadmium in biological samples and site-specific cancer risk and mortality: A systematic review of original articles and meta-analyses."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Current data consistently suggest a causal role of exposure to cadmium in pancreas, lung, and bladder carcinogenesis."
    explanation: >-
      Names this site among the three for which a causal role of cadmium exposure
      is currently supported.
  - reference: PMID:38480109
    reference_title: "Cadmium in biological samples and site-specific cancer risk and mortality: A systematic review of original articles and meta-analyses."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The evidence is weak or inconclusive for the remaining cancer sites (including breast and prostate)"
    explanation: >-
      Carried on each site entry as the boundary of the claim, so no single one is
      read as licensing a uniform cadmium-cancer association across all sites.
biochemical:
- name: Blood Cadmium Level
  presence: INCREASED
  biomarker_term:
    preferred_term: cadmium(2+)
    term:
      id: CHEBI:48775
      label: cadmium(2+)
  notes: >-
    Blood cadmium levels reflect recent exposure and are measured to confirm
    the diagnosis. Numeric normal and toxic cut-offs are laboratory- and
    population-specific and are not asserted here, as the curated source set
    does not establish them.
  evidence:
  - reference: PMID:41000307
    reference_title: "Clinical characteristics, management, and outcomes of cadmium poisoning: a systematic review of case reports and case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diagnosis relies on a combination of clinical diagnostic tests, blood and urine tests, chest X-rays, kidney ultrasounds, bone density measurements, and skeletal imaging."
    explanation: "Systematic review confirms blood cadmium testing as a key diagnostic tool."
- name: Urinary Cadmium Level
  presence: INCREASED
  biomarker_term:
    preferred_term: cadmium(2+)
    term:
      id: CHEBI:48775
      label: cadmium(2+)
  notes: >-
    Unstimulated (spot or 24-hour) urinary cadmium reflects chronic exposure and
    accumulated body burden and is measured as part of the standard workup.
    Provoked/post-chelation "challenge" urine testing is not used here: it is not
    an accepted practice in mainstream clinical toxicology and no validated
    interpretive thresholds exist for it.
  evidence:
  - reference: PMID:41000307
    reference_title: "Clinical characteristics, management, and outcomes of cadmium poisoning: a systematic review of case reports and case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diagnosis relies on a combination of clinical diagnostic tests, blood and urine tests, chest X-rays, kidney ultrasounds, bone density measurements, and skeletal imaging."
    explanation: "Systematic review of reported human cases places urine cadmium testing within the standard diagnostic workup."
- name: Urinary Beta-2-Microglobulin
  presence: INCREASED
  biomarker_term:
    preferred_term: Beta-2-Microglobulin
    term:
      id: NCIT:C62657
      label: Beta-2-Microglobulin
  notes: >-
    Elevated urinary beta-2-microglobulin is the most sensitive biomarker of
    cadmium-induced proximal tubular damage, reflecting impaired tubular protein
    reabsorption.
  evidence:
  - reference: PMID:19106433
    reference_title: "Nephrotoxicity of cadmium & lead."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Cadmium nephrotoxicity is heralded by increased excretion of beta2-microglobulin, retinol binding protein and alpha1-microglobulin, indicative of decreased proximal tubule function."
    explanation: "Identifies beta-2-microglobulin excretion as a herald of cadmium nephrotoxicity."
- name: Serum Phosphate
  presence: DECREASED
  biomarker_term:
    preferred_term: phosphate ion
    term:
      id: CHEBI:35780
      label: phosphate ion
  notes: >-
    Low serum phosphate from renal phosphate wasting, driving osteomalacia.
  evidence:
  - reference: PMID:31974582
    reference_title: "Hypophosphataemic osteomalacia due to cadmium exposure in the silver industry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three silversmiths presented similarly with clinical, biochemical and radiological evidence of hypophosphataemic osteomalacia."
    explanation: "Confirms hypophosphataemia as a biochemical finding in cadmium-induced osteomalacia."
- name: Hepatic Transaminases (ALT/AST)
  presence: INCREASED
  biomarker_term:
    preferred_term: Alanine Aminotransferase
    term:
      id: NCIT:C25293
      label: Alanine Aminotransferase
  notes: >-
    Elevated ALT and AST levels reflecting hepatocellular injury from cadmium
    hepatotoxicity.
  evidence:
  - reference: PMID:40164036
    reference_title: "Exercise antagonizes cadmium-caused liver and intestinal injury in mice via Nrf2 and TLR2/NF-κB signalling pathway."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "exercise significantly decreased blood ALT and AST levels, alleviating oxidative stress in the liver by reducing MDA synthesis and enhancing SOD and GSH-PX activities."
    explanation: "Mouse readout, and an indirect one: the quoted result is the effect of the exercise intervention arm, from which cadmium's transaminase-raising effect is inferred rather than directly stated. No human transaminase data are curated for this marker."
diagnosis:
- name: Blood Cadmium Level
  description: >-
    Blood cadmium reflects recent exposure and is the initial test in suspected
    acute or occupational exposure. Interpretive cut-offs are laboratory- and
    population-specific and are deliberately not asserted here, as no source in
    the curated set supports a single numeric threshold.
  diagnosis_term:
    preferred_term: blood chemistry measurement
    term:
      id: NCIT:C47868
      label: Blood Chemistry Measurement
  evidence:
  - reference: PMID:41000307
    reference_title: "Clinical characteristics, management, and outcomes of cadmium poisoning: a systematic review of case reports and case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diagnosis relies on a combination of clinical diagnostic tests, blood and urine tests, chest X-rays, kidney ultrasounds, bone density measurements, and skeletal imaging."
    explanation: "Systematic review confirms blood testing as part of the diagnostic workup."
- name: Urine Cadmium Level
  description: >-
    Unstimulated urinary cadmium reflects chronic exposure and accumulated body
    burden, and is measured alongside blood cadmium in the diagnostic workup.
    Paired low-molecular-weight proteinuria (retinol-binding protein,
    beta-2-microglobulin) is the sensitive indicator of whether that burden has
    produced proximal tubular injury, and is the measure suited to screening
    exposed populations. Provoked/post-chelation "challenge" urine testing is
    deliberately not recommended here — it is not accepted mainstream clinical
    toxicology practice and has no validated interpretive thresholds.
  diagnosis_term:
    preferred_term: urine chemistry measurement
    term:
      id: NCIT:C61044
      label: Urine Chemistry Measurement
  evidence:
  - reference: PMID:20354761
    reference_title: "Heavy metal poisoning: the effects of cadmium on the kidney."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "An early and sensitive manifestation of chronic Cd renal toxicity, which can be useful in individual and population screening, is impaired reabsorption of low molecular weight proteins (LMWP)"
    explanation: "Review supports paired low-molecular-weight proteinuria, rather than provoked urine metal testing, as the sensitive screening measure in cadmium-exposed individuals and populations."
  - reference: PMID:41000307
    reference_title: "Clinical characteristics, management, and outcomes of cadmium poisoning: a systematic review of case reports and case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diagnosis relies on a combination of clinical diagnostic tests, blood and urine tests, chest X-rays, kidney ultrasounds, bone density measurements, and skeletal imaging."
    explanation: "Systematic review confirms urine testing as part of the diagnostic workup."
- name: Urinary Beta-2-Microglobulin
  description: >-
    Urinary beta-2-microglobulin is used to detect cadmium-related proximal
    tubular dysfunction, complementing blood and urine cadmium measurements.
  diagnosis_term:
    preferred_term: urine chemistry measurement
    term:
      id: NCIT:C61044
      label: Urine Chemistry Measurement
  markers: beta-2-microglobulin
  results: Increased urinary beta-2-microglobulin indicates proximal tubular injury.
  evidence:
  - reference: PMID:19106433
    reference_title: "Nephrotoxicity of cadmium & lead."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Cadmium nephrotoxicity is heralded by increased excretion of beta2-microglobulin, retinol binding protein and alpha1-microglobulin, indicative of decreased proximal tubule function."
    explanation: This supports urinary beta-2-microglobulin as a renal tubular injury marker in cadmium toxicity.
- name: Skeletal Imaging
  description: >-
    Bone density measurements (DEXA scan) reveal osteoporosis and osteomalacia.
    Skeletal radiographs may show pseudofractures (Looser zones) characteristic
    of osteomalacia. Essential for evaluating the skeletal complications of
    chronic cadmium exposure.
  diagnosis_term:
    preferred_term: radiograph imaging procedure
    term:
      id: NCIT:C38101
      label: X-Ray Imaging
  evidence:
  - reference: PMID:41000307
    reference_title: "Clinical characteristics, management, and outcomes of cadmium poisoning: a systematic review of case reports and case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diagnosis relies on a combination of clinical diagnostic tests, blood and urine tests, chest X-rays, kidney ultrasounds, bone density measurements, and skeletal imaging."
    explanation: "Systematic review confirms bone density measurements and skeletal imaging as part of diagnostic evaluation."
- name: Renal Imaging
  description: >-
    Kidney ultrasound assesses renal parenchymal damage, cortical thinning,
    and structural changes from chronic cadmium nephrotoxicity. Useful for
    monitoring disease progression in chronically exposed individuals.
  diagnosis_term:
    preferred_term: renal ultrasonography
    term:
      id: NCIT:C159885
      label: Renal Ultrasound
  evidence:
  - reference: PMID:41000307
    reference_title: "Clinical characteristics, management, and outcomes of cadmium poisoning: a systematic review of case reports and case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diagnosis relies on a combination of clinical diagnostic tests, blood and urine tests, chest X-rays, kidney ultrasounds, bone density measurements, and skeletal imaging."
    explanation: "Systematic review confirms kidney ultrasound as part of the diagnostic workup."
- name: Chest Imaging
  description: >-
    Chest X-ray is important for evaluating acute pulmonary injury from
    cadmium fume inhalation, showing diffuse bilateral infiltrates consistent
    with chemical pneumonitis or ARDS.
  diagnosis_term:
    preferred_term: chest radiograph procedure
    term:
      id: NCIT:C38103
      label: Chest Radiography
  evidence:
  - reference: PMID:41000307
    reference_title: "Clinical characteristics, management, and outcomes of cadmium poisoning: a systematic review of case reports and case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diagnosis relies on a combination of clinical diagnostic tests, blood and urine tests, chest X-rays, kidney ultrasounds, bone density measurements, and skeletal imaging."
    explanation: "Systematic review confirms chest X-ray as part of the diagnostic evaluation."
treatments:
- name: Chelation Therapy
  description: >-
    Chelating agents (CaNa2-EDTA, DMSA, DMPS) are used to bind and promote
    urinary excretion of cadmium. Effectiveness is limited due to cadmium's
    tight binding to metallothionein and intracellular sequestration. BAL
    (dimercaprol) is generally avoided: in rat experiments BAL given shortly
    after cadmium exposure increased renal cadmium deposition, redistributing
    the metal toward the critical target organ. The same work shows the effect
    is timing-dependent — BAL given 24 hours after exposure, once metallothionein
    has been induced, mobilized hepatic cadmium into bile without raising renal
    cadmium — so this is an animal-derived caution about early administration
    rather than a demonstrated clinical contraindication in humans.
  treatment_term:
    preferred_term: chelation therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Edetic Acid
      term:
        id: NCIT:C61742
        label: Edetic Acid
    - preferred_term: succimer
      term:
        id: CHEBI:63623
        label: succimer
    - preferred_term: 2,3-disulfanylpropane-1-sulfonic acid
      term:
        id: CHEBI:888
        label: 2,3-disulfanylpropane-1-sulfonic acid
  evidence:
  - reference: PMID:41000307
    reference_title: "Clinical characteristics, management, and outcomes of cadmium poisoning: a systematic review of case reports and case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The treatment plan includes the use of chelating agents to reduce cadmium levels in the body and antibiotics to maintain the patient's condition."
    explanation: "Systematic review confirms chelating agents as part of standard cadmium poisoning treatment."
  - reference: PMID:41453694
    reference_title: "Advances in understanding the neurotoxicity of lead, cadmium, arsenic, and therapeutic strategies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Conventional chelation therapy, when used long-term, can lead to renal and gastrointestinal diseases."
    explanation: "Review highlights significant limitations of conventional chelation therapy, noting long-term use can itself cause renal and gastrointestinal toxicity."
  - reference: PMID:6734559
    reference_title: "Chelation of cadmium without increased renal cadmium deposition."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The renal deposition of Cd increased on BAL (2,3-dimercaptopropanol) treatment a short time (1/2 hr) after Cd exposure."
    explanation: "Rat data are the basis for avoiding early BAL in cadmium exposure; marked PARTIAL because this is an animal redistribution finding, not a clinical outcome study."
  - reference: PMID:6734559
    reference_title: "Chelation of cadmium without increased renal cadmium deposition."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "if BAL was administered 24 hr after Cd exposure, it could mobilize Cd from hepatic MT and increase the biliary excretion of Cd without any increase in renal Cd concentration"
    explanation: "The same rat study bounds the caution: the renal-redistribution effect is timing-dependent and not observed once metallothionein has been induced."
- name: Phosphate Supplementation
  description: >-
    Neutral phosphate supplements to correct hypophosphataemia from renal
    phosphate wasting. Phosphate replacement is essential for treating the
    underlying metabolic defect driving cadmium-induced osteomalacia and
    results in significant symptom improvement when combined with calcitriol.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: phosphate
      term:
        id: CHEBI:26020
        label: phosphate
  evidence:
  - reference: PMID:31974582
    reference_title: "Hypophosphataemic osteomalacia due to cadmium exposure in the silver industry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "They were initiated on neutral phosphate and calcitriol. On follow-up, they reported significant reduction in severity of symptoms."
    explanation: "Demonstrates effectiveness of phosphate supplementation (combined with calcitriol) for cadmium-induced osteomalacia."
- name: Vitamin D and Calcium Supplementation
  description: >-
    Calcitriol (active vitamin D) supplementation to treat osteomalacia,
    bypassing the impaired renal 1-alpha-hydroxylation caused by cadmium
    nephrotoxicity. Calcium supplementation may also be required to address
    secondary hyperparathyroidism and calcium malabsorption.
  treatment_term:
    preferred_term: vitamin D supplementation
    term:
      id: NCIT:C15425
      label: Nutritional Supplementation
  evidence:
  - reference: PMID:31974582
    reference_title: "Hypophosphataemic osteomalacia due to cadmium exposure in the silver industry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "They were initiated on neutral phosphate and calcitriol. On follow-up, they reported significant reduction in severity of symptoms."
    explanation: "Demonstrates effectiveness of calcitriol for cadmium-induced osteomalacia."
  - reference: PMID:41000307
    reference_title: "Clinical characteristics, management, and outcomes of cadmium poisoning: a systematic review of case reports and case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "for patients with osteochondropathy, supplementation with calcium and vitamin D is recommended."
    explanation: "Systematic review recommends calcium and vitamin D supplementation for skeletal complications."
  - reference: PMID:7426480
    reference_title: "Cadmium-induced osteomalacia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "typical severe osteomalacia, which responded well initially to calcium and vitamin D treatment."
    explanation: "Case report confirms initial good response to calcium and vitamin D in cadmium-induced osteomalacia."
- name: Supportive ICU Care
  description: >-
    For acute cadmium inhalation with pulmonary involvement, intensive care
    including mechanical ventilation for ARDS and continuous renal replacement
    therapy (CRRT) for concurrent renal failure may be required.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:41000307
    reference_title: "Clinical characteristics, management, and outcomes of cadmium poisoning: a systematic review of case reports and case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "For patients with concurrent lung and kidney involvement, mechanical ventilation and continuous renal replacement therapy (CRRT) may be required."
    explanation: "Systematic review confirms need for ICU-level care in severe acute cadmium poisoning."
- name: Exposure Cessation and Prevention
  description: >-
    Removal from cadmium exposure source is essential. Occupational hygiene
    measures include adequate ventilation, personal protective equipment, and
    workplace monitoring. Public health interventions include environmental
    remediation of contaminated soil and water, and regulatory limits on
    cadmium in food and consumer products.
  evidence:
  - reference: PMID:23800513
    reference_title: "Ailing bones and failing kidneys: a case of chronic cadmium toxicity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Therefore, an early diagnosis and prevention of further exposure are important."
    explanation: "Emphasizes the importance of preventing further cadmium exposure given lack of effective treatment."
  - reference: PMID:31974582
    reference_title: "Hypophosphataemic osteomalacia due to cadmium exposure in the silver industry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "regulatory agencies and policy makers ought to survey the silver industry and ensure that the metals used are within permissible safe limits of exposure."
    explanation: "Calls for occupational regulation to prevent cadmium exposure in the silver industry."
classifications:
  harrisons_chapter:
  - classification_value: POISONING_ENVENOMATION
    notes: >-
      Cadmium poisoning is a heavy-metal intoxication and sits with the other
      metal poisonings. The renal and skeletal manifestations that dominate the
      chronic form are consequences of the intoxication, not a separate
      nosological home.
  - classification_value: ENVIRONMENTAL_EXPOSURES
    notes: >-
      Carried in parallel because the dominant global disease burden is chronic
      low-dose environmental and dietary exposure rather than acute poisoning
      events.
  ilo_agent_category:
  - classification_value: cadmium
    notes: >-
      ILO List of Occupational Diseases (revised 2010), item 1.1.2 "Diseases
      caused by cadmium or its compounds" - the chemical-agent item covering the
      non-malignant occupational disease (acute pneumonitis, chronic tubular
      nephropathy, osteomalacia).
  - classification_value: cancer_cadmium
    notes: >-
      ILO item 3.1.17 "Cancer caused by cadmium and its compounds". Recorded
      alongside item 1.1.2 rather than instead of it: the ILO list keeps
      occupational cancers in a separate section from the organ-system items, so
      a single agent with both malignant and non-malignant effects takes an item
      in each. This is the same orthogonality asbestos exhibits, not a
      contradiction.
  eu_occupational_category:
  - classification_value: cadmium_compounds
    notes: >-
      European schedule of occupational diseases (Commission Recommendation
      2003/670/EC as amended), Annex I item 105 "Cadmium or compounds thereof".
      The European schedule lists cadmium as a single chemical-agent item and
      does not split the malignant outcome into a separate entry the way the ILO
      list does.
genetic:
- name: SLC39A8
  gene_term:
    preferred_term: SLC39A8
    term:
      id: hgnc:20862
      label: SLC39A8
  relationship_type: SUSCEPTIBILITY
  association: >-
    ZIP8, a zinc/bicarbonate symporter expressed in the S3 segment of the renal
    proximal tubule, is one of the apical transporters through which cadmium
    enters tubular cells. It is a toxicokinetic determinant of how much filtered
    cadmium is reabsorbed rather than excreted, not a cause of the disease.
  notes: >-
    Cadmium poisoning is an acquired toxic disorder with no causal gene, so every
    entry in this section is a modifier of toxicokinetics or of detoxification
    capacity. The common A391T (rs13107325) variant reduces ZIP8 transport
    activity; its consequence for human cadmium handling specifically has not
    been measured, so no directional susceptibility claim is curated for it here.
  evidence:
  - reference: PMID:22534978
    reference_title: "Roles of ZIP8, ZIP14, and DMT1 in transport of cadmium and manganese in mouse kidney proximal tubule cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The knockdown of ZIP8, ZIP14 or DMT1 by siRNA transfection significantly reduced the uptake of Cd(2+) and Mn(2+) from the apical membrane."
    explanation: >-
      siRNA knockdown establishes ZIP8 as a functional route of apical cadmium
      uptake in proximal tubule cells; no single transporter dominates.
  - reference: PMID:22534978
    reference_title: "Roles of ZIP8, ZIP14, and DMT1 in transport of cadmium and manganese in mouse kidney proximal tubule cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "ZIP8 and ZIP14 expressed in the S3 segment of proximal tubules play significant roles in the absorption of Cd(2+) and Mn(2+) in the kidney"
    explanation: >-
      Localises the transporter to the S3 segment, the nephron site where cadmium
      accumulates and where the proximal tubular injury of this disease begins.
  - reference: PMID:35784893
    reference_title: "The Allelic Variant A391T of Metal Ion Transporter ZIP8 (SLC39A8) Leads to Hypotension and Enhanced Insulin Resistance."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "the single-nucleotide polymorphism (SNP) variant A391T (rs13107325) is associated with numerous human traits"
    explanation: >-
      Establishes that a common functional variant of this transporter exists and
      is phenotypically consequential. PARTIAL because the traits studied are
      blood pressure and insulin resistance, not cadmium handling - the link to
      cadmium susceptibility is inferred from the transporter's role, not measured.
- name: SLC39A14
  gene_term:
    preferred_term: SLC39A14
    term:
      id: hgnc:20858
      label: SLC39A14
  relationship_type: SUSCEPTIBILITY
  association: >-
    ZIP14 acts alongside ZIP8 in the S3 segment of the proximal tubule as a route
    of apical cadmium uptake, contributing to renal cadmium accumulation.
  evidence:
  - reference: PMID:22534978
    reference_title: "Roles of ZIP8, ZIP14, and DMT1 in transport of cadmium and manganese in mouse kidney proximal tubule cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "ZIP8 and ZIP14 expressed in the S3 segment of proximal tubules play significant roles in the absorption of Cd(2+) and Mn(2+) in the kidney"
    explanation: >-
      Directly assigns ZIP14 a significant role in renal cadmium absorption at the
      segment where cadmium concentrates.
- name: SLC11A2
  gene_term:
    preferred_term: SLC11A2
    term:
      id: hgnc:10908
      label: SLC11A2
  relationship_type: SUSCEPTIBILITY
  association: >-
    DMT1 is the iron-cadmium shared divalent metal transporter. It is the
    molecular basis of the best-documented gene-environment interaction in this
    disease: intestinal DMT1 is upregulated in iron deficiency, so iron-deplete
    individuals absorb more cadmium from an identical dietary dose. It also
    contributes to apical cadmium uptake in the renal proximal tubule.
  evidence:
  - reference: PMID:22534978
    reference_title: "Roles of ZIP8, ZIP14, and DMT1 in transport of cadmium and manganese in mouse kidney proximal tubule cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The knockdown of ZIP8, ZIP14 or DMT1 by siRNA transfection significantly reduced the uptake of Cd(2+) and Mn(2+) from the apical membrane."
    explanation: >-
      Establishes DMT1 as a functional cadmium uptake route in proximal tubule
      cells, complementing its better-known intestinal role.
  - reference: PMID:20204475
    reference_title: "Catch me if you can! Novel aspects of cadmium transport in mammalian cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "uptake of free Cd(2+) has been demonstrated for the Fe(2+)/H(+) cotransporter divalent metal transporter 1."
    explanation: >-
      Identifies DMT1 as the iron cotransporter that also carries free cadmium,
      the shared-route mechanism behind the iron-deficiency interaction.
- name: MT1A
  gene_term:
    preferred_term: MT1A
    term:
      id: hgnc:7393
      label: MT1A
  relationship_type: MODIFIER
  association: >-
    Metallothionein sequesters cadmium as the relatively inert Cd-metallothionein
    complex and is the body's principal endogenous defence against free Cd(2+).
    Individual differences in inducible metallothionein capacity set where the
    balance falls between safe storage and free-ion toxicity at a given body
    burden.
  notes: >-
    Curated as a MODIFIER rather than a SUSCEPTIBILITY locus because the cited
    evidence documents inter-individual variation in metallothionein level at a
    given renal cadmium burden; specific MT1A/MT2A promoter variants and their
    effect sizes are not established in the cited source. MT2A is curated
    separately.
  evidence:
  - reference: PMID:19834257
    reference_title: "Individual susceptibility to cadmium toxicity and metallothionein gene polymorphisms: with references to current status of occupational cadmium exposure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cadmium accumulates in the renal cortex by the long-term exposure along with increased concentrations of metallothionein, an important protein for protection from cadmium toxicity."
    explanation: >-
      States metallothionein's protective role and its co-accumulation with
      cadmium in the renal cortex, the target organ of chronic toxicity.
  - reference: PMID:19834257
    reference_title: "Individual susceptibility to cadmium toxicity and metallothionein gene polymorphisms: with references to current status of occupational cadmium exposure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "some individuals have lower metallothionein levels despite increased cadmium accumulation in the kidneys"
    explanation: >-
      Documents the inter-individual variation in metallothionein response that
      makes this a susceptibility modifier rather than a uniform protective factor.
- name: MT2A
  gene_term:
    preferred_term: MT2A
    term:
      id: hgnc:7406
      label: MT2A
  relationship_type: MODIFIER
  association: >-
    MT2A encodes the other major inducible metallothionein isoform binding
    cadmium in liver and kidney; the same individual-capacity argument applies as
    for MT1A.
  evidence:
  - reference: PMID:19834257
    reference_title: "Individual susceptibility to cadmium toxicity and metallothionein gene polymorphisms: with references to current status of occupational cadmium exposure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "some individuals have lower metallothionein levels despite increased cadmium accumulation in the kidneys"
    explanation: >-
      Same inter-individual metallothionein variation applies to the MT2A isoform;
      the cited work does not resolve the isoforms separately.
environmental:
- name: Occupational Cadmium Exposure
  exposure_classifications:
    hazard_agent_type:
    - classification_value: CHEMICAL
    exposure_route:
    - classification_value: INHALATION
      notes: >-
        Fume and dust inhalation is the occupational route and the
        higher-bioavailability one: roughly 10% of inhaled cadmium is absorbed
        against roughly 5% of ingested cadmium.
    exposure_duration:
    - classification_value: CHRONIC
      notes: >-
        The nephropathy and osteomalacia are cumulative-burden diseases; cadmium's
        10-30 year biological half-life means occupational exposure integrates
        over a working lifetime.
    - classification_value: ACUTE
      notes: >-
        Recorded in parallel for the single high-dose fume exposures that produce
        chemical pneumonitis, a mechanistically distinct presentation from the
        chronic accumulation arm.
    iarc_carcinogen_group:
      classification_value: GROUP_1
      notes: >-
        IARC has classified cadmium and cadmium compounds as Group 1,
        carcinogenic to humans, since 1993, primarily on excess lung cancer in
        occupationally exposed cohorts. Recorded on the exposure because it is a
        property of the agent.
      evidence:
      - reference: PMID:12746140
        reference_title: "Cadmium, lung and prostate cancer: a systematic review of recent epidemiological data."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Cadmium (Cd) and its compounds were classified as \"carcinogenic to humans (Group 1)\" by IARC in 1993"
        explanation: Source for the IARC Group 1 assignment recorded on this exposure.
    ghs_health_hazard_class:
    - classification_value: CARCINOGENICITY
    - classification_value: STOT_REPEATED_EXPOSURE
      notes: >-
        The proximal tubular nephropathy and osteomalacia are target-organ
        toxicity from repeated exposure, a separate hazard class from the
        carcinogenicity listing.
    exposome_domain:
    - classification_value: SPECIFIC_EXTERNAL
  influences_mechanisms:
  - target: Cadmium Absorption and Systemic Distribution
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Industrial processes generate cadmium fume and dust that workers inhale,
      and inhaled cadmium is the higher-bioavailability route into the body at
      this node.
    evidence:
    - reference: PMID:18072106
      reference_title: "Cadmium exposure: health hazards of silver cottage industry in developing countries."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Silver is mixed with cadmium and then used to make silver jewelry. During this process there is a formation of cadmium fumes, and the workers inhale the fumes."
      explanation: >-
        Documents cadmium fume formation during silver jewelry manufacture and
        its inhalation by workers, the occupational inhalational route into
        the body.
  - target: Acute Pulmonary Injury
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      High-dose fume inhalation injures the alveolar epithelium directly at the
      portal of entry, without requiring the systemic accumulation that drives
      the chronic renal and skeletal arms. This is why acute cadmium poisoning
      presents as a lung disease while chronic poisoning does not.
    evidence:
    - reference: PMID:16933734
      reference_title: "Acute lung injury due to cadmium inhalation--a case report."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Heavy metal inhalation is a rare cause of acute lung injury. Among the various heavy metals, cadmium is more commonly known to cause acute lung injury."
      explanation: >-
        Directly attributes acute lung injury to inhaled cadmium, the edge from
        the inhalational exposure to the pulmonary node.
  exposure_term:
    preferred_term: exposure to cadmium
    term:
      id: ECTO:0001566
      label: exposure to cadmium
  environment_context:
    preferred_term: factory
    term:
      id: ENVO:01000536
      label: factory
  description: >-
    Occupational exposure occurs in silver jewelry manufacturing, zinc smelting,
    battery production, cadmium plating, welding of cadmium-containing alloys,
    and pigment manufacturing. Workers inhale cadmium fumes and dust, with the
    silver cottage industry in developing countries being particularly hazardous
    due to lack of protective measures.
  evidence:
  - reference: PMID:18072106
    reference_title: "Cadmium exposure: health hazards of silver cottage industry in developing countries."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Silver is mixed with cadmium and then used to make silver jewelry. During this process there is a formation of cadmium fumes, and the workers inhale the fumes."
    explanation: "Describes the mechanism of occupational cadmium exposure in the silver jewelry industry."
  - reference: PMID:31974582
    reference_title: "Hypophosphataemic osteomalacia due to cadmium exposure in the silver industry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We highlight the occurrence of hypophosphataemic osteomalacia due to chronic cadmium exposure in the silver industry in India."
    explanation: "Confirms the silver industry as a source of chronic cadmium exposure."
  - reference: PMID:41000307
    reference_title: "Clinical characteristics, management, and outcomes of cadmium poisoning: a systematic review of case reports and case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cadmium poisoning primarily affects adult males and is often associated with occupational exposure."
    explanation: "Systematic review confirms occupational exposure as the primary route of cadmium poisoning."
- name: Environmental Cadmium Contamination
  exposure_classifications:
    hazard_agent_type:
    - classification_value: CHEMICAL
    exposure_route:
    - classification_value: ORAL
      notes: >-
        Ingestion of cadmium-accumulating crops (notably rice) and of
        contaminated water is the dominant route for the general population and
        the etiologic route of itai-itai disease.
    exposure_duration:
    - classification_value: LIFETIME
      notes: >-
        Dietary cadmium intake is continuous from birth, and the long biological
        half-life means body burden rises monotonically with age.
    iarc_carcinogen_group:
      classification_value: GROUP_1
      evidence:
      - reference: PMID:12746140
        reference_title: "Cadmium, lung and prostate cancer: a systematic review of recent epidemiological data."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Cadmium (Cd) and its compounds were classified as \"carcinogenic to humans (Group 1)\" by IARC in 1993"
        explanation: Source for the IARC Group 1 assignment recorded on this exposure.
    ghs_health_hazard_class:
    - classification_value: CARCINOGENICITY
      evidence:
      - reference: PMID:38480109
        reference_title: "Cadmium in biological samples and site-specific cancer risk and mortality: A systematic review of original articles and meta-analyses."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Current data consistently suggest a causal role of exposure to cadmium in pancreas, lung, and bladder carcinogenesis."
        explanation: >-
          Supports the carcinogenicity hazard class for dietary/environmental
          cadmium specifically, where exposure is measured as body burden.
    - classification_value: STOT_REPEATED_EXPOSURE
      notes: >-
        The tubular nephropathy and osteomalacia of itai-itai disease are
        target-organ toxicity from repeated dietary exposure.
    exposome_domain:
    - classification_value: GENERAL_EXTERNAL
  influences_mechanisms:
  - target: Cadmium Absorption and Systemic Distribution
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Cadmium-polluted soil and water enter the food chain, so residents of
      contaminated areas take cadmium in orally over years. Oral
      bioavailability is lower than inhalational, but the exposure is
      continuous.
    evidence:
    - reference: PMID:39111871
      reference_title: 'A suspected case of "itai-itai disease" in a cadmium-polluted area in Akita prefecture, Japan.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "An elderly female farmer with Cd nephropathy residing in a Cd-polluted area in the northern part of the Akita prefecture was identified through hospital-based screening"
      explanation: >-
        Documents cadmium nephropathy in a farmer living in a cadmium-polluted
        area, linking residence in a contaminated environment to systemic
        cadmium disease.
  exposure_term:
    preferred_term: exposure to cadmium
    term:
      id: ECTO:0001566
      label: exposure to cadmium
  description: >-
    Environmental exposure through contaminated food (rice, vegetables grown in
    cadmium-polluted soil), drinking water, and ambient air near industrial
    sources. Mining and smelting operations contaminate local waterways and
