Arsenic Poisoning

Environmental Pathograph 25 heavy metal poisoning

Arsenic poisoning (arsenicosis) is a toxic condition caused by acute or chronic exposure to inorganic arsenic, a metalloid found naturally in groundwater and soil and encountered through contaminated drinking water, occupational sources (mining, smelting, pesticide manufacturing), and certain traditional medicines. Acute arsenic ingestion causes severe gastrointestinal hemorrhage, cardiovascular collapse, and multi-organ failure. Chronic exposure produces a characteristic constellation of dermatological changes (hyperpigmentation, keratoses), peripheral neuropathy, hepatotoxicity, and increased cancer risk. Arsenic disrupts cellular function through inhibition of pyruvate dehydrogenase and other sulfhydryl- dependent enzymes, uncoupling oxidative phosphorylation by substituting for phosphate (arsenolysis), and generating reactive oxygen species. Endemic arsenicosis affects tens of millions in Bangladesh, West Bengal, and other regions with naturally high groundwater arsenic. Treatment of acute poisoning relies on chelation therapy with dimercaprol (BAL) or succimer (DMSA), while chronic arsenicosis management focuses on exposure cessation and symptomatic care.

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Subtypes

Acute Arsenic Poisoning

Acute arsenic poisoning from ingestion of large doses of inorganic arsenic, typically from intentional or accidental ingestion. Presents with severe gastroenteritis (rice-water diarrhea, abdominal pain, vomiting), cardiovascular collapse, QTc prolongation, seizures, encephalopathy, and multi-organ failure. The lethal dose of arsenic trioxide is approximately 100-300 mg in adults.

Chronic Arsenic Poisoning (Arsenicosis)

Chronic arsenicosis from prolonged low-level exposure, primarily through contaminated drinking water exceeding the WHO guideline of 10 mcg/L. Endemic in Bangladesh, West Bengal (India), parts of Southeast Asia, and South America. Characterized by progressive dermatological changes (melanosis, keratoses), peripheral neuropathy, hepatic fibrosis, and markedly increased cancer risk. The WHO considers chronic arsenicosis a major global public health concern.

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Pathophysiology

Gastrointestinal Absorption and Transport

Arsenic enters the body primarily through the gastrointestinal tract. Pentavalent arsenic (As(V)) is absorbed via sodium-dependent phosphate transporters (NaPiIIb) in the small intestine through a saturable, carrier-mediated process that is competitively inhibited by phosphate. Trivalent arsenic (As(III)) is absorbed via aquaglyceroporins (AQP3, AQP7, AQP10) and glucose transporters (GLUT2, GLUT5). The gut microbiome modulates arsenic bioavailability: sulfate-reducing bacteria produce thiolated arsenic species that are more toxic and more readily absorbed, and salivary/colonic microorganisms increase small intestinal absorption 1.2-2.7 fold.

transmembrane transport GO:0055085 ⚠ ABNORMAL

small intestine UBERON:0002108

Downstream

Hepatic Methylation and Biotransformation Absorbed arsenic is transported to the liver for methylation and biotransformation.

Inhibition of Sulfhydryl-Dependent Enzymes Trivalent arsenic (As3+) directly binds sulfhydryl groups on cellular enzymes.

Arsenolysis Pentavalent arsenic (As5+) competes with phosphate in enzymatic reactions.

Show evidence (3 references)

PMID:7631493 PARTIAL Model Organism

"Intestinal absorption of As appears carried out by a saturable transport process. The phosphate produces a pronounced decrease in the intestinal absorption of As due to the fact that phosphate and As can share the same transport mechanism which is an active secondary carrier-mediated system..."

Confirms arsenate absorption is via saturable, carrier-mediated phosphate transporters.

PMID:22214486 SUPPORT In Vitro

"Gene silencing of OATPB, AQP10, and GLUT5 for As(III) and NaPiIIb for As(V) significantly reduces uptake of the inorganic forms. These results indicate that these transporters may be involved in intestinal absorption of iAs."

Identifies specific transporters for As(III) and As(V) intestinal absorption.

PMID:24833621 SUPPORT In Vitro

"We found that SRB of human gastrointestinal origin, through their ability to produce H2S, were necessary and sufficient to induce As thiolation."

Confirms role of gut sulfate-reducing bacteria in arsenic thiolation increasing toxicity.

Hepatic Methylation and Biotransformation

Inorganic arsenic undergoes hepatic biotransformation via the Challenger pathway. Arsenic (+3 oxidation state) methyltransferase (AS3MT) catalyzes sequential methylation using S-adenosylmethionine (SAM) as the methyl donor, producing monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA). Glutathione-S-transferase omega (hGST-O) functions as MMA(V) reductase. While historically considered a detoxification pathway, the intermediate trivalent methylated species (MMA(III)) is more toxic than inorganic arsenic. Individual variation in AS3MT activity and polymorphisms influences susceptibility. Urinary arsenic speciation (typically 10-30% iAs, 10-20% MMA, 60-80% DMA) reflects methylation efficiency and disease risk.

hepatocyte CL:0000182

arsenic methylation GO:0071722 ↑ INCREASED

liver UBERON:0002107

Downstream

Oxidative Stress and ROS Generation The intermediate trivalent methylated species MMA(III) generates reactive oxygen species.

SAM Depletion Arsenic methylation consumes S-adenosylmethionine, depleting the cellular methyl donor pool.

Show evidence (2 references)

PMID:11484904 SUPPORT Human Clinical

"In humans, as in most mammalian species, inorganic arsenic is methylated to methylarsonic acid (MMA) and dimethylarsinic acid (DMA) by alternating reduction of pentavalent arsenic to trivalent and addition of a methyl group from S-adenosylmethionine."

Describes the sequential methylation pathway for arsenic biotransformation in humans.

PMID:12505313 SUPPORT Human Clinical

"Glutathione, and possibly other thiols, serve as reducing agents. The liver is the most important site of arsenic methylation, but most organs show arsenic methylating activity."

Confirms liver as primary site of arsenic methylation with glutathione as reducing agent.

Inhibition of Sulfhydryl-Dependent Enzymes

Trivalent arsenic (arsenite, As3+) binds to sulfhydryl groups in proteins, inhibiting key enzymes in intermediary metabolism. The pyruvate dehydrogenase complex is a primary target, where arsenic binds to the dihydrolipoamide cofactor of the E2 subunit, blocking the conversion of pyruvate to acetyl-CoA. This impairs aerobic energy production and leads to metabolic acidosis. Arsenic also inhibits other sulfhydryl-dependent enzymes involved in cellular energy metabolism and biosynthetic pathways.

pyruvate metabolic process GO:0006090 ↓ DECREASED

Downstream

Mitochondrial Dysfunction PDH complex inhibition blocks acetyl-CoA entry into the TCA cycle, impairing mitochondrial energy production.

Show evidence (1 reference)

PMID:9806419 SUPPORT In Vitro

"Only pyruvate dehydrogenase, one of eight purified enzymes examined so far, is inhibited by micromolar arsenic."

Demonstrates enzyme-specific inhibition by arsenic, confirming pyruvate dehydrogenase as a primary target.

Arsenolysis

Pentavalent arsenic (arsenate, As5+) is a structural analog of phosphate and competes with phosphate in enzymatic reactions. Arsenate substitutes for phosphate in glycolysis, forming an unstable arsenate ester that spontaneously hydrolyzes, uncoupling substrate-level phosphorylation without generating ATP. This process, termed arsenolysis, disrupts cellular energy metabolism and contributes to multi-organ dysfunction.

glycolytic process GO:0006096 ⚠ ABNORMAL

Downstream

Mitochondrial Dysfunction Uncoupling of substrate-level phosphorylation impairs cellular ATP generation.

Show evidence (1 reference)

PMID:20078116 NO_EVIDENCE In Vitro

"As(V) absorption was inhibited by 10 mM phosphate, and a phosphate transporter therefore could take part in intestinal absorption."

Confirms competitive relationship between arsenate and phosphate, consistent with structural analogy.

Oxidative Stress and ROS Generation

Arsenic metabolism generates reactive oxygen species (ROS) through multiple mechanisms including mitochondrial electron transport chain disruption, NADPH oxidase (Nox2) activation in endothelial cells, and nitric oxide synthase stimulation producing reactive nitrogen species. Arsenic depletes antioxidant enzymes (catalase, SOD, glutathione peroxidase, glutathione reductase) and glutathione (GSH). Consequences include lipid peroxidation (MDA formation), protein carbonylation, and DNA oxidative damage (8-OHdG). Peroxynitrite formation from superoxide and NO causes protein nitration.

response to oxidative stress GO:0006979 ↑ INCREASED

Downstream

DNA Repair Inhibition via Zinc Finger Protein Disruption ROS/RNS modify zinc finger proteins, compounding direct arsenite binding effects on DNA repair.

Peripheral Nerve Axonopathy Lipid peroxidation in sciatic and sural nerves drives axonal degeneration.

Hepatocellular Oxidative Injury Hepatic glutathione depletion and NADPH oxidase activation cause progressive liver damage.

Cardiovascular Endothelial Dysfunction Endothelial Nox2 activation and NO scavenging impair vascular function.

Renal Tubular Injury ROS production and glutathione depletion damage proximal tubular cells.

Cutaneous Arsenical Toxicity Oxidative stress in arsenic-laden keratin-rich epidermis and nail matrix perturbs keratinocyte and melanocyte homeostasis.

Show evidence (2 references)

PMID:21554949 SUPPORT Human Clinical

"Arsenic alters cellular glutathione levels either by utilizing this electron donor for the conversion of pentavalent to trivalent arsenicals or directly binding with it or by oxidizing glutathione via arsenic-induced free radical generation."

Comprehensive review confirming arsenic-induced oxidative stress through glutathione depletion and free radical generation.

PMID:25788710 SUPPORT In Vitro

"The most sensitive target of arsenic toxicity in the vasculature is the endothelium, and incubation of these cells with low concentrations of arsenite, a naturally occurring and highly toxic inorganic form of arsenic, rapidly induces reactive oxygen species (ROS) formation via activation of a..."

Identifies endothelial Nox2 activation as a specific mechanism of arsenic-induced ROS generation.

Mitochondrial Dysfunction

Arsenic causes decreased activity of mitochondrial electron transport chain complexes I, II, and IV, reduced mitochondrial membrane potential, impaired ATP synthesis, mitochondrial swelling, and cytochrome c release initiating apoptosis. Arsenic induces mtDNA damage (including a characteristic 3867 bp deletion) and downregulates mitochondrial biogenesis regulators (PGC-1alpha, NRF-1, NRF-2, Tfam). These effects are central to arsenic toxicity in multiple organ systems.

mitochondrion organization GO:0007005 ⚠ ABNORMAL

Downstream

Oxidative Stress and ROS Generation Impaired electron transport chain generates superoxide radicals (positive feedback loop).

Hepatocellular Oxidative Injury Mitochondrial dysfunction in hepatocytes triggers apoptotic cascades.

Renal Tubular Injury Mitochondrial dysfunction in proximal tubular cells activates SIRT1/PINK1 mitophagy axis disruption.

Show evidence (1 reference)

PMID:25764338 SUPPORT Model Organism

"Chronic sodium arsenite treatment (25 ppm for 12 weeks) resulted in decreased activity of mitochondrial complexes I, II, and IV followed by increased ROS generation."

Demonstrates arsenic-induced mitochondrial complex inhibition and consequent ROS generation in rat brain.

DNA Repair Inhibition via Zinc Finger Protein Disruption

Arsenite binds to zinc finger domains in key DNA repair proteins, displacing zinc ions and altering protein conformation. PARP-1 (poly(ADP-ribose) polymerase-1) is inhibited by arsenite binding to its zinc finger domain, abolishing DNA-binding ability and enzymatic activity. XPC (xeroderma pigmentosum complementation group C), a key nucleotide excision repair protein, undergoes transcriptional inhibition and proteasomal degradation. Arsenic disrupts base excision repair (BER), nucleotide excision repair (NER), double-strand break repair, and interstrand crosslink (ICL) repair. This comprehensive DNA repair inhibition, rather than direct mutagenesis, is a major mechanism of arsenic carcinogenesis.

DNA repair GO:0006281 ↓ DECREASED

Downstream

Arsenic-Induced Carcinogenesis Impaired DNA repair allows accumulation of mutations and genomic instability.

Show evidence (2 references)

PMID:24275069 SUPPORT In Vitro

"Poly(ADP-ribose) polymerase-1 (PARP-1), a zinc finger DNA repair protein, has been identified as a sensitive molecular target for arsenic. The zinc finger domains of PARP-1 protein function as a critical structure in DNA recognition and binding."

Demonstrates arsenite binding to PARP-1 zinc finger domains leading to zinc loss and DNA repair inhibition.

PMID:31986875 SUPPORT Other

"Results from recent studies suggest zinc finger proteins as crucial molecular targets for direct binding to As3+ or for modifications by arsenic-induced ROS/RNS, which may constitute a common mechanism underlying arsenic-induced perturbations of DNA repair."

Review confirming zinc finger proteins as central targets in arsenic-induced DNA repair disruption.

SAM Depletion

Arsenic methylation via the Challenger pathway consumes S-adenosylmethionine (SAM), depleting the cellular methyl donor pool. SAM is the universal methyl donor for DNA, histone, and protein methylation reactions. Chronic arsenic exposure progressively depletes SAM, reducing the availability of methyl groups for normal epigenetic maintenance. The depletion of SAM also reduces N6-methyladenine (6mA) levels through ALKBH4 demethylase upregulation.

S-adenosylmethionine metabolic process GO:0046500 ⚠ ABNORMAL

Downstream

Global DNA Hypomethylation Reduced SAM availability causes genome-wide loss of DNA methylation marks.

Tumor Suppressor Gene Silencing SAM depletion paradoxically redistributes methylation to tumor suppressor promoters.

Show evidence (1 reference)

PMID:20514360 NO_EVIDENCE Human Clinical

"Changes in gene methylation status, mediated by arsenic, have been proposed to activate oncogene expression or silence tumor suppressor genes, leading to long-term changes in the activity of genes controlling cell transformation."

Reviews arsenic-mediated DNA methylation changes driven by SAM depletion.

Global DNA Hypomethylation

SAM depletion from arsenic methylation causes genome-wide loss of DNA methylation, leading to genomic instability through reactivation of transposable elements, activation of normally silenced repetitive sequences, and aberrant oncogene expression. Global hypomethylation is an early and consistent epigenetic alteration in arsenic-exposed populations and tissues.

epigenetic regulation of gene expression GO:0040029 ↕ DYSREGULATED

Downstream

Arsenic-Induced Carcinogenesis Genomic instability from global hypomethylation promotes oncogenic transformation.

Show evidence (1 reference)

PMID:20514360 PARTIAL Human Clinical

Describes global methylation changes leading to oncogene activation.

Tumor Suppressor Gene Silencing

Despite global DNA hypomethylation, arsenic causes paradoxical hypermethylation of tumor suppressor gene promoters, silencing their expression. Histone modifications compound this effect: increased repressive marks (H3K9me2) via G9a methyltransferase upregulation and decreased activating marks (H3K4me3) reinforce transcriptional silencing. Arsenic also disrupts CTCF binding and 3D genome architecture, causing oncogenic rewiring of enhancer-promoter interactions.

negative regulation of gene expression, epigenetic GO:0045814 ↑ INCREASED

Downstream

Arsenic-Induced Carcinogenesis Loss of tumor suppressor function permits uncontrolled cell proliferation.

Show evidence (1 reference)

PMID:20514360 PARTIAL Human Clinical

Describes arsenic-mediated silencing of tumor suppressor genes through methylation changes.

Arsenic-Induced Carcinogenesis

Arsenic carcinogenesis results from the convergence of multiple pathways: DNA repair inhibition (preventing correction of mutations), epigenetic dysregulation (activating oncogenes and silencing tumor suppressors), and chronic oxidative stress (causing DNA damage). Unlike most carcinogens, arsenic is not a direct mutagen; rather, it acts as a co-carcinogen through these indirect mechanisms. Epidemiological evidence establishes arsenic as a cause of cancers of the skin, lung, liver, bladder, and prostate.

epigenetic regulation of gene expression GO:0040029 ↕ DYSREGULATED

Show evidence (2 references)

PMID:36858772 SUPPORT Human Clinical

"Epidemiological evidence shows arsenic induces cancers of the skin, lung, liver, and bladder among other tissues."

Confirms epidemiological evidence for arsenic-induced carcinogenesis across multiple tissue types.

PMID:30223072 SUPPORT Human Clinical

"Epidemiological studies have established a strong association between inorganic arsenic (iAs) exposure in drinking water and an increased incidence of cancer including bladder, liver, lung, prostate, and skin cancer."

Review confirming strong epidemiological association between arsenic exposure and multiple cancer types.

Peripheral Nerve Axonopathy

Arsenic causes a distal symmetric sensorimotor polyneuropathy through axonal degeneration, particularly of small myelinated and unmyelinated fibers. Mechanisms include oxidative stress with lipid peroxidation (most pronounced in sciatic and sural nerves), mitochondrial instability, thiamine deficiency, decreased acetylcholinesterase activity, and cytoskeletal disruption with reduced neurofilament proteins. Recovery is slow and often incomplete, with abnormal neurological signs persisting years after exposure.

Schwann cell CL:0002573

neuron projection development GO:0031175 ⚠ ABNORMAL

peripheral nerve UBERON:0001021

Downstream

Peripheral Neuropathy Distal axonal degeneration of sensory-predominant peripheral fibers produces a distal symmetric sensorimotor polyneuropathy.

Show evidence (2 references)

PMID:31336801 SUPPORT Human Clinical

"Several mechanisms that seem to play key roles in As-induced neurotoxicity, including oxidative stress, apoptosis, thiamine deficiency, and decreased acetyl cholinesterase activity, are described. The observed neurotoxicity predominantly affects peripheral nerves in sensory fibers, with a lesser..."

Review of arsenic neurotoxicity mechanisms confirming sensory-predominant peripheral neuropathy.

PMID:196051 SUPPORT Human Clinical

"Four patients are described who developed a peripheral neuropathy 10 days to 3 weeks after ingestion of a single dose of arsenic. All improved slowly, but after 6 to 8 years 3 of them still had abnormal neurological symptoms and signs."

Clinical evidence of arsenic neuropathy onset timing and slow, incomplete recovery.

Hepatocellular Oxidative Injury

Chronic arsenic exposure causes progressive hepatocellular injury through NADPH oxidase-mediated oxidative stress and glutathione depletion. The progression follows distinct phases: initial oxidative stress with glutathione depletion (6 months), followed by hepatic steatosis with elevated aminotransferases (12 months). Molecular mechanisms include PPARalpha-dependent autophagy and HIF-1alpha/VEGF signaling. High-fat diet significantly amplifies arsenic-induced liver injury through synergistic upregulation of pro-inflammatory and pro-fibrotic genes.

hepatocyte CL:0000182

hepatocyte apoptotic process GO:0097284 ↑ INCREASED

liver UBERON:0002107

Downstream

Hepatic Stellate Cell Activation Sustained hepatocellular injury activates hepatic stellate cells via TGF-beta1 and microRNA-21 crosstalk.

Hepatomegaly Hepatocellular injury with steatosis and elevated transaminases enlarges the liver, producing hepatomegaly.

Show evidence (1 reference)

PMID:21134390 SUPPORT Model Organism

"Hepatic NADPH oxidase activity progressively increased in arsenic exposure with concomitant development of hepatic oxidative stress."

Mouse model demonstrating progressive NADPH oxidase-mediated oxidative stress in arsenic hepatotoxicity.

Hepatic Stellate Cell Activation

Chronic hepatocellular injury activates hepatic stellate cells via TGF-beta1 upregulation and microRNA-21-mediated hepatocyte-stellate cell crosstalk. Activated stellate cells transdifferentiate into myofibroblast-like cells, initiating fibrogenic signaling cascades that drive extracellular matrix remodeling.

hepatic stellate cell CL:0000632

hepatic stellate cell activation GO:0035733 ↑ INCREASED

liver UBERON:0002107

Downstream

Hepatic Fibrosis Activated stellate cells synthesize excess collagen and extracellular matrix, driving progressive fibrosis.

Show evidence (1 reference)

PMID:10641134 SUPPORT Model Organism

"A significant increase in the hepatic protein and collagen was seen compared with controls; hepatic 4-hydroxyproline levels, indicative of fibrogenesis, were increased 4-14 folds with different dosages of arsenic compared to the controls."

Stellate cell activation is evidenced by downstream collagen deposition and fibrogenesis in murine arsenic exposure model.

Hepatic Fibrosis

Activated hepatic stellate cells synthesize excess collagen and extracellular matrix proteins, leading to progressive hepatic fibrosis. Hepatic 4-hydroxyproline levels increase 4-14 fold with chronic arsenic exposure (15+ months), indicating dose-dependent fibrogenesis.

collagen biosynthetic process GO:0032964 ↑ INCREASED

liver UBERON:0002107

Show evidence (1 reference)

PMID:10641134 SUPPORT Model Organism

Murine model confirming dose-dependent hepatic fibrogenesis with chronic arsenic ingestion.

Cardiovascular Endothelial Dysfunction

Arsenic causes endothelial dysfunction through impaired nitric oxide balance (eNOS inactivation, superoxide scavenging of NO), NADPH oxidase (Nox2) activation generating superoxide, COX-2 upregulation, and protein nitration. Vascular consequences include accelerated atherosclerosis, hypertension, endothelial apoptosis, increased platelet aggregation, and reduced fibrinolysis. Cardiac effects include QT interval prolongation, ventricular arrhythmias, and toxic cardiomyopathy. Blackfoot disease, an endemic peripheral vascular disease in southwestern Taiwan, is associated with chronic arsenic exposure from artesian well water.

endothelial cell CL:0000115

nitric oxide mediated signal transduction GO:0007263 ↓ DECREASED

blood vessel UBERON:0001981

Downstream

Hypertension Impaired endothelial nitric oxide balance and vascular remodeling raise systemic vascular resistance, producing hypertension.

QTc Prolongation Arsenic cardiotoxicity prolongs ventricular repolarization, producing QTc prolongation and a risk of torsades de pointes.

Show evidence (2 references)

PMID:19015167 SUPPORT Human Clinical

"Epidemiological studies have shown that chronic arsenic exposure is associated with increased morbidity and mortality from cardiovascular disease."

Establishes epidemiological link between arsenic exposure and cardiovascular disease.

PMID:25788710 SUPPORT In Vitro

Demonstrates endothelial Nox2 activation as the primary mechanism of arsenic-induced vascular ROS.

Renal Tubular Injury

Arsenic causes nephrotoxicity primarily targeting proximal tubular cells through mitochondrial dysfunction, NF-kappaB and p38 MAPK activation, ROS production, and glutathione depletion. Dysregulated autophagy (early induction followed by impaired autophagic flux, especially in females via estrogen-mediated mechanisms) contributes to cell death. The SIRT1/PINK1/mitophagy axis is disrupted. Chronic exposure leads to tubular dilation, basement membrane disruption, collagen deposition, decreased eGFR, and progressive chronic kidney disease.

epithelial cell of proximal tubule CL:0002306

proximal tubule UBERON:0004134

Show evidence (1 reference)

PMID:25703706 SUPPORT Human Clinical

"Arsenic is one of the most abundant contaminants in water and soil, and many epidemiological studies have found an association between arsenic and type 2 diabetes mellitus, hypertension and cancer; however, there is a scarcity of epidemiological studies about its association with kidney disease,..."