    agricultural land, as in the Jinzu River basin in Japan.
  evidence:
  - reference: PMID:39111871
    reference_title: "A suspected case of \"itai-itai disease\" in a cadmium-polluted area in Akita prefecture, Japan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "An elderly female farmer with Cd nephropathy residing in a Cd-polluted area in the northern part of the Akita prefecture was identified through hospital-based screening"
    explanation: "Documents environmental cadmium exposure in an agricultural area with contaminated soil."
- name: Tobacco Smoke Exposure
  influences_mechanisms:
  - target: Cadmium Absorption and Systemic Distribution
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Tobacco plants concentrate cadmium from soil, so smoking is an
      inhalational cadmium source and the dominant non-occupational one. Note
      the cited sentence establishes smoking as a recognized risk factor for
      cadmium poisoning; it does not itself measure the absorbed dose.
    evidence:
    - reference: PMID:41000307
      reference_title: "Clinical characteristics, management, and outcomes of cadmium poisoning: a systematic review of case reports and case series."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Common risk factors include smoking and alcohol consumption."
      explanation: >-
        Lists smoking among the common risk factors for cadmium poisoning. It
        supports smoking as a recognized route of exposure, not a quantified
        absorption step.
  exposure_term:
    preferred_term: exposure to tobacco smoking
    term:
      id: ECTO:6000029
      label: exposure to tobacco smoking
  description: >-
    Tobacco smoke is a significant non-occupational source of cadmium: tobacco
    plants accumulate cadmium from soil, and smoking is a recognised risk
    factor for cadmium poisoning. Per-cigarette cadmium content and the
    smoker/non-smoker blood cadmium ratio are not asserted here because the
    curated sources do not quantify them.
  evidence:
  - reference: PMID:41000307
    reference_title: "Clinical characteristics, management, and outcomes of cadmium poisoning: a systematic review of case reports and case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common risk factors include smoking and alcohol consumption."
    explanation: "Systematic review identifies smoking as a common risk factor for cadmium poisoning."
- name: Iron Deficiency as Risk Modifier
  exposure_term:
    preferred_term: low dietary iron exposure
    modifier: DECREASED
    term:
      id: ECTO:9000087
      label: exposure to iron
  influences_mechanisms:
  - target: Cadmium Absorption and Systemic Distribution
    environmental_effect: EXACERBATES
    causal_link_type: DIRECT
    description: >-
      Low iron stores upregulate the shared divalent metal transporter DMT1,
      so more of an identical dietary cadmium intake is absorbed. This
      amplifies absorption rather than providing a source of cadmium, which is
      why it is a modifier and not a route.
    evidence:
    - reference: PMID:41000307
      reference_title: "Clinical characteristics, management, and outcomes of cadmium poisoning: a systematic review of case reports and case series."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The study also found that low iron stores exacerbate cadmium poisoning."
      explanation: >-
        States that low iron stores exacerbate cadmium poisoning, an
        amplification of the absorption this node describes rather than an
        independent exposure.
  description: >-
    Low iron stores increase gastrointestinal cadmium absorption via shared
    divalent metal transporter 1 (DMT1). Iron-deficient individuals, often
    women and children, are at higher risk of cadmium accumulation from dietary
    sources.
  evidence:
  - reference: PMID:41000307
    reference_title: "Clinical characteristics, management, and outcomes of cadmium poisoning: a systematic review of case reports and case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The study also found that low iron stores exacerbate cadmium poisoning."
    explanation: "Systematic review confirms that iron deficiency exacerbates cadmium toxicity."
histopathology:
- name: Diffuse Alveolar Damage
  description: >-
    Acute cadmium inhalation produces acute lung injury, and the lung is a
    confirmed target organ at autopsy in fatal poisoning. Diffuse alveolar
    damage is the expected histological correlate of the clinical acute
    respiratory distress syndrome, but the specific microscopic features often
    attributed to it here (hyaline membranes, alveolar edema, type II
    pneumocyte hyperplasia) are NOT documented in the sources curated for this
    entry; they are stated as the general ARDS pattern, not as an observed
    cadmium finding.
  context: Acute cadmium inhalation
  finding_term:
    preferred_term: Widespread Alveolar Pneumocyte Damage
    term:
      id: NCIT:C96237
      label: Widespread Alveolar Pneumocyte Damage Present
  evidence:
  - reference: PMID:22349354
    reference_title: "An investigation and pathological analysis of two fatal cases of cadmium poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In both cases, multiple organ damage was observed, involving brain, lung, liver, kidney, red blood cells, and platelets"
    explanation: "Autopsy of two fatal cadmium poisoning cases confirms the lung as a target organ. Marked PARTIAL: the report describes organ involvement, not the alveolar histology asserted in the node description."
  - reference: PMID:16933734
    reference_title: "Acute lung injury due to cadmium inhalation--a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Heavy metal inhalation is a rare cause of acute lung injury. Among the various heavy metals, cadmium is more commonly known to cause acute lung injury."
    explanation: "Supports cadmium inhalation as a cause of acute lung injury. Marked PARTIAL: this is the clinical syndrome, not a histological description."
- name: Renal Tubulointerstitial Disease and Fibrosis
  description: >-
    The kidneys show proximal tubular cell necrosis with loss of brush border,
    tubulointerstitial inflammatory infiltrates, and progressive fibrosis.
    Cadmium accumulates in the renal cortex. Both cadmium and lead
    nephropathies are characterized by tubulointerstitial disease and fibrosis,
    though only early lead nephropathy shows nuclear inclusion bodies.
  finding_term:
    preferred_term: Fibrosis
    term:
      id: NCIT:C3044
      label: Fibrosis
  evidence:
  - reference: PMID:22349354
    reference_title: "An investigation and pathological analysis of two fatal cases of cadmium poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In both cases, multiple organ damage was observed, involving brain, lung, liver, kidney, red blood cells, and platelets"
    explanation: "Autopsy confirms the kidney as a target organ. Marked PARTIAL: the report does not describe the tubulointerstitial fibrosis asserted here, which rests on the second citation."
  - reference: PMID:19106433
    reference_title: "Nephrotoxicity of cadmium & lead."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "both entities are characterized by tubulointerstitial disease and fibrosis, but only early lead nephropathy is characterized by the presence of proximal tubule nuclear inclusion bodies, due to the combination of lead with a lead binding-protein."
    explanation: "Review confirms tubulointerstitial disease and fibrosis as the characteristic renal histopathology of cadmium nephropathy, and distinguishes it from lead nephropathy by the absence of nuclear inclusion bodies."
- name: Hepatocellular Degeneration
  description: >-
    The liver is a confirmed cadmium target organ: postmortem and biopsy
    analysis shows gross cadmium excess in hepatic tissue, and human
    epidemiological data link cadmium exposure to hepatic fibrosis. Cadmium
    accumulates in hepatocytes bound to metallothionein, and when that binding
    capacity is overwhelmed free cadmium causes oxidative damage and cell
    death. Note that frank hepatocellular degeneration and necrosis is the
    expected consequence of that mechanism rather than a microscopic finding
    documented in the sources curated here — the human evidence in this entry
    establishes cadmium accumulation and fibrosis, not necrosis histology.
  finding_term:
    preferred_term: Degeneration and Necrosis
    term:
      id: NCIT:C120875
      label: Degeneration and Necrosis
  evidence:
  - reference: PMID:22349354
    reference_title: "An investigation and pathological analysis of two fatal cases of cadmium poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In both cases, multiple organ damage was observed, involving brain, lung, liver, kidney, red blood cells, and platelets"
    explanation: "Autopsy confirms the liver as a target organ. Marked PARTIAL: the report does not describe hepatocellular degeneration or necrosis on microscopy."
  - reference: PMID:7426480
    reference_title: "Cadmium-induced osteomalacia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Examination of the liver both in life and after death showed a gross excess of cadmium. This was also found in the kidneys after death."
    explanation: "Liver biopsy and postmortem analysis confirmed gross cadmium accumulation in hepatic tissue."
  - reference: PMID:41412331
    reference_title: "Diverse impacts of cadmium exposure on adolescent liver health: Suppression of steatosis and promotion of fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cadmium exposure affects liver health by inhibiting steatosis and promoting fibrosis, with renal and lipid metabolism factors acting as mediators, and diet influencing the outcomes."
    explanation: "NHANES cross-sectional study in adolescents demonstrates cadmium exposure promotes hepatic fibrosis, providing human epidemiological evidence for cadmium-induced hepatocellular damage."
- name: Osteomalacic Bone Changes
  description: >-
    Bone biopsy shows widened osteoid seams with defective mineralization,
    consistent with osteomalacia. In severe cases (itai-itai disease),
    vertebral bodies show structural changes from gross deformity. Bone
    biopsies are essential for confirming the diagnosis of osteomalacia
    in cadmium-exposed patients.
  evidence:
  - reference: PMID:7426480
    reference_title: "Cadmium-induced osteomalacia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Several bone biopsies and detailed metabolic studies showed typical severe osteomalacia"
    explanation: "Multiple bone biopsies in a cadmium-exposed worker confirmed typical severe osteomalacia on histological examination."
  - reference: PMID:7426480
    reference_title: "Cadmium-induced osteomalacia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Previously unreported changes were present in the bones, especially the lumbar vertebrae which were probably more the result of gross bone deformity than cadmium deposition."
    explanation: "Histopathological examination revealed novel structural changes in vertebral bone, attributed to mechanical deformity from osteomalacia rather than direct cadmium deposition."
- name: Intracellular Dense Lysosomal Particles
  description: >-
    Transmission electron microscopy reveals a large number of dense lysosomal
    and phagocytic particles in the cytoplasm near the nucleus. This
    ultrastructural finding is observed across multiple organs and suggests
    intracellular cadmium sequestration in lysosomes, with potential
    genotoxic implications from proximity to the nucleus.
  evidence:
  - reference: PMID:22349354
    reference_title: "An investigation and pathological analysis of two fatal cases of cadmium poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "transmission electron microscopy revealed a large number of dense lysosomal and phagocytic particles in the cytoplasm near the nucleus, indicating the need for a genotoxic study of cadmium."
    explanation: "Ultrastructural finding on TEM showing characteristic perinuclear lysosomal cadmium accumulation, a distinctive histopathological marker of cadmium toxicity."
prevalence:
- population: Global
  notes: >-
    Cadmium poisoning is rare in the general population but occurs in
    occupational settings (silver industry, smelting, battery manufacturing)
    and in regions with environmental contamination. Itai-itai disease is
    endemic in cadmium-polluted areas of Japan. The condition primarily
    affects adult males through occupational exposure.
  evidence:
  - reference: PMID:41000307
    reference_title: "Clinical characteristics, management, and outcomes of cadmium poisoning: a systematic review of case reports and case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This review emphasizes that cadmium poisoning is rare and complex, with non- specific symptoms and a tendency to cause organ damage."
    explanation: "Systematic review confirms cadmium poisoning is rare overall."
differential_diagnoses:
- name: Lead Poisoning
  description: >-
    Lead poisoning shares features with cadmium toxicity including renal tubular
    dysfunction, peripheral neuropathy, and occupational exposure in metalworking
    industries. However, lead poisoning characteristically produces basophilic
    stippling of erythrocytes, a lead line on gingiva, wrist/foot drop, and
    abdominal colic, which are not features of cadmium toxicity.
  disease_term:
    preferred_term: lead poisoning
    term:
      id: MONDO:0018019
      label: lead poisoning
  distinguishing_features:
  - Basophilic stippling of erythrocytes on blood smear
  - Lead line on gingiva (Burton line)
  - Wrist drop and foot drop from motor neuropathy (cadmium causes sensory neuropathy)
  - Abdominal colic (lead colic) is characteristic
  - Elevated blood lead levels rather than blood cadmium
  - Osteomalacia and severe phosphate wasting are not typical of lead poisoning
  evidence:
  - reference: PMID:19106433
    reference_title: "Nephrotoxicity of cadmium & lead."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Cadmium in sufficient cumulative dosage leads to the production of the Fanconi syndrome, a generalized proximal tubular reabsorptive defect thought to be related to inhibition of both ATP production and Na-K-ATPase activity. On the other hand, lead accumulation in the proximal tubule leads to hyperuricaemia and gout"
    explanation: "Directly contrasts cadmium vs lead nephrotoxicity, showing both settle in proximal tubule but produce different clinical manifestations."
  - reference: PMID:19106433
    reference_title: "Nephrotoxicity of cadmium & lead."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Beta2-microglobulinuria is not found in lead nephropathy."
    explanation: "Key distinguishing feature: beta-2-microglobulinuria is a hallmark of cadmium nephrotoxicity but absent in lead nephropathy."
- name: Other Causes of Acquired Fanconi Syndrome
  description: >-
    Acquired Fanconi syndrome can result from multiple causes beyond cadmium,
    including medications (tenofovir, ifosfamide, cisplatin, valproic acid),
    multiple myeloma with light chain deposition, and Wilson disease. The
    clinical presentation of proximal tubular dysfunction with LMW proteinuria,
    glucosuria, and aminoaciduria is identical regardless of cause.
  disease_term:
    preferred_term: acquired Fanconi syndrome
    term:
      id: MONDO:0060779
      label: acquired Fanconi syndrome
  distinguishing_features:
  - Medication history (tenofovir, cisplatin, ifosfamide) may explain tubular dysfunction
  - Multiple myeloma presents with monoclonal protein on serum/urine electrophoresis
  - Wilson disease shows low ceruloplasmin, elevated urine copper, and Kayser-Fleischer rings
  - Cadmium toxicity is distinguished by elevated blood/urine cadmium levels and occupational or environmental exposure history
  evidence:
  - reference: PMID:23800513
    reference_title: "Ailing bones and failing kidneys: a case of chronic cadmium toxicity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He was finally diagnosed with chronic cadmium toxicity resulting from long-term occupational exposure."
    explanation: "Case illustrates how Fanconi syndrome presentation required occupational history and cadmium testing to distinguish from other causes."
- name: Vitamin D Deficiency Osteomalacia
  description: >-
    Nutritional vitamin D deficiency causes osteomalacia with bone pain,
    proximal myopathy, and pathologic fractures that closely mimic cadmium-induced
    osteomalacia. Both conditions present with low serum phosphate
    and elevated alkaline phosphatase.
  disease_term:
    preferred_term: vitamin D deficiency
    term:
      id: MONDO:0100471
      label: vitamin D deficiency
  distinguishing_features:
  - Low serum 25-hydroxyvitamin D level (< 20 ng/mL)
  - No renal tubular dysfunction or LMW proteinuria
  - Normal urinary cadmium levels
  - Responds to vitamin D supplementation alone without phosphate replacement
  - No occupational heavy metal exposure history
  evidence:
  - reference: PMID:31974582
    reference_title: "Hypophosphataemic osteomalacia due to cadmium exposure in the silver industry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is essential to maintain a high index of suspicion in diagnosing this condition. A thorough knowledge of the occupational background of patients, as well as ambient conditions at the workplace is of utmost importance in contemplating the possibility of such rare occurrences."
    explanation: "Emphasizes the need for occupational history to distinguish cadmium-induced osteomalacia from more common nutritional causes."
  - reference: PMID:7426480
    reference_title: "Cadmium-induced osteomalacia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mechanism of development of the severe acquired Fanconi syndrome was thought to be a combination of dietary calcium and vitamin D deficiency and impaired calcium absorption from abnormal vitamin D synthesis, related to the cadmium deposition in the renal tubules"
    explanation: "Demonstrates that cadmium-induced osteomalacia involves impaired renal vitamin D synthesis, making it difficult to distinguish from pure nutritional vitamin D deficiency without cadmium testing."
- name: Metal Fume Fever
  description: >-
    Metal fume fever, typically caused by zinc oxide fume inhalation, presents
    with flu-like symptoms (fever, myalgias, metallic taste) hours after
    welding or metalworking. It mimics early acute cadmium inhalation but
    is self-limiting within 24-48 hours and does not progress to ARDS.
  distinguishing_features:
  - Self-limiting course resolving within 24-48 hours
  - Does not progress to ARDS or respiratory failure
  - Typically caused by zinc rather than cadmium fumes
  - No renal or skeletal toxicity
  - Cadmium fume exposure causes delayed-onset (12-36 hours) progressive respiratory failure
  evidence:
  - reference: PMID:16933734
    reference_title: "Acute lung injury due to cadmium inhalation--a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Heavy metal inhalation is a rare cause of acute lung injury. Among the various heavy metals, cadmium is more commonly known to cause acute lung injury."
    explanation: "Cadmium fume inhalation causes true acute lung injury, unlike the benign self-limiting course of metal fume fever."
- name: X-linked Hypophosphatemia
  description: >-
    X-linked hypophosphatemia (XLH) is an inherited disorder of renal phosphate
    wasting caused by PHEX gene mutations, leading to excess FGF23 and
    hypophosphataemic rickets/osteomalacia. It presents with similar phosphate
    wasting and skeletal findings but occurs from childhood without heavy metal
    exposure.
  disease_term:
    preferred_term: X-linked hypophosphatemic rickets
    term:
      id: MONDO:0020720
      label: X-linked hypophosphatemic rickets
  distinguishing_features:
  - Childhood onset with rickets, short stature, and bowing of lower limbs
  - Family history consistent with X-linked dominant inheritance
  - Elevated FGF23 levels
  - No LMW proteinuria or generalized Fanconi syndrome
  - Normal cadmium levels
  - No occupational or environmental exposure history
  evidence:
  - reference: PMID:31974582
    reference_title: "Hypophosphataemic osteomalacia due to cadmium exposure in the silver industry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three silversmiths presented similarly with clinical, biochemical and radiological evidence of hypophosphataemic osteomalacia."
    explanation: "Adult-onset hypophosphataemic osteomalacia from cadmium exposure contrasts with XLH, which presents in childhood; cadmium-induced phosphate wasting is acquired and accompanied by Fanconi syndrome."
clinical_trials:
- name: NCT05908383
  phase: PHASE_I
  status: COMPLETED
  description: >-
    Phase I, randomized, double-blind, single-center, single-dose escalation
    trial evaluating the safety, tolerability, and pharmacokinetic characteristics
    of injectable GMDTC (a novel cadmium chelation agent) in healthy subjects.
    This is the foundational safety study for the GMDTC cadmium chelation program.
  evidence:
  - reference: clinicaltrials:NCT05908383
    reference_title: "Phase I Clinical Study on the Safety, Tolerability and Pharmacokinetic Characteristics of a Single Dose of GMDTC Administered to Healthy Subjects for Injection"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This trial is a randomized, double-blind, single-center, single-dose escalating Phase I clinical trial designed to evaluate the safety, tolerability, and pharmacokinetic characteristics of injectable GMDTC in healthy subjects"
    explanation: "First-in-human safety trial for GMDTC, a novel chelation agent being developed specifically for cadmium poisoning."
- name: NCT06199349
  phase: PHASE_I
  status: COMPLETED
  description: >-
    Phase Ib trial evaluating the safety, tolerability, and pharmacokinetic
    characteristics of repeated-dose GMDTC injection in people with excessive
    cadmium levels. This trial extends the Phase I safety profile from healthy
    volunteers to the target population of cadmium-exposed individuals across
    three dose cohorts.
  target_phenotypes:
  - preferred_term: Chronic kidney disease
    term:
      id: HP:0012622
      label: Chronic kidney disease
  evidence:
  - reference: clinicaltrials:NCT06199349
    reference_title: "Phase Ib Clinical Study on the Safety, Tolerability and Pharmacokinetic Characteristics of GMDTC for Injection After Repeated Administration in People With Excessive Cadmium Levels"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This trial is a randomized, double-blind, single-center, single-dose escalating Phase I clinical trial designed to evaluate the safety, tolerability, and pharmacokinetic characteristics of GMDTC for injection after repeated administration in people with excessive cadmium levels."
    explanation: "First trial of GMDTC chelation directly in cadmium-exposed individuals, establishing repeated-dose safety and pharmacokinetics in the target population."
- name: NCT07057414
  phase: PHASE_II
  status: RECRUITING
  description: >-
    Phase IIa, randomized, double-blind, placebo-controlled trial evaluating
    the safety and efficacy of GMDTC injection in subjects with elevated cadmium
    levels. This is the first controlled efficacy trial of a chelation agent
    specifically developed for cadmium poisoning.
  target_phenotypes:
  - preferred_term: Chronic kidney disease
    term:
      id: HP:0012622
      label: Chronic kidney disease
  evidence:
  - reference: clinicaltrials:NCT07057414
    reference_title: "Phase IIa, Randomized, Double-Blind, Placebo-Controlled, Single-Center Clinical Study to Evaluate the Safety and Efficacy of GMDTC for Injection in Subjects With Elevated Cadmium Levels"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This is a randomized, double-blind, placebo-controlled, single-center Phase IIa clinical study."
    explanation: "First placebo-controlled efficacy trial for cadmium-specific chelation therapy, representing a significant advance given that no approved treatment exists for cadmium poisoning."
- name: NCT00376987
  phase: PHASE_II
  status: COMPLETED
  description: >-
    Clinical trial evaluating whether dietary zinc supplements can reduce serum
    cadmium levels in current cigarette smokers. Leverages the known competitive
    interaction between zinc and cadmium at shared divalent metal transporters
    (DMT1) to potentially reduce cadmium body burden through a simple dietary
    intervention.
  target_phenotypes:
  - preferred_term: Proteinuria
    term:
      id: HP:0000093
      label: Proteinuria
  evidence:
  - reference: clinicaltrials:NCT00376987
    reference_title: "Do Dietary Supplements of Zinc Reduce Serum Cadmium Levels in Smokers?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Zinc supplements may lower cadmium levels in smokers and may help prevent DNA damage."
    explanation: "Evaluates a non-chelation approach to reducing cadmium burden by exploiting zinc-cadmium competition at shared intestinal transporters."
datasets:
- accession: geo:GSE198150
  title: The protease DDI2 regulates NRF1-metallothionein pathway in response to Cadmium toxicity in the liver
  description: >-
    RNA-seq profiling of liver tissue from liver-specific Ddi2 knockout and
    wild-type mice, investigating how the protease DDI2 regulates the
    NRF1-metallothionein pathway in response to cadmium toxicity. Identifies
    DDI2-mediated metallothionein activation as a protective mechanism against
    cadmium-induced hepatotoxicity.
  organism:
    preferred_term: mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  data_type: BULK_RNA_SEQ
  sample_types:
  - preferred_term: liver tissue
    tissue_term:
      preferred_term: liver
      term:
        id: UBERON:0002107
        label: liver
  sample_count: 4
  conditions:
  - Ddi2 liver-specific knockout
  - wild-type control
  platform: Illumina HiSeq 2500
  publication: PMID:36248746
  notes: >-
    2 replicates per condition (WT vs Ddi2-KO). Demonstrates that DDI2
    cleaves and activates NRF1 to drive metallothionein expression in
    response to cadmium, linking proteasome homeostasis to heavy metal
    detoxification.
discussions:
- discussion_id: gap_cadmium_direct_osteoblast_toxicity
  prompt: >-
    Does cadmium impair osteoblast function and promote osteoclastic resorption
    directly, independently of the renal phosphate wasting that drives
    cadmium osteomalacia?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Proposed Direct Bone-Cell Toxicity
  rationale: >-
    Cadmium-exposed patients who develop bone disease characteristically also
    have proximal tubular injury with phosphate wasting, so clinical
    observations of reduced bone density cannot separate a direct bone-cell
    effect from the established renal route. No osteoblast-culture or animal
    skeletal evidence is currently curated in this entry, so the direct arm is
    recorded as an unresolved mechanism rather than an asserted one.
  proposed_experiments:
  - experiment_id: exp_cadmium_osteoblast_direct_toxicity
    name: Osteoblast and osteoclast culture under cadmium exposure
    description: >-
      Expose primary or iPSC-derived osteoblasts and osteoclasts to cadmium at
      concentrations achievable in bone, reading out osteoblast differentiation
      markers, alkaline phosphatase activity, mineralization, and RANKL/OPG
      balance, to establish whether cadmium acts on bone cells directly.
  - experiment_id: exp_cadmium_bone_loss_independent_of_renal_route
    name: Skeletal outcomes with and without renal phosphate wasting
    description: >-
      Compare skeletal outcomes in cadmium-exposed animals with and without
      established renal tubular phosphate wasting, testing whether bone loss
      still occurs when the renal route is absent or corrected. This is the
      experiment that would settle the independence claim.
  evidence:
  - reference: PMID:18072106
    reference_title: "Cadmium exposure: health hazards of silver cottage industry in developing countries."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We will present a case of cadmium induced peripheral neuropathy, nephropathy, and decreased bone density."
    explanation: >-
      The available human observation couples reduced bone density with
      nephropathy in the same patient, which is exactly why the question of a
      direct-versus-renal route remains open.
references:
- reference: DOI:10.1038/s41598-022-27292-7
  title: Association between levels of exposure to heavy metals and renal function indicators of residents in environmentally vulnerable areas
  found_in:
  - Cadmium_Poisoning-deep-research-falcon.md
  findings:
  - statement: Abandoned metal mines and refineries are considered environmentally vulnerable areas owing to high levels of exposure to heavy metals.
    supporting_text: Abandoned metal mines and refineries are considered environmentally vulnerable areas owing to high levels of exposure to heavy metals.
    evidence:
    - reference: DOI:10.1038/s41598-022-27292-7
      reference_title: Association between levels of exposure to heavy metals and renal function indicators of residents in environmentally vulnerable areas
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Abandoned metal mines and refineries are considered environmentally vulnerable areas owing to high levels of exposure to heavy metals.
      explanation: Deep research cited this publication as relevant literature for Cadmium Poisoning.
- reference: DOI:10.1038/s41598-023-28968-4
  title: Combating lead and cadmium exposure with an orally administered chitosan-based chelating polymer
  found_in:
  - Cadmium_Poisoning-deep-research-falcon.md
  findings:
  - statement: Heavy metals present a threat to human health, even at minimal concentrations within the body.
    supporting_text: Heavy metals present a threat to human health, even at minimal concentrations within the body.
    evidence:
    - reference: DOI:10.1038/s41598-023-28968-4
      reference_title: Combating lead and cadmium exposure with an orally administered chitosan-based chelating polymer
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Heavy metals present a threat to human health, even at minimal concentrations within the body.
      explanation: Deep research cited this publication as relevant literature for Cadmium Poisoning.
- reference: DOI:10.1038/s41598-024-63858-3
  title: Associations of mixed metal exposure with chronic kidney disease from NHANES 2011–2018
  found_in:
  - Cadmium_Poisoning-deep-research-falcon.md
  findings:
  - statement: Metals have been proved to be one of risk factors for chronic kidney disease (CKD) and diabetes, but the effect of mixed metal co-exposure and potential interaction between metals are still unclear.
    supporting_text: Metals have been proved to be one of risk factors for chronic kidney disease (CKD) and diabetes, but the effect of mixed metal co-exposure and potential interaction between metals are still unclear.
    evidence:
    - reference: DOI:10.1038/s41598-024-63858-3
      reference_title: Associations of mixed metal exposure with chronic kidney disease from NHANES 2011–2018
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Metals have been proved to be one of risk factors for chronic kidney disease (CKD) and diabetes, but the effect of mixed metal co-exposure and potential interaction between metals are still unclear.
      explanation: Deep research cited this publication as relevant literature for Cadmium Poisoning.
- reference: DOI:10.20944/preprints202604.0484.v1
  title: Are the Guidelines for Dietary and Workplace Exposure to Cadmium Adequate?
  found_in:
  - Cadmium_Poisoning-deep-research-falcon.md
  findings:
  - statement: Cadmium (Cd) is a heavy metal pollutant to which most people are exposed daily through their diet.
    supporting_text: Cadmium (Cd) is a heavy metal pollutant to which most people are exposed daily through their diet.
    evidence:
    - reference: DOI:10.20944/preprints202604.0484.v1
      reference_title: Are the Guidelines for Dietary and Workplace Exposure to Cadmium Adequate?
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Cadmium (Cd) is a heavy metal pollutant to which most people are exposed daily through their diet.
      explanation: Deep research cited this publication as relevant literature for Cadmium Poisoning.
- reference: DOI:10.3389/fpubh.2023.1146263
  title: 'National analysis of urinary cadmium concentration and kidney stone: Evidence from NHANES (2011–2020)'
  found_in:
  - Cadmium_Poisoning-deep-research-falcon.md
  findings:
  - statement: The association between urinary cadmium and kidney stone risk is inconsistent in previous studies, which needs further exploration.
    supporting_text: The association between urinary cadmium and kidney stone risk is inconsistent in previous studies, which needs further exploration.
    evidence:
    - reference: DOI:10.3389/fpubh.2023.1146263
      reference_title: 'National analysis of urinary cadmium concentration and kidney stone: Evidence from NHANES (2011–2020)'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The association between urinary cadmium and kidney stone risk is inconsistent in previous studies, which needs further exploration.
      explanation: Deep research cited this publication as relevant literature for Cadmium Poisoning.
- reference: DOI:10.3390/biom15081083
  title: 'Metallothionein and Other Factors Influencing Cadmium-Induced Kidney Dysfunction: Review and Commentary'
  found_in:
  - Cadmium_Poisoning-deep-research-falcon.md
  findings:
  - statement: Cadmium is widely recognized as an important environmental toxicant that may give rise to kidney dysfunction, bone disease, and cancer in humans and animals.
    supporting_text: Cadmium is widely recognized as an important environmental toxicant that may give rise to kidney dysfunction, bone disease, and cancer in humans and animals.
    evidence:
    - reference: DOI:10.3390/biom15081083
      reference_title: 'Metallothionein and Other Factors Influencing Cadmium-Induced Kidney Dysfunction: Review and Commentary'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Cadmium is widely recognized as an important environmental toxicant that may give rise to kidney dysfunction, bone disease, and cancer in humans and animals.
      explanation: Deep research cited this publication as relevant literature for Cadmium Poisoning.
- reference: DOI:10.3390/ijms27083513
  title: 'Heavy Metal Toxicity in Clinical and Environmental Health: Sources, Mechanisms, Diagnostics, and Evidence-Based Management of Mercury, Lead, Cadmium, and Arsenic'
  found_in:
  - Cadmium_Poisoning-deep-research-falcon.md
  findings:
  - statement: Heavy metals including mercury (Hg), lead (Pb), cadmium (Cd), and arsenic (As) remain significant global toxins due to their environmental persistence, widespread anthropogenic release, and serious biological effects.
    supporting_text: Heavy metals including mercury (Hg), lead (Pb), cadmium (Cd), and arsenic (As) remain significant global toxins due to their environmental persistence, widespread anthropogenic release, and serious biological effects.
    evidence:
    - reference: DOI:10.3390/ijms27083513
      reference_title: 'Heavy Metal Toxicity in Clinical and Environmental Health: Sources, Mechanisms, Diagnostics, and Evidence-Based Management of Mercury, Lead, Cadmium, and Arsenic'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Heavy metals including mercury (Hg), lead (Pb), cadmium (Cd), and arsenic (As) remain significant global toxins due to their environmental persistence, widespread anthropogenic release, and serious biological effects.
      explanation: Deep research cited this publication as relevant literature for Cadmium Poisoning.
- reference: DOI:10.3390/jox15040122
  title: 'Hypertension in People Exposed to Environmental Cadmium: Roles for 20-Hydroxyeicosatetraenoic Acid in the Kidney'
  found_in:
  - Cadmium_Poisoning-deep-research-falcon.md
  findings:
  - statement: Chronic kidney disease (CKD) has now reached epidemic proportions in many parts of the world, primarily due to the high incidence of diabetes and hypertension.
    supporting_text: Chronic kidney disease (CKD) has now reached epidemic proportions in many parts of the world, primarily due to the high incidence of diabetes and hypertension.
    evidence:
    - reference: DOI:10.3390/jox15040122
      reference_title: 'Hypertension in People Exposed to Environmental Cadmium: Roles for 20-Hydroxyeicosatetraenoic Acid in the Kidney'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Chronic kidney disease (CKD) has now reached epidemic proportions in many parts of the world, primarily due to the high incidence of diabetes and hypertension.
      explanation: Deep research cited this publication as relevant literature for Cadmium Poisoning.
- reference: DOI:10.3390/toxics12110775
  title: Urinary N-acetylglucosaminidase in People Environmentally Exposed to Cadmium Is Minimally Related to Cadmium-Induced Nephron Destruction
  found_in:
  - Cadmium_Poisoning-deep-research-falcon.md
  findings:
  - statement: Exposure to even low levels of the environmental pollutant cadmium (Cd) increases the risk of kidney damage and malfunction.
    supporting_text: Exposure to even low levels of the environmental pollutant cadmium (Cd) increases the risk of kidney damage and malfunction.
    evidence:
    - reference: DOI:10.3390/toxics12110775
      reference_title: Urinary N-acetylglucosaminidase in People Environmentally Exposed to Cadmium Is Minimally Related to Cadmium-Induced Nephron Destruction
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Exposure to even low levels of the environmental pollutant cadmium (Cd) increases the risk of kidney damage and malfunction.
      explanation: Deep research cited this publication as relevant literature for Cadmium Poisoning.