Reviews evidence for arsenic-mediated nephrotoxicity and its association with CKD markers.

Cutaneous Arsenical Toxicity

Arsenic deposits in keratin-rich epidermis and the nail matrix, where arsenite binds keratin sulfhydryl groups and drives local oxidative stress, perturbing keratinocyte proliferation and differentiation and melanocyte pigmentation. These direct cutaneous toxic effects—distinct from frank malignant transformation—produce the pathognomonic non-malignant skin and nail signs of chronic arsenicosis (arsenical melanosis and palmoplantar keratoses) and the transient nail-matrix disruption seen as Mees lines.

keratinocyte CL:0000312

keratinocyte differentiation GO:0030216 ⚠ ABNORMAL

skin epidermis UBERON:0001003

Downstream

Hyperpigmentation (Arsenical Melanosis) Arsenic-induced melanocyte dysregulation produces diffuse and raindrop-pattern hyperpigmentation.

Palmoplantar Keratoses Arsenic-driven keratinocyte hyperproliferation and altered differentiation produce punctate/nodular palmoplantar keratoses.

Mees Lines Transient arsenic disruption of nail-matrix keratinization produces transverse white bands (Mees lines).

Show evidence (1 reference)

PMID:11218669 SUPPORT Human Clinical

"Chronic arsenic toxicity (CAT) manifests predominantly as cutaneous lesions in the form of melanosis, keratosis and neoplastic changes."

Histopathological study confirming melanosis and keratosis as the predominant non-malignant cutaneous manifestations of chronic arsenic toxicity.

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Pathograph

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Phenotypes

Blood 2

Gastrointestinal Hemorrhage VERY_FREQUENT Gastrointestinal hemorrhage HP:0002239

Show evidence (1 reference)

PMID:11869818 SUPPORT Human Clinical

"Skin pigmentation changes, palmar and plantar hyperkeratoses, gastrointestinal symptoms, anemia, and liver disease are common."

Review documenting gastrointestinal symptoms as common manifestations of arsenic poisoning.

Anemia FREQUENT Anemia HP:0001903

Show evidence (1 reference)

PMID:435641 SUPPORT Human Clinical

"A patient with severe arsenic poisoning that resulted in marked peripheral blood and bone marrow abnormalities, including megaloblastic erythropoiesis experienced many of the previously reported hematologic complications of arsenic poisoning: leukopenia, granulocytopenia, absolute eosinophilia,..."

Case report documenting the full spectrum of arsenic-induced hematologic abnormalities.

Cardiovascular 2

QTc Prolongation FREQUENT Prolonged QTc interval HP:0005184

Show evidence (1 reference)

PMID:19015167 SUPPORT Human Clinical

"Epidemiological studies have shown that chronic arsenic exposure is associated with increased morbidity and mortality from cardiovascular disease."

Epidemiological evidence linking arsenic to cardiovascular morbidity including cardiac effects.

Hypertension FREQUENT Hypertension HP:0000822

Show evidence (1 reference)

PMID:19015167 SUPPORT Human Clinical

"Epidemiological studies have shown that chronic arsenic exposure is associated with increased morbidity and mortality from cardiovascular disease."

Epidemiological evidence confirming cardiovascular disease association including hypertension.

Digestive 1

Hepatomegaly FREQUENT Hepatomegaly HP:0002240

Show evidence (1 reference)

PMID:11869818 SUPPORT Human Clinical

"Skin pigmentation changes, palmar and plantar hyperkeratoses, gastrointestinal symptoms, anemia, and liver disease are common. Noncirrhotic portal hypertension with bleeding esophageal varices, splenomegaly, and hypersplenism may occur."

Confirms liver disease and noncirrhotic portal hypertension as common features of chronic arsenic poisoning.

Endocrine 1

Diabetes Mellitus OCCASIONAL Diabetes mellitus HP:0000819

Show evidence (1 reference)

PMID:21914528 SUPPORT Human Clinical

"Many studies have indicated a dose-response relationship between accumulative arsenic exposure and the prevalence of diabetes mellitus (DM) in arseniasis-endemic areas in Taiwan and Bangladesh, where arsenic exposure occurs through drinking water."

Review confirming dose-response relationship between arsenic exposure and diabetes in endemic areas.

Integument 3

Hyperpigmentation (Arsenical Melanosis) VERY_FREQUENT Hyperpigmentation of the skin HP:0000953

Arsenical melanosis is considered pathognomonic for chronic arsenic exposure.

Show evidence (2 references)

PMID:11218669 SUPPORT Human Clinical

"Chronic arsenic toxicity (CAT) manifests predominantly as cutaneous lesions in the form of melanosis, keratosis and neoplastic changes."

Histopathological study confirming melanosis as a predominant cutaneous manifestation of chronic arsenic toxicity.

PMID:11869818 SUPPORT Human Clinical

"Skin pigmentation changes, palmar and plantar hyperkeratoses, gastrointestinal symptoms, anemia, and liver disease are common."

Review confirming skin pigmentation changes as common features of chronic arsenic poisoning.

Palmoplantar Keratoses VERY_FREQUENT Palmoplantar keratoderma HP:0000982

Show evidence (1 reference)

PMID:32809405 SUPPORT Human Clinical

"Arsenical keratosis is a precancerous dermatosis observed in patients with chronic arsenic toxicity. This condition is characterized by corn-like, yellowish, hyperkeratotic papules and plaques, primarily affecting the palms and soles."

Clinical description confirming arsenical keratosis as precancerous palmoplantar lesions.

Mees Lines FREQUENT Leukonychia HP:0001820

Nervous System 2

Peripheral Neuropathy FREQUENT Peripheral neuropathy HP:0009830

Show evidence (2 references)

PMID:196051 SUPPORT Human Clinical

Clinical case series documenting neuropathy onset timing and incomplete long-term recovery.

PMID:31336801 SUPPORT Human Clinical

"The observed neurotoxicity predominantly affects peripheral nerves in sensory fibers, with a lesser effect on motor fibers."

Review confirming sensory-predominant peripheral neuropathy pattern in arsenic neurotoxicity.

Encephalopathy OCCASIONAL Encephalopathy HP:0001298

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Genetic Associations

AS3MT Polymorphisms (Associated)

Gene: AS3MT hgnc:17452

Show evidence (1 reference)

PMID:11484904 SUPPORT Human Clinical

Describes the methylation pathway that AS3MT polymorphisms modulate.

GSTT1/GSTM1 Polymorphisms (Associated)

Gene: GSTM1 hgnc:4632

Show evidence (2 references)

PMID:16353154 PARTIAL Human Clinical

"Individuals with GSTM1-positive (at least one allele) had significantly higher risk of arsenic-induced skin lesions (odds ratio, 1.73; 95% confidence interval, 1.24-2.22). These results show a protective role of GSTM1 null in arsenic toxicity."

Study in 422 arsenic-exposed West Bengal subjects found GSTM1-positive genotype (not null) associated with higher skin lesion risk, suggesting GST-mediated conjugation may generate reactive arsenic species.

PMID:17284320 PARTIAL Human Clinical

"GSTT1 homozygous wildtype status was associated with increased odds of skin lesions compared to the null status (OR1.56 95% CI 1.10-2.19)."

Case-control study of 1200 Bangladeshi subjects found GSTT1 wildtype (not null) associated with increased skin lesion risk.

MPO Polymorphisms (Associated)

Gene: MPO hgnc:7218

Show evidence (1 reference)

PMID:14580687 SUPPORT Human Clinical

"Subjects carrying the high-risk MPO genotype and with high arsenic exposure were at almost six times (OR 5.8; 95% CI 1.1-30.1) elevated risk of developing hyperkeratosis as compared to those carrying the low-risk genotype and with low arsenic exposure."

Case-control study demonstrating MPO genotype-arsenic interaction in hyperkeratosis risk.

CAT Polymorphisms (Associated)

Gene: CAT hgnc:1516

Show evidence (1 reference)

PMID:14580687 SUPPORT Human Clinical

"highly exposed subjects carrying the high-risk CAT genotype were at more than four times (OR 4.6; 95% CI 1.4-15.6) elevated risk of developing hyperkeratosis as compared to those carrying the low-risk genotype and with low arsenic exposure"

Case-control study demonstrating CAT genotype-arsenic interaction in hyperkeratosis risk.

💊

Medical Actions

Chelation Therapy with Dimercaprol (BAL)

Action: chelation therapy Ontology label: chelator agent therapy MAXO:0001223

Dimercaprol (British Anti-Lewisite, BAL) is the first-line chelation agent for acute symptomatic arsenic poisoning. Administered intramuscularly, it forms water-soluble chelates with arsenic that are renally excreted. Most effective when given within hours of acute ingestion. Side effects include hypertension, tachycardia, nausea, and pain at injection site.

Show evidence (1 reference)

PMID:32033229 SUPPORT Human Clinical

"In acute cases, initial treatment with BAL combined with DMPS should be considered."

Review of arsenic therapeutic agents recommending BAL as initial chelation treatment for acute arsenic poisoning.

Chelation Therapy with Succimer (DMSA)

Action: chelation therapy Ontology label: chelator agent therapy MAXO:0001223

Succimer (dimercaptosuccinic acid, DMSA) is an oral chelating agent used for less severe arsenic poisoning and as step-down therapy after initial BAL treatment. Better tolerated than BAL with fewer side effects. Also used in pediatric arsenic exposure due to oral administration route.

Show evidence (1 reference)

PMID:32033229 SUPPORT Human Clinical

"The development of chelating agents, such as the dithiols BAL (dimercaptopropanol), DMPS (dimercapto-propanesulfonate) and DMSA (dimercaptosuccinic acid), took advantage of the fact that As had high affinity towards vicinal dithiols."

Review confirming DMSA as a therapeutic dithiol chelator for arsenic based on arsenic's affinity for vicinal dithiol groups.

Unithiol (DMPS)

Action: chelation therapy Ontology label: chelator agent therapy MAXO:0001223

2,3-dimercapto-1-propanesulfonic acid (DMPS, Unithiol) is an alternative chelating agent available in Europe and some other countries. Can be given orally or intravenously. Some evidence suggests superiority to BAL for arsenic chelation.

Show evidence (1 reference)

PMID:32033229 SUPPORT Human Clinical

"in acute and subacute and even some cases with chronic As poisonings chelation treatment with therapeutic dithiols, in particular DMPS appears promising as regards alleviation of symptoms"

Review identifying DMPS as a particularly promising chelation agent for arsenic poisoning across acute, subacute, and chronic presentations.

Whole Bowel Irrigation

Action: supportive care MAXO:0000950

Whole bowel irrigation with polyethylene glycol solution is recommended for gastrointestinal decontamination after acute arsenic ingestion, as arsenic is poorly adsorbed by activated charcoal. Should be initiated early before arsenic absorption is complete.

Show evidence (1 reference)

PMID:22541879 SUPPORT Human Clinical

"the patient was managed with whole bowel irrigation with a polyethylene glycol solution, maintenance intravenous hydration, and observation on a telemetry unit"

Case report of massive arsenic trisulfide ingestion successfully managed with whole bowel irrigation alone without chelation.

Exposure Cessation and Safe Water

Action: chemical exposure avoidance MAXO:0000071

The most critical intervention for chronic arsenicosis is elimination of arsenic exposure, primarily through provision of arsenic-free drinking water. Water treatment options include oxidation-coagulation-filtration, adsorption (iron-based media), membrane filtration (reverse osmosis), and switching to alternative water sources (deep tubewells, rainwater harvesting).

Show evidence (1 reference)

PMID:12378292 SUPPORT Human Clinical

"Well-switching should be more systematically encouraged in Araihazar and many other parts of Bangladesh and West Bengal, India."

Field study demonstrating well-switching as a viable arsenic mitigation strategy, with 90% of inhabitants living within 100m of a safe well.

🌍

Environmental Factors

Contaminated Groundwater

Natural geological contamination of groundwater with inorganic arsenic is the primary source of chronic arsenic exposure worldwide. The WHO guideline value is 10 mcg/L but many countries use 50 mcg/L as the permissible limit. Approximately 140 million people in 50 countries drink water with arsenic exceeding WHO guidelines. Major affected regions include the Bengal Delta (Bangladesh and West Bengal), the Mekong Delta, northern China, and the Chaco-Pampean plain of Argentina.

Show evidence (1 reference)

PMID:28005215 SUPPORT Human Clinical

"It is proven fact that uptake of inorganic As for a long period can lead to chronic As poisoning and a variety of adverse health effects such as skin, lung and bladder cancer, in addition to cardiovascular diseases, diabetes and gastrointestinal symptoms."

Review of arsenic exposure pathways confirming health effects of chronic exposure through contaminated sources.

Occupational Arsenic Exposure

Occupational exposure occurs in mining and smelting of arsenopyrite-bearing ores, copper smelting, pesticide manufacturing, wood preservation (CCA-treated lumber), semiconductor manufacturing, and glass production. Inhalation of arsenic-containing dusts and fumes is the primary route. Historical occupational exposure contributed to recognition of arsenic as a carcinogen.

Show evidence (1 reference)

PMID:19079717 SUPPORT Human Clinical

"Within categories of arsenic concentration, the association between respiratory cancer and cumulative arsenic exposure was consistent with linearity."

Cohort study of copper smelter workers demonstrating linear dose-response between inhaled inorganic arsenic and respiratory cancer risk.

Dietary Arsenic Exposure

Rice accumulates inorganic arsenic from paddy soils and irrigation water, making it a significant dietary source particularly in populations with high rice consumption. Other dietary sources include seafood (primarily organic arsenobetaine, which is less toxic), poultry (from roxarsone feed additive, now withdrawn in many countries), and certain fruit juices.

Show evidence (1 reference)

PMID:26586021 SUPPORT Human Clinical

"exposure to inorganic arsenic represents a risk to the health of the European population, particularly to young children. Regulatory measures to reduce exposure are urgently required."

EFSA-based review identifying rice and other food categories as significant sources of dietary inorganic arsenic exposure, particularly for young children.

Traditional and Herbal Medicines

Certain traditional medicines, particularly Ayurvedic preparations, Chinese herbal medicines, and folk remedies contain intentionally added arsenic compounds. Arsenic trioxide has been used therapeutically in traditional Chinese medicine for centuries and is now an approved treatment for acute promyelocytic leukemia.

Show evidence (1 reference)

PMID:22843016 SUPPORT Human Clinical

"The most severe adverse effects caused by these adulterations were agranulocytosis, meningitis, multi-organ failure, perinatal stroke, arsenic, lead or mercury poisoning, malignancies or carcinomas, hepatic encephalopathy, hepatorenal syndrome, nephrotoxicity, rhabdomyolysis, metabolic acidosis,..."

Overview of systematic reviews confirming arsenic poisoning among severe adverse effects from contaminated herbal medicinal products, particularly traditional Indian and Chinese remedies.

🔬

Biochemical Markers

Urinary Arsenic (Total and Speciated) (INCREASED)

Show evidence (1 reference)

PMID:12505313 SUPPORT Human Clinical

"Glutathione, and possibly other thiols, serve as reducing agents. The liver is the most important site of arsenic methylation, but most organs show arsenic methylating activity."

Describes urinary arsenic metabolites as products of hepatic methylation pathway.

Blood Arsenic (INCREASED)

Show evidence (1 reference)

PMID:22208756 SUPPORT Human Clinical

"the detection of As or its derivatives in the blood is an indication of the dose ingested but it is not evidence of chronic intoxication"

Systematic review confirming blood arsenic as a biomarker of recent dose but not chronic exposure.

Hair and Nail Arsenic (INCREASED)

Show evidence (2 references)

PMID:21740555 SUPPORT Human Clinical

"arsenic concentrations in the drinking water were strongly correlated with arsenic concentrations in the subjects' hair and nails"

Cross-sectional study in Bangladesh demonstrating dose-response correlation between water arsenic and hair/nail arsenic concentrations.

PMID:33075355 SUPPORT Human Clinical

"Toenail arsenic can serve as a reliable measure of toxic inorganic arsenic exposure in chronic disease research, particularly promising for cancer and cardiovascular conditions."

Systematic review of 129 studies confirming toenails as a reliable biomarker of long-term arsenic exposure.

Hepatic Transaminases (AST/ALT) (INCREASED)

Show evidence (1 reference)

PMID:21740555 SUPPORT Human Clinical

"the respective activities of ALP, AST and ALT were found to be significantly increased in the high-exposure groups compared to the lowest-exposure groups before and after adjustments were made for different covariates"

Cross-sectional study in 200 Bangladeshi residents demonstrating dose-response elevation of hepatic transaminases with arsenic exposure.

Beta-2-Microglobulin (Urinary) (INCREASED)

Show evidence (1 reference)

PMID:14761355 SUPPORT Human Clinical

"There were positive correlations and significant dose-effect among the concentrations of urinary cadmium, arsenic and levels of Ubeta2-MG, UALB, UNAG (P<0.05, P<0.01)."

Occupational study demonstrating significant dose-effect relationship between arsenic exposure and urinary beta-2-microglobulin levels.

N-Acetyl-Beta-D-Glucosaminidase (NAG) (INCREASED)

Show evidence (2 references)

PMID:21622483 SUPPORT Human Clinical

"These facts suggest that a relatively low-level exposure to inorganic arsenic produces renal tubular damage in humans."

Study in 867 Korean adults demonstrating urinary arsenic as a significant determinant of NAG activity, indicating renal tubular damage.

PMID:20077223 SUPPORT Human Clinical

"NAG, MDA, and 8-OHdG were positively correlated with both Cd and As in urine."

Population study confirming positive correlation between urinary arsenic and NAG activity as a marker of tubular damage.

8-Hydroxy-2-Deoxyguanosine (8-OHdG) (INCREASED)

Show evidence (2 references)

PMID:16545696 SUPPORT Human Clinical

"the mean urinary concentrations of total arsenic and 8-oxodGuo were significantly higher for exposed workers compared with the nonexposed workers"

Study of 90 semiconductor workers demonstrating elevated urinary 8-OHdG in arsenic-exposed workers, correlating with MMA levels.

PMID:20077223 SUPPORT Human Clinical

"NAG, MDA, and 8-OHdG were positively correlated with both Cd and As in urine."

Population study confirming positive correlation between urinary arsenic and 8-OHdG as a marker of oxidative DNA damage.

🔀

Differential Diagnoses

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

Lead Poisoning MONDO:0018019

Distinguishing Features

Lead causes motor-predominant neuropathy (wrist/foot drop) rather than sensory-predominant neuropathy
Lead lines on gingiva and basophilic stippling are characteristic of lead but not arsenic
Lead does not cause arsenical melanosis or palmoplantar keratoses
Blood lead level is diagnostic for lead poisoning

Cadmium Poisoning MONDO:0043523

Distinguishing Features

Cadmium primarily affects kidney (proximal tubular dysfunction, Fanconi syndrome) and bone (osteomalacia)
Cadmium does not cause melanosis or keratoses
Arsenic predominantly affects skin and peripheral nerves

Thallium Poisoning MONDO:0041996

Distinguishing Features

Thallium causes dramatic alopecia, a hallmark distinguishing feature absent in arsenic poisoning
Thallium causes painful sensory neuropathy and gastrointestinal symptoms
Arsenic causes hyperpigmentation and keratoses rather than hair loss

Pellagra Not Yet Curated MONDO:0019975

Distinguishing Features

Niacin deficiency causes dermatitis in sun-exposed areas (photosensitive distribution)
The classic triad of dermatitis, diarrhea, and dementia differs from arsenicosis
Arsenical skin lesions are non-photosensitive (melanosis and palmoplantar keratoses)

📊

Related Datasets

Genome wide DNA methylation analysis of arsenic exposure and non-exposure population and patients with skin lesions geo:GSE109914

Methylation profiling comparing arsenic-exposed individuals, non-exposed controls, and patients with arsenical skin lesions using Illumina HumanMethylation450 BeadChip across approximately 450,000 CpG sites.

human METHYLATION n=119 Illumina Infinium...

peripheral blood

Conditions: arsenic-exposed individuals (n=66) non-exposed controls (n=35) patients with arsenical skin lesions (n=18)

Exposures: exposure to arsenic ECTO:9000032

Large population-level study from Bangladesh comparing methylation profiles across exposure groups. Useful for identifying epigenetic biomarkers of arsenic exposure and arsenicosis progression.

Genome-wide DNA methylation profiles of arsenic exposed subjects through drinking water in Pakistan geo:GSE157111

Investigation of DNA methylation changes in individuals exposed to elevated groundwater arsenic levels in Pakistan, stratified by low, medium, and high exposure levels using MeDIP with NimbleGen arrays.

human METHYLATION n=57 NimbleGen 2.1M Deluxe Promoter arrays

peripheral blood

Conditions: low arsenic exposure medium arsenic exposure high arsenic exposure

Exposures: exposure to arsenic in water via ingestion ECTO:0080000

Dose-stratified methylation study from Pakistan enabling analysis of dose-response epigenetic changes associated with chronic arsenic exposure through drinking water.

Gene expression profiles of subjects exposed to arsenic through drinking water in Pakistan geo:GSE110852

Microarray-based transcriptome analysis of individuals exposed to elevated groundwater arsenic levels across different exposure categories, identifying arsenic-associated gene expression changes.

human MICROARRAY n=57 Agilent SurePrint G3 Human Gene...

peripheral blood

Conditions: arsenic-exposed individuals control subjects

Exposures: exposure to arsenic in water via ingestion ECTO:0080000

Companion transcriptomic study to GSE157111, enabling integrated analysis of gene expression and DNA methylation changes in the same arsenic-exposed Pakistani population.

Arsenic-associated differential DNA methylation in human uroepithelial cells geo:GSE58499

Analysis of promoter methylation in bladder uroepithelial cells from individuals with varying arsenic exposure in Mexico, identifying genes with increased methylation linked to metabolic disease and cancer signaling pathways.

human METHYLATION n=46 Affymetrix GeneChip Human Promoter 1.0R Array

bladder uroepithelial cells

Conditions: varying arsenic exposure levels

Exposures: exposure to arsenic ECTO:9000032

Clinically relevant study linking arsenic exposure to epigenetic changes in target tissue (urothelium) relevant to arsenic-induced bladder cancer risk.

🔬

Clinical Trials

NCT01442727 PHASE_III COMPLETED

A 48-week randomized, double-blinded, placebo-controlled Phase III trial evaluating whether daily selenium supplementation counters arsenic toxicity in Bangladeshi arsenicosis patients. Based on preclinical evidence that selenium promotes arsenic excretion via formation of the seleno-bis(S-glutathionyl) arsinium ion through the hepatobiliary system.