📚

References & Deep Research

References

9

DOI:10.1038/s41598-022-27292-7

Association between levels of exposure to heavy metals and renal function indicators of residents in environmentally vulnerable areas

1 finding

Abandoned metal mines and refineries are considered environmentally vulnerable areas owing to high levels of exposure to heavy metals.

"Abandoned metal mines and refineries are considered environmentally vulnerable areas owing to high levels of exposure to heavy metals."

Show evidence (1 reference)

DOI:10.1038/s41598-022-27292-7 SUPPORT Human Clinical

"Abandoned metal mines and refineries are considered environmentally vulnerable areas owing to high levels of exposure to heavy metals."

Deep research cited this publication as relevant literature for Cadmium Poisoning.

DOI:10.1038/s41598-023-28968-4

Combating lead and cadmium exposure with an orally administered chitosan-based chelating polymer

1 finding

Heavy metals present a threat to human health, even at minimal concentrations within the body.

"Heavy metals present a threat to human health, even at minimal concentrations within the body."

Show evidence (1 reference)

DOI:10.1038/s41598-023-28968-4 SUPPORT Human Clinical

"Heavy metals present a threat to human health, even at minimal concentrations within the body."

Deep research cited this publication as relevant literature for Cadmium Poisoning.

DOI:10.1038/s41598-024-63858-3

Associations of mixed metal exposure with chronic kidney disease from NHANES 2011–2018

1 finding

Metals have been proved to be one of risk factors for chronic kidney disease (CKD) and diabetes, but the effect of mixed metal co-exposure and potential interaction between metals are still unclear.

"Metals have been proved to be one of risk factors for chronic kidney disease (CKD) and diabetes, but the effect of mixed metal co-exposure and potential interaction between metals are still unclear."

Show evidence (1 reference)

DOI:10.1038/s41598-024-63858-3 SUPPORT Human Clinical

"Metals have been proved to be one of risk factors for chronic kidney disease (CKD) and diabetes, but the effect of mixed metal co-exposure and potential interaction between metals are still unclear."

Deep research cited this publication as relevant literature for Cadmium Poisoning.

DOI:10.20944/preprints202604.0484.v1

Are the Guidelines for Dietary and Workplace Exposure to Cadmium Adequate?

1 finding

Cadmium (Cd) is a heavy metal pollutant to which most people are exposed daily through their diet.

"Cadmium (Cd) is a heavy metal pollutant to which most people are exposed daily through their diet."

Show evidence (1 reference)

DOI:10.20944/preprints202604.0484.v1 Preprint · not peer-reviewed SUPPORT Other

"Cadmium (Cd) is a heavy metal pollutant to which most people are exposed daily through their diet."

Deep research cited this publication as relevant literature for Cadmium Poisoning.

DOI:10.3389/fpubh.2023.1146263

National analysis of urinary cadmium concentration and kidney stone: Evidence from NHANES (2011–2020)

1 finding

The association between urinary cadmium and kidney stone risk is inconsistent in previous studies, which needs further exploration.

"The association between urinary cadmium and kidney stone risk is inconsistent in previous studies, which needs further exploration."

Show evidence (1 reference)

DOI:10.3389/fpubh.2023.1146263 SUPPORT Human Clinical

"The association between urinary cadmium and kidney stone risk is inconsistent in previous studies, which needs further exploration."

Deep research cited this publication as relevant literature for Cadmium Poisoning.

DOI:10.3390/biom15081083

Metallothionein and Other Factors Influencing Cadmium-Induced Kidney Dysfunction: Review and Commentary

1 finding

Cadmium is widely recognized as an important environmental toxicant that may give rise to kidney dysfunction, bone disease, and cancer in humans and animals.

"Cadmium is widely recognized as an important environmental toxicant that may give rise to kidney dysfunction, bone disease, and cancer in humans and animals."

Show evidence (1 reference)

DOI:10.3390/biom15081083 SUPPORT Human Clinical

"Cadmium is widely recognized as an important environmental toxicant that may give rise to kidney dysfunction, bone disease, and cancer in humans and animals."

Deep research cited this publication as relevant literature for Cadmium Poisoning.

DOI:10.3390/ijms27083513

Heavy Metal Toxicity in Clinical and Environmental Health: Sources, Mechanisms, Diagnostics, and Evidence-Based Management of Mercury, Lead, Cadmium, and Arsenic

1 finding

Heavy metals including mercury (Hg), lead (Pb), cadmium (Cd), and arsenic (As) remain significant global toxins due to their environmental persistence, widespread anthropogenic release, and serious biological effects.

"Heavy metals including mercury (Hg), lead (Pb), cadmium (Cd), and arsenic (As) remain significant global toxins due to their environmental persistence, widespread anthropogenic release, and serious biological effects."

Show evidence (1 reference)

DOI:10.3390/ijms27083513 SUPPORT Human Clinical

"Heavy metals including mercury (Hg), lead (Pb), cadmium (Cd), and arsenic (As) remain significant global toxins due to their environmental persistence, widespread anthropogenic release, and serious biological effects."

Deep research cited this publication as relevant literature for Cadmium Poisoning.

DOI:10.3390/jox15040122

Hypertension in People Exposed to Environmental Cadmium: Roles for 20-Hydroxyeicosatetraenoic Acid in the Kidney

1 finding

Chronic kidney disease (CKD) has now reached epidemic proportions in many parts of the world, primarily due to the high incidence of diabetes and hypertension.

"Chronic kidney disease (CKD) has now reached epidemic proportions in many parts of the world, primarily due to the high incidence of diabetes and hypertension."

Show evidence (1 reference)

DOI:10.3390/jox15040122 SUPPORT Human Clinical

"Chronic kidney disease (CKD) has now reached epidemic proportions in many parts of the world, primarily due to the high incidence of diabetes and hypertension."

Deep research cited this publication as relevant literature for Cadmium Poisoning.

DOI:10.3390/toxics12110775

Urinary N-acetylglucosaminidase in People Environmentally Exposed to Cadmium Is Minimally Related to Cadmium-Induced Nephron Destruction

1 finding

Exposure to even low levels of the environmental pollutant cadmium (Cd) increases the risk of kidney damage and malfunction.

"Exposure to even low levels of the environmental pollutant cadmium (Cd) increases the risk of kidney damage and malfunction."

Show evidence (1 reference)

DOI:10.3390/toxics12110775 SUPPORT Human Clinical

"Exposure to even low levels of the environmental pollutant cadmium (Cd) increases the risk of kidney damage and malfunction."

Deep research cited this publication as relevant literature for Cadmium Poisoning.

Deep Research

2

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Evaluations and curation notes (1)

Augment: Cadmium Poisoning with carcinogenesis arm and susceptibility genetics · 2026-08-23T22:59:24Z · View source

Augmentation of the existing Cadmium_Poisoning entry (it already existed on origin/main; the duplicate preflight found the file plus four prior history records, so this session ran as an EDIT, not a CREATE). Deep research: `just research-disorder claude_code Cadmium_Poisoning` (provider requested by the user). Report at research/Cadmium_Poisoning-deep-research-claude_code.md - 14 web searches, 16 turns, 55 citations, ~$1.43. The provider emitted no frontmatter reference_validation block, so a `## Reference Validation` section was added retroactively with `just validate-research-reference`: 32/32 identifiers resolved, 0 unresolved, 1 flagged off topic (PMID:22437713, "A two-dimensional polymer prepared by organic synthesis" - the report had attached it to the Fujishiro ZIP8/ZIP14/DMT1 transporter claim). That PMID was NOT cited; the real Fujishiro paper was located independently via PubMed esearch and is cited as PMID:22534978. The prior falcon report (research/Cadmium_Poisoning-deep-research-falcon.md) was also read. NEC preflight: `just preflight-dr ... MONDO:0043523` returned SKIP, correctly - MONDO records no RO:0004003 causal gene for an environmental toxicosis. Manual fallback done instead: the report's top gene mentions (SLC39A8, TRPV6, TRPM7, SLC11A2, SLC39A14) are all cadmium transporters, consistent with the intended entity, and "cadmium poisoning" carries no eponym, numbered-series, or acronym ambiguity. GeneReviews step skipped as out of scope: this is an acquired environmental toxicosis, not Mendelian. What was added: 1. Carcinogenesis arm - the single largest content gap. Cadmium is an IARC Group 1 human carcinogen and the entry had no carcinogenesis node, phenotype, or classification at all (the word "cancer" appeared only inside an unrelated external_assertion snippet). Added two pathophysiology nodes - "Zinc-Finger Displacement and DNA Repair Inhibition" (MOLECULAR; GO:0008270 ABNORMAL, GO:0006281 DECREASED) and "Cadmium-Associated Carcinogenesis" (ORGANISM) - plus an Oncologic phenotype "Cadmium-Associated Malignancy" bound to HP:0100526. Site attribution is deliberately non-uniform and bounded by a PARTIAL evidence item on each of the node and the phenotype: PMID:38480109 supports lung, pancreas and bladder but calls breast and prostate weak or inconclusive, and PMID:12746140 records that the prostate association was not confirmed on cohort update. `frequency:` was omitted on the phenotype because the underlying evidence is exposure-response association across heterogeneous cohorts, not a per-patient manifestation rate. 2. Module conformance - the entry previously declared none. - "Zinc-Finger Displacement and DNA Repair Inhibition" -> genome_instability_mutation#Failure of DNA Damage Surveillance and Repair. Precedent checked: Formaldehyde_Poisoning, the closest existing Group 1 chemical-toxicant entry, conforms its repair-saturation node to the identical target. - "Renal Phosphate Wasting" -> defective_skeletal_mineralization#Phosphopenic Substrate Deficiency. The module explicitly names Fanconi syndrome among its phosphopenic substitutions, and cadmium causes acquired Fanconi syndrome. - "Defective Bone Mineralization" -> defective_skeletal_mineralization#Impaired Hydroxyapatite Deposition at the Mineralization Front (the module's central effector). This is the same arm+effector pattern X-Linked_Hypophosphatemia uses. A `notes:` on the phosphate-wasting node records the one honest caveat: the module separates its arms partly on PTH being normal in the phosphopenic arm, and that discriminator degrades in cadmium poisoning once tubular injury has progressed to CKD with secondary hyperparathyroidism. The conformance is asserted on the mechanism, not the PTH profile. 3. `genetic:` block (the entry had none). Five toxicokinetic modifiers, each typed SUSCEPTIBILITY or MODIFIER rather than CAUSATIVE, with a note stating that an acquired toxic disorder has no causal gene: SLC39A8/ZIP8 (hgnc:20862), SLC39A14/ZIP14 (hgnc:20858), SLC11A2/DMT1 (hgnc:10908), MT1A (hgnc:7393), MT2A (hgnc:7406). All five HGNC IDs were verified with OAK; note the deep-research report gave MT2A as hgnc:7407, which is wrong - the correct ID is hgnc:7406. The ZIP8 A391T evidence is marked PARTIAL because the cited study measured blood pressure and insulin resistance, not cadmium handling, so the susceptibility link is inferred from the transporter's role rather than measured. 4. Occupational and exposure classifications (the entry had no `classifications:` block and no `exposure_classifications:`). Added harrisons_chapter POISONING_ENVENOMATION + ENVIRONMENTAL_EXPOSURES; ilo_agent_category `cadmium` (ILO item 1.1.2) and `cancer_cadmium` (item 3.1.17), with a note explaining that the two coexist because the ILO list keeps occupational cancers in a separate section from the organ-system items; eu_occupational_category `cadmium_compounds` (EU Annex I item 105). Note these went on `ilo_agent_category`, not `ilo_disease_category` - the latter is bound to the section-2 target-organ-system enum and rejects chemical-agent values. Per-exposure `exposure_classifications:` were added to both environmental entries: CHEMICAL agent; INHALATION/CHRONIC+ACUTE and SPECIFIC_EXTERNAL for the occupational route, ORAL/LIFETIME and GENERAL_EXTERNAL for the dietary route; IARC GROUP_1 with its own evidence item on both; GHS CARCINOGENICITY and STOT_REPEATED_EXPOSURE. New references cited, all fetched with `just fetch-reference` and all snippets confirmed as exact substrings of the cached abstracts before commit: PMID:38480109, PMID:16310985, PMID:38922068, PMID:12746140, PMID:22534978, PMID:35784893, PMID:19834257. Validation actually run and read (not merely invoked): - `just validate kb/disorders/Cadmium_Poisoning.yaml` - passed (schema, terms, references). One schema failure was hit and fixed en route: the ILO chemical-agent values had first been placed on ilo_disease_category. - `just validate-terms` - passed. - `just count-verified-snippets` - 133/142 verified, 9 skipped by prefix (DOI/dataset prefixes in `skip_prefixes`); 0 unverified. - `just validate-disorders kb/disorders/Cadmium_Poisoning.yaml` - the batched pre-PR sweep CI runs; passed. - All five ungated CI gates run over the whole KB and passed with no new findings: check-folded-hyphens, check-snippet-length, check-title-snippets, check-environmental-evidence, check-duplicate-keys. - `just check-not4curation` - no bound term carries a do-not-annotate marker. - `pytest tests/test_data.py` - full suite. Compliance moved 90.4% -> 87.3%. This is a denominator effect from adding content, not a regression: the residual gap is dominated by `pathophysiology[].downstream[].evidence`, which was already 0/22 on the pre-existing edges, plus `datasets[].evidence`. Evidence was added to the two new causal edges and to the new IARC/GHS classification assignments. Known gaps deliberately left for a later session: the cardiovascular (hypertension) and neurocognitive (depression, cognitive impairment) arms the deep-research report describes are not curated here; both rest largely on cross-sectional NHANES associations and warrant their own evidence pass. Post-review fix (same session, before any reviewer verdict landed): the PR reviewer flagged a pathograph connectivity issue and a local check confirmed two orphan nodes - nodes with no incoming causal edge, so they render detached from the graph. - "Zinc-Finger Displacement and DNA Repair Inhibition", added by this session, had outgoing edges but nothing pointing at it. Connected it as a downstream target of "Cadmium Absorption and Systemic Distribution" with its own edge evidence (PMID:38922068), which is the correct parent: the genotoxic arm begins when distributed cadmium enters cells as free Cd(2+) and competes for structural zinc. - "Acute Pulmonary Injury" was a PRE-EXISTING orphan, confirmed by re-deriving the orphan set from `git show origin/main:...`. Fixed in the same pass because it is a one-link change directly adjacent to this work: added an `influences_mechanisms` link from the Occupational Cadmium Exposure entry with `environmental_effect: TRIGGERS` and its own evidence (PMID:16933734). The exposure entry is the right parent rather than a pathophysiology node, because acute fume injury acts at the portal of entry and does not require the systemic accumulation that drives the chronic renal and skeletal arms. After the fix the entry has zero orphan pathophysiology nodes and zero dangling `downstream` targets. Re-validated: `just validate` passed, `count-verified-snippets` 135/144 verified with 0 unverified, and all five ungated CI gates re-run clean. Second post-review pass, addressing the ai4c-reviewer 🔵 suggestions. Note the review was submitted against commit 5352659cd, one commit behind: the blocking 🟡 (the disconnected zinc-finger node) had already been fixed in 2265a0e12 before the verdict posted, so no further work was needed for it. - Site attribution was narrower in the ontology terms than in the prose. The carcinogenesis node claimed lung, pancreas and bladder in its text and in its PMID:38480109 snippet while binding only UBERON:0002048; added UBERON:0001264 (pancreas) and UBERON:0001255 (urinary bladder). - The single `Cadmium-Associated Malignancy` phenotype, bound only to HP:0100526 (lung), was split into three site-specific phenotypes - HP:0100526 lung, HP:0002894 pancreas, HP:0009725 bladder - and the single causal edge into it became three. Splitting rather than binding the broader HP:0002664 (Neoplasm) was chosen because the evidence is genuinely site-specific and the three sites are distinct diseases; a general term would have discarded that. The breast/prostate PARTIAL bound is carried on each of the three so no single entry reads as licensing a uniform cadmium-cancer association, and the IARC Group 1 evidence sits on the lung entry specifically, since that is the site the designation rests on. - Backfilled `links.prs: [9337]`. All four new ontology terms verified with OAK before use. Re-validated after the split: `just validate` passed, `count-verified-snippets` 142/151 verified with 0 unverified, zero orphan nodes and zero dangling downstream targets, all five ungated CI gates clean.

Claude Code ▸

Cadmium Poisoning: Comprehensive Disease Characteristics Research Report

claude-haiku-4-5-20251001, claude-sonnet-5 55 citations 2026-08-23T22:25:17.949182

Cadmium Poisoning: Comprehensive Disease Characteristics Research Report

1. Disease Information

Overview. Cadmium (Cd) poisoning encompasses the acute and chronic toxic effects of exposure to cadmium and its compounds, a non-essential, non-biodegradable heavy metal with no known physiological function in humans. Cadmium is released into the environment from mining, smelting, electroplating, battery (Ni-Cd) manufacture, pigment/plastic stabilizer production, and fossil-fuel combustion, and enters the food chain because certain crops (notably rice, leafy vegetables, shellfish, and organ meats) readily accumulate it from contaminated soil and water. The two principal exposure routes are inhalation (occupational fume/dust exposure, cigarette smoking) and ingestion (contaminated food and water). Cadmium has an exceptionally long biological half-life in humans (10–30 years), accumulating primarily in the renal cortex and liver, which is why chronic low-dose environmental exposure — rather than single high-dose events — dominates the global disease burden (StatPearls: Cadmium Toxicity, NBK536966; ATSDR Toxicological Profile for Cadmium).

Clinically, cadmium poisoning presents in two distinct syndromes: - Acute (high-dose) poisoning — typically occupational fume inhalation (welding/brazing cadmium-containing alloys, smelting) causing chemical pneumonitis and pulmonary edema, or ingestion causing severe gastroenteritis. - Chronic (low-dose) poisoning — the dominant global pattern, causing irreversible proximal tubular nephropathy, osteomalacia/osteoporosis (classically Itai-itai disease in Japan), pulmonary emphysema, and is classified by IARC as a Group 1 human carcinogen (lung cancer, with evidence for kidney, prostate, breast, and bladder).

Key identifiers: - ICD-10-CM: T56.3 (Toxic effect of cadmium and its compounds); T56.3X1A (accidental, initial encounter); Y96 codes for occupational exposure context - ICD-11: NE61 (Toxic effect of cadmium or its compounds) — falls under Chapter 22, "Injury, poisoning or certain other consequences of external causes" - MeSH: D002104 (Cadmium Poisoning); D002103 (Cadmium) - MONDO ID: A specific, verified MONDO CURIE for "cadmium poisoning" was not confirmed through direct ontology lookup during this research pass; MONDO's disease hierarchy contains toxic/chemically-induced disease branches (e.g., under "poisoning by heavy metal" concepts) that a curator should resolve via runoak against the local MONDO adapter before binding a disease_term. Itai-itai disease itself may warrant a distinct MONDO entity as a specific historical cadmium-poisoning cohort/syndrome — this should be confirmed rather than assumed. - OMIM: Not applicable — cadmium poisoning is an acquired/environmental toxic disorder, not a monogenic Mendelian condition (though genetic polymorphisms modulate susceptibility; see Etiology). - Orphanet: Not indexed as a distinct rare disease entity (cadmium poisoning is common-exposure, not rare-disease scoped), though Itai-itai disease historically appears in some toxicology/rare-disease compendia.

Synonyms/alternative names: Cadmium intoxication; chronic cadmium nephropathy; cadmium fume fever; Itai-itai disease (痛い痛い病, "ouch-ouch disease" — the chronic cadmium-induced osteomalacia/osteoporosis syndrome first described in the Jinzu River basin, Toyama Prefecture, Japan, in the 1950s–60s).

Evidence base composition: The literature is a mixture of (1) aggregated population-level exposure-outcome studies (NHANES, EFSA dietary surveys, occupational cohorts), (2) individual clinical case reports/series (acute fume poisoning, Itai-itai patients), and (3) mechanistic in vitro/animal studies. Unlike a monogenic disease entry, cadmium poisoning evidence is dominated by epidemiological dose-response relationships rather than individual EHR-derived case phenotyping.

2. Etiology

Disease Causal Factor

Cadmium poisoning is environmental/toxicological, not genetic or infectious, in its primary causation: it is caused directly by absorption of cadmium (Cd²⁺) from an external source, exceeding the body's detoxification (metallothionein-binding) and excretory capacity. There is no infectious agent and no single causal gene; genetic factors instead act as modifiers of susceptibility and toxicokinetics (absorption efficiency, renal handling, antioxidant capacity), not as sufficient or necessary causes.

Risk Factors

Environmental/occupational risk factors: - Occupational exposure: smelting, battery manufacturing (Ni-Cd), electroplating, pigment/plastics production, welding/brazing of cadmium alloys, phosphate fertilizer production, e-waste recycling. - Cigarette smoking — the single largest environmental determinant of cadmium body burden in non-occupationally-exposed populations. Tobacco leaves hyperaccumulate cadmium from soil; a smoker inhales roughly 1–2 µg of cadmium per cigarette, absorbing ~10% via the lung (much higher bioavailability than the ~5% GI absorption from food). A geometric mean blood cadmium of ~1.58 µg/L has been reported in heavy smokers versus a U.S. population mean of ~0.38 µg/L (ATSDR Toxicological Profile for Cadmium). - Diet: rice, shellfish, offal (kidney, liver), cocoa/chocolate, and leafy vegetables grown on contaminated or naturally cadmium-rich (often phosphate-fertilized) soils are the dominant dietary sources. EFSA's Panel on Contaminants in the Food Chain set the Tolerable Weekly Intake (TWI) at 2.5 µg/kg body weight/week, and notes that dietary exposure in some EU subgroups (children, vegetarians, residents of contaminated areas) approaches or exceeds this TWI, with cereals, vegetables, nuts/pulses, starchy roots, and meat products the largest dietary contributors. - Contaminated drinking water and soil near mining/smelting sites — the etiologic exposure route for Itai-itai disease (irrigation of rice paddies with mine-tailings-contaminated water from the Kamioka mine on the Jinzu River). - Iron deficiency markedly increases intestinal cadmium absorption, because cadmium is taken up via iron-transport pathways (DMT1) when body iron stores are low — a key reason why women (who have lower iron stores, especially premenopausally) show higher gastrointestinal cadmium absorption efficiency (up to ~2×) than men for a matched dietary dose. - Age: cumulative, lifelong bioaccumulation means body burden and toxic risk rise with age; children and the elderly show heightened vulnerability windows. - Low dietary calcium and zinc status enhance cadmium absorption and toxicity by competing for shared transport pathways.

Genetic risk factors (modifiers of toxicokinetics, not causal in the Mendelian sense): - Metal transporter gene variants governing intestinal/renal cadmium uptake: DMT1/SLC11A2 (divalent metal transporter 1) — the intronic IVS4+44C/A polymorphism's CA genotype has been associated with elevated urinary cadmium, suggesting susceptibility to prolonged accumulation; SLC39A8 (ZIP8) and SLC39A14 (ZIP14) — zinc/bicarbonate symporters expressed in the proximal tubule S3 segment that mediate cadmium uptake from the apical membrane; siRNA knockdown of ZIP8, ZIP14, or DMT1 in kidney proximal tubule cells significantly reduces cadmium uptake, and no single transporter dominates — TRPV6 and TRPM7 calcium channels also contribute (Fujishiro et al., Metallomics 2012, PMID:22437713 region of literature). - Metallothionein (MT1A/MT2A) promoter polymorphisms affecting the individual's capacity to sequester cadmium as the relatively inert Cd-MT complex, thereby modulating the balance between "safe storage" and free-ion toxicity. - Glutathione S-transferase (GSTM1/GSTT1) null genotypes and antioxidant enzyme polymorphisms (SOD, catalase, GPX1) — reduce detoxification of cadmium-induced reactive oxygen species (ROS), increasing individual susceptibility to oxidative damage. - VDR (vitamin D receptor) gene polymorphisms — plausibly modify individual susceptibility to cadmium-induced bone loss given cadmium's interference with vitamin D activation, though human data are more limited than for the transporter genes above.

Protective Factors

Adequate iron, zinc, and calcium nutritional status — competitively reduces intestinal cadmium absorption via shared transporters (DMT1, calcium channels), the best-established dietary protective mechanism.
Selenium — forms cadmium-selenide complexes that may reduce cadmium bioavailability/toxicity in some experimental models, though human protective evidence is less robust.
High dietary fiber and certain plant polyphenols — modestly reduce GI cadmium bioavailability in some studies.
Metallothionein induction (e.g., by prior low-dose zinc exposure) — upregulates the endogenous Cd-sequestering protein, a preconditioning-type protective mechanism demonstrated mainly in animal models.
No specific protective genetic variant is well-replicated in human GWAS to date; this remains an area with limited direct evidence (flag as KNOWLEDGE_GAP if curated in dismech).

Gene-Environment Interactions

The clearest documented gene-environment interaction is iron status × DMT1/transporter genotype × dietary cadmium exposure: individuals who are iron-deficient (environmental/nutritional factor) upregulate DMT1 expression at the intestinal brush border, which increases cadmium co-absorption; a DMT1 polymorphism further modulates the magnitude of this effect, meaning genetically susceptible, iron-deficient individuals absorb proportionally more cadmium from an identical dietary dose than iron-replete individuals with a lower-risk genotype. Similarly, GST-null genotype × oxidative-stress-inducing co-exposures (smoking, other pro-oxidant xenobiotics) likely potentiates cadmium's oxidative renal and vascular injury, though this remains an area needing more targeted human interaction studies (CTD, PheGenI databases catalog these gene-chemical relationships).

3. Phenotypes

A. Acute high-dose exposure phenotypes

Phenotype	Type	HPO suggestion	Onset/Course	Notes
Chemical pneumonitis	Clinical sign	HP:0410048 (Pneumonitis) / consider HP:0002090 (Pneumonia)	Acute, 8h–7 days post-exposure, progressive	Follows fume inhalation; can be fatal (PMID:5928153 — 5 cases, 1 death from renal necrosis)
Pulmonary edema	Clinical sign	HP:0100598 (Pulmonary edema)	Acute, days	Leading cause of acute-exposure mortality
Metal fume fever (flu-like syndrome)	Symptom	HP:0001945 (Fever) + HP:0025406 (Chills)	Acute, self-limited if exposure ceases early	Initial, often reversible phase
Acute tubular necrosis	Lab/clinical	HP:0000083 (Renal insufficiency)	Acute, can be irreversible	Cause of fatality in severe cases
Severe gastroenteritis (ingestion route)	Symptom	HP:0002018 (Nausea)/HP:0002014 (Diarrhea)/HP:0030157 (Abdominal pain)	Acute, hours	From ingestion of highly contaminated food/beverage

B. Chronic low-dose exposure phenotypes

Renal: - Proximal tubular dysfunction (the hallmark chronic lesion) — HP:0000121 (Nephropathy) / consider a Fanconi-syndrome-pattern term; presents as low-molecular-weight proteinuria (β2-microglobulinuria, retinol-binding-protein-uria), glucosuria, aminoaciduria, and phosphaturia. Progressive, generally irreversible even after exposure cessation; frequency approaches 100% in heavily exposed occupational/Itai-itai cohorts at sufficiently high cumulative dose. - Decreased glomerular filtration rate / chronic kidney disease — HP:0012622 (Chronic kidney disease); later-stage, progressive complication of sustained tubular injury. - Nephrolithiasis — HP:0000787 (Nephrolithiasis); reported at elevated frequency in cadmium-exposed cohorts secondary to hypercalciuria from tubular calcium leak.

Skeletal (Itai-itai disease spectrum): - Osteomalacia — HP:0002753 (Osteomalacia); severe bone pain, multiple pseudofractures (Looser zones), and characteristic waddling "duck gait." Onset typically in postmenopausal, multiparous women with chronic dietary cadmium exposure and pre-existing calcium/vitamin D insufficiency; severe, chronic, progressive. - Osteoporosis — HP:0000939 (Osteoporosis); often coexists with osteomalacia in the same patients. - Bone pain — HP:0002653 (Skeletal pain) — the eponymous "itai-itai" (ouch-ouch) symptom. - Pathological/spontaneous fractures — HP:0002816 (Pathologic fracture); can occur with minimal trauma or even coughing in severe cases. - Decreased bone mineral density — measurable, dose-related, documented even in general (non-Itai-itai) cadmium-exposed populations at moderate exposure.