Target Phenotypes: Hyperpigmentation of the skin HP:0000953

Show evidence (1 reference)

clinicaltrials:NCT01442727 SUPPORT

"Approximately 100 million people throughout the world consume water contaminated with arsenic at levels above carcinogenic thresholds, including 40 million in Bangladesh alone, with up to one-fourth of deaths attributed to arsenic exposure in the worst-affected regions. There are no proven..."

Phase III trial testing selenium supplementation as a therapeutic intervention for chronic arsenic toxicity and cancer prevention.

NCT01050556 PHASE_IV COMPLETED

A Phase IV trial examining whether folic acid, alone or with creatine supplementation, can lower blood arsenic concentrations and improve arsenic detoxification. Folic acid enhances arsenic methylation capacity by supporting one-carbon metabolism, potentially facilitating arsenic excretion as DMA.

Show evidence (1 reference)

clinicaltrials:NCT01050556 SUPPORT

"The purpose of this study is to determine whether folic acid, alone or together with creatine supplementation, can lower blood arsenic concentrations and improve the ability to detoxify arsenic."

Trial evaluating nutritional supplementation as a strategy to enhance arsenic methylation and reduce blood arsenic levels.

NCT01748669 PHASE_II COMPLETED

A Phase II trial evaluating the effectiveness of oral garlic oil capsules in treating arsenical palmar keratosis over 12 weeks. Garlic contains organosulfur compounds that may facilitate arsenic excretion and reduce body arsenic load.

Target Phenotypes: Palmoplantar keratoderma HP:0000982

Show evidence (1 reference)

clinicaltrials:NCT01748669 SUPPORT

"Twenty patients of mild to moderate degree of arsenical palmer keratosis will be treated with garlic oil capsule orally for 12 weeks to examine its effectiveness in reducing body arsenic load and clinical symptoms."

Phase II trial testing garlic oil as a therapeutic intervention for arsenical palmar keratosis.

NCT02377635 PHASE_II COMPLETED

A Phase I/II clinical trial studying the pharmacodynamics of selenium supplements in volunteers with high arsenic load from drinking water. Participants were maintained in a local clinic with monitored intake and excretion of both arsenic and selenium to establish proof of concept for selenium-based remediation strategies.

Show evidence (1 reference)

clinicaltrials:NCT02377635 SUPPORT

"This clinical trial should prove that selenium can treat arsenic exposure in humans by promoting excretion."

Proof-of-concept Phase I/II trial for selenium-mediated arsenic excretion in chronically exposed populations.