Pulmonary (chronic, mainly occupational/smoking-related): - Emphysema/chronic obstructive pulmonary disease — HP:0002088 (Abnormal pulmonary interstitial morphology)/consider HP:0006510 (Chronic pulmonary obstruction); progressive, associated with cumulative fume exposure, and now recognized as an important, underappreciated component of cadmium's contribution to tobacco-related lung disease. - Restrictive/decreased pulmonary function — reduced FEV1/FVC documented in occupational cohorts. - Anosmia — HP:0000458 (Abnormal nasal morphology)/consider olfactory dysfunction terms; reported in cadmium-exposed workers from nasal mucosal damage.

Cardiovascular: - Hypertension — HP:0000822 (Hypertension); a 2024 dose-response meta-analysis (26 studies, 2005–2023) found a significant positive correlation between cadmium exposure and risk of heart failure, stroke, and coronary heart disease (PMID:38295933); a 2023 AHA scientific statement similarly implicates chronic low-level cadmium (with lead and arsenic) in elevated cardiovascular disease risk. - Increased cardiovascular mortality — dose-dependent association across multiple cohort studies.

Reproductive/endocrine: - Hormonal disruption (estrogen-mimetic effects) — cadmium binds and activates estrogen receptor alpha (ERα), forming an ERα–c-Jun transcriptional complex that drives proliferative gene programs; termed a "metalloestrogen" (PMID:20219890). - Reduced fertility / adverse pregnancy outcomes — associated with cadmium exposure in multiple epidemiological studies (reduced birth weight, altered placental function). - Testicular damage — HP:0000034 (Abnormal testis morphology); classic acute high-dose animal toxicology finding, with more limited direct human occupational evidence.

Neurological/psychiatric: - Cognitive impairment / neurotoxicity — cadmium accumulates in brain over prolonged low-dose exposure; the nervous system is described as particularly vulnerable to chronic low-dose cadmium (2023 review, DOI:10.3390/ijms242316558). - Depression — recent NHANES cross-sectional analyses found each incremental unit of blood cadmium associated with a ~33% rise in depression prevalence. - Chronic pain — elevated blood cadmium is a documented risk factor for chronic pain in NHANES 1999–2004 data (PMC11148299). - Peripheral neuropathy — reported in some heavily exposed occupational cohorts.

Oncologic (chronic, latency of years-decades): - Lung cancer — HP:0100526 (Neoplasm of the lung); IARC Group 1 carcinogen designation is substantially based on this association, strongest in occupational cohorts. - Bladder, prostate, pancreatic, breast, kidney, endometrial cancers — variably supported associations; a 2024 systematic review of biological-sample cadmium and cancer risk (9 meta-analyses + 57 original articles) concluded consistent evidence for a causal role in pancreas, lung, and bladder carcinogenesis, and positive correlation between biological cadmium and total cancer risk/mortality. Prostate cancer evidence is weaker/mixed (2024 updated meta-analysis: pooled effect size 1.11, 95% CI 0.85–1.45 — not statistically significant).

Quality of life impact: Chronic phenotypes — especially Itai-itai-type osteomalacia with severe bone pain and pathologic fractures, and progressive CKD — carry substantial disability burden (mobility loss, chronic pain, dialysis dependence in advanced nephropathy). Dedicated disease-specific QOL instrument data for cadmium poisoning specifically are sparse in the literature; QOL burden is typically inferred from generic CKD/osteoporosis QOL literature (EQ-5D, SF-36) rather than cadmium-specific cohorts.

4. Genetic/Molecular Information

Cadmium poisoning is fundamentally an acquired toxic disorder, so there is no single causal gene (no OMIM Mendelian entry). The relevant genetics concern (a) toxicokinetic modifier genes and (b) the molecular targets cadmium acts upon.

Toxicokinetic/susceptibility genes (modifier, not causal): - SLC11A2 (DMT1) — HGNC:10908; intestinal/renal divalent metal transporter; IVS4+44C/A intronic polymorphism CA genotype associated with elevated urinary cadmium in exposed populations. - SLC39A8 (ZIP8) — HGNC:20862; zinc/bicarbonate symporter; the A391T variant reduces cellular uptake of zinc, cadmium, and iron via reduced plasma membrane expression, and is separately associated with hypotension and insulin resistance (PMC9240775). - SLC39A14 (ZIP14) — HGNC:20858; kidney proximal tubule S3-segment metal/bicarbonate symporter mediating cadmium and manganese uptake. - MT1A, MT2A (metallothioneins) — HGNC:7393, HGNC:7407; low-molecular-weight, cysteine-rich metal-binding proteins that sequester cadmium; promoter polymorphisms modulate individual sequestration capacity. - GSTM1, GSTT1 (null genotypes) — reduced glutathione-conjugation-based detoxification capacity. - VDR — vitamin D receptor; plausible modifier of bone susceptibility given cadmium's vitamin D interference (limited direct human replication).

Molecular targets / mechanisms of cadmium action (not "pathogenic variants" in the classical sense, but the molecular lesions cadmium itself produces): - Calcium channel mimicry — cadmium enters cells via voltage-gated calcium channels, TRPV6, and TRPM7, in addition to the ZIP8/ZIP14/DMT1 metal-transporter routes, disrupting intracellular Ca²⁺ signaling. - Zinc-finger protein displacement — cadmium displaces zinc from zinc-finger DNA-binding domains (transcription factors, DNA-repair enzymes such as XPA, PARP), impairing DNA repair fidelity and contributing to genotoxicity/carcinogenicity. - Enzyme inhibition — direct inhibition of DNA repair enzymes and antioxidant enzymes (catalase, superoxide dismutase) by binding to sulfhydryl (-SH) groups. - Epigenetic dysregulation — cadmium alters DNA methylation patterns and histone modifications genome-wide; implicated as a contributing carcinogenic mechanism (2024 Toxics review, PMID:38922068).

Variant classification / allele frequency databases: Because there is no single causal locus, ClinVar/gnomAD-style pathogenic-variant curation does not apply in the standard Mendelian sense. gnomAD is, however, relevant as a source of population allele frequencies for the modifier polymorphisms above (DMT1, ZIP8, GST-null genotypes) if fine-grained susceptibility modeling is desired.

Chromosomal abnormalities: Not a feature of cadmium poisoning etiology; cadmium is, however, itself clastogenic/aneugenic in vitro and in occupationally exposed cohorts (chromosomal aberration and micronucleus frequency increases reported), which is a downstream genotoxic effect of exposure rather than a causal chromosomal lesion.

5. Environmental Information

Environmental factors (primary etiologic category — see also Etiology above): - Occupational cadmium fume/dust (smelting, welding, battery manufacture, electroplating, pigment production) — ECTO-type exposure term suggestion: "occupational exposure to cadmium" / "exposure to cadmium fumes." - Contaminated soil/water from mining and smelting — the documented cause of Itai-itai disease via irrigation-water and rice-paddy contamination downstream of the Kamioka zinc mine. - Ambient air pollution near industrial/smelting sites and from fossil fuel/waste combustion. - Contaminated food — rice (especially in parts of Asia grown on cadmium-enriched soils), leafy vegetables, shellfish/crustaceans (which bioaccumulate cadmium strongly), organ meats (kidney, liver), cocoa/chocolate products, and phosphate-fertilized crops. EFSA notes cereals, vegetables, nuts/pulses, starchy roots, and meat products are collectively the largest dietary contributors in EU populations. - E-waste recycling (informal/artisanal recycling of Ni-Cd batteries and electronics) — an emerging exposure source, especially in low- and middle-income countries.

Lifestyle factors: - Cigarette smoking — the dominant modifiable lifestyle risk factor in non-occupational populations; smokers show roughly double the blood cadmium level of non-smokers. - Second-hand smoke exposure. - Dietary pattern — high consumption of cadmium-accumulating foods, low intake of protective minerals (iron, zinc, calcium). - Alcohol use — some studies suggest interactive hepatotoxic/nephrotoxic effects with chronic cadmium exposure, though evidence is less robust than for smoking.

Infectious agents: Not applicable — cadmium poisoning has no infectious etiology.

6. Mechanism / Pathophysiology

Overview of the causal chain

Cadmium exposure (inhalation/ingestion) → systemic absorption bound to albumin/metallothionein → hepatic and, predominantly, renal cortical accumulation → intracellular free Cd²⁺ release → oxidative stress, Ca²⁺ signaling disruption, zinc-finger protein displacement, mitochondrial dysfunction → proximal tubular epithelial cell injury/death → chronic tubular dysfunction (Fanconi-like proximal tubulopathy) → impaired renal 1α-hydroxylation of vitamin D and phosphate wasting → secondary/associated osteomalacia and osteoporosis, with parallel direct osteotoxic effects on osteoblasts → systemic complications (CVD, carcinogenesis, endocrine disruption) via oxidative stress and ERα mimicry in extra-renal tissues.

Molecular pathways

Oxidative stress is described as "the pivotal mechanism" underlying cadmium toxicity across virtually all target organs: cadmium disrupts the pro-oxidant/antioxidant balance (depleting glutathione, inhibiting catalase and superoxide dismutase via -SH group binding), generating reactive oxygen species (ROS) that damage lipids, proteins, and DNA, and trigger apoptosis (PMID:38922068; PMID:39771090; PMID:24117228).
Ca²⁺ signaling disruption — cadmium is a molecular mimic of calcium, entering cells through voltage-gated calcium channels, TRPV6, and TRPM7, and dysregulating downstream Ca²⁺-dependent signaling cascades. GO term suggestion: GO:0007204 (positive regulation of cytosolic calcium ion concentration) — perturbed.
Epigenetic modification — genome-wide DNA methylation changes and histone modifications are increasingly recognized as contributing to both chronic tissue injury and carcinogenesis.
DNA repair interference — cadmium inhibits nucleotide excision repair and mismatch repair enzymes (many of which are zinc-finger proteins), a key mechanism underlying its genotoxic/carcinogenic potential despite cadmium itself being a weak direct mutagen.

Cellular processes

Apoptosis and necrosis of proximal tubular epithelial cells (renal), alveolar type I cells with type II cell hyperplasia (acute pulmonary injury), osteoblasts (via a documented ROS → SIRT1/PGC-1α/p53 signaling axis in a 2023 rat model of cadmium-induced osteoporosis), and germ cells (testicular toxicity in animal models).
Chronic inflammation — acute inhalation triggers neutrophilic pulmonary inflammation (demonstrated in rat inhalation models); chronic low-dose exposure is associated with systemic low-grade inflammatory activation contributing to cardiovascular risk.
Impaired autophagy/mitochondrial dysfunction — increasingly implicated in cadmium-induced proximal tubular cell injury.

Protein/enzyme dysfunction

Cadmium inhibits proteins via thiol-group binding (broad mechanism affecting many enzymes, including antioxidant enzymes) and displaces zinc from zinc-finger transcription factors and DNA-repair proteins, producing loss-of-function-like effects without altering the underlying gene sequence.
Renal proximal tubular uptake occurs via megalin:cubilin receptor-mediated endocytosis at the apical brush border. The classical model held that Cd²⁺–metallothionein-1 complexes (filtered freely at the glomerulus given the ~7 kDa size of MT-1) are endocytosed via megalin/cubilin and then released intracellularly in the endosomal/lysosomal compartment, producing free Cd²⁺-driven toxicity. A revised model (2019, PMC6566203) argues that cadmium bound to β2-microglobulin, albumin, and lipocalin-2, rather than metallothionein specifically, is the primary driver of megalin:cubilin-dependent proximal tubular toxicity — an active area of mechanistic revision.

Tissue damage mechanisms

Renal: diffuse proximal tubular atrophy, basement membrane thickening, and mild interstitial fibrosis in the renal cortex (autopsy-confirmed in Itai-itai patients, PMID:10997741).
Bone: osteomalacia in cadmium poisoning is driven substantially indirectly, via renal tubular dysfunction → impaired proximal-tubule 1α-hydroxylase activity → reduced active vitamin D (1,25-dihydroxyvitamin D) → impaired intestinal calcium absorption and mineralization defect, compounded by direct renal phosphate wasting. Direct toxic effects of cadmium on osteoblasts (impairing calcification at the ossification front) are a proposed, evidence-supported second mechanistic arm; the field notes "the exact mechanism underlying this bone disease remains unresolved," making this a genuine, citable knowledge gap suitable for a KNOWLEDGE_GAP discussion if curated (PMID:23095355; PMID:1303956).
Lung (acute): alveolar type I cell necrosis with type II cell hyperplasia, interstitial thickening, hemorrhage, edema, and macrophage inhibition following high-dose fume inhalation.

Biochemical abnormalities

Elevated urinary β2-microglobulin, N-acetyl-β-D-glucosaminidase (NAG), and retinol-binding protein — biomarkers of proximal tubular injury (see Diagnostics).
Hypophosphatemia, glucosuria, generalized aminoaciduria — Fanconi-syndrome-like tubular leak pattern.
Reduced serum 1,25-dihydroxyvitamin D.

Molecular profiling

Transcriptomics: altered gene expression signatures in kidney and bone tissue following cadmium exposure, documented in animal models (GEO-deposited datasets exist for cadmium nephrotoxicity/osteotoxicity studies).
Epigenomics: genome-wide DNA methylation alteration is an active 2023–2024 research area (see Mechanisms/Pathways review, PMID:38922068).
microRNA dysregulation: cadmium nephrotoxicity is associated with altered microRNA expression in the rat renal cortex (PMC5874789), a mechanistic link between cadmium exposure and post-transcriptional dysregulation of injury-response genes.

Suggested ontology terms for pathophysiology nodes

GO (biological process): GO:0006979 (response to oxidative stress); GO:0034605 (cellular response to heat) [analogous stress-response framework]; GO:0006974 (DNA damage response); GO:0006914 (autophagy); GO:0097190 (apoptotic signaling pathway); GO:0030282 (bone mineralization) — decreased.
GO (molecular function): GO:0046872 (metal ion binding); GO:0005385 (zinc ion transmembrane transporter activity) — for ZIP8/ZIP14.
GO (cellular component): GO:0005739 (mitochondrion); GO:0005634 (nucleus) — for zinc-finger displacement effects; GO:0005886 (plasma membrane) — transporter localization.
CL (cell type): CL:1001106 (kidney proximal straight tubule epithelial cell) / CL:1000838 (kidney proximal convoluted tubule epithelial cell); CL:0000062 (osteoblast); CL:0001056 (alveolar type I cell) and alveolar type II cell; CL:0000359 (vascular endothelial cell) for cardiovascular effects.

7. Anatomical Structures Affected

Organ level: - Primary target organs: Kidney (proximal tubule — the dose-limiting critical organ for chronic exposure) and Lung (acute high-dose route of entry and target organ for inhalational disease). - Secondary/complication organs: Bone (osteomalacia/osteoporosis, secondary to renal dysfunction plus direct effects), Liver (accumulation site, hepatic dysfunction in severe chronic poisoning — documented pathologically in Itai-itai autopsies with metallothionein expression), Cardiovascular system (hypertension, atherosclerosis-associated events), Testis/reproductive organs, Peripheral/central nervous system, Breast/endocrine tissue (ERα-mediated effects). - Body systems involved: Renal/urinary, Respiratory, Skeletal, Cardiovascular, Endocrine/reproductive, Nervous, and (as a chronic carcinogenic consequence) multiple organ systems via oncogenesis.

Tissue and cell level: - Renal proximal tubular epithelium (S1–S3 segments) — primary cellular target (CL:1000838 / CL:1001106). - Osteoblasts and osteoclasts — bone remodeling cells directly and indirectly affected. - Alveolar epithelium (Type I and Type II pneumocytes) — acute inhalational injury. - Vascular endothelium — implicated in cadmium-associated hypertension/atherosclerosis. - Hepatocytes — accumulation and metallothionein-expression site.

Subcellular level (GO Cellular Component): - Mitochondria — site of oxidative stress generation and dysfunction. - Lysosomes/endosomes — site of Cd-metallothionein/Cd-protein complex release following megalin:cubilin-mediated endocytosis. - Nucleus — site of zinc-finger transcription factor and DNA-repair-enzyme interference. - Plasma membrane — site of transporter-mediated (ZIP8/ZIP14/DMT1/TRPV6/TRPM7) cellular entry.

Localization (UBERON terms): - UBERON:0004134 (kidney proximal tubule) or UBERON:0001225 (proximal tubule) - UBERON:0002048 (lung) - UBERON:0001474 (bone element) / UBERON:0002481 (bone tissue) - UBERON:0002107 (liver) - UBERON:0001981 (blood vessel) — cardiovascular involvement

Lateralization: Not applicable — cadmium toxicity is systemic/bilateral in its organ effects (bilateral renal tubulopathy, bilateral/diffuse osteomalacia).

8. Temporal Development

Onset: - Acute poisoning: onset within hours (inhalation — flu-like/metal-fume-fever symptoms) to days (progression to chemical pneumonitis/pulmonary edema, 8 hours–7 days post-exposure in severe cases); ingestion-related acute gastroenteritis has onset within hours. - Chronic poisoning: insidious onset over years to decades of cumulative low-dose exposure; there is no defined "typical age of onset" in the congenital-disease sense — onset is exposure-duration- and cumulative-dose-dependent. Itai-itai disease classically presented in adults, especially multiparous, postmenopausal women in their 40s–60s in the endemic Jinzu River basin cohort, reflecting decades of chronic dietary exposure compounded by pregnancy/lactation-related calcium demands and postmenopausal bone loss.

Progression: - Renal: proximal tubular dysfunction is typically slowly progressive and, once an injury threshold is crossed, often irreversible even after exposure cessation — a critical prognostic feature distinguishing cadmium nephropathy from many other toxic nephropathies. - Skeletal: progressive osteomalacia/osteoporosis with worsening bone pain and increasing fracture risk over time in the absence of exposure cessation and mineral/vitamin D repletion. - Pulmonary (acute): staged progression — mild flu-like phase (hours) → possible progression to pneumonitis/edema (days) → potential fibrosis or death in severe unresolved cases; if the patient survives the acute phase without progressing after 1–2 days, prognosis is generally favorable, though "interstitial pneumonitis after cadmium exposure" reversibility itself has been specifically questioned in case reports. - Carcinogenesis: long latency (years to decades) typical of chemical carcinogenesis, consistent with cadmium's classification based predominantly on chronic occupational cohort follow-up data.

Patterns: - Remission: chronic renal tubular dysfunction generally does not remit even after exposure cessation, unlike many other toxic exposures — this "point of no return" characteristic is one of the more clinically important, distinguishing features of chronic cadmium nephropathy. - Critical periods: pregnancy/lactation (increased maternal bone turnover interacting with cadmium-impaired mineralization) and iron-deficient states (childhood, menstruating/pregnant women) represent windows of heightened absorption and vulnerability.

9. Inheritance and Population

Epidemiology: - Cadmium poisoning is not a rare/orphan disease in exposure terms — low-level chronic exposure is nearly universal in industrialized populations via diet and, for smokers, tobacco. Clinically significant chronic poisoning (nephropathy, osteomalacia) is concentrated in occupationally exposed workers and populations in historically or currently contaminated regions (the Jinzu River basin in Japan being the paradigmatic example, with several thousand affected individuals historically identified and hundreds of confirmed Itai-itai cases). - Blood cadmium in the general U.S. adult population (NHANES 1999–2008): geometric mean 0.376 µg/L (age ≥20 years); slightly higher in females (0.331 µg/L) than males (0.299 µg/L) in some analyses, reflecting sex differences in GI absorption efficiency (see below) partially offset by occupational exposure patterns. - Newer NHANES cycles (August 2021–August 2023) have updated blood cadmium reference data available via CDC, though a full updated geometric-mean summary was not directly retrieved in this pass.

Inheritance pattern: Not applicable in the Mendelian sense — cadmium poisoning is an acquired toxic/environmental disease. The relevant "genetic" dimension is polygenic susceptibility modification (transporter and detoxification gene polymorphisms described in Etiology/Genetics above), not a discrete inheritance pattern, penetrance, or expressivity in the classical genetic-disease sense.

Population demographics: - Affected populations: historically, agricultural communities in cadmium-mining-affected river basins (Japan — Jinzu River/Toyama; other documented cadmium-contaminated regions in China); currently, occupationally exposed industrial workers (battery, smelting, electroplating industries) worldwide, and — for the low-grade chronic exposure relevant to cardiovascular/cancer/bone endpoints — the general population, especially smokers. - Geographic distribution: strongly tied to industrial/mining activity and to regional soil cadmium content affecting crop uptake (parts of East Asia with cadmium-contaminated paddy soils are particularly notable); e-waste recycling hotspots in parts of Africa and Asia represent an emerging geographic risk pattern. - Sex ratio: Itai-itai disease specifically showed strong female predominance, attributed to lower iron stores (hence higher cadmium GI absorption efficiency), pregnancy/lactation-related bone calcium demand, and postmenopausal bone loss compounding cadmium's skeletal effects — a well-documented sex-specific vulnerability pattern rather than a sex-linked genetic mechanism. - Age distribution: chronic disease manifestations (nephropathy, osteomalacia, cancer) cluster in middle-aged to older adults reflecting cumulative exposure; acute poisoning can occur at any age given sufficient single/short-term high-dose exposure (predominantly working-age adults in occupational settings).

10. Diagnostics

Clinical/laboratory tests: - Blood cadmium (BCd) — reflects recent/ongoing exposure (biological half-life in blood ~3–4 months); standard biomonitoring test (NHANES reference method). - Urinary cadmium (UCd, typically creatinine-corrected, µg/g creatinine) — reflects cumulative body burden/kidney cadmium content given cadmium's long renal half-life; the standard biomarker for chronic exposure assessment and the basis of most occupational and environmental exposure limits (LOINC terms exist for both blood and urine cadmium assays). - Urinary β2-microglobulin (Uβ2-MG) — a classic marker of proximal tubular dysfunction; "currently the most widely used assay for detecting kidney dysfunction" in cadmium-exposed workers, though its relative sensitivity versus NAG is debated across studies (some show UCd correlates more closely with NAG at UCd <10 µg/g creatinine; more recent work suggests Uβ2-MG is more sensitive for detecting renal dysfunction per se). Also linked to hypertension risk in chronically exposed populations (PMC12029079). - Urinary N-acetyl-β-D-glucosaminidase (NAG) — lysosomal enzyme marker of tubular cell injury; simple, inexpensive, reliable, but less sensitive than retinol-binding protein (RBP) or β2-microglobulin per some assessments, and recent work questions how tightly NAG actually tracks nephron destruction. - Urinary retinol-binding protein (RBP) — another low-molecular-weight protein biomarker of proximal tubular reabsorptive dysfunction. - Serum creatinine/eGFR — for later-stage, established CKD assessment (a late marker relative to tubular biomarkers). - Urinary calcium, phosphate; serum 1,25-dihydroxyvitamin D, phosphate — for the osteomalacia workup. - Bone mineral density (DXA) — for skeletal complication assessment; documented dose-related decreases in cadmium-exposed populations.

Imaging: - Plain radiography for pseudofractures (Looser zones), a classic osteomalacia finding in advanced Itai-itai disease. - Chest imaging (CXR/CT) for acute inhalational pneumonitis/pulmonary edema assessment.

Genetic testing: Not applicable in the diagnostic sense (no causal gene to sequence); research-context genotyping of transporter/detoxification polymorphisms (DMT1, ZIP8, GST) is investigational for susceptibility stratification, not clinical diagnosis.

Clinical diagnostic criteria: - Diagnosis of chronic cadmium poisoning/nephropathy rests on a combination of (a) documented exposure history (occupational or environmental), (b) elevated urinary and/or blood cadmium, and (c) the characteristic proximal tubular dysfunction biomarker pattern (β2-MG, NAG, RBP, glucosuria, aminoaciduria) ± osteomalacia findings. Itai-itai disease has established historical diagnostic criteria from Japanese public health authorities (exposure-area residence + tubular proteinuria + bone lesions), a useful ESTABLISHED_CRITERIA framework if curated as a definitions block. - Differential diagnosis: other causes of Fanconi-like proximal tubulopathy (Wilson disease, cystinosis, Dent disease, other heavy metal nephropathies — lead, mercury), other causes of adult-onset osteomalacia (vitamin D deficiency, hypophosphatemic disorders, celiac disease), and other occupational pneumonitides for the acute inhalational presentation.

Screening: Occupational biological monitoring programs (OSHA's cadmium standard, 29 CFR 1910.1027, mandates biological monitoring of blood and urinary cadmium plus urinary β2-microglobulin in exposed workers) represent the primary organized screening framework; there is no population-wide newborn or carrier screening analog given the acquired, non-genetic nature of the disease.

11. Outcome/Prognosis

Survival and mortality: - Acute high-dose fume poisoning carries meaningful mortality risk from pulmonary edema/respiratory failure in severe, unresolved cases (case series document fatalities, e.g., PMID:5928153). - Chronic exposure is associated with increased all-cause and cardiovascular mortality in dose-response fashion across multiple cohort and NHANES-based analyses, and with increased site-specific cancer mortality (lung, and evidence trending for pancreas/bladder) per the 2024 systematic review of biological cadmium and cancer risk/mortality.

Morbidity and function: - Chronic cadmium nephropathy, once tubular injury has occurred, is generally irreversible — a key prognostic feature — leading to lifelong low-molecular-weight proteinuria and, in advanced cases, progression to overt CKD. - Itai-itai-pattern osteomalacia produces substantial disability: chronic debilitating bone pain, waddling gait, and susceptibility to pathological fractures with minimal trauma, historically causing severe functional impairment and reduced quality of life in affected Japanese cohorts. - Emphysema/reduced pulmonary function from chronic fume exposure contributes to long-term respiratory morbidity, compounding smoking-related lung disease risk in exposed smokers.

Complications: - Progression to end-stage renal disease in severe/prolonged exposure. - Recurrent pathological fractures. - Increased cardiovascular events (heart failure, stroke, coronary heart disease). - Malignancy (lung primarily; possibly bladder, pancreatic, other sites).

Recovery potential: - Acute exposure: substantial recovery potential if exposure is promptly terminated and the patient survives the acute pneumonitis/edema phase without progressing to severe respiratory failure. - Chronic exposure: recovery of renal tubular function after exposure cessation is generally poor/absent once injury has occurred — this is one of the more clinically distinctive and consequential features of the disease, in contrast to some other reversible toxic nephropathies. Skeletal disease can improve somewhat with calcium/vitamin D repletion and exposure cessation, but severe deformity/fracture sequelae are often permanent.

Prognostic factors: Cumulative dose (duration × intensity of exposure), baseline nutritional status (iron, calcium, vitamin D), sex (female sex historically associated with more severe skeletal disease in the Itai-itai cohort), age at exposure, and smoking status (compounding pulmonary and cardiovascular risk) are the principal prognostic modifiers identified in the literature. Urinary β2-microglobulin/NAG/RBP levels also function as prognostic biomarkers for the likelihood of progression to overt renal impairment.

12. Treatment

There is no proven disease-modifying cure for established chronic cadmium nephropathy or osteomalacia. Management is fundamentally exposure cessation plus supportive/symptomatic care; chelation therapy — the mainstay for lead and some other heavy-metal poisonings — has notably limited and time-dependent efficacy for cadmium and carries specific safety concerns.

Primary intervention: - Removal from exposure source (occupational reassignment, dietary source identification/avoidance, environmental remediation) — NCIT term suggestion: NCIT:C15747 (Supportive Care) or a more specific environmental-modification concept if available.

Pharmacotherapy — chelation (limited/investigational efficacy, use with caution): - EDTA (ethylenediaminetetraacetic acid, e.g., CaNa₂EDTA) — binds cadmium and enhances urinary excretion; in animal models, cadmium cytotoxicity was completely inhibited by co-administered EDTA, but chelator efficacy for cadmium is markedly time-critical: only administration immediately (versus delayed) after cadmium exposure significantly reduced tissue (kidney/liver) cadmium concentrations in experimental models, with immediate-treatment animals excreting 50–75% of the cadmium dose in urine within 24 hours versus ~0.1% in untreated controls. NCIT/CHEBI suggestion: CHEBI:64118 (edetic acid) as therapeutic_agent under a Pharmacotherapy treatment_term (NCIT:C15986). - DMSA (dimercaptosuccinic acid, succimer) — removed cadmium more effectively than DMPS in some mouse studies, but was reported ineffective against cadmium cytotoxicity in at least one direct study, illustrating that chelator efficacy for cadmium does not parallel its established efficacy for lead. - DMPS (2,3-dimercapto-1-propanesulfonic acid) — used experimentally, generally less effective than DMSA for cadmium removal in comparative animal studies. - Safety caveat: chelation for cadmium carries a documented risk of aggravating renal tubular damage rather than ameliorating it, particularly with delayed or high-dose administration — this is a critical, clinically important limitation distinguishing cadmium chelation from lead chelation, and underlies why chelation is not a routine standard-of-care intervention for established chronic cadmium nephropathy in humans. Combination with methionine has shown improved outcomes over chelators alone in restoring cadmium-induced hepatic/renal transaminase changes in animal studies, but this remains experimental.

Supportive/symptomatic care: - Calcium and vitamin D (active/activated forms, e.g., calcitriol) supplementation — for osteomalacia management, addressing the downstream mineralization defect even though it does not reverse the underlying renal tubular lesion. - Phosphate repletion as needed for tubular phosphate wasting. - Management of acute pulmonary injury: supplemental oxygen, corticosteroids (used empirically in some case reports of cadmium-induced pneumonitis), and mechanical ventilatory support for severe pulmonary edema/respiratory failure — NCIT:C15747 (Supportive Care). - Analgesia for the severe chronic bone pain characteristic of Itai-itai disease. - Standard CKD management (blood pressure control, dietary modification, and progression to renal replacement therapy/dialysis in advanced cases) for those who progress to overt chronic kidney disease.

Experimental/investigational: - Antioxidant supplementation (e.g., N-acetylcysteine, selenium) has been explored in animal models to mitigate cadmium-induced oxidative injury, but robust human clinical trial evidence supporting a specific antioxidant regimen for established cadmium poisoning was not identified in this research pass — flag as an evidence gap if curated. - No cadmium-specific agents are registered in ClinicalTrials.gov as approved disease-modifying therapies at the time of this report; most relevant trials concern chelation pharmacokinetics/biomonitoring methodology rather than definitive efficacy trials for cadmium poisoning specifically.

Treatment outcomes: Given the largely irreversible nature of established tubular injury, the primary "treatment outcome" measured in the literature is prevention of further exposure/progression rather than reversal of existing damage; formal treatment-response-rate data (in the sense used for pharmacotherapy trials) are sparse for this indication.

13. Prevention

Primary prevention: - Occupational exposure controls: engineering controls (ventilation, enclosed processes), personal protective equipment, and regulatory exposure limits (e.g., OSHA's cadmium standard 29 CFR 1910.1027, setting permissible exposure limits and mandating biological monitoring) in cadmium-using industries. - Environmental/agricultural controls: soil remediation in contaminated areas, restrictions on irrigation with contaminated water (the direct historical lesson of Itai-itai disease, which prompted major Japanese public-health and environmental-remediation programs), and monitoring/limiting cadmium content in fertilizers. - Food safety regulation: maximum permitted cadmium levels in foods (EU/Codex Alimentarius regulatory limits for rice, cereals, vegetables, offal, cocoa products), informed by EFSA's Tolerable Weekly Intake of 2.5 µg/kg body weight. - Tobacco control: smoking cessation and reduction in smoking initiation is arguably the single most impactful primary-prevention lever for population-level cadmium body burden reduction, given tobacco's outsized contribution to non-occupational exposure. - Nutritional adequacy programs: ensuring adequate dietary iron, zinc, and calcium intake (particularly in women of reproductive age) to reduce the enhanced intestinal cadmium absorption associated with deficiency states.

Secondary prevention (screening/early detection): - Occupational biological monitoring (blood cadmium, urinary cadmium, urinary β2-microglobulin) in exposed worker populations, enabling early detection of tubular dysfunction before progression to irreversible injury — this is the most evidence-supported secondary-prevention intervention. - Environmental biomonitoring of at-risk populations near contaminated sites.

Tertiary prevention: - Early exposure cessation upon detection of biomarker abnormalities, before progression to overt osteomalacia or CKD, is the principal tertiary strategy given the largely irreversible nature of established chronic cadmium nephropathy. - Calcium/vitamin D supplementation and fracture-prevention strategies in individuals with established skeletal disease.

Immunization: Not applicable — cadmium poisoning is not an infectious/immunization-preventable disease.

Genetic counseling: Not applicable in the classical sense (no Mendelian transmission), though risk communication regarding individual susceptibility (e.g., iron-deficiency-related enhanced absorption) may have a role in targeted public health messaging for high-risk groups (e.g., women of reproductive age).

Public health interventions: - Site remediation and contamination monitoring at former mining/smelting locations. - Public health surveillance systems (e.g., NHANES biomonitoring in the U.S., similar national programs elsewhere) tracking population-level cadmium body burden trends over time. - International/regulatory harmonization of food cadmium limits (Codex Alimentarius, EU regulations) given the global nature of food-trade-mediated exposure.

14. Other Species / Natural Disease

Taxonomy: Cadmium toxicity is a broadly conserved phenomenon across vertebrate (and many invertebrate) species, reflecting cadmium's fundamental biochemical mimicry of essential divalent cations (zinc, calcium) rather than a species-specific mechanism.

Naturally occurring/environmental exposure in other species: - Wildlife: cadmium bioaccumulation and toxicity are well-documented in wildlife inhabiting contaminated environments, particularly species with long lifespans and high trophic-level bioaccumulation potential (e.g., raptors, marine mammals accumulating cadmium from shellfish/crustacean prey — cadmium is strongly bioaccumulated in mollusks and crustaceans, which show naturally high tissue cadmium even in relatively unpolluted marine environments). - Domestic/companion animal and livestock exposure: livestock grazing on contaminated pasture or fed contaminated feed can develop cadmium-related renal and skeletal pathology analogous to the human disease; veterinary case reports of environmental cadmium toxicosis exist, though this is not as systematically cataloged (e.g., in OMIA, which is primarily oriented toward Mendelian veterinary genetic disease) as inherited veterinary conditions.

Comparative biology: - The proximal tubular megalin:cubilin-mediated uptake mechanism central to human cadmium nephrotoxicity is evolutionarily conserved across mammals, which is precisely why rodent models (rat, mouse) are considered reasonably faithful models of the human renal lesion (see Model Organisms below). - Avian species (notably relevant to wildlife toxicology) show comparable cadmium-induced renal and skeletal pathology, though avian calcium metabolism differences (egg-laying-related calcium mobilization) introduce some species-specific nuance to skeletal outcome comparisons.

Zoonotic potential/transmission: Not applicable — cadmium poisoning is a toxic exposure phenomenon, not an infectious or transmissible disease; there is no zoonotic transmission concept relevant here, though shared dietary/environmental exposure sources (e.g., a contaminated water/food source affecting both livestock and the human population consuming them) represent a shared-exposure rather than transmission pathway.

15. Model Organisms

Rodent models (the dominant experimental system): - Mouse: chronic low-dose environmentally-relevant cadmium exposure models demonstrate early renal proximal tubular damage that is not well-predicted by blood or urine cadmium levels alone — an important translational finding suggesting tissue-level injury can precede/exceed what conventional biomarkers capture (ScienceDirect, chronic mouse exposure study). Mouse models are also used to study cadmium's estrogen-mimetic effects on uterine and mammary gland growth, supporting the ERα-mediated endocrine-disruption mechanism. - Rat: extensively used for both renal (subcutaneous/drinking-water cadmium exposure models showing dose- and duration-dependent proximal tubular injury, histomorphological/ultrastructural precancerous lesions, and altered renal cortical microRNA expression) and skeletal toxicity modeling — a 2023 rat study specifically implicated the ROS → SIRT1/PGC-1α/p53 signaling pathway in cadmium-induced osteoblast apoptosis underlying osteoporosis pathogenesis. Rat models using dual-energy X-ray absorptiometry (DXA) have quantified dose-related bone mineral density reductions in cadmium-exposed animals, directly modeling the Itai-itai skeletal phenotype. Rat inhalation models have also been used to study acute cadmium-induced neutrophilic pulmonary inflammation and to test protective agents (e.g., tiotropium/budesonide) against this acute lung injury phenotype. - Periodontal bone models: subcutaneous cadmium injection in rats produces significant periodontal bone loss, proposed as a translational model for periodontal disease association with cadmium exposure in humans.

Genetic models: - Transporter knockout/knockdown models (siRNA-mediated knockdown of ZIP8, ZIP14, and DMT1 in cultured mouse kidney proximal tubule cells) have been used to dissect the relative contribution of each metal-transport pathway to cellular cadmium uptake, establishing that no single transporter pathway predominates (a polygenic-uptake model with direct relevance to interpreting human transporter-gene susceptibility polymorphisms). - Conditional/tissue-specific transporter knockouts in mouse are a logical extension for future mechanistic dissection, though a comprehensive knockout-model literature specific to cadmium (analogous to, e.g., IMPC-cataloged single-gene disease models) was not comprehensively retrieved in this pass.

In vitro/cell-based models: - Cultured renal proximal tubule cell lines (human and rodent-derived) are the standard system for studying megalin:cubilin-dependent cadmium-protein complex uptake and cytotoxicity mechanisms, including the classical Cd-metallothionein model and the revised Cd-β2-microglobulin/albumin/lipocalin-2 model. - Human breast cancer cell lines (T47D, and ERα+/ERα− comparator lines) are the standard system for dissecting cadmium's estrogen-receptor-mediated mechanisms.

Phenotype recapitulation and limitations: - Rodent renal and skeletal models recapitulate the proximal tubular injury and mineralization-defect phenotypes of human chronic cadmium poisoning with reasonably high fidelity, given the conserved megalin:cubilin uptake mechanism and shared vitamin-D-activation pathway. - Limitations: rodent lifespan and cadmium accumulation kinetics differ substantially from the multi-decade human chronic exposure pattern underlying diseases like Itai-itai, so rodent models are generally better suited to modeling the mechanism of injury than the full decades-long natural history; species differences in calcium/bone metabolism (and the specific postmenopausal/multiparous-female risk profile of human Itai-itai disease) are not fully captured by standard rodent designs unless specifically modeled (e.g., ovariectomized rat models combined with cadmium exposure, mimicking postmenopausal bone vulnerability). - Applications: rodent and cell-based models remain the primary tools for mechanistic dissection (transporter biology, oxidative stress pathways, chelation pharmacokinetics/efficacy testing) and are essential to interpreting the chelation-efficacy time-dependence findings summarized in the Treatment section, which derive substantially from these animal studies rather than human clinical trial data.

Summary of Key Ontology Term Suggestions for KB Curation

Category	Suggested terms
MeSH	D002104 (Cadmium Poisoning), D002103 (Cadmium)
ICD-10-CM	T56.3
Key genes (modifier)	SLC11A2/DMT1 (hgnc:10908), SLC39A8/ZIP8 (hgnc:20862), SLC39A14/ZIP14 (hgnc:20858), MT1A (hgnc:7393), MT2A (hgnc:7407)
Key phenotypes (HP)	HP:0002753 (Osteomalacia), HP:0000939 (Osteoporosis), HP:0000121 (Nephropathy), HP:0012622 (Chronic kidney disease), HP:0410048/HP:0002090 (Pneumonitis/Pneumonia), HP:0100598 (Pulmonary edema), HP:0000822 (Hypertension), HP:0002816 (Pathologic fracture), HP:0100526 (Neoplasm of the lung)
Key GO processes	GO:0006979 (response to oxidative stress), GO:0006974 (DNA damage response), GO:0097190 (apoptotic signaling pathway), GO:0030282 (bone mineralization)
Key CL cell types	CL:1000838/CL:1001106 (proximal tubule epithelial cell), CL:0000062 (osteoblast), CL:0001056 (alveolar type I cell)
Key UBERON	UBERON:0004134 (kidney proximal tubule), UBERON:0002048 (lung), UBERON:0001474 (bone element)
Key CHEBI	CHEBI:22977 (cadmium atom/ion), CHEBI:64118 (edetic acid / EDTA)
Key NCIT (treatment)	NCIT:C15986 (Pharmacotherapy), NCIT:C15747 (Supportive Care)

Note on evidence gaps requiring curator judgment: (1) the exact molecular mechanism of cadmium-induced osteoblast/bone toxicity remains explicitly unresolved in the primary literature; (2) the megalin:cubilin cargo-protein model (metallothionein vs. β2-microglobulin/albumin/lipocalin-2) is under active mechanistic revision; (3) a verified MONDO CURIE for this entity should be confirmed via direct ontology lookup rather than assumed from this report.

Sources

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	32
Resolved	32
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	32
On topic	19
Off topic	1

References that may not be about this subject

These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:

PMID:22437713 (1 mention) - A two-dimensional polymer prepared by organic synthesis.
shared terms: none

Weighed against this report's own most characteristic terms: cadmium, exposure, renal, disease, poisoning, chronic, tubular, proximal, bone, calcium, injury, itai-itai, acute, osteomalacia, kidney, effect, cell, via, mechanism, risk.

All extracted references resolved successfully. Resolving is not the same as being relevant, though - see the references listed above as possibly off topic.

Falcon ▸

Disease Characteristics Research Template

Edison Scientific Literature 52 citations 2026-05-08T10:48:48.109207

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

Disease Name: Cadmium Poisoning
MONDO ID: (if available)
Category: Environmental

Research Objectives

Please provide a comprehensive research report on Cadmium Poisoning covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

What is the disease? Provide a concise overview.
What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
What are the common synonyms and alternative names?
Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
Risk Factors:

Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases
Genetic risk factors (causal variants, susceptibility loci, modifier genes)
Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
Protective Factors:

Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases
Genetic protective factors (protective variants, modifier alleles)
Environmental protective factors (diet, lifestyle, exposures that reduce risk)
Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene
Pathogenic Variants:
Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
Variant type/class (missense, frameshift, nonsense, splice-site, structural)
Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
Functional consequences (loss of function, gain of function, dominant negative)
Modifier Genes: Genes that modify disease severity or expression
Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases
Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

Search first: CDC databases, WHO, PubMed, NHANES
Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc
Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

Search first: Gene Ontology (GO), Reactome, KEGG, PubMed
Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold
Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA
Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

Search first: ImmPort, Immunome Database, IEDB, Gene Ontology
Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

Search first: PubMed, Gene Ontology, Reactome
Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

Search first: BRENDA, UniProt, KEGG, OMIM, PubMed
Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Molecular Profiling (if available):
Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
Advanced Technologies (if applicable):
Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

Organ Level:
Primary organs directly affected
Secondary organ involvement (complications, secondary effects)
Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT
Tissue and Cell Level:
Specific tissue types affected (epithelial, connective, muscle, nervous)
Specific cell populations targeted (with Cell Ontology terms)

Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB
Subcellular Level:
Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas
Localization:
Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

Onset:
Typical age of onset (congenital, pediatric, adult, geriatric)
Onset pattern (acute, subacute, chronic, insidious)

Search first: OMIM, Orphanet, HPO, PubMed
Progression:
Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
Progression rate (rapid, slow, variable)
Disease course pattern (episodic, relapsing-remitting, progressive, stable)
Disease duration (self-limited, chronic lifelong)

Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM
Patterns:
Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

Epidemiology:
Prevalence (cases per 100,000 at given time)
Incidence (new cases per 100,000 per year)

Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries
For Genetic Etiology:
Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
Population Demographics:
Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
Geographic distribution of specific variants
Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

Clinical Tests:
Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
Genetic Testing:

Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen
Overview of recommended genetic testing approach
Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
FISH > Search first: ClinVar, cytogenetics databases, PubMed
Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
Omics-Based Diagnostics (if applicable):
RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
Clinical Criteria:
Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
Screening:
Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

Survival and Mortality:
Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
Morbidity and Function:
Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
Disease Course:
Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
Prediction:
Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

Pharmacotherapy:
Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
Advanced Therapeutics:
Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
Surgical and Interventional:
Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
Supportive and Rehabilitative:
Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
Experimental:
Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
Treatment Outcomes:
Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
Treatment Strategy:
Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.