{ }

Source YAML

click to show

name: Arsenic Poisoning
creation_date: '2026-02-11T21:06:43Z'
updated_date: '2026-05-08T16:21:17Z'
description: >-
  Arsenic poisoning (arsenicosis) is a toxic condition caused by acute or chronic
  exposure to inorganic arsenic, a metalloid found naturally in groundwater and
  soil and encountered through contaminated drinking water, occupational sources
  (mining, smelting, pesticide manufacturing), and certain traditional medicines.
  Acute arsenic ingestion causes severe gastrointestinal hemorrhage, cardiovascular
  collapse, and multi-organ failure. Chronic exposure produces a characteristic
  constellation of dermatological changes (hyperpigmentation, keratoses), peripheral
  neuropathy, hepatotoxicity, and increased cancer risk. Arsenic disrupts cellular
  function through inhibition of pyruvate dehydrogenase and other sulfhydryl-
  dependent enzymes, uncoupling oxidative phosphorylation by substituting for
  phosphate (arsenolysis), and generating reactive oxygen species. Endemic arsenicosis
  affects tens of millions in Bangladesh, West Bengal, and other regions with
  naturally high groundwater arsenic. Treatment of acute poisoning relies on
  chelation therapy with dimercaprol (BAL) or succimer (DMSA), while chronic
  arsenicosis management focuses on exposure cessation and symptomatic care.
category: Environmental
parents:
- heavy metal poisoning
has_subtypes:
- name: Acute
  display_name: Acute Arsenic Poisoning
  description: >-
    Acute arsenic poisoning from ingestion of large doses of inorganic arsenic,
    typically from intentional or accidental ingestion. Presents with severe
    gastroenteritis (rice-water diarrhea, abdominal pain, vomiting), cardiovascular
    collapse, QTc prolongation, seizures, encephalopathy, and multi-organ failure.
    The lethal dose of arsenic trioxide is approximately 100-300 mg in adults.
- name: Chronic
  display_name: Chronic Arsenic Poisoning (Arsenicosis)
  description: >-
    Chronic arsenicosis from prolonged low-level exposure, primarily through
    contaminated drinking water exceeding the WHO guideline of 10 mcg/L. Endemic
    in Bangladesh, West Bengal (India), parts of Southeast Asia, and South America.
    Characterized by progressive dermatological changes (melanosis, keratoses),
    peripheral neuropathy, hepatic fibrosis, and markedly increased cancer risk.
    The WHO considers chronic arsenicosis a major global public health concern.
pathophysiology:
- name: Gastrointestinal Absorption and Transport
  description: >-
    Arsenic enters the body primarily through the gastrointestinal tract.
    Pentavalent arsenic (As(V)) is absorbed via sodium-dependent phosphate
    transporters (NaPiIIb) in the small intestine through a saturable,
    carrier-mediated process that is competitively inhibited by phosphate.
    Trivalent arsenic (As(III)) is absorbed via aquaglyceroporins (AQP3,
    AQP7, AQP10) and glucose transporters (GLUT2, GLUT5). The gut microbiome
    modulates arsenic bioavailability: sulfate-reducing bacteria produce
    thiolated arsenic species that are more toxic and more readily absorbed,
    and salivary/colonic microorganisms increase small intestinal absorption
    1.2-2.7 fold.
  biological_processes:
  - preferred_term: transmembrane transport
    modifier: ABNORMAL
    term:
      id: GO:0055085
      label: transmembrane transport
  locations:
  - preferred_term: small intestine
    term:
      id: UBERON:0002108
      label: small intestine
  evidence:
  - reference: PMID:7631493
    reference_title: "Gastrointestinal absorption of inorganic arsenic (V): The effect of concentration and interactions with phosphate and dichromate."
    supports: PARTIAL
    evidence_source: MODEL_ORGANISM
    snippet: "Intestinal absorption of As appears carried out by a saturable transport process. The phosphate produces a pronounced decrease in the intestinal absorption of As due to the fact that phosphate and As can share the same transport mechanism which is an active secondary carrier-mediated system depending on Na+ and H+ gradient."
    explanation: "Confirms arsenate absorption is via saturable, carrier-mediated phosphate transporters."
  - reference: PMID:22214486
    reference_title: "In vitro study of transporters involved in intestinal absorption of inorganic arsenic."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Gene silencing of OATPB, AQP10, and GLUT5 for As(III) and NaPiIIb for As(V) significantly reduces uptake of the inorganic forms. These results indicate that these transporters may be involved in intestinal absorption of iAs."
    explanation: "Identifies specific transporters for As(III) and As(V) intestinal absorption."
  - reference: PMID:24833621
    reference_title: "Arsenic thiolation and the role of sulfate-reducing bacteria from the human intestinal tract."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We found that SRB of human gastrointestinal origin, through their ability to produce H2S, were necessary and sufficient to induce As thiolation."
    explanation: "Confirms role of gut sulfate-reducing bacteria in arsenic thiolation increasing toxicity."
  downstream:
  - target: Hepatic Methylation and Biotransformation
    description: Absorbed arsenic is transported to the liver for methylation and biotransformation.
  - target: Inhibition of Sulfhydryl-Dependent Enzymes
    description: Trivalent arsenic (As3+) directly binds sulfhydryl groups on cellular enzymes.
  - target: Arsenolysis
    description: Pentavalent arsenic (As5+) competes with phosphate in enzymatic reactions.
- name: Hepatic Methylation and Biotransformation
  description: >-
    Inorganic arsenic undergoes hepatic biotransformation via the Challenger
    pathway. Arsenic (+3 oxidation state) methyltransferase (AS3MT) catalyzes
    sequential methylation using S-adenosylmethionine (SAM) as the methyl
    donor, producing monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA).
    Glutathione-S-transferase omega (hGST-O) functions as MMA(V) reductase.
    While historically considered a detoxification pathway, the intermediate
    trivalent methylated species (MMA(III)) is more toxic than inorganic arsenic.
    Individual variation in AS3MT activity and polymorphisms influences
    susceptibility. Urinary arsenic speciation (typically 10-30% iAs, 10-20%
    MMA, 60-80% DMA) reflects methylation efficiency and disease risk.
  biological_processes:
  - preferred_term: arsenic methylation
    modifier: INCREASED
    term:
      id: GO:0071722
      label: detoxification of arsenic-containing substance
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  evidence:
  - reference: PMID:11484904
    reference_title: "Role of metabolism in arsenic toxicity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In humans, as in most mammalian species, inorganic arsenic is methylated to methylarsonic acid (MMA) and dimethylarsinic acid (DMA) by alternating reduction of pentavalent arsenic to trivalent and addition of a methyl group from S-adenosylmethionine."
    explanation: "Describes the sequential methylation pathway for arsenic biotransformation in humans."
  - reference: PMID:12505313
    reference_title: "Mechanisms of arsenic biotransformation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Glutathione, and possibly other thiols, serve as reducing agents. The liver is the most important site of arsenic methylation, but most organs show arsenic methylating activity."
    explanation: "Confirms liver as primary site of arsenic methylation with glutathione as reducing agent."
  downstream:
  - target: Oxidative Stress and ROS Generation
    description: The intermediate trivalent methylated species MMA(III) generates reactive oxygen species.
  - target: SAM Depletion
    description: Arsenic methylation consumes S-adenosylmethionine, depleting the cellular methyl donor pool.
- name: Inhibition of Sulfhydryl-Dependent Enzymes
  description: >-
    Trivalent arsenic (arsenite, As3+) binds to sulfhydryl groups in proteins,
    inhibiting key enzymes in intermediary metabolism. The pyruvate dehydrogenase
    complex is a primary target, where arsenic binds to the dihydrolipoamide
    cofactor of the E2 subunit, blocking the conversion of pyruvate to acetyl-CoA.
    This impairs aerobic energy production and leads to metabolic acidosis.
    Arsenic also inhibits other sulfhydryl-dependent enzymes involved in
    cellular energy metabolism and biosynthetic pathways.
  biological_processes:
  - preferred_term: pyruvate metabolic process
    modifier: DECREASED
    term:
      id: GO:0006090
      label: pyruvate metabolic process
  evidence:
  - reference: PMID:9806419
    reference_title: "Arsenic toxicity is enzyme specific and its affects on ligation are not caused by the direct inhibition of DNA repair enzymes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Only pyruvate dehydrogenase, one of eight purified enzymes examined so far, is inhibited by micromolar arsenic."
    explanation: "Demonstrates enzyme-specific inhibition by arsenic, confirming pyruvate dehydrogenase as a primary target."
  downstream:
  - target: Mitochondrial Dysfunction
    description: PDH complex inhibition blocks acetyl-CoA entry into the TCA cycle, impairing mitochondrial energy production.
- name: Arsenolysis
  description: >-
    Pentavalent arsenic (arsenate, As5+) is a structural analog of phosphate and
    competes with phosphate in enzymatic reactions. Arsenate substitutes for
    phosphate in glycolysis, forming an unstable arsenate ester that spontaneously
    hydrolyzes, uncoupling substrate-level phosphorylation without generating ATP.
    This process, termed arsenolysis, disrupts cellular energy metabolism and
    contributes to multi-organ dysfunction.
  biological_processes:
  - preferred_term: glycolytic process
    modifier: ABNORMAL
    term:
      id: GO:0006096
      label: glycolytic process
  evidence:
  - reference: PMID:20078116
    reference_title: "Characterization of the intestinal absorption of arsenate, monomethylarsonic acid, and dimethylarsinic acid using the Caco-2 cell line."
    supports: NO_EVIDENCE
    evidence_source: IN_VITRO
    snippet: "As(V) absorption was inhibited by 10 mM phosphate, and a phosphate transporter therefore could take part in intestinal absorption."
    explanation: "Confirms competitive relationship between arsenate and phosphate, consistent with structural analogy."
  downstream:
  - target: Mitochondrial Dysfunction
    description: Uncoupling of substrate-level phosphorylation impairs cellular ATP generation.
- name: Oxidative Stress and ROS Generation
  description: >-
    Arsenic metabolism generates reactive oxygen species (ROS) through multiple
    mechanisms including mitochondrial electron transport chain disruption,
    NADPH oxidase (Nox2) activation in endothelial cells, and nitric oxide
    synthase stimulation producing reactive nitrogen species. Arsenic depletes
    antioxidant enzymes (catalase, SOD, glutathione peroxidase, glutathione
    reductase) and glutathione (GSH). Consequences include lipid peroxidation
    (MDA formation), protein carbonylation, and DNA oxidative damage (8-OHdG).
    Peroxynitrite formation from superoxide and NO causes protein nitration.
  biological_processes:
  - preferred_term: response to oxidative stress
    modifier: INCREASED
    term:
      id: GO:0006979
      label: response to oxidative stress
  evidence:
  - reference: PMID:21554949
    reference_title: "Arsenic-induced oxidative stress and its reversibility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Arsenic alters cellular glutathione levels either by utilizing this electron donor for the conversion of pentavalent to trivalent arsenicals or directly binding with it or by oxidizing glutathione via arsenic-induced free radical generation."
    explanation: "Comprehensive review confirming arsenic-induced oxidative stress through glutathione depletion and free radical generation."
  - reference: PMID:25788710
    reference_title: "Arsenic, reactive oxygen, and endothelial dysfunction."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The most sensitive target of arsenic toxicity in the vasculature is the endothelium, and incubation of these cells with low concentrations of arsenite, a naturally occurring and highly toxic inorganic form of arsenic, rapidly induces reactive oxygen species (ROS) formation via activation of a specific NADPH oxidase (Nox2)."
    explanation: "Identifies endothelial Nox2 activation as a specific mechanism of arsenic-induced ROS generation."
  downstream:
  - target: DNA Repair Inhibition via Zinc Finger Protein Disruption
    description: ROS/RNS modify zinc finger proteins, compounding direct arsenite binding effects on DNA repair.
  - target: Peripheral Nerve Axonopathy
    description: Lipid peroxidation in sciatic and sural nerves drives axonal degeneration.
  - target: Hepatocellular Oxidative Injury
    description: Hepatic glutathione depletion and NADPH oxidase activation cause progressive liver damage.
  - target: Cardiovascular Endothelial Dysfunction
    description: Endothelial Nox2 activation and NO scavenging impair vascular function.
  - target: Renal Tubular Injury
    description: ROS production and glutathione depletion damage proximal tubular cells.
  - target: Cutaneous Arsenical Toxicity
    description: Oxidative stress in arsenic-laden keratin-rich epidermis and nail matrix perturbs keratinocyte and melanocyte homeostasis.
- name: Mitochondrial Dysfunction
  description: >-
    Arsenic causes decreased activity of mitochondrial electron transport chain
    complexes I, II, and IV, reduced mitochondrial membrane potential, impaired
    ATP synthesis, mitochondrial swelling, and cytochrome c release initiating
    apoptosis. Arsenic induces mtDNA damage (including a characteristic 3867 bp
    deletion) and downregulates mitochondrial biogenesis regulators (PGC-1alpha,
    NRF-1, NRF-2, Tfam). These effects are central to arsenic toxicity in
    multiple organ systems.
  biological_processes:
  - preferred_term: mitochondrion organization
    modifier: ABNORMAL
    term:
      id: GO:0007005
      label: mitochondrion organization
  evidence:
  - reference: PMID:25764338
    reference_title: "Biochemical and Molecular Alterations Following Arsenic-Induced Oxidative Stress and Mitochondrial Dysfunction in Rat Brain."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Chronic sodium arsenite treatment (25 ppm for 12 weeks) resulted in decreased activity of mitochondrial complexes I, II, and IV followed by increased ROS generation."
    explanation: "Demonstrates arsenic-induced mitochondrial complex inhibition and consequent ROS generation in rat brain."
  downstream:
  - target: Oxidative Stress and ROS Generation
    description: Impaired electron transport chain generates superoxide radicals (positive feedback loop).
  - target: Hepatocellular Oxidative Injury
    description: Mitochondrial dysfunction in hepatocytes triggers apoptotic cascades.
  - target: Renal Tubular Injury
    description: Mitochondrial dysfunction in proximal tubular cells activates SIRT1/PINK1 mitophagy axis disruption.
- name: DNA Repair Inhibition via Zinc Finger Protein Disruption
  description: >-
    Arsenite binds to zinc finger domains in key DNA repair proteins, displacing
    zinc ions and altering protein conformation. PARP-1 (poly(ADP-ribose)
    polymerase-1) is inhibited by arsenite binding to its zinc finger domain,
    abolishing DNA-binding ability and enzymatic activity. XPC (xeroderma
    pigmentosum complementation group C), a key nucleotide excision repair
    protein, undergoes transcriptional inhibition and proteasomal degradation.
    Arsenic disrupts base excision repair (BER), nucleotide excision repair
    (NER), double-strand break repair, and interstrand crosslink (ICL) repair.
    This comprehensive DNA repair inhibition, rather than direct mutagenesis,
    is a major mechanism of arsenic carcinogenesis.
  biological_processes:
  - preferred_term: DNA repair
    modifier: DECREASED
    term:
      id: GO:0006281
      label: DNA repair
  evidence:
  - reference: PMID:24275069
    reference_title: "Arsenite binding-induced zinc loss from PARP-1 is equivalent to zinc deficiency in reducing PARP-1 activity, leading to inhibition of DNA repair."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Poly(ADP-ribose) polymerase-1 (PARP-1), a zinc finger DNA repair protein, has been identified as a sensitive molecular target for arsenic. The zinc finger domains of PARP-1 protein function as a critical structure in DNA recognition and binding."
    explanation: "Demonstrates arsenite binding to PARP-1 zinc finger domains leading to zinc loss and DNA repair inhibition."
  - reference: PMID:31986875
    reference_title: "Molecular Mechanisms of Arsenic-Induced Disruption of DNA Repair."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Results from recent studies suggest zinc finger proteins as crucial molecular targets for direct binding to As3+ or for modifications by arsenic-induced ROS/RNS, which may constitute a common mechanism underlying arsenic-induced perturbations of DNA repair."
    explanation: "Review confirming zinc finger proteins as central targets in arsenic-induced DNA repair disruption."
  downstream:
  - target: Arsenic-Induced Carcinogenesis
    description: Impaired DNA repair allows accumulation of mutations and genomic instability.
- name: SAM Depletion
  description: >-
    Arsenic methylation via the Challenger pathway consumes S-adenosylmethionine
    (SAM), depleting the cellular methyl donor pool. SAM is the universal methyl
    donor for DNA, histone, and protein methylation reactions. Chronic arsenic
    exposure progressively depletes SAM, reducing the availability of methyl
    groups for normal epigenetic maintenance. The depletion of SAM also reduces
    N6-methyladenine (6mA) levels through ALKBH4 demethylase upregulation.
  biological_processes:
  - preferred_term: S-adenosylmethionine metabolic process
    modifier: ABNORMAL
    term:
      id: GO:0046500
      label: S-adenosylmethionine metabolic process
  evidence:
  - reference: PMID:20514360
    reference_title: "Effects of arsenic exposure on DNA methylation and epigenetic gene regulation."
    supports: NO_EVIDENCE
    evidence_source: HUMAN_CLINICAL
    snippet: "Changes in gene methylation status, mediated by arsenic, have been proposed to activate oncogene expression or silence tumor suppressor genes, leading to long-term changes in the activity of genes controlling cell transformation."
    explanation: "Reviews arsenic-mediated DNA methylation changes driven by SAM depletion."
  downstream:
  - target: Global DNA Hypomethylation
    description: Reduced SAM availability causes genome-wide loss of DNA methylation marks.
  - target: Tumor Suppressor Gene Silencing
    description: SAM depletion paradoxically redistributes methylation to tumor suppressor promoters.
- name: Global DNA Hypomethylation
  description: >-
    SAM depletion from arsenic methylation causes genome-wide loss of DNA
    methylation, leading to genomic instability through reactivation of
    transposable elements, activation of normally silenced repetitive
    sequences, and aberrant oncogene expression. Global hypomethylation
    is an early and consistent epigenetic alteration in arsenic-exposed
    populations and tissues.
  biological_processes:
  - preferred_term: epigenetic regulation of gene expression
    modifier: DYSREGULATED
    term:
      id: GO:0040029
      label: epigenetic regulation of gene expression
  evidence:
  - reference: PMID:20514360
    reference_title: "Effects of arsenic exposure on DNA methylation and epigenetic gene regulation."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Changes in gene methylation status, mediated by arsenic, have been proposed to activate oncogene expression or silence tumor suppressor genes, leading to long-term changes in the activity of genes controlling cell transformation."
    explanation: "Describes global methylation changes leading to oncogene activation."
  downstream:
  - target: Arsenic-Induced Carcinogenesis
    description: Genomic instability from global hypomethylation promotes oncogenic transformation.
- name: Tumor Suppressor Gene Silencing
  description: >-
    Despite global DNA hypomethylation, arsenic causes paradoxical
    hypermethylation of tumor suppressor gene promoters, silencing their
    expression. Histone modifications compound this effect: increased
    repressive marks (H3K9me2) via G9a methyltransferase upregulation and
    decreased activating marks (H3K4me3) reinforce transcriptional silencing.
    Arsenic also disrupts CTCF binding and 3D genome architecture, causing
    oncogenic rewiring of enhancer-promoter interactions.
  biological_processes:
  - preferred_term: negative regulation of gene expression, epigenetic
    modifier: INCREASED
    term:
      id: GO:0045814
      label: negative regulation of gene expression, epigenetic
  evidence:
  - reference: PMID:20514360
    reference_title: "Effects of arsenic exposure on DNA methylation and epigenetic gene regulation."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Changes in gene methylation status, mediated by arsenic, have been proposed to activate oncogene expression or silence tumor suppressor genes, leading to long-term changes in the activity of genes controlling cell transformation."
    explanation: "Describes arsenic-mediated silencing of tumor suppressor genes through methylation changes."
  downstream:
  - target: Arsenic-Induced Carcinogenesis
    description: Loss of tumor suppressor function permits uncontrolled cell proliferation.
- name: Arsenic-Induced Carcinogenesis
  description: >-
    Arsenic carcinogenesis results from the convergence of multiple pathways:
    DNA repair inhibition (preventing correction of mutations), epigenetic
    dysregulation (activating oncogenes and silencing tumor suppressors), and
    chronic oxidative stress (causing DNA damage). Unlike most carcinogens,
    arsenic is not a direct mutagen; rather, it acts as a co-carcinogen through
    these indirect mechanisms. Epidemiological evidence establishes arsenic as
    a cause of cancers of the skin, lung, liver, bladder, and prostate.
  biological_processes:
  - preferred_term: epigenetic regulation of gene expression
    modifier: DYSREGULATED
    term:
      id: GO:0040029
      label: epigenetic regulation of gene expression
  evidence:
  - reference: PMID:36858772
    reference_title: "Arsenic and cancer: Evidence and mechanisms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Epidemiological evidence shows arsenic induces cancers of the skin, lung, liver, and bladder among other tissues."
    explanation: "Confirms epidemiological evidence for arsenic-induced carcinogenesis across multiple tissue types."
  - reference: PMID:30223072
    reference_title: "A review on arsenic carcinogenesis: Epidemiology, metabolism, genotoxicity and epigenetic changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Epidemiological studies have established a strong association between inorganic arsenic (iAs) exposure in drinking water and an increased incidence of cancer including bladder, liver, lung, prostate, and skin cancer."
    explanation: "Review confirming strong epidemiological association between arsenic exposure and multiple cancer types."
- name: Peripheral Nerve Axonopathy
  description: >-
    Arsenic causes a distal symmetric sensorimotor polyneuropathy through
    axonal degeneration, particularly of small myelinated and unmyelinated
    fibers. Mechanisms include oxidative stress with lipid peroxidation (most
    pronounced in sciatic and sural nerves), mitochondrial instability,
    thiamine deficiency, decreased acetylcholinesterase activity, and
    cytoskeletal disruption with reduced neurofilament proteins. Recovery is
    slow and often incomplete, with abnormal neurological signs persisting
    years after exposure.
  cell_types:
  - preferred_term: Schwann cell
    term:
      id: CL:0002573
      label: Schwann cell
  biological_processes:
  - preferred_term: neuron projection development
    modifier: ABNORMAL
    term:
      id: GO:0031175
      label: neuron projection development
  locations:
  - preferred_term: peripheral nerve
    term:
      id: UBERON:0001021
      label: nerve
  evidence:
  - reference: PMID:31336801
    reference_title: "Arsenic Neurotoxicity in Humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Several mechanisms that seem to play key roles in As-induced neurotoxicity, including oxidative stress, apoptosis, thiamine deficiency, and decreased acetyl cholinesterase activity, are described. The observed neurotoxicity predominantly affects peripheral nerves in sensory fibers, with a lesser effect on motor fibers."
    explanation: "Review of arsenic neurotoxicity mechanisms confirming sensory-predominant peripheral neuropathy."
  - reference: PMID:196051
    reference_title: "Peripheral neuropathy following a single exposure to arsenic. Clincal course in four patients with electrophysiological and histological studies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Four patients are described who developed a peripheral neuropathy 10 days to 3 weeks after ingestion of a single dose of arsenic. All improved slowly, but after 6 to 8 years 3 of them still had abnormal neurological symptoms and signs."
    explanation: "Clinical evidence of arsenic neuropathy onset timing and slow, incomplete recovery."
  downstream:
  - target: Peripheral Neuropathy
    description: Distal axonal degeneration of sensory-predominant peripheral fibers produces a distal symmetric sensorimotor polyneuropathy.
- name: Hepatocellular Oxidative Injury
  description: >-
    Chronic arsenic exposure causes progressive hepatocellular injury through
    NADPH oxidase-mediated oxidative stress and glutathione depletion. The
    progression follows distinct phases: initial oxidative stress with
    glutathione depletion (6 months), followed by hepatic steatosis with
    elevated aminotransferases (12 months). Molecular mechanisms include
    PPARalpha-dependent autophagy and HIF-1alpha/VEGF signaling. High-fat
    diet significantly amplifies arsenic-induced liver injury through
    synergistic upregulation of pro-inflammatory and pro-fibrotic genes.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  biological_processes:
  - preferred_term: hepatocyte apoptotic process
    modifier: INCREASED
    term:
      id: GO:0097284
      label: hepatocyte apoptotic process
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  evidence:
  - reference: PMID:21134390
    reference_title: "Oxidative stress and hepatic stellate cell activation are key events in arsenic induced liver fibrosis in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Hepatic NADPH oxidase activity progressively increased in arsenic exposure with concomitant development of hepatic oxidative stress."
    explanation: "Mouse model demonstrating progressive NADPH oxidase-mediated oxidative stress in arsenic hepatotoxicity."
  downstream:
  - target: Hepatic Stellate Cell Activation
    description: Sustained hepatocellular injury activates hepatic stellate cells via TGF-beta1 and microRNA-21 crosstalk.
  - target: Hepatomegaly
    description: Hepatocellular injury with steatosis and elevated transaminases enlarges the liver, producing hepatomegaly.
- name: Hepatic Stellate Cell Activation
  description: >-
    Chronic hepatocellular injury activates hepatic stellate cells via
    TGF-beta1 upregulation and microRNA-21-mediated hepatocyte-stellate
    cell crosstalk. Activated stellate cells transdifferentiate into
    myofibroblast-like cells, initiating fibrogenic signaling cascades
    that drive extracellular matrix remodeling.
  cell_types:
  - preferred_term: hepatic stellate cell
    term:
      id: CL:0000632
      label: hepatic stellate cell
  biological_processes:
  - preferred_term: hepatic stellate cell activation
    modifier: INCREASED
    term:
      id: GO:0035733
      label: hepatic stellate cell activation
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  evidence:
  - reference: PMID:10641134
    reference_title: "Hepatic fibrogenesis using chronic arsenic ingestion: studies in a murine model."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "A significant increase in the hepatic protein and collagen was seen compared with controls; hepatic 4-hydroxyproline levels, indicative of fibrogenesis, were increased 4-14 folds with different dosages of arsenic compared to the controls."
    explanation: "Stellate cell activation is evidenced by downstream collagen deposition and fibrogenesis in murine arsenic exposure model."
  downstream:
  - target: Hepatic Fibrosis
    description: Activated stellate cells synthesize excess collagen and extracellular matrix, driving progressive fibrosis.
- name: Hepatic Fibrosis
  description: >-
    Activated hepatic stellate cells synthesize excess collagen and
    extracellular matrix proteins, leading to progressive hepatic fibrosis.
    Hepatic 4-hydroxyproline levels increase 4-14 fold with chronic arsenic
    exposure (15+ months), indicating dose-dependent fibrogenesis.
  biological_processes:
  - preferred_term: collagen biosynthetic process
    modifier: INCREASED
    term:
      id: GO:0032964
      label: collagen biosynthetic process
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  evidence:
  - reference: PMID:10641134
    reference_title: "Hepatic fibrogenesis using chronic arsenic ingestion: studies in a murine model."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "A significant increase in the hepatic protein and collagen was seen compared with controls; hepatic 4-hydroxyproline levels, indicative of fibrogenesis, were increased 4-14 folds with different dosages of arsenic compared to the controls."
    explanation: "Murine model confirming dose-dependent hepatic fibrogenesis with chronic arsenic ingestion."
- name: Cardiovascular Endothelial Dysfunction
  description: >-
    Arsenic causes endothelial dysfunction through impaired nitric oxide balance
    (eNOS inactivation, superoxide scavenging of NO), NADPH oxidase (Nox2)
    activation generating superoxide, COX-2 upregulation, and protein nitration.
    Vascular consequences include accelerated atherosclerosis, hypertension,
    endothelial apoptosis, increased platelet aggregation, and reduced
    fibrinolysis. Cardiac effects include QT interval prolongation, ventricular
    arrhythmias, and toxic cardiomyopathy. Blackfoot disease, an endemic
    peripheral vascular disease in southwestern Taiwan, is associated with
    chronic arsenic exposure from artesian well water.
  cell_types:
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  biological_processes:
  - preferred_term: nitric oxide mediated signal transduction
    modifier: DECREASED
    term:
      id: GO:0007263
      label: nitric oxide mediated signal transduction
  locations:
  - preferred_term: blood vessel
    term:
      id: UBERON:0001981
      label: blood vessel
  evidence:
  - reference: PMID:19015167
    reference_title: "Arsenic and cardiovascular disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Epidemiological studies have shown that chronic arsenic exposure is associated with increased morbidity and mortality from cardiovascular disease."
    explanation: "Establishes epidemiological link between arsenic exposure and cardiovascular disease."
  - reference: PMID:25788710
    reference_title: "Arsenic, reactive oxygen, and endothelial dysfunction."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The most sensitive target of arsenic toxicity in the vasculature is the endothelium, and incubation of these cells with low concentrations of arsenite, a naturally occurring and highly toxic inorganic form of arsenic, rapidly induces reactive oxygen species (ROS) formation via activation of a specific NADPH oxidase (Nox2)."
    explanation: "Demonstrates endothelial Nox2 activation as the primary mechanism of arsenic-induced vascular ROS."
  downstream:
  - target: Hypertension
    description: Impaired endothelial nitric oxide balance and vascular remodeling raise systemic vascular resistance, producing hypertension.
  - target: QTc Prolongation
    description: Arsenic cardiotoxicity prolongs ventricular repolarization, producing QTc prolongation and a risk of torsades de pointes.
- name: Renal Tubular Injury
  description: >-
    Arsenic causes nephrotoxicity primarily targeting proximal tubular cells
    through mitochondrial dysfunction, NF-kappaB and p38 MAPK activation,
    ROS production, and glutathione depletion. Dysregulated autophagy
    (early induction followed by impaired autophagic flux, especially in
    females via estrogen-mediated mechanisms) contributes to cell death.
    The SIRT1/PINK1/mitophagy axis is disrupted. Chronic exposure leads
    to tubular dilation, basement membrane disruption, collagen deposition,
    decreased eGFR, and progressive chronic kidney disease.
  cell_types:
  - preferred_term: epithelial cell of proximal tubule
    term:
      id: CL:0002306
      label: epithelial cell of proximal tubule
  locations:
  - preferred_term: proximal tubule
    term:
      id: UBERON:0004134
      label: proximal tubule
  evidence:
  - reference: PMID:25703706
    reference_title: "Arsenic-mediated nephrotoxicity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Arsenic is one of the most abundant contaminants in water and soil, and many epidemiological studies have found an association between arsenic and type 2 diabetes mellitus, hypertension and cancer; however, there is a scarcity of epidemiological studies about its association with kidney disease, and the evidence linking urinary arsenic excretion with CKD, higher urinary excretion of low molecular proteins, albuminuria or other markers of renal in injury is still limited, and more studies are necessary to characterize the role of arsenic on renal injury and CKD progression."
    explanation: "Reviews evidence for arsenic-mediated nephrotoxicity and its association with CKD markers."
- name: Cutaneous Arsenical Toxicity
  description: >-
    Arsenic deposits in keratin-rich epidermis and the nail matrix, where
    arsenite binds keratin sulfhydryl groups and drives local oxidative stress,
    perturbing keratinocyte proliferation and differentiation and melanocyte
    pigmentation. These direct cutaneous toxic effects—distinct from frank
    malignant transformation—produce the pathognomonic non-malignant skin and
    nail signs of chronic arsenicosis (arsenical melanosis and palmoplantar
    keratoses) and the transient nail-matrix disruption seen as Mees lines.
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: keratinocyte differentiation
    modifier: ABNORMAL
    term:
      id: GO:0030216
      label: keratinocyte differentiation
  locations:
  - preferred_term: skin epidermis
    term:
      id: UBERON:0001003
      label: skin epidermis
  evidence:
  - reference: PMID:11218669
    reference_title: "Histopathology of skin lesions in chronic arsenic toxicity--grading of changes and study of proliferative markers."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Chronic arsenic toxicity (CAT) manifests predominantly as cutaneous lesions in the form of melanosis, keratosis and neoplastic changes."
    explanation: "Histopathological study confirming melanosis and keratosis as the predominant non-malignant cutaneous manifestations of chronic arsenic toxicity."
  downstream:
  - target: Hyperpigmentation (Arsenical Melanosis)
    description: Arsenic-induced melanocyte dysregulation produces diffuse and raindrop-pattern hyperpigmentation.
  - target: Palmoplantar Keratoses
    description: Arsenic-driven keratinocyte hyperproliferation and altered differentiation produce punctate/nodular palmoplantar keratoses.
  - target: Mees Lines
    description: Transient arsenic disruption of nail-matrix keratinization produces transverse white bands (Mees lines).
phenotypes:
- name: Hyperpigmentation (Arsenical Melanosis)
  phenotype_term:
    preferred_term: Hyperpigmentation of the skin
    term:
      id: HP:0000953
      label: Hyperpigmentation of the skin
  frequency: VERY_FREQUENT
  description: >-
    Diffuse or spotted hyperpigmentation, particularly on the trunk and
    extremities, is one of the earliest and most characteristic skin
    manifestations of chronic arsenic exposure. Described as a raindrop
    pattern of pigmentation against a background of diffuse darkening.
    Often coexists with hyperkeratosis and is a risk factor for skin cancer.
  notes: Arsenical melanosis is considered pathognomonic for chronic arsenic exposure.
  evidence:
  - reference: PMID:11218669
    reference_title: "Histopathology of skin lesions in chronic arsenic toxicity--grading of changes and study of proliferative markers."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Chronic arsenic toxicity (CAT) manifests predominantly as cutaneous lesions in the form of melanosis, keratosis and neoplastic changes."
    explanation: "Histopathological study confirming melanosis as a predominant cutaneous manifestation of chronic arsenic toxicity."
  - reference: PMID:11869818
    reference_title: "Chronic arsenic poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Skin pigmentation changes, palmar and plantar hyperkeratoses, gastrointestinal symptoms, anemia, and liver disease are common."
    explanation: "Review confirming skin pigmentation changes as common features of chronic arsenic poisoning."
- name: Palmoplantar Keratoses
  phenotype_term:
    preferred_term: Palmoplantar keratoderma
    term:
      id: HP:0000982
      label: Palmoplantar keratoderma
  frequency: VERY_FREQUENT
  description: >-
    Punctate, nodular, or diffuse keratoses on palms and soles are a hallmark of
    chronic arsenic exposure. These precancerous lesions may progress to squamous
    cell carcinoma. Graded from mild spotted keratosis to severe diffuse
    palmoplantar and dorsal keratosis. They develop months to years after initial
    exposure and persist even after arsenic exposure ceases.
  evidence:
  - reference: PMID:32809405
    reference_title: "Arsenical Keratosis(Archived)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Arsenical keratosis is a precancerous dermatosis observed in patients with chronic arsenic toxicity. This condition is characterized by corn-like, yellowish, hyperkeratotic papules and plaques, primarily affecting the palms and soles."
    explanation: "Clinical description confirming arsenical keratosis as precancerous palmoplantar lesions."
- name: Peripheral Neuropathy
  phenotype_term:
    preferred_term: Peripheral neuropathy
    term:
      id: HP:0009830
      label: Peripheral neuropathy
  frequency: FREQUENT
  description: >-
    Distal symmetric sensorimotor polyneuropathy with paresthesias, numbness,
    and weakness. Sensory symptoms typically precede motor involvement.
    Resembles Guillain-Barre syndrome. Electrophysiological studies show
    axonal sensory neuropathy with reduced nerve conduction velocity. In
    acute poisoning, neuropathy may develop 10 days to 3 weeks after exposure.
    Recovery is slow and often incomplete.
  evidence:
  - reference: PMID:196051
    reference_title: "Peripheral neuropathy following a single exposure to arsenic. Clincal course in four patients with electrophysiological and histological studies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Four patients are described who developed a peripheral neuropathy 10 days to 3 weeks after ingestion of a single dose of arsenic. All improved slowly, but after 6 to 8 years 3 of them still had abnormal neurological symptoms and signs."
    explanation: "Clinical case series documenting neuropathy onset timing and incomplete long-term recovery."
  - reference: PMID:31336801
    reference_title: "Arsenic Neurotoxicity in Humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The observed neurotoxicity predominantly affects peripheral nerves in sensory fibers, with a lesser effect on motor fibers."
    explanation: "Review confirming sensory-predominant peripheral neuropathy pattern in arsenic neurotoxicity."
- name: Gastrointestinal Hemorrhage
  phenotype_term:
    preferred_term: Gastrointestinal hemorrhage
    term:
      id: HP:0002239
      label: Gastrointestinal hemorrhage
  frequency: VERY_FREQUENT
  context: Acute poisoning
  description: >-
    Acute arsenic ingestion causes severe hemorrhagic gastroenteritis with
    profuse watery diarrhea (cholera-like), abdominal pain, nausea, and vomiting.
    Mucosal necrosis and submucosal edema may lead to hematemesis and
    bloody diarrhea. Metallic taste is an early symptom.
  evidence:
  - reference: PMID:11869818
    reference_title: "Chronic arsenic poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Skin pigmentation changes, palmar and plantar hyperkeratoses, gastrointestinal symptoms, anemia, and liver disease are common."
    explanation: "Review documenting gastrointestinal symptoms as common manifestations of arsenic poisoning."
- name: QTc Prolongation
  phenotype_term:
    preferred_term: Prolonged QTc interval
    term:
      id: HP:0005184
      label: Prolonged QTc interval
  frequency: FREQUENT
  context: Acute poisoning
  description: >-
    Arsenic causes QTc interval prolongation and torsades de pointes, which
    may lead to ventricular fibrillation and sudden cardiac death. This is a
    major cause of mortality in acute arsenic poisoning.
  evidence:
  - reference: PMID:19015167
    reference_title: "Arsenic and cardiovascular disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Epidemiological studies have shown that chronic arsenic exposure is associated with increased morbidity and mortality from cardiovascular disease."
    explanation: "Epidemiological evidence linking arsenic to cardiovascular morbidity including cardiac effects."
- name: Mees Lines
  phenotype_term:
    preferred_term: Leukonychia
    term:
      id: HP:0001820
      label: Leukonychia
  frequency: FREQUENT
  description: >-
    Transverse white bands across the fingernails (Mees lines) appearing 4-6
    weeks after acute arsenic exposure. These reflect transient disruption of
    nail matrix keratinization and are a classic but non-specific clinical sign.
- name: Hepatomegaly
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
  frequency: FREQUENT
  description: >-
    Hepatomegaly from arsenic-induced hepatotoxicity, often with elevated
    transaminases. Chronic exposure leads to hepatic steatosis, non-cirrhotic
    portal hypertension, hepatoportal sclerosis, and hepatic fibrosis.
  evidence:
  - reference: PMID:11869818
    reference_title: "Chronic arsenic poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Skin pigmentation changes, palmar and plantar hyperkeratoses, gastrointestinal symptoms, anemia, and liver disease are common. Noncirrhotic portal hypertension with bleeding esophageal varices, splenomegaly, and hypersplenism may occur."
    explanation: "Confirms liver disease and noncirrhotic portal hypertension as common features of chronic arsenic poisoning."
- name: Anemia
  phenotype_term:
    preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  frequency: FREQUENT
  description: >-
    Arsenic causes bone marrow suppression leading to anemia. Multiple forms
    observed including megaloblastic, dyserythropoietic, and hemolytic anemia.
    Basophilic stippling of erythrocytes may be present. Severe cases show
    pancytopenia with leucopenia and granulocytopenia. Absolute eosinophilia
    has also been reported.
  evidence:
  - reference: PMID:435641
    reference_title: "Arsenic-induced bone marrow toxicity: ultrastructural and electron-probe analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A patient with severe arsenic poisoning that resulted in marked peripheral blood and bone marrow abnormalities, including megaloblastic erythropoiesis experienced many of the previously reported hematologic complications of arsenic poisoning: leukopenia, granulocytopenia, absolute eosinophilia, and profound anemia."
    explanation: "Case report documenting the full spectrum of arsenic-induced hematologic abnormalities."