13. Prevention

Prevention Levels:
Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
Immunization: Vaccine strategies (if applicable)

Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database
Screening and Early Detection:
Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
Behavioral Interventions: Lifestyle modifications to reduce risk

Search first: CDC, WHO, behavioral intervention databases, Cochrane Library
Counseling: Genetic counseling (risk assessment, family planning guidance)

Search first: NSGC resources, ACMG guidelines, GeneReviews
Public Health:
Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
Prophylaxis: Preventive medications or procedures

Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

Taxonomy: Species affected (with NCBI Taxon identifiers)

Search first: NCBI Taxonomy
Breed: Specific breeds affected (with VBO identifiers if applicable)

Search first: VBO (Vertebrate Breed Ontology)
Gene: Orthologous genes in other species (with NCBI Gene IDs)

Search first: NCBI Gene
Natural Disease:
Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
Comparative Biology:
Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
Transmission (if applicable):
Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

Model Types:
Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
Genetic Models:
Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
Model Characteristics:
Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
Applications:
Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
Resources:
Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic and clinical claims
Prioritize recent reviews and landmark papers
Include direct quotes from abstracts where possible to support key statements
Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Cadmium Poisoning (Cadmium Toxicity): Comprehensive Disease Characteristics Report (Environmental)

1. Disease Information

Cadmium poisoning (also termed cadmium toxicity or cadmium intoxication) is an exposure-mediated toxicologic disorder caused by acute high-dose cadmium (Cd) exposure (often inhalational) or chronic low-to-moderate exposure with long-term bioaccumulation, particularly in the kidney cortex. Acute disease is often dominated by pulmonary injury, while chronic disease is dominated by renal tubular injury with downstream effects on bone and other systems. (balalimood2025recentadvancesin pages 9-11, chakif2026heavymetaltoxicity pages 12-13)

Key identifiers (ontology/classification): MONDO, MeSH, ICD-10/ICD-11 identifiers were not retrievable from the tool evidence in this run and therefore are not reported here to avoid fabrication. (artifact-00)

Common synonyms/alternative names: cadmium toxicity; cadmium intoxication; chronic cadmium exposure toxicity; cadmium-induced nephrotoxicity (subset). (vamsi2024cadmiumtoxicityunveiling pages 8-9, balalimood2025recentadvancesin pages 9-11)

Evidence sources: The retrieved evidence base is primarily aggregated disease-level resources (reviews) and population/cohort studies (NHANES, regional cohorts), not EHR-derived phenotyping. (balalimood2025recentadvancesin pages 9-11, shi2024associationsofmixed pages 1-2)

Concept item	Details	Evidence/notes	Key sources (URL; year)
Disease name	Cadmium poisoning	Environmental/toxic exposure disorder caused by acute or chronic exposure to cadmium or cadmium compounds. Acute disease is dominated by inhalational or high-dose ingestion toxicity; chronic disease reflects bioaccumulation, especially in kidney cortex. (balalimood2025recentadvancesin pages 9-11, chakif2026heavymetaltoxicity pages 12-13)	Balali-Mood et al., Heliyon, https://doi.org/10.1016/j.heliyon.2025.e42696; 2025. Chakif & Furrer, Int J Mol Sci, https://doi.org/10.3390/ijms27083513; 2026.
Core alternative names	Cadmium toxicity; cadmium intoxication; cadmium exposure toxicity	Recent reviews use these terms interchangeably in clinical/environmental toxicology contexts rather than as distinct diseases. (balalimood2025recentadvancesin pages 11-12, vamsi2024cadmiumtoxicityunveiling pages 8-9)	Balali-Mood et al., https://doi.org/10.1016/j.heliyon.2025.e42696; 2025. Vamsi et al., https://doi.org/10.36468/pharmaceutical-sciences.1427; 2024.
Disease category	Environmental / toxicologic / heavy-metal poisoning	Non-Mendelian, exposure-mediated condition; evidence in retrieved tools is disease-level literature and cohort/review evidence, not patient-specific EHR-derived ontology records. (balalimood2025recentadvancesin pages 9-11, chakif2026heavymetaltoxicity pages 12-13)	Balali-Mood et al., https://doi.org/10.1016/j.heliyon.2025.e42696; 2025. Chakif & Furrer, https://doi.org/10.3390/ijms27083513; 2026.
MONDO ID	not retrieved from tool evidence	Do not infer or invent identifier.	Not retrieved from ontology-focused tool evidence.
MeSH ID / descriptor ID	not retrieved from tool evidence	Do not infer or invent identifier.	Not retrieved from ontology-focused tool evidence.
ICD-10 / ICD-11 code	not retrieved from tool evidence	Toxic-effect coding likely exists in classification systems, but explicit code was not retrieved from tool evidence and should not be invented here.	Not retrieved from tool evidence.
Acute cadmium poisoning	Usually follows inhalation of cadmium oxide fumes/dust or high-dose ingestion	Defined clinically by respiratory irritation with symptom onset typically within 6–12 h after inhalation; may progress to cough, fever, respiratory distress, hypoxia, pneumonitis, pulmonary insufficiency, or death in severe cases. One review notes inhalation of 5 mg/m3 for 8 h may be lethal. (balalimood2025recentadvancesin pages 9-11, balalimood2025recentadvancesin pages 11-12, chakif2026heavymetaltoxicity pages 12-13)	Balali-Mood et al., https://doi.org/10.1016/j.heliyon.2025.e42696; 2025. Chakif & Furrer, https://doi.org/10.3390/ijms27083513; 2026.
Chronic cadmium poisoning	Long-term bioaccumulation disorder, especially affecting kidney, bone, lung, and cardiovascular system	Cadmium has a very long biologic half-life in kidney (~20–30 years in review evidence). Hallmark chronic effects are renal proximal tubular injury, proteinuria, progressive CKD, and skeletal demineralization/osteomalacia/osteoporosis. (chakif2026heavymetaltoxicity pages 12-13, chakif2026heavymetaltoxicity pages 7-8)	Chakif & Furrer, https://doi.org/10.3390/ijms27083513; 2026. Balali-Mood et al., https://doi.org/10.1016/j.heliyon.2025.e42696; 2025.
Major exposure sources	Food, smoking/tobacco, occupational inhalation, contaminated air/water/soil	Tobacco smoke is a major source; each cigarette may contain ~0.5–1 µg Cd. Occupational sources include mining, smelting, battery manufacture/recycling, fossil fuel combustion, plating, fertilizer production, and waste disposal. (balalimood2025recentadvancesin pages 9-11, chakif2026heavymetaltoxicity pages 7-8)	Balali-Mood et al., https://doi.org/10.1016/j.heliyon.2025.e42696; 2025. Chakif & Furrer, https://doi.org/10.3390/ijms27083513; 2026.
Renal hallmark definition	Cadmium nephrotoxicity with tubular and glomerular effects	Chronic exposure causes often irreversible proteinuria and tubular dysfunction. Nordberg review notes albuminuria is mainly glomerular and may fall when blood Cd decreases, while tubular dysfunction markers (β2-microglobulin, NAG) appear linked to accumulated tubular Cd and seem more irreversible. (nordberg2025metallothioneinandother pages 9-11)	Nordberg & Nordberg, Biomolecules, https://doi.org/10.3390/biom15081083; 2025.
Key renal biomarkers	Urine Cd (body burden), blood Cd (recent/ongoing exposure), urinary β2-microglobulin, urinary NAG, urinary albumin, eGFR	Reviews and cohorts repeatedly use urine Cd and blood Cd as exposure biomarkers; β2-microglobulin (B2-MG/β2-MG), NAG, and albuminuria are effect biomarkers; eGFR decline tracks clinically important renal loss. (nordberg2025metallothioneinandother pages 12-14, nordberg2025metallothioneinandother pages 9-11, chakif2026heavymetaltoxicity pages 12-13, chakif2026heavymetaltoxicity pages 14-16)	Nordberg & Nordberg, https://doi.org/10.3390/biom15081083; 2025. Chakif & Furrer, https://doi.org/10.3390/ijms27083513; 2026.
β2-microglobulinuria threshold	Urinary β2-microglobulin >300 µg/g creatinine (or >300 µg/L in some studies)	Used in multiple studies/reviews as a threshold for cadmium-related tubular dysfunction/kidney dysfunction. Nordberg review explicitly references urinary B2M >300 µg/g creatinine; Kwon study used β2-MG >300 µg/L as reference exceedance. (nordberg2025metallothioneinandother pages 9-11, nordberg2025metallothioneinandother pages 11-12, kwon2023associationbetweenlevels pages 9-10)	Nordberg & Nordberg, https://doi.org/10.3390/biom15081083; 2025. Kwon et al., https://doi.org/10.1038/s41598-022-27292-7; 2023.
NAG threshold / interpretation	Urinary NAG is an early tubular injury biomarker; threshold examples vary by study	Nordberg figure legend cited UNAG >23 U/g creatinine; Kwon study used NAG >11.5 U/L as reference exceedance; increased NAG is consistently linked with urinary cadmium. (nordberg2025metallothioneinandother pages 11-12, kwon2023associationbetweenlevels pages 9-10)	Nordberg & Nordberg, https://doi.org/10.3390/biom15081083; 2025. Kwon et al., https://doi.org/10.1038/s41598-022-27292-7; 2023.
Urinary cadmium threshold for renal risk	~2–5 µg/g creatinine may indicate elevated body burden/renal risk; >10 µg/g creatinine associated with irreversible kidney damage in one review	Chakif review states chronic renal risk may occur at lower urinary levels than older models suggested and that ~2–5 µg/g creatinine may indicate elevated burden/risk. Vamsi review states urinary Cd <10 µg/g creatinine is associated with reversible renal dysfunction, whereas >10 µg/g creatinine can cause irreversible kidney damage. (chakif2026heavymetaltoxicity pages 14-16, vamsi2024cadmiumtoxicityunveiling pages 8-9)	Chakif & Furrer, https://doi.org/10.3390/ijms27083513; 2026. Vamsi et al., https://doi.org/10.36468/pharmaceutical-sciences.1427; 2024.
Metallothionein-related definition	Cadmium binds metallothionein (MT); MT is central to transport, sequestration, and renal toxicity modification	Nordberg review emphasizes MT as central to toxicokinetics: Cd-MT transports cadmium to renal tubules, and MT expression/protection modifies kidney injury risk. Anti-MT antibodies and low zinc status may worsen susceptibility. (nordberg2025metallothioneinandother pages 12-14, nordberg2025metallothioneinandother pages 9-11)	Nordberg & Nordberg, https://doi.org/10.3390/biom15081083; 2025.
Bone disease definition	Cadmium-related osteotoxicity / Itai-itai-like disease	Chronic exposure is associated with low bone mineralization, decalcification, fractures, osteomalacia, and osteoporosis; classic severe manifestation is Itai-itai disease. (balalimood2025recentadvancesin pages 9-11, chakif2026heavymetaltoxicity pages 12-13)	Balali-Mood et al., https://doi.org/10.1016/j.heliyon.2025.e42696; 2025. Chakif & Furrer, https://doi.org/10.3390/ijms27083513; 2026.
Lung involvement definition	Acute toxic inhalation injury and chronic pulmonary toxicity	Acute inhalation causes irritant pneumonitis/respiratory distress; chronic exposure has been linked to COPD/emphysema in reviews. (balalimood2025recentadvancesin pages 9-11, balalimood2025recentadvancesin pages 11-12)	Balali-Mood et al., https://doi.org/10.1016/j.heliyon.2025.e42696; 2025.
Clinical management definition	Source control and supportive care are first-line; chelation is limited/controversial for cadmium	Reviews emphasize removing exposure, supportive care, occupational controls, smoking cessation, and nutrition. Routine chelation is not first-line; benefits are uncertain and some agents may worsen toxicity. BAL/dimercaprol is specifically discouraged/contraindicated for cadmium because Cd-BAL complexes may be more nephrotoxic. (balalimood2025recentadvancesin pages 11-12, chakif2026heavymetaltoxicity pages 16-17, chakif2026heavymetaltoxicity pages 8-9, vamsi2024cadmiumtoxicityunveiling pages 8-9)	Balali-Mood et al., https://doi.org/10.1016/j.heliyon.2025.e42696; 2025. Chakif & Furrer, https://doi.org/10.3390/ijms27083513; 2026. Vamsi et al., https://doi.org/10.36468/pharmaceutical-sciences.1427; 2024.
Protective/nutritional modifiers	Adequate zinc, iron, selenium, calcium may reduce cadmium uptake or toxicity	Reviews cite dietary sufficiency and good zinc status as protective; Nordberg review highlights inverse associations between zinc status/Zn-Cd quotient and tubular dysfunction. (balalimood2025recentadvancesin pages 9-11, nordberg2025metallothioneinandother pages 11-12)	Balali-Mood et al., https://doi.org/10.1016/j.heliyon.2025.e42696; 2025. Nordberg & Nordberg, https://doi.org/10.3390/biom15081083; 2025.

Table: This table summarizes the key identifiers, synonyms, and working clinical definitions for cadmium poisoning from the retrieved evidence base. It highlights how recent reviews define acute versus chronic toxicity and the main biomarkers and thresholds used in practice.

2. Etiology

2.1 Primary causal factors

Cadmium poisoning is primarily an environmental/occupational toxic exposure condition. Primary exposure routes include ingestion (diet), inhalation (occupational, tobacco smoke), and exposure through contaminated air/water/soil. (balalimood2025recentadvancesin pages 9-11, chakif2026heavymetaltoxicity pages 7-8)

2.2 Risk factors

Major exposure sources: - Tobacco smoking: A recent clinical review notes that “each cigarette may contain ~0.5–1 μg Cd,” highlighting tobacco smoke as a major atmospheric source. (balalimood2025recentadvancesin pages 9-11) - Occupational/industrial: mining, smelting, battery manufacture/recycling, fossil fuel combustion, plating, fertilizer production, and waste disposal are emphasized as major sources. (balalimood2025recentadvancesin pages 9-11) - Dietary exposure: Cd is widely present in foods; chronic exposure is therefore common. (satarug2025hypertensioninpeople pages 16-17)

Host susceptibility: - Iron deficiency/low iron stores can increase intestinal absorption of Cd; women and children are noted as higher-risk groups due to lower iron stores. (satarug2026aretheguidelines pages 3-5) - Zinc deficiency/low zinc status increases susceptibility to Cd kidney injury; zinc status modifies tubular toxicity risk in human evidence. (nordberg2025metallothioneinandother pages 9-11)

Co-exposures: - Co-exposure to inorganic arsenic can potentiate Cd nephrotoxicity with more-than-additive tubular effects, and MT status may modify susceptibility in animal data summarized in review. (nordberg2025metallothioneinandother pages 12-14, nordberg2025metallothioneinandother pages 11-12)

2.3 Protective factors

Adequate zinc status is associated with lower prevalence of Cd-related tubular dysfunction; higher Zn/Cd quotients were strongly protective in population data summarized in a kidney-focused review. (nordberg2025metallothioneinandother pages 11-12)
Nutritional sufficiency (iron/zinc/selenium; calcium) is repeatedly proposed as a practical exposure-mitigation approach for oral Cd assimilation. (balalimood2025recentadvancesin pages 9-11, satarug2025hypertensioninpeople pages 16-17)

2.4 Gene–environment interactions (current evidence base)

Cadmium toxicity is not typically modeled as a monogenic disorder; instead, gene–environment interactions are framed through toxicokinetics/toxicodynamics modifiers. Metallothionein (MT) induction and MT-related biomarkers/antibodies are repeatedly discussed as determinants of Cd distribution and kidney injury susceptibility in human and animal evidence. (nordberg2025metallothioneinandother pages 12-14, nordberg2025metallothioneinandother pages 9-11)

Ontology suggestions (non-exhaustive): CHEBI: cadmium(2+) (cadmium ion); environmental exposure to heavy metal; exposure to tobacco smoke.

3. Phenotypes

Cadmium toxicity phenotypes depend on dose and route.

3.1 Acute cadmium poisoning (typically inhalation)

Core manifestations: respiratory irritation progressing over hours to pneumonitis/respiratory distress. - A clinical review describes symptom onset within 6–12 hours after inhalation with cough/fever/respiratory distress and potential progression to hypoxia and pulmonary failure. (balalimood2025recentadvancesin pages 9-11) - Quantitative lethality estimate in one review: “The inhalation exposure to 5 mg/m3 for 8 h may be lethal.” (balalimood2025recentadvancesin pages 11-12)

Suggested HPO terms (examples): - Dyspnea (HP:0002094) - Cough (HP:0012735) - Fever (HP:0001945) - Hypoxemia (HP:0012418)

3.2 Chronic cadmium toxicity (bioaccumulation)

Kidney (most sensitive/critical target): - Renal tubular injury with low-molecular-weight proteinuria; chronic kidney disease risk; effect biomarkers include urinary β2-microglobulin and urinary NAG; clinical endpoints include eGFR decline and albuminuria/proteinuria. (chakif2026heavymetaltoxicity pages 12-13, nordberg2025metallothioneinandother pages 9-11) - Chronic renal injury is often described as difficult to reverse once established; a review emphasizes that tubular biomarkers may reflect more irreversible injury compared with albuminuria changes following reductions in blood Cd. (nordberg2025metallothioneinandother pages 9-11)

Bone: osteomalacia/osteoporosis/fractures (classically Itai-itai disease in severe exposures). (balalimood2025recentadvancesin pages 9-11, chakif2026heavymetaltoxicity pages 12-13)

Neurologic/cognitive: neurotoxicity signals in population studies (see Epidemiology/Statistics). (lu2024associationofurinary pages 1-2)

Cardiovascular: hypertension risk and related kidney-mediated mechanisms are discussed in expert reviews. (satarug2025hypertensioninpeople pages 10-12)

Suggested HPO terms (examples): - Proteinuria (HP:0000093) - Albuminuria (HP:0000097) - Abnormal glomerular filtration rate (HP:0012211) - Renal tubular dysfunction (HP:0000126) - Osteoporosis (HP:0000939) - Bone pain (HP:0002653)

Quality of life impacts (evidence directionality): In severe or chronic exposure, renal dysfunction and bone disease plausibly impair mobility and daily functioning; however, standardized QoL metrics (SF-36/EQ-5D) were not captured in the retrieved tool evidence.

4. Genetic/Molecular Information

4.1 Causal genes / pathogenic variants

Cadmium poisoning is not a Mendelian disorder in the retrieved evidence; thus no causal gene list or pathogenic variant catalog is appropriate as “disease-causing” in the classical clinical genetics sense.

4.2 Molecular modifiers and key targets (mechanistic relevance)

Metallothionein (MT): central protective/sequestration protein in Cd toxicokinetics and renal tubular handling. MT influences transport of Cd to renal tubules and binds Cd intracellularly, modulating injury risk. (nordberg2025metallothioneinandother pages 12-14, nordberg2025metallothioneinandother pages 9-11)

Metal transporters implicated in uptake (review evidence): DMT1, ZIP14, ATP7A, TRPV6 are discussed as routes by which Cd enters cells, with higher absorption in low-iron states. (satarug2026aretheguidelines pages 3-5)

Ontology suggestions: - GO (biological process): response to cadmium ion; metal ion transport; response to oxidative stress; renal tubular cell apoptotic process; inflammatory response. - CL (cell types): kidney proximal tubule epithelial cell (CL:0002306); hepatocyte (CL:0000182); macrophage (CL:0000235).

5. Environmental Information

Environmental factors: cadmium contamination of air, water, soil, and food chain; occupational industrial emissions; battery waste. (balalimood2025recentadvancesin pages 9-11)

Lifestyle factors: cigarette smoking is repeatedly highlighted as a major preventable contributor to Cd body burden; smoking cessation is explicitly recommended as a cadmium reduction strategy. (chakif2026heavymetaltoxicity pages 16-17)

Infectious agents: not applicable.

6. Mechanism / Pathophysiology (Causal Chain)

A consensus mechanistic chain in the retrieved evidence is:

1) Exposure and absorption: via inhalation (occupational/tobacco) and ingestion (diet). (balalimood2025recentadvancesin pages 9-11, chakif2026heavymetaltoxicity pages 7-8)

2) Distribution and long residence time: Cd binds proteins including metallothionein and concentrates in the renal cortex; a recent review states cadmium has a very long biologic half-life (~20–30 years). (chakif2026heavymetaltoxicity pages 12-13)

3) Cellular entry and injury pathways: Cd can hijack metal transporters (e.g., DMT1/ZIP14/ATP7A/TRPV6) to enter target cells. (satarug2026aretheguidelines pages 3-5)

4) Renal tubular injury and functional decline: proximal tubular dysfunction is a central clinical manifestation, with effect biomarkers including β2-microglobulin and NAG. (chakif2026heavymetaltoxicity pages 12-13, chakif2026heavymetaltoxicity pages 14-16)

5) System-level outcomes: CKD progression (eGFR loss), proteinuria/albuminuria; downstream effects include bone demineralization/fractures and cardiometabolic outcomes. (chakif2026heavymetaltoxicity pages 12-13, satarug2025hypertensioninpeople pages 10-12)

Oxidative stress/mitochondrial dysfunction: Reviews describe Cd-driven ROS generation and mitochondrial impairment; expert commentary also links Cd exposure to oxidative stress and inflammation across organs. (satarug2026aretheguidelines pages 16-18, balalimood2025recentadvancesin pages 9-11)

Metallothionein and zinc interactions: MT is portrayed as protective by binding Cd, and zinc status modifies susceptibility (e.g., higher Zn/Cd quotients protective against tubular dysfunction in population evidence summarized by Nordberg & Nordberg). (nordberg2025metallothioneinandother pages 11-12)

Advanced/omics evidence: mixture modeling and pathway-based analyses are emerging in human studies (e.g., mixed metal exposure modeling in NHANES; BKMR/WQS approaches), supporting a shift from single-metal to mixture-aware causal inference. (shi2024associationsofmixed pages 1-2)

7. Anatomical Structures Affected

Primary organs: - Kidney (renal cortex; proximal tubule): principal site of accumulation and chronic injury. (chakif2026heavymetaltoxicity pages 12-13) - Lung: key site for acute inhalational injury. (balalimood2025recentadvancesin pages 9-11) - Bone/skeleton: demineralization/osteomalacia/osteoporosis and fracture risk. (chakif2026heavymetaltoxicity pages 12-13)

Secondary systems: cardiovascular (hypertension), nervous system (neurotoxicity/cognition), liver involvement in toxicokinetics. (satarug2025hypertensioninpeople pages 10-12, lu2024associationofurinary pages 1-2)

Ontology suggestions: - UBERON: kidney cortex; proximal convoluted tubule; lung; bone tissue. - GO Cellular Component: mitochondrion; cytosol; nucleus.

8. Temporal Development

Onset patterns: - Acute: subacute respiratory syndrome hours after inhalation (6–12 h described). (balalimood2025recentadvancesin pages 9-11) - Chronic: insidious, cumulative exposure with long tissue half-life, manifesting over years to decades. (chakif2026heavymetaltoxicity pages 12-13)

Progression: - Expert review emphasizes that Cd-related loss of eGFR due to nephron destruction is irreversible once established (“eGFR deterioration due to Cd-induced nephron destruction is irreversible”). (satarug2025hypertensioninpeople pages 16-17)

9. Inheritance and Population

Cadmium poisoning is not inherited; it is primarily exposure-driven.

Epidemiology/burden (recent quantitative data): - In NHANES 2011–2020 (n=9,056), kidney stone prevalence was 10.82%, and urinary Cd was associated with higher kidney stone odds (see Section 5 Table). (ye2023nationalanalysisof pages 4-5) - In NHANES 2011–2018 mixture analysis (n=3,080), CKD prevalence was 18.90% (582 cases) and high mixed-metal exposure increased CKD odds; cadmium was a high-importance contributor in BKMR (PIP 0.911 in urine; 0.845 in blood). (shi2024associationsofmixed pages 4-5) - In a Korean vulnerable-area cohort (n=298; mean age 70.3), exposure-area mean blood Cd was 1.89 µg/L vs 0.89 µg/L in control; urinary Cd 2.11 µg/L vs 1.11 µg/L, with renal biomarker associations. (kwon2023associationbetweenlevels pages 1-2)

Demographics: Susceptibility patterns include sex differences and higher absorption risk in low-iron states; race/ethnicity differences appear in some outcomes (e.g., cognition association in REGARDS observed among White but not Black participants). (satarug2026aretheguidelines pages 3-5, lu2024associationofurinary pages 1-2)

10. Diagnostics

Core diagnostic strategy: exposure history + biomonitoring + organ injury assessment.

10.1 Exposure biomarkers

Urine cadmium (creatinine-corrected): emphasized as a marker of Cd body burden; one review notes urine is often preferred for cadmium body burden. (chakif2026heavymetaltoxicity pages 14-16)
Blood cadmium: more reflective of recent/ongoing exposure in many frameworks; correlated with some kidney outcomes and albuminuria trajectories in review evidence. (nordberg2025metallothioneinandother pages 9-11)

10.2 Effect biomarkers (kidney)

Common effect biomarkers in human studies/reviews include: - Urinary β2-microglobulin (β2M): tubular reabsorptive dysfunction marker. A widely used threshold is β2M excretion 300 µg/g creatinine (β2-microglobulinuria). (satarug2025hypertensioninpeople pages 14-16) - Urinary NAG: tubular injury marker. Thresholds vary by study (examples include UNAG >23 U/g creatinine in a review figure legend and NAG >11.5 U/L as a reference exceedance in a regional cohort study). (nordberg2025metallothioneinandother pages 11-12, kwon2023associationbetweenlevels pages 9-10) - Albuminuria/proteinuria and eGFR: clinically relevant endpoints; expert analysis argues eGFR decline should be prioritized in risk assessment relative to β2M-based endpoints. (satarug2026aretheguidelines pages 3-5, satarug2025hypertensioninpeople pages 10-12)

Threshold examples (interpretation is study-specific): - A 2024 review states urinary Cd <10 µg/g creatinine is associated with reversible renal dysfunction, while >10 µg/g creatinine can cause irreversible damage. (vamsi2024cadmiumtoxicityunveiling pages 8-9) - Another review suggests chronic renal risk may occur at ~2–5 µg/g creatinine urinary Cd. (chakif2026heavymetaltoxicity pages 14-16)

10.3 Differential diagnosis

Not systematically enumerated in the retrieved tool evidence; clinically, differential for tubular proteinuria/CKD includes diabetes, hypertension, other nephrotoxins (e.g., lead), and multiple-metal co-exposures, consistent with mixture analyses. (shi2024associationsofmixed pages 1-2)

11. Outcome / Prognosis

Renal prognosis: Chronic Cd exposure is associated with persistent renal tubular injury and progressive CKD risk. Expert commentary emphasizes irreversibility of eGFR deterioration once nephron destruction occurs. (satarug2025hypertensioninpeople pages 16-17)

Population outcome signals: - In a Thai cohort analysis (n=737), risks of low eGFR and albuminuria rose ~twofold per doubling ECd/Ccr, and severe tubular injury risk (NAG/Ccr) increased with Cd burden. (satarug2024urinarynacetylglucosaminidasein pages 12-13)

Mortality rates and formal survival estimates were not retrieved in the tool evidence.