- name: Encephalopathy
  phenotype_term:
    preferred_term: Encephalopathy
    term:
      id: HP:0001298
      label: Encephalopathy
  frequency: OCCASIONAL
  context: Acute poisoning
  description: >-
    Acute arsenic poisoning may cause encephalopathy with confusion, delirium,
    seizures, cerebral edema, and coma. Cognitive impairment including memory
    deficits and executive function impairment may occur with chronic exposure.
- name: Hypertension
  phenotype_term:
    preferred_term: Hypertension
    term:
      id: HP:0000822
      label: Hypertension
  frequency: FREQUENT
  context: Chronic exposure
  description: >-
    Chronic arsenic exposure is associated with hypertension through endothelial
    dysfunction, reduced nitric oxide bioavailability, and vascular remodeling.
    Epidemiological studies in arsenic-endemic areas show dose-response
    relationships between arsenic exposure and hypertension.
  evidence:
  - reference: PMID:19015167
    reference_title: "Arsenic and cardiovascular disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Epidemiological studies have shown that chronic arsenic exposure is associated with increased morbidity and mortality from cardiovascular disease."
    explanation: "Epidemiological evidence confirming cardiovascular disease association including hypertension."
- name: Diabetes Mellitus
  phenotype_term:
    preferred_term: Diabetes mellitus
    term:
      id: HP:0000819
      label: Diabetes mellitus
  frequency: OCCASIONAL
  context: Chronic exposure
  description: >-
    Chronic arsenic exposure is associated with increased risk of type 2 diabetes
    mellitus through beta-cell dysfunction and insulin resistance. Elevated
    HbA1c and dysglycemia have been documented in arsenic-exposed populations.
  evidence:
  - reference: PMID:21914528
    reference_title: "Arsenic and diabetes: current perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Many studies have indicated a dose-response relationship between accumulative arsenic exposure and the prevalence of diabetes mellitus (DM) in arseniasis-endemic areas in Taiwan and Bangladesh, where arsenic exposure occurs through drinking water."
    explanation: "Review confirming dose-response relationship between arsenic exposure and diabetes in endemic areas."
biochemical:
- name: Urinary Arsenic (Total and Speciated)
  biomarker_term:
    preferred_term: arsenic
    term:
      id: CHEBI:27563
      label: arsenic atom
  presence: INCREASED
  notes: >-
    24-hour urinary total arsenic is the primary biomarker of recent arsenic
    exposure. Arsenic speciation (inorganic arsenic, MMA, DMA) provides additional
    information on methylation capacity and risk stratification. Urinary arsenic
    >50 mcg/L suggests significant exposure. Speciation distinguishes inorganic
    arsenic exposure from dietary organic arsenic (arsenobetaine from seafood).
    Typical urinary profile: 10-30% iAs, 10-20% MMA, 60-80% DMA.
  evidence:
  - reference: PMID:12505313
    reference_title: "Mechanisms of arsenic biotransformation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Glutathione, and possibly other thiols, serve as reducing agents. The liver is the most important site of arsenic methylation, but most organs show arsenic methylating activity."
    explanation: "Describes urinary arsenic metabolites as products of hepatic methylation pathway."
- name: Blood Arsenic
  biomarker_term:
    preferred_term: arsenic
    term:
      id: CHEBI:27563
      label: arsenic atom
  presence: INCREASED
  notes: >-
    Blood (whole blood) arsenic levels reflect recent acute exposure but are less
    useful for chronic exposure assessment due to rapid clearance from blood.
    Normal levels are <1 mcg/dL. Levels >6 mcg/dL indicate significant exposure.
  evidence:
  - reference: PMID:22208756
    reference_title: "What is the best biomarker to assess arsenic exposure via drinking water?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the detection of As or its derivatives in the blood is an indication of the dose ingested but it is not evidence of chronic intoxication"
    explanation: "Systematic review confirming blood arsenic as a biomarker of recent dose but not chronic exposure."
- name: Hair and Nail Arsenic
  biomarker_term:
    preferred_term: arsenic
    term:
      id: CHEBI:27563
      label: arsenic atom
  presence: INCREASED
  notes: >-
    Hair and nail arsenic concentrations provide a long-term exposure biomarker,
    reflecting exposure over the preceding months to years. Hair arsenic
    >1 mcg/g suggests chronic exposure. Segmental hair analysis can provide a
    timeline of exposure.
  evidence:
  - reference: PMID:21740555
    reference_title: "Dose-response relationship between arsenic exposure and the serum enzymes for liver function tests in the individuals exposed to arsenic: a cross sectional study in Bangladesh."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "arsenic concentrations in the drinking water were strongly correlated with arsenic concentrations in the subjects' hair and nails"
    explanation: "Cross-sectional study in Bangladesh demonstrating dose-response correlation between water arsenic and hair/nail arsenic concentrations."
  - reference: PMID:33075355
    reference_title: "Toenails as a biomarker of exposure to arsenic: A review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Toenail arsenic can serve as a reliable measure of toxic inorganic arsenic exposure in chronic disease research, particularly promising for cancer and cardiovascular conditions."
    explanation: "Systematic review of 129 studies confirming toenails as a reliable biomarker of long-term arsenic exposure."
- name: Hepatic Transaminases (AST/ALT)
  presence: INCREASED
  notes: >-
    Elevated ALT and AST reflecting arsenic-induced hepatocellular injury.
    Levels may be mildly to moderately elevated in chronic exposure and
    markedly elevated in acute poisoning with hepatic failure.
  evidence:
  - reference: PMID:21740555
    reference_title: "Dose-response relationship between arsenic exposure and the serum enzymes for liver function tests in the individuals exposed to arsenic: a cross sectional study in Bangladesh."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the respective activities of ALP, AST and ALT were found to be significantly increased in the high-exposure groups compared to the lowest-exposure groups before and after adjustments were made for different covariates"
    explanation: "Cross-sectional study in 200 Bangladeshi residents demonstrating dose-response elevation of hepatic transaminases with arsenic exposure."
- name: Beta-2-Microglobulin (Urinary)
  presence: INCREASED
  notes: >-
    Elevated urinary beta-2-microglobulin is a biomarker of proximal tubular
    damage in arsenic-induced nephrotoxicity.
  evidence:
  - reference: PMID:14761355
    reference_title: "[Renal dysfunction in workers exposed to arsenic and cadmium]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There were positive correlations and significant dose-effect among the concentrations of urinary cadmium, arsenic and levels of Ubeta2-MG, UALB, UNAG (P<0.05, P<0.01)."
    explanation: "Occupational study demonstrating significant dose-effect relationship between arsenic exposure and urinary beta-2-microglobulin levels."
- name: N-Acetyl-Beta-D-Glucosaminidase (NAG)
  presence: INCREASED
  notes: >-
    Elevated urinary NAG activity is a sensitive biomarker of early tubular
    damage in arsenic-exposed populations.
  evidence:
  - reference: PMID:21622483
    reference_title: "Effects of low-level arsenic exposure on urinary N-acetyl-β-D-glucosaminidase activity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These facts suggest that a relatively low-level exposure to inorganic arsenic produces renal tubular damage in humans."
    explanation: "Study in 867 Korean adults demonstrating urinary arsenic as a significant determinant of NAG activity, indicating renal tubular damage."
  - reference: PMID:20077223
    reference_title: "Risk assessment of low-level cadmium and arsenic on the kidney."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "NAG, MDA, and 8-OHdG were positively correlated with both Cd and As in urine."
    explanation: "Population study confirming positive correlation between urinary arsenic and NAG activity as a marker of tubular damage."
- name: 8-Hydroxy-2-Deoxyguanosine (8-OHdG)
  biomarker_term:
    preferred_term: 8-OHdG
    term:
      id: CHEBI:40304
      label: 8-hydroxy-2'-deoxyguanosine
  presence: INCREASED
  notes: >-
    Elevated urinary 8-OHdG is a marker of oxidative DNA damage from arsenic
    exposure. Correlates with arsenic dose and duration of exposure.
  evidence:
  - reference: PMID:16545696
    reference_title: "Effects of arsenic exposure among semiconductor workers: a cautionary note on urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the mean urinary concentrations of total arsenic and 8-oxodGuo were significantly higher for exposed workers compared with the nonexposed workers"
    explanation: "Study of 90 semiconductor workers demonstrating elevated urinary 8-OHdG in arsenic-exposed workers, correlating with MMA levels."
  - reference: PMID:20077223
    reference_title: "Risk assessment of low-level cadmium and arsenic on the kidney."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "NAG, MDA, and 8-OHdG were positively correlated with both Cd and As in urine."
    explanation: "Population study confirming positive correlation between urinary arsenic and 8-OHdG as a marker of oxidative DNA damage."
genetic:
- name: AS3MT Polymorphisms
  gene_term:
    preferred_term: AS3MT
    term:
      id: hgnc:17452
      label: AS3MT
  association: Associated
  notes: >-
    Polymorphisms in the arsenic (+3 oxidation state) methyltransferase (AS3MT)
    gene at 10q24.32 influence arsenic metabolism efficiency. The Met287Thr
    variant affects methylation capacity. This locus shows strong signals of
    positive selection in populations with historically high arsenic exposure
    (e.g., Atacameno in northern Chile). Variants associated with higher
    DMA/MMA ratios (better methylation) confer relative protection against
    arsenic toxicity.
  evidence:
  - reference: PMID:11484904
    reference_title: "Role of metabolism in arsenic toxicity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In humans, as in most mammalian species, inorganic arsenic is methylated to methylarsonic acid (MMA) and dimethylarsinic acid (DMA) by alternating reduction of pentavalent arsenic to trivalent and addition of a methyl group from S-adenosylmethionine."
    explanation: "Describes the methylation pathway that AS3MT polymorphisms modulate."
- name: GSTT1/GSTM1 Polymorphisms
  gene_term:
    preferred_term: GSTM1
    term:
      id: hgnc:4632
      label: GSTM1
  association: Associated
  notes: >-
    Polymorphisms in glutathione S-transferase T1 (GSTT1, HGNC:4641) and M1
    (GSTM1) modulate arsenic detoxification via glutathione conjugation of
    arsenic metabolites. The role of null genotypes is complex: some studies
    report that GSTT1 wildtype and GSTM1-positive status are associated with
    increased risk of arsenic-induced skin lesions, suggesting null genotypes
    may paradoxically be protective by preventing formation of reactive
    glutathione-arsenic conjugates.
  evidence:
  - reference: PMID:16353154
    reference_title: "Cytogenetic damage and genetic variants in the individuals susceptible to arsenic-induced cancer through drinking water."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Individuals with GSTM1-positive (at least one allele) had significantly higher risk of arsenic-induced skin lesions (odds ratio, 1.73; 95% confidence interval, 1.24-2.22). These results show a protective role of GSTM1 null in arsenic toxicity."
    explanation: "Study in 422 arsenic-exposed West Bengal subjects found GSTM1-positive genotype (not null) associated with higher skin lesion risk, suggesting GST-mediated conjugation may generate reactive arsenic species."
  - reference: PMID:17284320
    reference_title: "A case-control study of GST polymorphisms and arsenic related skin lesions."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "GSTT1 homozygous wildtype status was associated with increased odds of skin lesions compared to the null status (OR1.56 95% CI 1.10-2.19)."
    explanation: "Case-control study of 1200 Bangladeshi subjects found GSTT1 wildtype (not null) associated with increased skin lesion risk."
- name: MPO Polymorphisms
  gene_term:
    preferred_term: MPO
    term:
      id: hgnc:7218
      label: MPO
  association: Associated
  notes: >-
    Polymorphisms in the oxidative stress gene myeloperoxidase (MPO) are associated
    with increased likelihood of developing arsenical skin lesions including
    hyperkeratosis.
  evidence:
  - reference: PMID:14580687
    reference_title: "Susceptibility to arsenic-induced hyperkeratosis and oxidative stress genes myeloperoxidase and catalase."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Subjects carrying the high-risk MPO genotype and with high arsenic exposure were at almost six times (OR 5.8; 95% CI 1.1-30.1) elevated risk of developing hyperkeratosis as compared to those carrying the low-risk genotype and with low arsenic exposure."
    explanation: "Case-control study demonstrating MPO genotype-arsenic interaction in hyperkeratosis risk."
- name: CAT Polymorphisms
  gene_term:
    preferred_term: CAT
    term:
      id: hgnc:1516
      label: CAT
  association: Associated
  notes: >-
    Polymorphisms in the catalase (CAT) gene are associated with increased
    likelihood of developing arsenical skin lesions including hyperkeratosis.
  evidence:
  - reference: PMID:14580687
    reference_title: "Susceptibility to arsenic-induced hyperkeratosis and oxidative stress genes myeloperoxidase and catalase."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "highly exposed subjects carrying the high-risk CAT genotype were at more than four times (OR 4.6; 95% CI 1.4-15.6) elevated risk of developing hyperkeratosis as compared to those carrying the low-risk genotype and with low arsenic exposure"
    explanation: "Case-control study demonstrating CAT genotype-arsenic interaction in hyperkeratosis risk."
environmental:
- name: Contaminated Groundwater
  exposure_term:
    preferred_term: exposure to arsenic in water via ingestion
    term:
      id: ECTO:0080000
      label: exposure to arsenic in water via ingestion
  description: >-
    Natural geological contamination of groundwater with inorganic arsenic is the
    primary source of chronic arsenic exposure worldwide. The WHO guideline value
    is 10 mcg/L but many countries use 50 mcg/L as the permissible limit.
    Approximately 140 million people in 50 countries drink water with arsenic
    exceeding WHO guidelines. Major affected regions include the Bengal Delta
    (Bangladesh and West Bengal), the Mekong Delta, northern China, and the
    Chaco-Pampean plain of Argentina.
  evidence:
  - reference: PMID:28005215
    reference_title: "ARSENIC: A Review on Exposure Pathways, Accumulation, Mobility and Transmission into the Human Food Chain."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is proven fact that uptake of inorganic As for a long period can lead to chronic As poisoning and a variety of adverse health effects such as skin, lung and bladder cancer, in addition to cardiovascular diseases, diabetes and gastrointestinal symptoms."
    explanation: "Review of arsenic exposure pathways confirming health effects of chronic exposure through contaminated sources."
- name: Occupational Arsenic Exposure
  exposure_term:
    preferred_term: exposure to arsenic
    term:
      id: ECTO:9000032
      label: exposure to arsenic
  description: >-
    Occupational exposure occurs in mining and smelting of arsenopyrite-bearing
    ores, copper smelting, pesticide manufacturing, wood preservation (CCA-treated
    lumber), semiconductor manufacturing, and glass production. Inhalation of
    arsenic-containing dusts and fumes is the primary route. Historical
    occupational exposure contributed to recognition of arsenic as a carcinogen.
  evidence:
  - reference: PMID:19079717
    reference_title: "Respiratory cancer and inhaled inorganic arsenic in copper smelters workers: a linear relationship with cumulative exposure that increases with concentration."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Within categories of arsenic concentration, the association between respiratory cancer and cumulative arsenic exposure was consistent with linearity."
    explanation: "Cohort study of copper smelter workers demonstrating linear dose-response between inhaled inorganic arsenic and respiratory cancer risk."
- name: Dietary Arsenic Exposure
  exposure_term:
    preferred_term: exposure to arsenic via ingestion
    term:
      id: ECTO:0900004
      label: exposure to arsenic via ingestion
  description: >-
    Rice accumulates inorganic arsenic from paddy soils and irrigation water,
    making it a significant dietary source particularly in populations with
    high rice consumption. Other dietary sources include seafood (primarily
    organic arsenobetaine, which is less toxic), poultry (from roxarsone feed
    additive, now withdrawn in many countries), and certain fruit juices.
  evidence:
  - reference: PMID:26586021
    reference_title: "High exposure to inorganic arsenic by food: the need for risk reduction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "exposure to inorganic arsenic represents a risk to the health of the European population, particularly to young children. Regulatory measures to reduce exposure are urgently required."
    explanation: "EFSA-based review identifying rice and other food categories as significant sources of dietary inorganic arsenic exposure, particularly for young children."
- name: Traditional and Herbal Medicines
  exposure_term:
    preferred_term: exposure to arsenic via ingestion
    term:
      id: ECTO:0900004
      label: exposure to arsenic via ingestion
  description: >-
    Certain traditional medicines, particularly Ayurvedic preparations, Chinese
    herbal medicines, and folk remedies contain intentionally added arsenic
    compounds. Arsenic trioxide has been used therapeutically in traditional
    Chinese medicine for centuries and is now an approved treatment for acute
    promyelocytic leukemia.
  evidence:
  - reference: PMID:22843016
    reference_title: "Contamination and adulteration of herbal medicinal products (HMPs): an overview of systematic reviews."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most severe adverse effects caused by these adulterations were agranulocytosis, meningitis, multi-organ failure, perinatal stroke, arsenic, lead or mercury poisoning, malignancies or carcinomas, hepatic encephalopathy, hepatorenal syndrome, nephrotoxicity, rhabdomyolysis, metabolic acidosis, renal or liver failure, cerebral edema, coma, intracerebral haemorrhage, and death."
    explanation: "Overview of systematic reviews confirming arsenic poisoning among severe adverse effects from contaminated herbal medicinal products, particularly traditional Indian and Chinese remedies."
treatments:
- name: Chelation Therapy with Dimercaprol (BAL)
  treatment_term:
    preferred_term: chelation therapy
    term:
      id: MAXO:0001223
      label: chelator agent therapy
  description: >-
    Dimercaprol (British Anti-Lewisite, BAL) is the first-line chelation agent
    for acute symptomatic arsenic poisoning. Administered intramuscularly, it
    forms water-soluble chelates with arsenic that are renally excreted.
    Most effective when given within hours of acute ingestion. Side effects
    include hypertension, tachycardia, nausea, and pain at injection site.
  evidence:
  - reference: PMID:32033229
    reference_title: "Arsenic Toxicity: Molecular Targets and Therapeutic Agents."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In acute cases, initial treatment with BAL combined with DMPS should be considered."
    explanation: "Review of arsenic therapeutic agents recommending BAL as initial chelation treatment for acute arsenic poisoning."
- name: Chelation Therapy with Succimer (DMSA)
  treatment_term:
    preferred_term: chelation therapy
    term:
      id: MAXO:0001223
      label: chelator agent therapy
  description: >-
    Succimer (dimercaptosuccinic acid, DMSA) is an oral chelating agent used for
    less severe arsenic poisoning and as step-down therapy after initial BAL
    treatment. Better tolerated than BAL with fewer side effects. Also used
    in pediatric arsenic exposure due to oral administration route.
  evidence:
  - reference: PMID:32033229
    reference_title: "Arsenic Toxicity: Molecular Targets and Therapeutic Agents."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The development of chelating agents, such as the dithiols BAL (dimercaptopropanol), DMPS (dimercapto-propanesulfonate) and DMSA (dimercaptosuccinic acid), took advantage of the fact that As had high affinity towards vicinal dithiols."
    explanation: "Review confirming DMSA as a therapeutic dithiol chelator for arsenic based on arsenic's affinity for vicinal dithiol groups."
- name: Unithiol (DMPS)
  treatment_term:
    preferred_term: chelation therapy
    term:
      id: MAXO:0001223
      label: chelator agent therapy
  description: >-
    2,3-dimercapto-1-propanesulfonic acid (DMPS, Unithiol) is an alternative
    chelating agent available in Europe and some other countries. Can be given
    orally or intravenously. Some evidence suggests superiority to BAL for
    arsenic chelation.
  evidence:
  - reference: PMID:32033229
    reference_title: "Arsenic Toxicity: Molecular Targets and Therapeutic Agents."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "in acute and subacute and even some cases with chronic As poisonings chelation treatment with therapeutic dithiols, in particular DMPS appears promising as regards alleviation of symptoms"
    explanation: "Review identifying DMPS as a particularly promising chelation agent for arsenic poisoning across acute, subacute, and chronic presentations."
- name: Whole Bowel Irrigation
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  description: >-
    Whole bowel irrigation with polyethylene glycol solution is recommended for
    gastrointestinal decontamination after acute arsenic ingestion, as arsenic
    is poorly adsorbed by activated charcoal. Should be initiated early
    before arsenic absorption is complete.
  evidence:
  - reference: PMID:22541879
    reference_title: "Massive human ingestion of orpiment (arsenic trisulfide)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the patient was managed with whole bowel irrigation with a polyethylene glycol solution, maintenance intravenous hydration, and observation on a telemetry unit"
    explanation: "Case report of massive arsenic trisulfide ingestion successfully managed with whole bowel irrigation alone without chelation."
- name: Exposure Cessation and Safe Water
  treatment_term:
    preferred_term: chemical exposure avoidance
    term:
      id: MAXO:0000071
      label: chemical exposure avoidance
  description: >-
    The most critical intervention for chronic arsenicosis is elimination of
    arsenic exposure, primarily through provision of arsenic-free drinking water.
    Water treatment options include oxidation-coagulation-filtration, adsorption
    (iron-based media), membrane filtration (reverse osmosis), and switching to
    alternative water sources (deep tubewells, rainwater harvesting).
  evidence:
  - reference: PMID:12378292
    reference_title: "Promotion of well-switching to mitigate the current arsenic crisis in Bangladesh."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Well-switching should be more systematically encouraged in Araihazar and many other parts of Bangladesh and West Bengal, India."
    explanation: "Field study demonstrating well-switching as a viable arsenic mitigation strategy, with 90% of inhabitants living within 100m of a safe well."
diagnosis:
- name: Urinary Arsenic Speciation
  diagnosis_term:
    preferred_term: urine chemistry measurement
    term:
      id: MAXO:0000789
      label: urine chemistry measurement
  description: >-
    24-hour urine collection with arsenic speciation (inorganic arsenic, MMA,
    DMA) is the gold standard for confirming arsenic exposure. Total urinary
    arsenic >50 mcg/L is abnormal. Speciation distinguishes inorganic arsenic
    exposure from dietary organic arsenic (arsenobetaine from seafood).
- name: Hair and Nail Analysis
  diagnosis_term:
    preferred_term: biomarker analysis
    term:
      id: MAXO:0000018
      label: biomarker analysis
  description: >-
    Hair and nail arsenic analysis provides long-term exposure assessment.
    Hair arsenic >1 mcg/g and nail arsenic >1.5 mcg/g suggest chronic exposure.
    Useful when exposure occurred weeks to months prior and urinary arsenic
    may have normalized.
- name: Nerve Conduction Studies
  diagnosis_term:
    preferred_term: nerve conduction study
    term:
      id: MAXO:0035059
      label: nerve conduction study
  description: >-
    Electrophysiological studies showing axonal sensory neuropathy with reduced
    nerve conduction velocity support the diagnosis of arsenic-induced
    neuropathy. Sural nerve biopsy may show early-stage axonal degeneration.
prevalence:
- subtype: Chronic
  population: Bangladesh
  percentage: 12.6
  notes: >-
    Estimated prevalence of arsenicosis in exposed populations of Bangladesh.
    Approximately 35-77 million people drink water with arsenic >10 mcg/L.
  evidence:
  - reference: PMID:12718695
    reference_title: "Magnitude of arsenic toxicity in tube-well drinking water in Bangladesh and its adverse effects on human health including cancer: evidence from a review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "More than 50 percent of the total population is estimated at risk of contamination. Already thousands of people have been affected by the disease arsenicosis."
    explanation: "Literature review documenting the magnitude of arsenic contamination in Bangladesh tube-well water, with 59 of 64 districts affected."
- population: Global
  percentage:
  notes: >-
    An estimated 140 million people in at least 50 countries drink water
    containing arsenic above the WHO guideline value of 10 mcg/L. Actual
    prevalence of clinical arsenicosis is difficult to estimate globally.
  evidence:
  - reference: PMID:28005215
    reference_title: "ARSENIC: A Review on Exposure Pathways, Accumulation, Mobility and Transmission into the Human Food Chain."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is proven fact that uptake of inorganic As for a long period can lead to chronic As poisoning and a variety of adverse health effects such as skin, lung and bladder cancer, in addition to cardiovascular diseases, diabetes and gastrointestinal symptoms."
    explanation: "Review of global arsenic exposure documenting widespread contamination and associated health effects across multiple countries."
differential_diagnoses:
- name: Lead Poisoning
  disease_term:
    preferred_term: lead poisoning
    term:
      id: MONDO:0018019
      label: lead poisoning
  distinguishing_features:
  - Lead causes motor-predominant neuropathy (wrist/foot drop) rather than sensory-predominant neuropathy
  - Lead lines on gingiva and basophilic stippling are characteristic of lead but not arsenic
  - Lead does not cause arsenical melanosis or palmoplantar keratoses
  - Blood lead level is diagnostic for lead poisoning
- name: Cadmium Poisoning
  disease_term:
    preferred_term: cadmium poisoning
    term:
      id: MONDO:0043523
      label: cadmium poisoning
  distinguishing_features:
  - Cadmium primarily affects kidney (proximal tubular dysfunction, Fanconi syndrome) and bone (osteomalacia)
  - Cadmium does not cause melanosis or keratoses
  - Arsenic predominantly affects skin and peripheral nerves
- name: Thallium Poisoning
  disease_term:
    preferred_term: thallium poisoning
    term:
      id: MONDO:0041996
      label: thallium poisoning
  distinguishing_features:
  - Thallium causes dramatic alopecia, a hallmark distinguishing feature absent in arsenic poisoning
  - Thallium causes painful sensory neuropathy and gastrointestinal symptoms
  - Arsenic causes hyperpigmentation and keratoses rather than hair loss
- name: Pellagra
  disease_term:
    preferred_term: pellagra
    term:
      id: MONDO:0019975
      label: pellagra
  distinguishing_features:
  - Niacin deficiency causes dermatitis in sun-exposed areas (photosensitive distribution)
  - The classic triad of dermatitis, diarrhea, and dementia differs from arsenicosis
  - Arsenical skin lesions are non-photosensitive (melanosis and palmoplantar keratoses)
clinical_trials:
- name: NCT01442727
  phase: PHASE_III
  status: COMPLETED
  description: >-
    A 48-week randomized, double-blinded, placebo-controlled Phase III trial
    evaluating whether daily selenium supplementation counters arsenic toxicity
    in Bangladeshi arsenicosis patients. Based on preclinical evidence that
    selenium promotes arsenic excretion via formation of the
    seleno-bis(S-glutathionyl) arsinium ion through the hepatobiliary system.
  target_phenotypes:
  - preferred_term: Hyperpigmentation of the skin
    term:
      id: HP:0000953
      label: Hyperpigmentation of the skin
  evidence:
  - reference: clinicaltrials:NCT01442727
    supports: SUPPORT
    snippet: "Approximately 100 million people throughout the world consume water contaminated with arsenic at levels above carcinogenic thresholds, including 40 million in Bangladesh alone, with up to one-fourth of deaths attributed to arsenic exposure in the worst-affected regions. There are no proven therapies for treating chronic arsenic toxicity or for preventing arsenical cancers."
    explanation: "Phase III trial testing selenium supplementation as a therapeutic intervention for chronic arsenic toxicity and cancer prevention."
- name: NCT01050556
  phase: PHASE_IV
  status: COMPLETED
  description: >-
    A Phase IV trial examining whether folic acid, alone or with creatine
    supplementation, can lower blood arsenic concentrations and improve
    arsenic detoxification. Folic acid enhances arsenic methylation capacity
    by supporting one-carbon metabolism, potentially facilitating arsenic
    excretion as DMA.
  evidence:
  - reference: clinicaltrials:NCT01050556
    supports: SUPPORT
    snippet: "The purpose of this study is to determine whether folic acid, alone or together with creatine supplementation, can lower blood arsenic concentrations and improve the ability to detoxify arsenic."
    explanation: "Trial evaluating nutritional supplementation as a strategy to enhance arsenic methylation and reduce blood arsenic levels."
- name: NCT01748669
  phase: PHASE_II
  status: COMPLETED
  description: >-
    A Phase II trial evaluating the effectiveness of oral garlic oil capsules
    in treating arsenical palmar keratosis over 12 weeks. Garlic contains
    organosulfur compounds that may facilitate arsenic excretion and reduce
    body arsenic load.
  target_phenotypes:
  - preferred_term: Palmoplantar keratoderma
    term:
      id: HP:0000982
      label: Palmoplantar keratoderma
  evidence:
  - reference: clinicaltrials:NCT01748669
    supports: SUPPORT
    snippet: "Twenty patients of mild to moderate degree of arsenical palmer keratosis will be treated with garlic oil capsule orally for 12 weeks to examine its effectiveness in reducing body arsenic load and clinical symptoms."
    explanation: "Phase II trial testing garlic oil as a therapeutic intervention for arsenical palmar keratosis."
- name: NCT02377635
  phase: PHASE_II
  status: COMPLETED
  description: >-
    A Phase I/II clinical trial studying the pharmacodynamics of selenium
    supplements in volunteers with high arsenic load from drinking water.
    Participants were maintained in a local clinic with monitored intake and
    excretion of both arsenic and selenium to establish proof of concept for
    selenium-based remediation strategies.
  evidence:
  - reference: clinicaltrials:NCT02377635
    supports: SUPPORT
    snippet: "This clinical trial should prove that selenium can treat arsenic exposure in humans by promoting excretion."
    explanation: "Proof-of-concept Phase I/II trial for selenium-mediated arsenic excretion in chronically exposed populations."
datasets:
- accession: geo:GSE109914
  title: Genome wide DNA methylation analysis of arsenic exposure and non-exposure population and patients with skin lesions
  description: >-
    Methylation profiling comparing arsenic-exposed individuals, non-exposed
    controls, and patients with arsenical skin lesions using Illumina
    HumanMethylation450 BeadChip across approximately 450,000 CpG sites.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: METHYLATION
  sample_types:
  - preferred_term: peripheral blood
    tissue_term:
      preferred_term: blood
      term:
        id: UBERON:0000178
        label: blood
  sample_count: 119
  conditions:
  - arsenic-exposed individuals (n=66)
  - non-exposed controls (n=35)
  - patients with arsenical skin lesions (n=18)
  exposures:
  - preferred_term: exposure to arsenic
    term:
      id: ECTO:9000032
      label: exposure to arsenic
  platform: Illumina Infinium HumanMethylation450 BeadChip
  notes: >-
    Large population-level study from Bangladesh comparing methylation
    profiles across exposure groups. Useful for identifying epigenetic
    biomarkers of arsenic exposure and arsenicosis progression.
- accession: geo:GSE157111
  title: Genome-wide DNA methylation profiles of arsenic exposed subjects through drinking water in Pakistan
  description: >-
    Investigation of DNA methylation changes in individuals exposed to
    elevated groundwater arsenic levels in Pakistan, stratified by low,
    medium, and high exposure levels using MeDIP with NimbleGen arrays.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: METHYLATION
  sample_types:
  - preferred_term: peripheral blood
    tissue_term:
      preferred_term: blood
      term:
        id: UBERON:0000178
        label: blood
  sample_count: 57
  conditions:
  - low arsenic exposure
  - medium arsenic exposure
  - high arsenic exposure
  exposures:
  - preferred_term: exposure to arsenic in water via ingestion
    term:
      id: ECTO:0080000
      label: exposure to arsenic in water via ingestion
  platform: NimbleGen 2.1M Deluxe Promoter arrays
  notes: >-
    Dose-stratified methylation study from Pakistan enabling analysis of
    dose-response epigenetic changes associated with chronic arsenic
    exposure through drinking water.
- accession: geo:GSE110852
  title: Gene expression profiles of subjects exposed to arsenic through drinking water in Pakistan
  description: >-
    Microarray-based transcriptome analysis of individuals exposed to
    elevated groundwater arsenic levels across different exposure
    categories, identifying arsenic-associated gene expression changes.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: MICROARRAY
  sample_types:
  - preferred_term: peripheral blood
    tissue_term:
      preferred_term: blood
      term:
        id: UBERON:0000178
        label: blood
  sample_count: 57
  conditions:
  - arsenic-exposed individuals
  - control subjects
  exposures:
  - preferred_term: exposure to arsenic in water via ingestion
    term:
      id: ECTO:0080000
      label: exposure to arsenic in water via ingestion
  platform: Agilent SurePrint G3 Human Gene Expression Microarray
  notes: >-
    Companion transcriptomic study to GSE157111, enabling integrated
    analysis of gene expression and DNA methylation changes in the same
    arsenic-exposed Pakistani population.
- accession: geo:GSE58499
  title: Arsenic-associated differential DNA methylation in human uroepithelial cells
  description: >-
    Analysis of promoter methylation in bladder uroepithelial cells from
    individuals with varying arsenic exposure in Mexico, identifying
    genes with increased methylation linked to metabolic disease and
    cancer signaling pathways.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: METHYLATION
  sample_types:
  - preferred_term: bladder uroepithelial cells
    tissue_term:
      preferred_term: urinary bladder
      term:
        id: UBERON:0001255
        label: urinary bladder
  sample_count: 46
  conditions:
  - varying arsenic exposure levels
  exposures:
  - preferred_term: exposure to arsenic
    term:
      id: ECTO:9000032
      label: exposure to arsenic
  platform: Affymetrix GeneChip Human Promoter 1.0R Array
  notes: >-
    Clinically relevant study linking arsenic exposure to epigenetic
    changes in target tissue (urothelium) relevant to arsenic-induced
    bladder cancer risk.
references:
- reference: DOI:10.1093/toxres/tfad111
  title: 'Arsenic toxicity: sources, pathophysiology and mechanism'
  found_in:
  - Arsenic_Poisoning-deep-research-falcon.md
  findings:
  - statement: Arsenic is a naturally occurring element that poses a significant threat to human health due to its widespread presence in the environment, affecting millions worldwide.
    supporting_text: Arsenic is a naturally occurring element that poses a significant threat to human health due to its widespread presence in the environment, affecting millions worldwide.
    evidence:
    - reference: DOI:10.1093/toxres/tfad111
      reference_title: 'Arsenic toxicity: sources, pathophysiology and mechanism'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Arsenic is a naturally occurring element that poses a significant threat to human health due to its widespread presence in the environment, affecting millions worldwide.
      explanation: Deep research cited this publication as relevant literature for Arsenic Poisoning.
- reference: DOI:10.1371/journal.pgen.1011248
  title: Unraveling the genetics of arsenic toxicity with cellular morphology QTL
  found_in:
  - Arsenic_Poisoning-deep-research-falcon.md
  findings:
  - statement: The health risks that arise from environmental exposures vary widely within and across human populations, and these differences are largely determined by genetic variation and gene-by-environment (gene–environment) interactions.
    supporting_text: The health risks that arise from environmental exposures vary widely within and across human populations, and these differences are largely determined by genetic variation and gene-by-environment (gene–environment) interactions.
    evidence:
    - reference: DOI:10.1371/journal.pgen.1011248
      reference_title: Unraveling the genetics of arsenic toxicity with cellular morphology QTL
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: The health risks that arise from environmental exposures vary widely within and across human populations, and these differences are largely determined by genetic variation and gene-by-environment (gene–environment) interactions.
      explanation: Deep research cited this publication as relevant literature for Arsenic Poisoning.
- reference: DOI:10.1371/journal.pone.0287937
  title: A comprehensive survey and analysis of international drinking water regulations for inorganic chemicals with comparisons to the World Health Organization’s drinking-water guidelines
  found_in:
  - Arsenic_Poisoning-deep-research-falcon.md
  findings:
  - statement: The World Health Organization (WHO) has published criteria for determining the quality of drinking water since 1958.
    supporting_text: The World Health Organization (WHO) has published criteria for determining the quality of drinking water since 1958.
    evidence:
    - reference: DOI:10.1371/journal.pone.0287937
      reference_title: A comprehensive survey and analysis of international drinking water regulations for inorganic chemicals with comparisons to the World Health Organization’s drinking-water guidelines
      supports: SUPPORT
      evidence_source: OTHER
      snippet: The World Health Organization (WHO) has published criteria for determining the quality of drinking water since 1958.
      explanation: Deep research cited this publication as relevant literature for Arsenic Poisoning.
- reference: DOI:10.3390/foods14132229
  title: 'Arsenic in Water and Food: Toxicity and Human Exposure'
  found_in:
  - Arsenic_Poisoning-deep-research-falcon.md
  findings:
  - statement: Arsenic is a human carcinogen present in drinking water and food, especially rice, rice products and seafood.
    supporting_text: Arsenic is a human carcinogen present in drinking water and food, especially rice, rice products and seafood.
    evidence:
    - reference: DOI:10.3390/foods14132229
      reference_title: 'Arsenic in Water and Food: Toxicity and Human Exposure'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Arsenic is a human carcinogen present in drinking water and food, especially rice, rice products and seafood.
      explanation: Deep research cited this publication as relevant literature for Arsenic Poisoning.
- reference: DOI:10.3390/ijms262110761
  title: Arsenome, Arsenobolome, and Arsenobiolome
  found_in:
  - Arsenic_Poisoning-deep-research-falcon.md
  findings:
  - statement: Arsenome, Arsenobolome, and Arsenobiolome
    supporting_text: A complete characterisation of the potential biological implications of any chemical species requires assessing as much information as possible about the dose of all physicochemical forms involved in its metabolic pathways or any other biological activity (beneficial or harmful).
    evidence:
    - reference: DOI:10.3390/ijms262110761
      reference_title: Arsenome, Arsenobolome, and Arsenobiolome
      supports: SUPPORT
      evidence_source: OTHER
      snippet: A complete characterisation of the potential biological implications of any chemical species requires assessing as much information as possible about the dose of all physicochemical forms involved in its metabolic pathways or any other biological activity (beneficial or harmful).
      explanation: Deep research cited this publication as relevant literature for Arsenic 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:
  - Arsenic_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 Arsenic Poisoning.
- reference: DOI:10.3390/pollutants4020013
  title: 'Arsenic Contamination Needs Serious Attention: An Opinion and Global Scenario'
  found_in:
  - Arsenic_Poisoning-deep-research-falcon.md
  findings:
  - statement: Arsenic (As) contamination is a serious global concern, polluting our natural resources, including water and soil, and posing a danger to the environment and public health.
    supporting_text: Arsenic (As) contamination is a serious global concern, polluting our natural resources, including water and soil, and posing a danger to the environment and public health.
    evidence:
    - reference: DOI:10.3390/pollutants4020013
      reference_title: 'Arsenic Contamination Needs Serious Attention: An Opinion and Global Scenario'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Arsenic (As) contamination is a serious global concern, polluting our natural resources, including water and soil, and posing a danger to the environment and public health.
      explanation: Deep research cited this publication as relevant literature for Arsenic Poisoning.
- reference: DOI:10.3390/w15122185
  title: 'Arsenic in Drinking Water and Urinary Tract Cancers: A Systematic Review Update'
  found_in:
  - Arsenic_Poisoning-deep-research-falcon.md
  findings:
  - statement: 'Problem: There remains uncertainty around cancer risk at lower levels of arsenic in drinking water.'
    supporting_text: 'Problem: There remains uncertainty around cancer risk at lower levels of arsenic in drinking water.'
    evidence:
    - reference: DOI:10.3390/w15122185
      reference_title: 'Arsenic in Drinking Water and Urinary Tract Cancers: A Systematic Review Update'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: 'Problem: There remains uncertainty around cancer risk at lower levels of arsenic in drinking water.'
      explanation: Deep research cited this publication as relevant literature for Arsenic Poisoning.