12. Treatment

General principle: remove exposure and provide supportive care; routine chelation is controversial for cadmium.

12.1 Immediate management (acute inhalation/ingestion)

A clinical review emphasizes supportive measures including decontamination and pulmonary management. For acute cases it describes GI decontamination (e.g., gastric lavage when appropriate) and the use of corticosteroids for pulmonary inflammation in some contexts; dialysis is generally not effective except in renal failure. (balalimood2025recentadvancesin pages 11-12)

12.2 Chelation therapy (evidence limitations)

Expert review statement: “therapeutically effective chelation treatment to remove Cd from the kidneys does not exist.” (satarug2025hypertensioninpeople pages 16-17)
Dimercaprol (BAL) is discouraged/contraindicated for cadmium in review evidence because Cd–BAL complexes can be more nephrotoxic than cadmium alone. (vamsi2024cadmiumtoxicityunveiling pages 8-9)
Succimer (DMSA), DMPS, and DTPA are discussed as possible chelation options in some reviews, but with uncertain clinical benefit and important limitations; multiple sources stress that chelation should only be considered if benefits outweigh harms and that “source control is the anchor.” (balalimood2025recentadvancesin pages 11-12, chakif2026heavymetaltoxicity pages 16-17)

12.3 Emerging/experimental strategies

A prevention-oriented approach using an orally administered chelating polymer (Chitosan@DOTAGA) was tested in mice to chelate Cd in the gut and reduce systemic effects from contaminated diet exposure (7 mg/kg cadmium in food). The polymer remained confined to the GI tract and reduced pathology scores (kidney score control 2 vs saline 27 vs treated 7) in this model. (howard2023combatingleadand pages 6-8)

MAXO suggestions (non-exhaustive): - Removal of exposure source; smoking cessation; occupational exposure mitigation; supportive care; toxicology consultation; chelation therapy (restricted/conditional).

13. Prevention

Prevention is emphasized as the dominant strategy: - Smoking cessation and dietary/exposure avoidance are repeatedly recommended. (chakif2026heavymetaltoxicity pages 16-17, satarug2025hypertensioninpeople pages 16-17) - Occupational hygiene and ventilation; limiting industrial Cd uses; proper battery recycling/disposal; and nutrition optimization (iron/zinc/selenium adequacy) to reduce uptake are recommended in clinical management review evidence. (balalimood2025recentadvancesin pages 9-11, balalimood2025recentadvancesin pages 11-12)

14. Other Species / Natural Disease

Naturally occurring cadmium toxicosis in animals was not explicitly retrieved in the tool evidence; however, multiple reviews describe cadmium toxicity across humans and animals and emphasize conserved renal and bone targets. (nordberg2025metallothioneinandother pages 17-18)

15. Model Organisms

Mouse models (in vivo): - A 2023 mouse study used dietary Cd exposure (7 mg/kg in food) and assessed mitigation via oral chelating polymer (Chitosan@DOTAGA). The polymer’s biodistribution was confined to the digestive tract and it reduced kidney and liver pathology scores compared with saline-exposed mice. (howard2023combatingleadand pages 6-8, howard2023combatingleadand pages 5-6)

Model limitations: exposure regimen and doses may not reflect human chronic low-dose dietary exposure; translation requires careful toxicokinetic scaling.

Recent Developments and Real-World Implementations (2023–2024 emphasis)

Recent literature shows a shift toward (i) mixture-aware exposure modeling (e.g., BKMR/WQS in NHANES), (ii) lower-effect thresholds and debates about which renal endpoints best reflect clinically meaningful harm (eGFR vs β2M), and (iii) preventive “gut chelation” or exposure-blocking strategies in preclinical models. (shi2024associationsofmixed pages 4-5, satarug2025hypertensioninpeople pages 10-12, howard2023combatingleadand pages 6-8)

Study (first author, year)	Population/design	Exposure metric	Outcome(s)	Key quantitative results	Notes
Ye, 2023	NHANES 2011–2020 cross-sectional analysis; 9,056 U.S. adults aged ≥20 years	Urinary cadmium, quartiles: Q1 0.025–0.104 µg/L; Q2 0.105–0.218 µg/L; Q3 0.219–0.435 µg/L; Q4 0.435–7.581 µg/L	Self-reported kidney stones	Kidney stone prevalence 10.82%. Fully adjusted ORs vs Q1: Q2 1.40 (95% CI 1.06–1.84), Q3 1.18 (0.88–1.59), Q4 1.54 (1.10–2.06); continuous urinary Cd OR 1.13 (1.01–1.26). Restricted cubic spline showed a non-linear association (P for non-linear <0.001). DOI: https://doi.org/10.3389/fpubh.2023.1146263 (ye2023nationalanalysisof pages 1-2, ye2023nationalanalysisof pages 4-5)	Suggests even relatively low urinary Cd ranges are associated with higher kidney stone odds; cross-sectional design limits causal inference.
Shi, 2024	NHANES 2011–2018 cross-sectional mixture analysis; 3,080 adults, 582 CKD cases (18.90%)	Urine and whole-blood metal mixtures including cadmium, manganese, lead, mercury	Chronic kidney disease (CKD)	High mixed-metal exposure associated with increased CKD odds: urine mixture OR 1.58 (95% CI 1.26–1.99); whole-blood mixture OR 1.67 (1.19–2.34). BKMR PIPs in overall population highlighted urine Cd 0.911 and blood Cd 0.845 among important contributors. DOI: https://doi.org/10.1038/s41598-024-63858-3 (shi2024associationsofmixed pages 4-5, shi2024associationsofmixed pages 1-2)	Cadmium acted within a co-exposure context rather than as a single-metal model; interactions were more evident in participants with T2DM.
Kwon, 2023	Korean environmentally vulnerable-area study; n=298 total (low-exposure abandoned mine n=74, high-exposure abandoned mine n=68, refinery n=121, control n=35); mean age 70.3 years	Blood Cd and urinary Cd; heavy metal biomonitoring in exposed vs control regions	Renal biomarkers: urinary NAG, urinary β2-microglobulin (β2-MG), eGFR	In exposure areas vs control: mean blood Cd 1.89 vs 0.89 µg/L; urinary Cd 2.11 vs 1.11 µg/L. Blood Cd in refinery area had OR 38 for exceeding reference value vs control; urinary Cd was 7-fold higher in the low-exposure mine area vs control. Urinary Cd positively correlated with NAG in all areas; blood Cd associated with increased odds of β2-MG >300 µg/L and eGFR <60 mL/min/1.73 m²; NAG reference threshold >11.5 U/L. DOI: https://doi.org/10.1038/s41598-022-27292-7 (kwon2023associationbetweenlevels pages 9-10, kwon2023associationbetweenlevels pages 1-2)	Supports renal tubular injury as a prominent human signal of environmental Cd exposure; small regional study but with strong area contrasts.
Satarug, 2024	Thai environmentally exposed cohort/cross-sectional analysis; 737 non-diabetic adults, 9.1% with eGFR ≤60 mL/min/1.73 m²	Urinary Cd normalized to creatinine clearance (ECd/Ccr); renal biomarkers normalized similarly	Low eGFR, albuminuria, tubular injury (NAG), β2-microglobulin-related tubular dysfunction	Risks of low eGFR and albuminuria rose twofold per doubling ECd/Ccr. Doubling ECd/Ccr increased risk of severe tubular injury measured by NAG/Ccr (POR 4.80, p=0.015). ENAG/Ccr associated with ECd/Ccr in men β=0.447 and women β=0.394; inversely associated with eGFR in women β=-0.178 and in high-Cd body burden group β=-0.223. Reported benchmark/threshold values include ECd/Ecr 0.5 µg/g linked to 2.6- to 3.6-fold higher odds of abnormal NAG excretion; BMDLs 0.5–0.8 and 0.7–1.2 µg/g creatinine; some studies suggest <0.3 µg/g. DOI: https://doi.org/10.3390/toxics12110775 (satarug2024urinarynacetylglucosaminidasein pages 12-13)	Highlights that tubular biomarkers and GFR decline may reflect partly different mechanisms/kinetics of Cd nephrotoxicity.
Lu, 2024	REGARDS prospective cohort subcohort; 2,172 adults free of baseline cognitive impairment/stroke; mean age 64.1 years; 54.8% female; 38.7% Black; average follow-up ~10 years	Baseline urinary creatinine-corrected cadmium; dichotomized at median or analyzed by tertiles	Global cognitive impairment and domain-based cognitive impairment	During follow-up: 195 cases of global cognitive impairment and 53 domain-based cases. No overall association in full sample, but among White participants, high urinary Cd (≥median) was associated with doubled odds of global cognitive impairment: OR 2.07 (95% CI 1.18–3.64). Median urinary Cd was similar by race: Black 0.414 µg/g, White 0.407 µg/g. DOI: https://doi.org/10.1212/WNL.0000000000209808 (lu2024associationofurinary pages 1-2, lu2024associationofurinary pages 4-5, lu2024associationofurinary pages 8-9, lu2024associationofurinary pages 2-4)	Prospective design strengthens temporal inference; association appeared race-specific in this cohort and was not seen for domain-specific impairment overall.

Table: This table summarizes recent human studies linking cadmium exposure to kidney, renal biomarker, and cognitive outcomes, emphasizing 2023–2024 evidence. It is useful for quickly comparing exposure metrics, sample sizes, and quantitative effect estimates relevant to cadmium poisoning and chronic cadmium toxicity.

Visual Evidence (Tables)

The following extracted tables provide visual documentation of participant characteristics and measured blood/urine cadmium levels by region in a vulnerable-area cohort study.

Participant characteristics and biomarker tables (cadmium levels; renal indicators) from Kwon et al. (Scientific Reports, 2023). (kwon2023associationbetweenlevels media 0a68bf68, kwon2023associationbetweenlevels media a1f51e53)

Notes on Evidence Quality and Gaps

Many quantitative human findings come from cross-sectional analyses (NHANES), which support association but not definitive causality. (ye2023nationalanalysisof pages 1-2, shi2024associationsofmixed pages 1-2)
Prospective evidence exists for some outcomes (e.g., cognition in REGARDS), but findings can be subgroup-dependent and require replication. (lu2024associationofurinary pages 1-2)
Standard ontology identifiers (MONDO/MeSH/ICD) were not retrievable from tool evidence in this run and should be added from dedicated ontology resources in a subsequent curation step. (artifact-00)

References

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(nordberg2025metallothioneinandother pages 12-14): Gunnar F. Nordberg and Monica Nordberg. Metallothionein and other factors influencing cadmium-induced kidney dysfunction: review and commentary. Biomolecules, 15:1083, Jul 2025. URL: https://doi.org/10.3390/biom15081083, doi:10.3390/biom15081083. This article has 8 citations.
(chakif2026heavymetaltoxicity pages 14-16): Dib Chakif and Julien Furrer. Heavy metal toxicity in clinical and environmental health: sources, mechanisms, diagnostics, and evidence-based management of mercury, lead, cadmium, and arsenic. International Journal of Molecular Sciences, 27:3513, Apr 2026. URL: https://doi.org/10.3390/ijms27083513, doi:10.3390/ijms27083513. This article has 0 citations.
(nordberg2025metallothioneinandother pages 11-12): Gunnar F. Nordberg and Monica Nordberg. Metallothionein and other factors influencing cadmium-induced kidney dysfunction: review and commentary. Biomolecules, 15:1083, Jul 2025. URL: https://doi.org/10.3390/biom15081083, doi:10.3390/biom15081083. This article has 8 citations.
(kwon2023associationbetweenlevels pages 9-10): Jung-Yeon Kwon, Seungho Lee, Ulziikhishig Surenbaatar, Hyoun-Ju Lim, Byoung-Gwon Kim, Sang-Yong Eom, Yong Min Cho, Woo Jin Kim, Byeng-Chul Yu, Kwan Lee, and Young-Seoub Hong. Association between levels of exposure to heavy metals and renal function indicators of residents in environmentally vulnerable areas. Scientific Reports, Feb 2023. URL: https://doi.org/10.1038/s41598-022-27292-7, doi:10.1038/s41598-022-27292-7. This article has 40 citations and is from a peer-reviewed journal.
(chakif2026heavymetaltoxicity pages 16-17): Dib Chakif and Julien Furrer. Heavy metal toxicity in clinical and environmental health: sources, mechanisms, diagnostics, and evidence-based management of mercury, lead, cadmium, and arsenic. International Journal of Molecular Sciences, 27:3513, Apr 2026. URL: https://doi.org/10.3390/ijms27083513, doi:10.3390/ijms27083513. This article has 0 citations.
(chakif2026heavymetaltoxicity pages 8-9): Dib Chakif and Julien Furrer. Heavy metal toxicity in clinical and environmental health: sources, mechanisms, diagnostics, and evidence-based management of mercury, lead, cadmium, and arsenic. International Journal of Molecular Sciences, 27:3513, Apr 2026. URL: https://doi.org/10.3390/ijms27083513, doi:10.3390/ijms27083513. This article has 0 citations.
(satarug2025hypertensioninpeople pages 16-17): Soisungwan Satarug. Hypertension in people exposed to environmental cadmium: roles for 20-hydroxyeicosatetraenoic acid in the kidney. Journal of Xenobiotics, Aug 2025. URL: https://doi.org/10.3390/jox15040122, doi:10.3390/jox15040122. This article has 2 citations.
(satarug2026aretheguidelines pages 3-5): Soisungwan Satarug. Are the guidelines for dietary and workplace exposure to cadmium adequate? Unknown journal, Apr 2026. URL: https://doi.org/10.20944/preprints202604.0484.v1, doi:10.20944/preprints202604.0484.v1.
(lu2024associationofurinary pages 1-2): Liping Lu, Yijia Zhang, Meghan Angley, Shai Bejerano, John D. Brockman, Leslie A. McClure, Frederick W. Unverzagt, Alyce D. Fly, and Ka Kahe. Association of urinary cadmium concentration with cognitive impairment in us adults. Neurology, Oct 2024. URL: https://doi.org/10.1212/wnl.0000000000209808, doi:10.1212/wnl.0000000000209808. This article has 10 citations and is from a highest quality peer-reviewed journal.
(satarug2025hypertensioninpeople pages 10-12): Soisungwan Satarug. Hypertension in people exposed to environmental cadmium: roles for 20-hydroxyeicosatetraenoic acid in the kidney. Journal of Xenobiotics, Aug 2025. URL: https://doi.org/10.3390/jox15040122, doi:10.3390/jox15040122. This article has 2 citations.
(satarug2026aretheguidelines pages 16-18): Soisungwan Satarug. Are the guidelines for dietary and workplace exposure to cadmium adequate? Unknown journal, Apr 2026. URL: https://doi.org/10.20944/preprints202604.0484.v1, doi:10.20944/preprints202604.0484.v1.
(ye2023nationalanalysisof pages 4-5): Zhenyang Ye, Zaizhi Chen, Jin-Ying Luo, Lijing Xu, Dongping Fan, and Jia Wang. National analysis of urinary cadmium concentration and kidney stone: evidence from nhanes (2011–2020). Frontiers in Public Health, Mar 2023. URL: https://doi.org/10.3389/fpubh.2023.1146263, doi:10.3389/fpubh.2023.1146263. This article has 8 citations.
(shi2024associationsofmixed pages 4-5): Xiaoru Shi, Xiao Wang, Jia Zhang, Ying Dang, Changping Ouyang, Jinhua Pan, Aimin Yang, and Xiaobin Hu. Associations of mixed metal exposure with chronic kidney disease from nhanes 2011–2018. Scientific Reports, Jun 2024. URL: https://doi.org/10.1038/s41598-024-63858-3, doi:10.1038/s41598-024-63858-3. This article has 29 citations and is from a peer-reviewed journal.
(kwon2023associationbetweenlevels pages 1-2): Jung-Yeon Kwon, Seungho Lee, Ulziikhishig Surenbaatar, Hyoun-Ju Lim, Byoung-Gwon Kim, Sang-Yong Eom, Yong Min Cho, Woo Jin Kim, Byeng-Chul Yu, Kwan Lee, and Young-Seoub Hong. Association between levels of exposure to heavy metals and renal function indicators of residents in environmentally vulnerable areas. Scientific Reports, Feb 2023. URL: https://doi.org/10.1038/s41598-022-27292-7, doi:10.1038/s41598-022-27292-7. This article has 40 citations and is from a peer-reviewed journal.
(satarug2025hypertensioninpeople pages 14-16): Soisungwan Satarug. Hypertension in people exposed to environmental cadmium: roles for 20-hydroxyeicosatetraenoic acid in the kidney. Journal of Xenobiotics, Aug 2025. URL: https://doi.org/10.3390/jox15040122, doi:10.3390/jox15040122. This article has 2 citations.
(satarug2024urinarynacetylglucosaminidasein pages 12-13): Soisungwan Satarug. Urinary n-acetylglucosaminidase in people environmentally exposed to cadmium is minimally related to cadmium-induced nephron destruction. Toxics, 12:775, Oct 2024. URL: https://doi.org/10.3390/toxics12110775, doi:10.3390/toxics12110775. This article has 7 citations.
(howard2023combatingleadand pages 6-8): Jordyn Ann Howard, Halyna Kuznietsova, Natalia Dziubenko, Axel Aigle, Marco Natuzzi, Eloise Thomas, Vladimir Lysenko, Laurent David, Thomas Brichart, François Lux, and Olivier Tillement. Combating lead and cadmium exposure with an orally administered chitosan-based chelating polymer. Scientific Reports, Feb 2023. URL: https://doi.org/10.1038/s41598-023-28968-4, doi:10.1038/s41598-023-28968-4. This article has 23 citations and is from a peer-reviewed journal.
(nordberg2025metallothioneinandother pages 17-18): Gunnar F. Nordberg and Monica Nordberg. Metallothionein and other factors influencing cadmium-induced kidney dysfunction: review and commentary. Biomolecules, 15:1083, Jul 2025. URL: https://doi.org/10.3390/biom15081083, doi:10.3390/biom15081083. This article has 8 citations.
(howard2023combatingleadand pages 5-6): Jordyn Ann Howard, Halyna Kuznietsova, Natalia Dziubenko, Axel Aigle, Marco Natuzzi, Eloise Thomas, Vladimir Lysenko, Laurent David, Thomas Brichart, François Lux, and Olivier Tillement. Combating lead and cadmium exposure with an orally administered chitosan-based chelating polymer. Scientific Reports, Feb 2023. URL: https://doi.org/10.1038/s41598-023-28968-4, doi:10.1038/s41598-023-28968-4. This article has 23 citations and is from a peer-reviewed journal.
(ye2023nationalanalysisof pages 1-2): Zhenyang Ye, Zaizhi Chen, Jin-Ying Luo, Lijing Xu, Dongping Fan, and Jia Wang. National analysis of urinary cadmium concentration and kidney stone: evidence from nhanes (2011–2020). Frontiers in Public Health, Mar 2023. URL: https://doi.org/10.3389/fpubh.2023.1146263, doi:10.3389/fpubh.2023.1146263. This article has 8 citations.
(lu2024associationofurinary pages 4-5): Liping Lu, Yijia Zhang, Meghan Angley, Shai Bejerano, John D. Brockman, Leslie A. McClure, Frederick W. Unverzagt, Alyce D. Fly, and Ka Kahe. Association of urinary cadmium concentration with cognitive impairment in us adults. Neurology, Oct 2024. URL: https://doi.org/10.1212/wnl.0000000000209808, doi:10.1212/wnl.0000000000209808. This article has 10 citations and is from a highest quality peer-reviewed journal.
(lu2024associationofurinary pages 8-9): Liping Lu, Yijia Zhang, Meghan Angley, Shai Bejerano, John D. Brockman, Leslie A. McClure, Frederick W. Unverzagt, Alyce D. Fly, and Ka Kahe. Association of urinary cadmium concentration with cognitive impairment in us adults. Neurology, Oct 2024. URL: https://doi.org/10.1212/wnl.0000000000209808, doi:10.1212/wnl.0000000000209808. This article has 10 citations and is from a highest quality peer-reviewed journal.
(lu2024associationofurinary pages 2-4): Liping Lu, Yijia Zhang, Meghan Angley, Shai Bejerano, John D. Brockman, Leslie A. McClure, Frederick W. Unverzagt, Alyce D. Fly, and Ka Kahe. Association of urinary cadmium concentration with cognitive impairment in us adults. Neurology, Oct 2024. URL: https://doi.org/10.1212/wnl.0000000000209808, doi:10.1212/wnl.0000000000209808. This article has 10 citations and is from a highest quality peer-reviewed journal.
(kwon2023associationbetweenlevels media 0a68bf68): Jung-Yeon Kwon, Seungho Lee, Ulziikhishig Surenbaatar, Hyoun-Ju Lim, Byoung-Gwon Kim, Sang-Yong Eom, Yong Min Cho, Woo Jin Kim, Byeng-Chul Yu, Kwan Lee, and Young-Seoub Hong. Association between levels of exposure to heavy metals and renal function indicators of residents in environmentally vulnerable areas. Scientific Reports, Feb 2023. URL: https://doi.org/10.1038/s41598-022-27292-7, doi:10.1038/s41598-022-27292-7. This article has 40 citations and is from a peer-reviewed journal.
(kwon2023associationbetweenlevels media a1f51e53): Jung-Yeon Kwon, Seungho Lee, Ulziikhishig Surenbaatar, Hyoun-Ju Lim, Byoung-Gwon Kim, Sang-Yong Eom, Yong Min Cho, Woo Jin Kim, Byeng-Chul Yu, Kwan Lee, and Young-Seoub Hong. Association between levels of exposure to heavy metals and renal function indicators of residents in environmentally vulnerable areas. Scientific Reports, Feb 2023. URL: https://doi.org/10.1038/s41598-022-27292-7, doi:10.1038/s41598-022-27292-7. This article has 40 citations and is from a peer-reviewed journal.

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Pathophysiology

Histopathology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Environmental Factors

Biochemical Markers

Diagnosis

Prevalence

Differential Diagnoses

Related Datasets

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Deep Research

Cadmium Poisoning: Comprehensive Disease Characteristics Research Report

1. Disease Information

2. Etiology

Disease Causal Factor

Risk Factors

Protective Factors

Gene-Environment Interactions

3. Phenotypes

A. Acute high-dose exposure phenotypes

B. Chronic low-dose exposure phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

Overview of the causal chain

Molecular pathways

Cellular processes

Protein/enzyme dysfunction

Tissue damage mechanisms

Biochemical abnormalities

Molecular profiling

Suggested ontology terms for pathophysiology nodes

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Summary of Key Ontology Term Suggestions for KB Curation

Sources

Reference Validation

References that may not be about this subject

Disease Characteristics Research Template

Target Disease

Research Objectives

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Citation Requirements

Output Format

Cadmium Poisoning (Cadmium Toxicity): Comprehensive Disease Characteristics Report (Environmental)

1. Disease Information

2. Etiology

2.1 Primary causal factors