📚

References & Deep Research

References

DOI:10.1093/toxres/tfad111

Arsenic toxicity: sources, pathophysiology and mechanism

1 finding

Arsenic is a naturally occurring element that poses a significant threat to human health due to its widespread presence in the environment, affecting millions worldwide.

"Arsenic is a naturally occurring element that poses a significant threat to human health due to its widespread presence in the environment, affecting millions worldwide."

Show evidence (1 reference)

DOI:10.1093/toxres/tfad111 SUPPORT Human Clinical

"Arsenic is a naturally occurring element that poses a significant threat to human health due to its widespread presence in the environment, affecting millions worldwide."

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

DOI:10.1371/journal.pgen.1011248

Unraveling the genetics of arsenic toxicity with cellular morphology QTL

1 finding

The health risks that arise from environmental exposures vary widely within and across human populations, and these differences are largely determined by genetic variation and gene-by-environment (gene–environment) interactions.

"The health risks that arise from environmental exposures vary widely within and across human populations, and these differences are largely determined by genetic variation and gene-by-environment (gene–environment) interactions."

Show evidence (1 reference)

DOI:10.1371/journal.pgen.1011248 SUPPORT Model Organism

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

DOI:10.1371/journal.pone.0287937

A comprehensive survey and analysis of international drinking water regulations for inorganic chemicals with comparisons to the World Health Organization’s drinking-water guidelines

1 finding

The World Health Organization (WHO) has published criteria for determining the quality of drinking water since 1958.

"The World Health Organization (WHO) has published criteria for determining the quality of drinking water since 1958."

Show evidence (1 reference)

DOI:10.1371/journal.pone.0287937 SUPPORT Other

"The World Health Organization (WHO) has published criteria for determining the quality of drinking water since 1958."

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

DOI:10.3390/foods14132229

Arsenic in Water and Food: Toxicity and Human Exposure

1 finding

Arsenic is a human carcinogen present in drinking water and food, especially rice, rice products and seafood.

"Arsenic is a human carcinogen present in drinking water and food, especially rice, rice products and seafood."

Show evidence (1 reference)

DOI:10.3390/foods14132229 SUPPORT Human Clinical

"Arsenic is a human carcinogen present in drinking water and food, especially rice, rice products and seafood."

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

DOI:10.3390/ijms262110761

Arsenome, Arsenobolome, and Arsenobiolome

1 finding

Arsenome, Arsenobolome, and Arsenobiolome

"A complete characterisation of the potential biological implications of any chemical species requires assessing as much information as possible about the dose of all physicochemical forms involved in its metabolic pathways or any other biological activity (beneficial or harmful)."

Show evidence (1 reference)

DOI:10.3390/ijms262110761 SUPPORT Other

Deep research cited this publication as relevant literature for Arsenic 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

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

DOI:10.3390/pollutants4020013

Arsenic Contamination Needs Serious Attention: An Opinion and Global Scenario

1 finding

Arsenic (As) contamination is a serious global concern, polluting our natural resources, including water and soil, and posing a danger to the environment and public health.

"Arsenic (As) contamination is a serious global concern, polluting our natural resources, including water and soil, and posing a danger to the environment and public health."

Show evidence (1 reference)

DOI:10.3390/pollutants4020013 SUPPORT Human Clinical

"Arsenic (As) contamination is a serious global concern, polluting our natural resources, including water and soil, and posing a danger to the environment and public health."

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

DOI:10.3390/w15122185

Arsenic in Drinking Water and Urinary Tract Cancers: A Systematic Review Update

1 finding

Problem: There remains uncertainty around cancer risk at lower levels of arsenic in drinking water.

"Problem: There remains uncertainty around cancer risk at lower levels of arsenic in drinking water."

Show evidence (1 reference)

DOI:10.3390/w15122185 SUPPORT Other

"Problem: There remains uncertainty around cancer risk at lower levels of arsenic in drinking water."

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

Deep Research

Falcon ▸

1. Disease Information

Edison Scientific Literature 29 citations 2026-05-08T09:19:48.807697

1. Disease Information

1.1 Concise overview

Arsenic poisoning refers to adverse clinical outcomes resulting from exposure to arsenic compounds, most importantly inorganic arsenic (iAs). Acute intoxication often follows ingestion of iAs and can present within ~30 minutes to 2 hours with severe gastroenteritis, hypotension, cardiac conduction abnormalities (including QT prolongation), neurologic toxicity (delirium, seizures), and acute kidney injury. (balalimood2025recentadvancesin pages 12-13)

Chronic arsenic poisoning is commonly termed arsenicosis and results from long-term low-dose exposure, typically via contaminated drinking water and/or diet. It features characteristic dermatologic findings (hyperpigmentation with “raindrop” pattern, palmoplantar hyperkeratosis), peripheral neuropathy, vascular disease, and increased risk of cancers (skin, bladder, lung, and others). (ganie2024arsenictoxicitysources pages 2-3, chakif2026heavymetaltoxicity pages 12-13)

1.2 Synonyms and alternative names

Chronic arsenic toxicity is explicitly described as arsenicosis, historically also called arseniasis, arsenism, arsenicism. (ganie2024arsenictoxicitysources pages 2-3)

1.3 Key identifiers (ontology/terminology)

ICD-10/ICD-11: Not found in retrieved sources.
MeSH: Not found in retrieved sources.
MONDO: Not found in retrieved sources.

1.4 Evidence provenance

The information summarized here is derived from aggregated disease-level resources (systematic reviews, regulatory assessments, narrative reviews) and mechanistic/model-system studies, rather than individual EHR extractions. (balalimood2025recentadvancesin pages 12-13, visciano2025arsenicinwater pages 10-12, issanov2023arsenicindrinking pages 1-2)

2. Etiology

2.1 Causal factors

Environmental/toxic exposure: Exposure to inorganic arsenic species—especially As(III) (arsenite) and As(V) (arsenate)—from groundwater, food, industrial sources, and in some circumstances inhalational exposures (including arsine gas). (balalimood2025recentadvancesin pages 12-13, ganie2024arsenictoxicitysources pages 1-2)
Chemical species matter: Trivalent arsenicals are emphasized as more toxic due to strong interactions with sulfur-containing proteins/thiols. (ganie2024arsenictoxicitysources pages 1-2)

2.2 Risk factors

Environmental/occupational

Drinking-water contamination is repeatedly highlighted as a principal route in high-burden regions (e.g., South Asia). (ganie2024arsenictoxicitysources pages 1-2)
Global burden: An opinion/global scenario paper reports groundwater arsenic contamination affecting 106 countries and exposing ~230 million people (ATSDR 2022 ranking and WHO “top 10 chemicals” framing also noted). (bhat2024arseniccontaminationneeds pages 1-2)

Host and contextual risk modifiers

Genetic susceptibility: Inter-individual differences in arsenic metabolism (methylation phenotype) are linked to susceptibility; methylation depends on AS3MT and related pathways. (ganie2024arsenictoxicitysources pages 2-3, pullella2024elucidatingtherelationship pages 37-41)
Nutritional status / one‑carbon metabolism: Methyl-donor availability (folate and related nutrients) modifies arsenic methylation capacity and may influence toxicity. (pereira2025arsenomearsenobolomeand pages 20-22, abuawad2023thefolicacid pages 7-8)

2.3 Protective factors

Nutritional supplementation improving methylation indices (human evidence): In the FACT trial (Bangladesh; randomized, double-blind, placebo-controlled), folic acid supplementation improved blood arsenic methylation indices and metabolite profiles (increased SMI and %DMAs, decreased %MMAs), suggesting improved detoxification via enhanced methylation. (abuawad2023thefolicacid pages 7-8, abuawad2023thefolicacid pages 1-2)

2.4 Gene–environment interactions

Mechanistic G×E framing: Variation in response to arsenic metabolites is genetically regulated in model systems; QTL mapping under MMA(III) exposure implicated detoxification and DNA repair loci (e.g., Abcc4, Txnrd1, Xrcc2), supporting gene-by-environment modulation of oxidative stress response and cell death trajectories. (o’connor2024unravelingthegenetics pages 1-2)

3. Phenotypes (clinical manifestations)

A structured phenotype-to-HPO mapping is provided in Artifact-01.

Clinical feature	Acute/Chronic	Description/onset notes	Suggested HPO term(s)	Evidence (citation IDs)
Nausea and vomiting	Acute	Common early gastrointestinal manifestations; acute symptoms may begin within ~30 minutes to 2 hours after ingestion	Nausea (HP:0002018); Vomiting (HP:0002013)	(balalimood2025recentadvancesin pages 12-13, chakif2026heavymetaltoxicity pages 12-13)
Diarrhea	Acute	Prominent early gastroenteritis in acute inorganic arsenic ingestion	Diarrhea (HP:0002014)	(balalimood2025recentadvancesin pages 12-13, balalimood2025recentadvancesin pages 13-14)
Abdominal pain	Acute	Early abdominal pain/cramping as part of acute gastroenteritis syndrome	Abdominal pain (HP:0002027)	(balalimood2025recentadvancesin pages 12-13)
Dehydration / hypovolemia	Acute	Follows severe vomiting and diarrhea; contributes to shock and mortality	Dehydration (HP:0001944); Hypovolemia	(balalimood2025recentadvancesin pages 12-13, balalimood2025recentadvancesin pages 13-14)
Hypotension	Acute	Reported in severe poisoning, often secondary to fluid loss and systemic toxicity	Hypotension (HP:0002615)	(balalimood2025recentadvancesin pages 12-13, chakif2026heavymetaltoxicity pages 12-13)
QT prolongation / arrhythmia	Acute	ECG abnormalities include prolonged QT and other conduction disturbances; can progress to torsades/serious arrhythmia	Prolonged QT interval (HP:0005184); Cardiac arrhythmia (HP:0011675)	(balalimood2025recentadvancesin pages 12-13, chakif2026heavymetaltoxicity pages 12-13, pereira2025arsenomearsenobolomeand pages 19-20)
Tremor	Acute	Neurologic sign reported in acute intoxication	Tremor (HP:0001337)	(balalimood2025recentadvancesin pages 12-13)
Delirium / encephalopathy	Acute	Severe neurotoxicity may include delirium and central nervous system dysfunction	Delirium (HP:0031258); Encephalopathy (HP:0001298)	(balalimood2025recentadvancesin pages 12-13, pereira2025arsenomearsenobolomeand pages 19-20)
Seizures	Acute	Can occur in severe poisoning as part of CNS involvement	Seizure (HP:0001250)	(balalimood2025recentadvancesin pages 12-13, balalimood2025recentadvancesin pages 13-14)
Proteinuria / hematuria	Acute	Renal involvement in acute poisoning may include urinary abnormalities and acute tubular injury	Proteinuria (HP:0000093); Hematuria (HP:0000790)	(balalimood2025recentadvancesin pages 12-13)
Acute kidney injury	Acute	Severe poisoning may cause acute tubular necrosis/renal failure	Acute kidney injury (HP:0031270)	(balalimood2025recentadvancesin pages 12-13, balalimood2025recentadvancesin pages 13-14)
Peripheral neuropathy	Subacute/Chronic	Characteristic sensory > motor neuropathy; may appear 2-4 weeks after acute exposure or develop with chronic exposure	Peripheral neuropathy (HP:0009830); Sensory neuropathy (HP:0000763); Motor neuropathy	(balalimood2025recentadvancesin pages 12-13, ganie2024arsenictoxicitysources pages 2-3, chakif2026heavymetaltoxicity pages 12-13, pereira2025arsenomearsenobolomeand pages 20-22)
Hyperpigmentation	Chronic	Classic skin manifestation, often diffuse or spotted; chronic arsenicosis hallmark	Hyperpigmentation of the skin (HP:0000953)	(balalimood2025recentadvancesin pages 12-13, chakif2026heavymetaltoxicity pages 12-13, pereira2025arsenomearsenobolomeand pages 20-22)
Raindrop-pattern pigmentation	Chronic	Characteristic mottled hyper/hypopigmented skin change in chronic arsenic toxicity	Mottled pigmentation	(balalimood2025recentadvancesin pages 12-13, chakif2026heavymetaltoxicity pages 12-13)
Palmoplantar hyperkeratosis	Chronic	Typical chronic dermal lesion; affects palms and soles	Palmoplantar hyperkeratosis (HP:0000982)	(balalimood2025recentadvancesin pages 12-13, chakif2026heavymetaltoxicity pages 12-13, pereira2025arsenomearsenobolomeand pages 20-22)
Desquamation	Chronic	Reported with chronic arsenic-related dermal injury	Desquamation (HP:0001029)	(pereira2025arsenomearsenobolomeand pages 20-22)
Mees lines	Chronic	Transverse white nail bands associated with chronic exposure	Leukonychia striata / Mees lines	(balalimood2025recentadvancesin pages 12-13)
Cognitive / attention impairment	Chronic	Chronic exposure linked to learning, memory, and attention deficits	Cognitive impairment (HP:0100543); Abnormality of attention	(ganie2024arsenictoxicitysources pages 2-3)
Hypertension / vascular disease	Chronic	Chronic exposure associated with peripheral vascular disease and hypertension; Blackfoot disease is a classic severe vascular manifestation	Hypertension (HP:0000822); Peripheral vascular disease; Blackfoot disease	(ganie2024arsenictoxicitysources pages 1-2, pereira2025arsenomearsenobolomeand pages 20-22)
Skin cancer	Chronic complication	Chronic inorganic arsenic exposure increases skin cancer risk	Skin neoplasm (HP:0012126)	(balalimood2025recentadvancesin pages 12-13, ganie2024arsenictoxicitysources pages 1-2)
Bladder cancer	Chronic complication	Strong epidemiologic association with long-term exposure	Bladder neoplasm (HP:0100747)	(chakif2026heavymetaltoxicity pages 12-13, pereira2025arsenomearsenobolomeand pages 20-22)
Lung cancer	Chronic complication	Established chronic carcinogenic outcome of inorganic arsenic exposure	Lung neoplasm (HP:0100526)	(chakif2026heavymetaltoxicity pages 12-13, ganie2024arsenictoxicitysources pages 1-2, pereira2025arsenomearsenobolomeand pages 20-22)
Kidney or liver cancer	Chronic complication	Reported among internal malignancies linked to chronic exposure	Renal neoplasm; Hepatic neoplasm	(ganie2024arsenictoxicitysources pages 1-2, pereira2025arsenomearsenobolomeand pages 20-22)

Table: This table maps major acute and chronic clinical manifestations of arsenic poisoning to suggested HPO terms for knowledge-base annotation. It emphasizes timing, characteristic arsenicosis features, and long-term cancer complications supported by recent review evidence.

Key time-course features: - Acute: Symptoms begin ~30 min–2 h after ingestion (GI symptoms prominent) with possible cardiovascular collapse and multi-organ injury. (balalimood2025recentadvancesin pages 12-13) - Subacute neurologic: Sensory deficits may appear 2–4 weeks post-exposure. (balalimood2025recentadvancesin pages 12-13) - Chronic: Dermatologic and neurologic manifestations plus long-term cancer risks. (balalimood2025recentadvancesin pages 12-13, chakif2026heavymetaltoxicity pages 12-13)

4. Genetic/Molecular Information

4.1 Causal genes

Arsenic poisoning is not a Mendelian genetic disease; however, genes that govern arsenic metabolism and response modify susceptibility. Strongly implicated genes/pathways include: - AS3MT (arsenic methyltransferase) for methylation of iAs to methylated metabolites. (ganie2024arsenictoxicitysources pages 2-3, singh2024arsenicexposurein pages 1-5) - Detoxification/transport and oxidative stress response genes highlighted in genetic mapping screens under MMA(III) exposure (Abcc4, Txnrd1) and DNA repair candidates (Xrcc2). (o’connor2024unravelingthegenetics pages 1-2)

4.2 Pathogenic variants

Specific human variant pathogenicity classifications (ACMG/ClinVar) were not present in retrieved sources.

4.3 Epigenetic information

Chronic iAs exposure is described as producing epigenetic alterations, including promoter hypermethylation (e.g., MLH1/MSH2), altered DNMT expression (↑DNMT1/DNMT3B, ↓DNMT3A), and global methylation changes linked to SAM depletion. (pereira2025arsenomearsenobolomeand pages 20-22, pullella2024elucidatingtherelationship pages 37-41)

5. Environmental Information

5.1 Environmental factors

Major exposure is via contaminated groundwater and diet; mining/manufacturing and geogenic sources are emphasized in recent reviews. (ganie2024arsenictoxicitysources pages 1-2)

5.2 Lifestyle factors

Dietary contributions can be substantial; risk assessments distinguish organic arsenic from seafood versus inorganic arsenic from water/food sources, requiring speciation for interpretation. (chakif2026heavymetaltoxicity pages 12-13, pullella2024elucidatingtherelationship pages 37-41)

6. Mechanism / Pathophysiology

A structured mechanism table with ontology mapping is provided in Artifact-03.

Mechanism (high level)	Molecular details/chain	Example genes/proteins	Suggested GO biological process terms	Suggested CL cell types	Suggested UBERON organs/tissues	Suggested CHEBI entities/arsenic species	Evidence (citation IDs)
Toxicokinetic uptake, biotransformation, and distribution	Ingested/inhaled inorganic arsenic is absorbed, distributed systemically, and methylated mainly in liver to MMA and DMA; As(V) enters via phosphate transporters, As(III) via aquaglyceroporins, then binds thiols and undergoes reduction/methylation using GSH, thioredoxin systems, SAM, and AS3MT. Urinary excretion is the main clearance route; skin, hair, nails, bone, and teeth can accumulate arsenic.	AS3MT, TXNRD1, thioredoxin, glutathione-related proteins, aquaglyceroporins, phosphate transporters	GO:0006730 one-carbon metabolic process; GO:0017144 drug metabolic process; GO:0042493 response to drug; GO:0055085 transmembrane transport	hepatocyte; erythrocyte; renal tubular epithelial cell	liver (UBERON:0002107); kidney (UBERON:0002113); skin (UBERON:0002097); blood (UBERON:0000178)	inorganic arsenic; arsenite(3+) / As(III); arsenate(V) / As(V); monomethylarsonous acid (MMAIII); dimethylarsinic acid (DMA)	(ganie2024arsenictoxicitysources pages 2-3, chakif2026heavymetaltoxicity pages 12-13, ganie2024arsenictoxicitysources pages 1-2, pullella2024elucidatingtherelationship pages 37-41)
Thiol binding and enzyme inhibition	Trivalent arsenicals bind sulfhydryl/lipoic-acid–dependent enzymes, disrupting central metabolism and redox homeostasis. MMA(III) binds lipoic acid and inhibits pyruvate dehydrogenase; As(V) can substitute for phosphate in metabolic intermediates, impairing ATP-generating reactions.	pyruvate dehydrogenase complex, lipoic acid–dependent enzymes, glyceraldehyde-3-phosphate dehydrogenase	GO:0006099 tricarboxylic acid cycle; GO:0006096 glycolytic process; GO:0046034 ATP metabolic process; GO:0055114 oxidation-reduction process	hepatocyte; cardiomyocyte; neuron	liver (UBERON:0002107); heart (UBERON:0000948); nervous system (UBERON:0001016)	arsenite(3+); arsenate(V); MMAIII; ADP-arsenate; glucose-6-arsenate	(pereira2025arsenomearsenobolomeand pages 19-20, ganie2024arsenictoxicitysources pages 2-3, chakif2026heavymetaltoxicity pages 12-13)
Oxidative and nitrosative stress	A central initiating event is ROS/RNS generation with lipid, protein, and DNA oxidation; reported biomarkers include MDA, protein carbonyls, and 8-hydroxydeoxyguanosine. MMA(III) and As(III) also interfere with nitric oxide biology, including NOS inhibition and peroxynitrite-related injury.	TXNRD1, Nrf2 pathway components, nitric oxide synthase, heme oxygenase, ferritin, metallothionein	GO:0006979 response to oxidative stress; GO:1903409 reactive oxygen species metabolic process; GO:0051409 response to nitrosative stress; GO:0034599 cellular response to oxidative stress	fibroblast; endothelial cell; keratinocyte; neuron	skin (UBERON:0002097); vasculature (UBERON:0004535); lung (UBERON:0002048); kidney (UBERON:0002113)	arsenite(3+); MMAIII; inorganic arsenic	(balalimood2025recentadvancesin pages 12-13, pereira2025arsenomearsenobolomeand pages 19-20, pereira2025arsenomearsenobolomeand pages 20-22, pullella2024elucidatingtherelationship pages 37-41, ganie2024arsenictoxicitysources pages 2-3)
NRF2-mediated antioxidant response and detoxification	Genetic and experimental studies identify NRF2-linked antioxidant defense, detoxification, and stress-response programs as major regulated responses to arsenic metabolites. Cellular morphology QTL mapped loci including Abcc4 and Txnrd1, supporting genetically controlled variability in response to MMAIII.	ABCC4, TXNRD1, NRF2 pathway genes, metallothioneins	GO:0034599 cellular response to oxidative stress; GO:0042744 hydrogen peroxide catabolic process; GO:0006805 xenobiotic metabolic process; GO:0046677 response to antibiotic	fibroblast; hepatocyte; renal epithelial cell	liver (UBERON:0002107); kidney (UBERON:0002113); skin (UBERON:0002097)	MMAIII; inorganic arsenic; arsenite(3+)	(pullella2024elucidatingtherelationship pages 37-41, ganie2024arsenictoxicitysources pages 2-3)
DNA damage and impaired DNA repair	Arsenic increases chromosomal abnormalities, sister chromatid exchange, oxidative DNA damage, and genomic instability. It inhibits DNA mismatch repair and broader DNA repair responses; cmQTL work highlighted DNA repair candidate Xrcc2. Chronic exposure is linked to 8-oxo-dG elevation and repair gene dysregulation.	XRCC2, MLH1, MSH2, p53-related pathways	GO:0006281 DNA repair; GO:0006974 cellular response to DNA damage stimulus; GO:0036297 interstrand cross-link repair; GO:0006302 double-strand break repair	fibroblast; keratinocyte; urothelial cell	skin (UBERON:0002097); urinary bladder (UBERON:0001255); lung (UBERON:0002048)	inorganic arsenic; arsenite(3+); MMAIII	(pereira2025arsenomearsenobolomeand pages 19-20, pereira2025arsenomearsenobolomeand pages 20-22, pullella2024elucidatingtherelationship pages 37-41, ganie2024arsenictoxicitysources pages 2-3)
Epigenetic dysregulation and methyl-donor depletion	Arsenic perturbs epigenetic control through SAM depletion, global hypomethylation, locus-specific hypermethylation (e.g., MLH1, MSH2), altered DNMT expression, mitochondrial D-loop hypomethylation, miRNA changes, and m6A-related signaling. Nutritional methyl-donor status (folate, choline, methionine, betaine, B vitamins) modifies toxicity.	DNMT1, DNMT3A, DNMT3B, MLH1, MSH2, METTL3, YTHDF2, JAK2, STAT3, AS3MT	GO:0006306 DNA methylation; GO:0016573 histone acetylation; GO:0032776 DNA methylation on cytosine; GO:0010608 post-transcriptional regulation of gene expression	keratinocyte; hepatocyte; stem/progenitor-like epithelial cell	skin (UBERON:0002097); liver (UBERON:0002107); urinary bladder (UBERON:0001255)	inorganic arsenic; arsenite(3+); methylated arsenicals	(pereira2025arsenomearsenobolomeand pages 20-22, pereira2025arsenomearsenobolomeand pages 19-20, pullella2024elucidatingtherelationship pages 37-41, abuawad2023thefolicacid pages 6-7, abuawad2023thefolicacid pages 7-8, abuawad2023thefolicacid pages 1-2)
Mitochondrial dysfunction and apoptosis	Arsenic disrupts mitochondrial respiration and oxidative phosphorylation, lowers ATP production, activates JNK/ERK and GRP78/CHOP stress pathways, and promotes apoptosis/cell death trajectories. These events link upstream redox injury to organ dysfunction and neuro/cardiotoxicity.	JNK, ERK, GRP78, CHOP, pyruvate dehydrogenase complex	GO:0007005 mitochondrion organization; GO:0008635 activation of apoptotic process; GO:1902600 proton transmembrane transport; GO:0070059 intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress	neuron; cardiomyocyte; hepatocyte	brain (UBERON:0000955); heart (UBERON:0000948); liver (UBERON:0002107)	MMAIII; arsenite(3+); inorganic arsenic	(pereira2025arsenomearsenobolomeand pages 19-20, ganie2024arsenictoxicitysources pages 2-3, chakif2026heavymetaltoxicity pages 12-13)
Inflammation, angiogenesis, and malignant transformation	Chronic exposure activates inflammatory signaling (including NF-kB-related and CD14-linked profiles), VEGF/angiogenesis, EMT-like programs, and altered signal transduction, helping connect long-term exposure to skin, bladder, lung, kidney, and liver cancers.	NFkB, VEGF, EGFR, CD14, p38 MAPK pathway components	GO:0006954 inflammatory response; GO:0001525 angiogenesis; GO:0001837 epithelial to mesenchymal transition; GO:0008284 positive regulation of cell population proliferation	endothelial cell; macrophage/monocyte; keratinocyte; urothelial cell	skin (UBERON:0002097); lung (UBERON:0002048); urinary bladder (UBERON:0001255); kidney (UBERON:0002113)	inorganic arsenic; arsenite(3+); methylated arsenicals	(pereira2025arsenomearsenobolomeand pages 20-22, pullella2024elucidatingtherelationship pages 37-41, chakif2026heavymetaltoxicity pages 12-13, ganie2024arsenictoxicitysources pages 1-2)
Electrophysiologic cardiotoxicity	Arsenic blocks repolarizing potassium currents (IKr, IKs), prolonging QT and predisposing to torsades/arrhythmias; this is a key downstream mechanism in acute severe poisoning.	IKr channel, IKs channel	GO:0086001 cardiac muscle cell action potential; GO:1903779 regulation of cardiac conduction; GO:0006813 potassium ion transport	cardiomyocyte	heart (UBERON:0000948)	arsenite(3+); inorganic arsenic	(pereira2025arsenomearsenobolomeand pages 19-20, balalimood2025recentadvancesin pages 12-13, chakif2026heavymetaltoxicity pages 12-13)
Population genetic susceptibility and gene-by-environment interaction	Toxic response varies with arsenic methylation phenotype and genetic background. Human and model-system evidence implicates AS3MT genotype in methylation/toxicity variability, while cell-based QTL mapping identified response loci including Abcc4, Txnrd1, and Xrcc2 under MMAIII exposure.	AS3MT, ABCC4, TXNRD1, XRCC2	GO:0006805 xenobiotic metabolic process; GO:0042221 response to chemical; GO:0006974 cellular response to DNA damage stimulus	fibroblast; hepatocyte	liver (UBERON:0002107); skin (UBERON:0002097); kidney (UBERON:0002113)	MMAIII; inorganic arsenic; arsenite(3+)	(ganie2024arsenictoxicitysources pages 2-3, pullella2024elucidatingtherelationship pages 37-41, abuawad2023thefolicacid pages 8-9, abuawad2023thefolicacid pages 1-2)

Table: This table summarizes major molecular and cellular mechanisms of arsenic poisoning and links them to suggested ontology terms for knowledge-base curation. It integrates toxicokinetics, oxidative stress, DNA damage, epigenetic dysregulation, mitochondrial injury, carcinogenic signaling, and genetic susceptibility.

6.1 Current mechanistic understanding (high-level causal chain)

Exposure and uptake (water/food/air) → systemic distribution and hepatic biotransformation to MMA/DMA. (ganie2024arsenictoxicitysources pages 2-3, chakif2026heavymetaltoxicity pages 12-13)
Molecular initiating events: thiol binding and inhibition of lipoic-acid–dependent enzymes; phosphate mimicry by arsenate; redox disruption. (pereira2025arsenomearsenobolomeand pages 19-20)
Cellular injury pathways: oxidative/nitrosative stress, mitochondrial dysfunction, ER stress, apoptosis, impaired DNA repair, and epigenetic dysregulation. (pereira2025arsenomearsenobolomeand pages 19-20, pereira2025arsenomearsenobolomeand pages 20-22)
Organ-level outcomes: GI injury/shock in acute poisoning; skin lesions/neuropathy/vascular disease and carcinogenesis in chronic exposure. (balalimood2025recentadvancesin pages 12-13, chakif2026heavymetaltoxicity pages 12-13)

7. Anatomical Structures Affected

Acute toxicity: gastrointestinal tract, cardiovascular system (cardiac conduction), kidney (acute tubular necrosis/AKI), liver, nervous system. (balalimood2025recentadvancesin pages 12-13)
Chronic toxicity: skin (hyperpigmentation, hyperkeratosis), peripheral nerves, vasculature (e.g., Blackfoot disease), and carcinogenesis in bladder, lung, and skin. (chakif2026heavymetaltoxicity pages 12-13, pereira2025arsenomearsenobolomeand pages 20-22)

Suggested UBERON targets are included in Artifact-03.

8. Temporal Development

Acute onset: minutes to hours after ingestion (30 min–2 h), with death possible within days if severe. (balalimood2025recentadvancesin pages 12-13)
Subacute stage: neuropathy may develop 2–4 weeks after exposure. (balalimood2025recentadvancesin pages 12-13)
Chronic course: prolonged exposure leads to arsenicosis; recovery can be prolonged and incomplete, particularly neuropathy. (balalimood2025recentadvancesin pages 13-14)

9. Inheritance and Population

9.1 Epidemiology and exposure burden

A global scenario/opinion report estimates arsenic-contaminated groundwater affects ~106 countries and exposes ~230 million people; WHO, EPA, and EU drinking-water limits are cited as 10 µg/L. (bhat2024arseniccontaminationneeds pages 1-2)

9.2 Regulatory coverage and inequity

WHO drinking-water guideline value for arsenic is 10 µg/L (0.01 mg/L) and is explicitly labeled “Provisional”, with rationale including treatment performance and analytical achievability rather than purely health-based derivation. (mitchell2023acomprehensivesurvey pages 6-8)
An international survey reports that 32% of the world’s population live in countries where the national arsenic standard is less protective than the WHO GV of 10 µg/L. (mitchell2023acomprehensivesurvey pages 2-4)

10. Diagnostics

A structured diagnostics table is provided in Artifact-02.

Table: This table summarizes clinically relevant diagnostic biomarkers and current treatment approaches for arsenic poisoning, including practical interpretation notes and quantitative thresholds reported in the retrieved evidence. It is useful for distinguishing recent versus chronic exposure and for mapping acute management options to the evidence base.

Key points: - Urine arsenic speciation (iAs/MMA/DMA) is emphasized as essential to distinguish inorganic exposure from seafood-related organic arsenic and to evaluate methylation phenotype. (chakif2026heavymetaltoxicity pages 12-13, pullella2024elucidatingtherelationship pages 37-41) - Quantitative cutoffs reported in retrieved sources include blood arsenic >130 nmol/L, 24‑h urinary total arsenic >100 µg/L, spot urine >50 µg/L, and toenail As >0.5 µg/g (noting these are presented in a review context and should be interpreted clinically). (pullella2024elucidatingtherelationship pages 41-44)

11. Outcome / Prognosis

11.1 Acute poisoning outcomes

Minimal lethal dose reported as 1–3 mg/kg, with an estimated lethal inorganic exposure around 0.6 mg/kg; death may occur within 1–4 days after ingestion. (balalimood2025recentadvancesin pages 12-13)
Arsine gas exposures above ~10 ppm are described as lethal. (balalimood2025recentadvancesin pages 12-13)

11.2 Long-term complications and quantitative cancer risks

A 2023 systematic review/meta-analysis update reported Bayesian pooled RRs for bladder cancer incidence of 1.25 at 10 µg/L, 2.11 at 50 µg/L, and 3.01 at 150 µg/L; and for kidney cancer of 1.37 at 10 µg/L, 1.95 at 50 µg/L, and 2.47 at 150 µg/L. (issanov2023arsenicindrinking pages 1-2)

12. Treatment

12.1 Acute management (real-world implementation)

Core management includes aggressive IV fluids/electrolytes, symptom control (antiemetics), arrhythmia and seizure management, and renal support including hemodialysis for AKI/oliguria. (balalimood2025recentadvancesin pages 13-14)
Chelation: key agents named include succimer (DMSA), DMPS, and dimercaprol (BAL); chelators are described as most effective minutes to hours after exposure. A suggested chelation target is 24‑h urinary arsenic <50 µg/L. (balalimood2025recentadvancesin pages 13-14)
Chronic/subacute arsenicosis: exposure cessation is primary, chelation has limited efficacy, and succimer is noted as preferred for prolonged cases with monitoring. (balalimood2025recentadvancesin pages 13-14)

12.2 Nutritional intervention evidence (human trial)

FACT trial (NCT01050556; Bangladesh; 2023 EHP): folic acid (400–800 µg/day) improved blood methylation profiles (increased SMI and %DMAs, decreased %MMAs), with partial reversal upon stopping supplementation, supporting sustained methyl-donor strategies (e.g., fortification) as a plausible mitigation adjunct. (abuawad2023thefolicacid pages 1-2, abuawad2023thefolicacid pages 7-8)

Suggested MAXO terms (names only): chelation therapy; hemodialysis; gastrointestinal decontamination; nutritional supplementation; exposure avoidance/remediation.

13. Prevention

Primary prevention: reduce iAs exposure through enforcement of drinking-water standards and mitigation/removal technologies; WHO GV is 10 µg/L (provisional) and set with feasibility constraints. (mitchell2023acomprehensivesurvey pages 6-8)
Population-scale mitigation urgency: global scenario evidence supports the large exposed population and multi-country distribution, motivating monitoring and remediation prioritization. (bhat2024arseniccontaminationneeds pages 1-2)

14. Other Species / Natural Disease

The retrieved sources did not provide well-documented naturally occurring “arsenicosis” case series in companion animals; however, the toxicant is relevant across species and arsenic exposure is discussed in livestock contexts in broader heavy-metal reviews (not specific to arsenic-only disease characterization).

15. Model Organisms

Humanized AS3MT mouse model (C57BL/6): A 2024 study used C57BL/6 mice carrying the human BORCS7/AS3MT locus; with 200 ppb arsenite exposures during different developmental windows, the model showed sex- and window-specific increases in fasting glycemia and impaired β-cell function (lower HOMA‑β in in utero exposed males), and it is presented as more human-relevant because standard mice methylate/detoxify iAs more efficiently than humans. (singh2024arsenicexposurein pages 1-5)
Genetically diverse in vitro model (Diversity Outbred fibroblasts): A 2024 PLOS Genetics study derived fibroblast lines from DO mice and exposed them to MMA(III), using high-content imaging to map cell morphology QTLs; loci included known detox genes (Abcc4, Txnrd1) and DNA repair (Xrcc2), enabling gene–environment mapping of arsenic sensitivity/resilience. (o’connor2024unravelingthegenetics pages 2-3, o’connor2024unravelingthegenetics pages 1-2)

Recent developments and expert analysis (2023–2024 emphasis)

Regulatory science update: WHO’s arsenic GV remains 10 µg/L (provisional) and is explicitly constrained by treatment/analytical feasibility, highlighting a persistent gap between health-based values and implementable standards. (mitchell2023acomprehensivesurvey pages 6-8)
Quantitative cancer risk at low-to-moderate exposures: Updated systematic review evidence supports elevated bladder and kidney cancer risk even at 10 µg/L, albeit with uncertainty, with increasing risks at 50 and 150 µg/L. (issanov2023arsenicindrinking pages 1-2)
Global public-health framing (expert opinion): Recent global scenario/opinion work emphasizes urgent mitigation given widespread exposure (230 million) and broad geographic footprint (106 countries). (bhat2024arseniccontaminationneeds pages 1-2)

Key concepts and definitions (summary tables)

Concept	Definition/notes	Synonyms	Key exposure route(s)	Identifier(s) explicitly available in retrieved evidence	Key citation ID
Acute arsenic poisoning	Rapid-onset toxicity, usually after ingestion of inorganic arsenic; symptoms may begin within ~30 min to 2 h and commonly include severe gastroenteritis, hypotension, QT prolongation/arrhythmia, neurologic toxicity, renal injury, and hepatic/hematologic abnormalities.	Acute arsenic toxicity	Ingestion; less commonly inhalation in occupational settings	Not found in retrieved sources	(balalimood2025recentadvancesin pages 12-13, chakif2026heavymetaltoxicity pages 12-13)
Chronic arsenic poisoning / arsenicosis	Slow accumulation of low-dose exposure over time causing multisystem disease, especially skin lesions, peripheral neuropathy, vascular disease, and elevated cancer risk; explicitly named “arsenicosis.”	Arsenicosis; arseniasis; arsenism; arsenicism	Chronic ingestion via drinking water/food; inhalation in some occupational settings	Not found in retrieved sources	(ganie2024arsenictoxicitysources pages 2-3, ganie2024arsenictoxicitysources pages 1-2, pereira2025arsenomearsenobolomeand pages 20-22)
Inorganic arsenic (iAs)	Toxicologically most important arsenic category; includes pentavalent arsenate and trivalent arsenite, undergoes hepatic methylation to MMA and DMA, and is associated with carcinogenic, vascular, neurologic, and dermatologic effects.	iAs; inorganic As	Ingestion from contaminated water/food; inhalation	Not found in retrieved sources	(ganie2024arsenictoxicitysources pages 2-3, chakif2026heavymetaltoxicity pages 12-13, ganie2024arsenictoxicitysources pages 1-2)
Arsenite As(III)	Trivalent inorganic arsenic; generally more toxic than As(V), strongly interacts with sulfhydryl-containing proteins and key enzymes, and is central to oxidative stress and mitochondrial dysfunction mechanisms.	Arsenite; As3+; trivalent arsenic; meta-arsenite	Ingestion; inhalation; some dermal absorption of trivalent forms	Not found in retrieved sources	(ganie2024arsenictoxicitysources pages 2-3, ganie2024arsenictoxicitysources pages 1-2, pereira2025arsenomearsenobolomeand pages 19-20)
Arsenate As(V)	Pentavalent inorganic arsenic; enters cells via phosphate transporters and can substitute for phosphate in biochemical reactions, disrupting cellular energetics before reduction/methylation.	Arsenate; As5+; pentavalent arsenic	Ingestion; inhalation	Not found in retrieved sources	(ganie2024arsenictoxicitysources pages 2-3, ganie2024arsenictoxicitysources pages 1-2, pereira2025arsenomearsenobolomeand pages 19-20)
Arsine gas AsH3	Extremely toxic gaseous arsenic species; inhalational exposure is a classic occupational hazard and can be rapidly lethal, with reported lethality above ~10 ppm in retrieved evidence.	Arsine; arsenic hydride	Inhalation	Not found in retrieved sources	(balalimood2025recentadvancesin pages 12-13)

Table: This table summarizes the main clinical and chemical concepts relevant to arsenic poisoning, including acute and chronic disease forms and major inorganic arsenic species. It is useful as a compact reference for terminology, exposure routes, and evidence-backed definitions from the retrieved literature.

Diagnostics and treatments (summary table)

Mechanisms and ontology mapping (summary table)

Mechanism (high level)	Molecular details/chain	Example genes/proteins	Suggested GO biological process terms	Suggested CL cell types	Suggested UBERON organs/tissues	Suggested CHEBI entities/arsenic species	Evidence (citation IDs)
Toxicokinetic uptake, biotransformation, and distribution	Ingested/inhaled inorganic arsenic is absorbed, distributed systemically, and methylated mainly in liver to MMA and DMA; As(V) enters via phosphate transporters, As(III) via aquaglyceroporins, then binds thiols and undergoes reduction/methylation using GSH, thioredoxin systems, SAM, and AS3MT. Urinary excretion is the main clearance route; skin, hair, nails, bone, and teeth can accumulate arsenic.	AS3MT, TXNRD1, thioredoxin, glutathione-related proteins, aquaglyceroporins, phosphate transporters	GO:0006730 one-carbon metabolic process; GO:0017144 drug metabolic process; GO:0042493 response to drug; GO:0055085 transmembrane transport	hepatocyte; erythrocyte; renal tubular epithelial cell	liver (UBERON:0002107); kidney (UBERON:0002113); skin (UBERON:0002097); blood (UBERON:0000178)	inorganic arsenic; arsenite(3+) / As(III); arsenate(V) / As(V); monomethylarsonous acid (MMAIII); dimethylarsinic acid (DMA)	(ganie2024arsenictoxicitysources pages 2-3, chakif2026heavymetaltoxicity pages 12-13, ganie2024arsenictoxicitysources pages 1-2, pullella2024elucidatingtherelationship pages 37-41)
Thiol binding and enzyme inhibition	Trivalent arsenicals bind sulfhydryl/lipoic-acid–dependent enzymes, disrupting central metabolism and redox homeostasis. MMA(III) binds lipoic acid and inhibits pyruvate dehydrogenase; As(V) can substitute for phosphate in metabolic intermediates, impairing ATP-generating reactions.	pyruvate dehydrogenase complex, lipoic acid–dependent enzymes, glyceraldehyde-3-phosphate dehydrogenase	GO:0006099 tricarboxylic acid cycle; GO:0006096 glycolytic process; GO:0046034 ATP metabolic process; GO:0055114 oxidation-reduction process	hepatocyte; cardiomyocyte; neuron	liver (UBERON:0002107); heart (UBERON:0000948); nervous system (UBERON:0001016)	arsenite(3+); arsenate(V); MMAIII; ADP-arsenate; glucose-6-arsenate	(pereira2025arsenomearsenobolomeand pages 19-20, ganie2024arsenictoxicitysources pages 2-3, chakif2026heavymetaltoxicity pages 12-13)
Oxidative and nitrosative stress	A central initiating event is ROS/RNS generation with lipid, protein, and DNA oxidation; reported biomarkers include MDA, protein carbonyls, and 8-hydroxydeoxyguanosine. MMA(III) and As(III) also interfere with nitric oxide biology, including NOS inhibition and peroxynitrite-related injury.	TXNRD1, Nrf2 pathway components, nitric oxide synthase, heme oxygenase, ferritin, metallothionein	GO:0006979 response to oxidative stress; GO:1903409 reactive oxygen species metabolic process; GO:0051409 response to nitrosative stress; GO:0034599 cellular response to oxidative stress	fibroblast; endothelial cell; keratinocyte; neuron	skin (UBERON:0002097); vasculature (UBERON:0004535); lung (UBERON:0002048); kidney (UBERON:0002113)	arsenite(3+); MMAIII; inorganic arsenic	(balalimood2025recentadvancesin pages 12-13, pereira2025arsenomearsenobolomeand pages 19-20, pereira2025arsenomearsenobolomeand pages 20-22, pullella2024elucidatingtherelationship pages 37-41, ganie2024arsenictoxicitysources pages 2-3)
NRF2-mediated antioxidant response and detoxification	Genetic and experimental studies identify NRF2-linked antioxidant defense, detoxification, and stress-response programs as major regulated responses to arsenic metabolites. Cellular morphology QTL mapped loci including Abcc4 and Txnrd1, supporting genetically controlled variability in response to MMAIII.	ABCC4, TXNRD1, NRF2 pathway genes, metallothioneins	GO:0034599 cellular response to oxidative stress; GO:0042744 hydrogen peroxide catabolic process; GO:0006805 xenobiotic metabolic process; GO:0046677 response to antibiotic	fibroblast; hepatocyte; renal epithelial cell	liver (UBERON:0002107); kidney (UBERON:0002113); skin (UBERON:0002097)	MMAIII; inorganic arsenic; arsenite(3+)	(pullella2024elucidatingtherelationship pages 37-41, ganie2024arsenictoxicitysources pages 2-3)
DNA damage and impaired DNA repair	Arsenic increases chromosomal abnormalities, sister chromatid exchange, oxidative DNA damage, and genomic instability. It inhibits DNA mismatch repair and broader DNA repair responses; cmQTL work highlighted DNA repair candidate Xrcc2. Chronic exposure is linked to 8-oxo-dG elevation and repair gene dysregulation.	XRCC2, MLH1, MSH2, p53-related pathways	GO:0006281 DNA repair; GO:0006974 cellular response to DNA damage stimulus; GO:0036297 interstrand cross-link repair; GO:0006302 double-strand break repair	fibroblast; keratinocyte; urothelial cell	skin (UBERON:0002097); urinary bladder (UBERON:0001255); lung (UBERON:0002048)	inorganic arsenic; arsenite(3+); MMAIII	(pereira2025arsenomearsenobolomeand pages 19-20, pereira2025arsenomearsenobolomeand pages 20-22, pullella2024elucidatingtherelationship pages 37-41, ganie2024arsenictoxicitysources pages 2-3)
Epigenetic dysregulation and methyl-donor depletion	Arsenic perturbs epigenetic control through SAM depletion, global hypomethylation, locus-specific hypermethylation (e.g., MLH1, MSH2), altered DNMT expression, mitochondrial D-loop hypomethylation, miRNA changes, and m6A-related signaling. Nutritional methyl-donor status (folate, choline, methionine, betaine, B vitamins) modifies toxicity.	DNMT1, DNMT3A, DNMT3B, MLH1, MSH2, METTL3, YTHDF2, JAK2, STAT3, AS3MT	GO:0006306 DNA methylation; GO:0016573 histone acetylation; GO:0032776 DNA methylation on cytosine; GO:0010608 post-transcriptional regulation of gene expression	keratinocyte; hepatocyte; stem/progenitor-like epithelial cell	skin (UBERON:0002097); liver (UBERON:0002107); urinary bladder (UBERON:0001255)	inorganic arsenic; arsenite(3+); methylated arsenicals	(pereira2025arsenomearsenobolomeand pages 20-22, pereira2025arsenomearsenobolomeand pages 19-20, pullella2024elucidatingtherelationship pages 37-41, abuawad2023thefolicacid pages 6-7, abuawad2023thefolicacid pages 7-8, abuawad2023thefolicacid pages 1-2)
Mitochondrial dysfunction and apoptosis	Arsenic disrupts mitochondrial respiration and oxidative phosphorylation, lowers ATP production, activates JNK/ERK and GRP78/CHOP stress pathways, and promotes apoptosis/cell death trajectories. These events link upstream redox injury to organ dysfunction and neuro/cardiotoxicity.	JNK, ERK, GRP78, CHOP, pyruvate dehydrogenase complex	GO:0007005 mitochondrion organization; GO:0008635 activation of apoptotic process; GO:1902600 proton transmembrane transport; GO:0070059 intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress	neuron; cardiomyocyte; hepatocyte	brain (UBERON:0000955); heart (UBERON:0000948); liver (UBERON:0002107)	MMAIII; arsenite(3+); inorganic arsenic	(pereira2025arsenomearsenobolomeand pages 19-20, ganie2024arsenictoxicitysources pages 2-3, chakif2026heavymetaltoxicity pages 12-13)
Inflammation, angiogenesis, and malignant transformation	Chronic exposure activates inflammatory signaling (including NF-kB-related and CD14-linked profiles), VEGF/angiogenesis, EMT-like programs, and altered signal transduction, helping connect long-term exposure to skin, bladder, lung, kidney, and liver cancers.	NFkB, VEGF, EGFR, CD14, p38 MAPK pathway components	GO:0006954 inflammatory response; GO:0001525 angiogenesis; GO:0001837 epithelial to mesenchymal transition; GO:0008284 positive regulation of cell population proliferation	endothelial cell; macrophage/monocyte; keratinocyte; urothelial cell	skin (UBERON:0002097); lung (UBERON:0002048); urinary bladder (UBERON:0001255); kidney (UBERON:0002113)	inorganic arsenic; arsenite(3+); methylated arsenicals	(pereira2025arsenomearsenobolomeand pages 20-22, pullella2024elucidatingtherelationship pages 37-41, chakif2026heavymetaltoxicity pages 12-13, ganie2024arsenictoxicitysources pages 1-2)
Electrophysiologic cardiotoxicity	Arsenic blocks repolarizing potassium currents (IKr, IKs), prolonging QT and predisposing to torsades/arrhythmias; this is a key downstream mechanism in acute severe poisoning.	IKr channel, IKs channel	GO:0086001 cardiac muscle cell action potential; GO:1903779 regulation of cardiac conduction; GO:0006813 potassium ion transport	cardiomyocyte	heart (UBERON:0000948)	arsenite(3+); inorganic arsenic	(pereira2025arsenomearsenobolomeand pages 19-20, balalimood2025recentadvancesin pages 12-13, chakif2026heavymetaltoxicity pages 12-13)
Population genetic susceptibility and gene-by-environment interaction	Toxic response varies with arsenic methylation phenotype and genetic background. Human and model-system evidence implicates AS3MT genotype in methylation/toxicity variability, while cell-based QTL mapping identified response loci including Abcc4, Txnrd1, and Xrcc2 under MMAIII exposure.	AS3MT, ABCC4, TXNRD1, XRCC2	GO:0006805 xenobiotic metabolic process; GO:0042221 response to chemical; GO:0006974 cellular response to DNA damage stimulus	fibroblast; hepatocyte	liver (UBERON:0002107); skin (UBERON:0002097); kidney (UBERON:0002113)	MMAIII; inorganic arsenic; arsenite(3+)	(ganie2024arsenictoxicitysources pages 2-3, pullella2024elucidatingtherelationship pages 37-41, abuawad2023thefolicacid pages 8-9, abuawad2023thefolicacid pages 1-2)

References

(balalimood2025recentadvancesin pages 12-13): Mahdi Balali-Mood, Nastaran Eizadi-Mood, Hossein Hassanian-Moghaddam, Leila Etemad, Mohammad Moshiri, Maryam Vahabzadeh, and Mahmood Sadeghi. Recent advances in the clinical management of intoxication by five heavy metals: mercury, lead, chromium, cadmium and arsenic. Heliyon, 11:e42696, Feb 2025. URL: https://doi.org/10.1016/j.heliyon.2025.e42696, doi:10.1016/j.heliyon.2025.e42696. This article has 65 citations.
(ganie2024arsenictoxicitysources pages 2-3): Shahid Yousuf Ganie, Darakhshan Javaid, Younis Ahmad Hajam, and Mohd Salim Reshi. Arsenic toxicity: sources, pathophysiology and mechanism. Toxicology research, 13 1:tfad111, Dec 2024. URL: https://doi.org/10.1093/toxres/tfad111, doi:10.1093/toxres/tfad111. This article has 170 citations.
(chakif2026heavymetaltoxicity pages 12-13): 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.
(visciano2025arsenicinwater pages 10-12): Pierina Visciano. Arsenic in water and food: toxicity and human exposure. Foods, 14:2229, Jun 2025. URL: https://doi.org/10.3390/foods14132229, doi:10.3390/foods14132229. This article has 11 citations.
(issanov2023arsenicindrinking pages 1-2): Alpamys Issanov, Betty Adewusi, Trevor J. B. Dummer, and Nathalie Saint-Jacques. Arsenic in drinking water and urinary tract cancers: a systematic review update. Water, Jun 2023. URL: https://doi.org/10.3390/w15122185, doi:10.3390/w15122185. This article has 17 citations.
(ganie2024arsenictoxicitysources pages 1-2): Shahid Yousuf Ganie, Darakhshan Javaid, Younis Ahmad Hajam, and Mohd Salim Reshi. Arsenic toxicity: sources, pathophysiology and mechanism. Toxicology research, 13 1:tfad111, Dec 2024. URL: https://doi.org/10.1093/toxres/tfad111, doi:10.1093/toxres/tfad111. This article has 170 citations.
(bhat2024arseniccontaminationneeds pages 1-2): Abhijnan Bhat, Kamna Ravi, Furong Tian, and Baljit Singh. Arsenic contamination needs serious attention: an opinion and global scenario. Pollutants, 4:196-211, Apr 2024. URL: https://doi.org/10.3390/pollutants4020013, doi:10.3390/pollutants4020013. This article has 76 citations.
(pullella2024elucidatingtherelationship pages 37-41): K Pullella. Elucidating the relationship between arsenic exposure and cancer risk in canada. Unknown journal, 2024.
(pereira2025arsenomearsenobolomeand pages 20-22): Fernando J. Pereira, Roberto López, and A. Javier Aller. Arsenome, arsenobolome, and arsenobiolome. International Journal of Molecular Sciences, 26:10761, Nov 2025. URL: https://doi.org/10.3390/ijms262110761, doi:10.3390/ijms262110761. This article has 0 citations.
(abuawad2023thefolicacid pages 7-8): Ahlam K. Abuawad, Anne K. Bozack, Ana Navas-Acien, Jeff Goldsmith, Xinhua Liu, Megan N. Hall, Vesna Ilievski, Angela M. Lomax-Luu, Faruque Parvez, Hasan Shahriar, Mohammad N. Uddin, Tariqul Islam, Joseph H. Graziano, and Mary V. Gamble. The folic acid and creatine trial: treatment effects of supplementation on arsenic methylation indices and metabolite concentrations in blood in a bangladeshi population. Environmental Health Perspectives, Mar 2023. URL: https://doi.org/10.1289/ehp11270, doi:10.1289/ehp11270. This article has 16 citations and is from a highest quality peer-reviewed journal.
(abuawad2023thefolicacid pages 1-2): Ahlam K. Abuawad, Anne K. Bozack, Ana Navas-Acien, Jeff Goldsmith, Xinhua Liu, Megan N. Hall, Vesna Ilievski, Angela M. Lomax-Luu, Faruque Parvez, Hasan Shahriar, Mohammad N. Uddin, Tariqul Islam, Joseph H. Graziano, and Mary V. Gamble. The folic acid and creatine trial: treatment effects of supplementation on arsenic methylation indices and metabolite concentrations in blood in a bangladeshi population. Environmental Health Perspectives, Mar 2023. URL: https://doi.org/10.1289/ehp11270, doi:10.1289/ehp11270. This article has 16 citations and is from a highest quality peer-reviewed journal.
(o’connor2024unravelingthegenetics pages 1-2): Callan O’Connor, Gregory R. Keele, Whitney Martin, Timothy Stodola, Daniel Gatti, Brian R. Hoffman, Ron Korstanje, Gary A. Churchill, and Laura G. Reinholdt. Unraveling the genetics of arsenic toxicity with cellular morphology qtl. PLOS Genetics, 20:e1011248, Apr 2024. URL: https://doi.org/10.1371/journal.pgen.1011248, doi:10.1371/journal.pgen.1011248. This article has 6 citations and is from a domain leading peer-reviewed journal.
(balalimood2025recentadvancesin pages 13-14): Mahdi Balali-Mood, Nastaran Eizadi-Mood, Hossein Hassanian-Moghaddam, Leila Etemad, Mohammad Moshiri, Maryam Vahabzadeh, and Mahmood Sadeghi. Recent advances in the clinical management of intoxication by five heavy metals: mercury, lead, chromium, cadmium and arsenic. Heliyon, 11:e42696, Feb 2025. URL: https://doi.org/10.1016/j.heliyon.2025.e42696, doi:10.1016/j.heliyon.2025.e42696. This article has 65 citations.
(pereira2025arsenomearsenobolomeand pages 19-20): Fernando J. Pereira, Roberto López, and A. Javier Aller. Arsenome, arsenobolome, and arsenobiolome. International Journal of Molecular Sciences, 26:10761, Nov 2025. URL: https://doi.org/10.3390/ijms262110761, doi:10.3390/ijms262110761. This article has 0 citations.
(singh2024arsenicexposurein pages 1-5): N Singh. Arsenic exposure in c57bl/6 mice carrying human as3mt elevates fasting glycemia and impairs beta cell function according to sex and developmental window …. Unknown journal, 2024.
(abuawad2023thefolicacid pages 6-7): Ahlam K. Abuawad, Anne K. Bozack, Ana Navas-Acien, Jeff Goldsmith, Xinhua Liu, Megan N. Hall, Vesna Ilievski, Angela M. Lomax-Luu, Faruque Parvez, Hasan Shahriar, Mohammad N. Uddin, Tariqul Islam, Joseph H. Graziano, and Mary V. Gamble. The folic acid and creatine trial: treatment effects of supplementation on arsenic methylation indices and metabolite concentrations in blood in a bangladeshi population. Environmental Health Perspectives, Mar 2023. URL: https://doi.org/10.1289/ehp11270, doi:10.1289/ehp11270. This article has 16 citations and is from a highest quality peer-reviewed journal.
(abuawad2023thefolicacid pages 8-9): Ahlam K. Abuawad, Anne K. Bozack, Ana Navas-Acien, Jeff Goldsmith, Xinhua Liu, Megan N. Hall, Vesna Ilievski, Angela M. Lomax-Luu, Faruque Parvez, Hasan Shahriar, Mohammad N. Uddin, Tariqul Islam, Joseph H. Graziano, and Mary V. Gamble. The folic acid and creatine trial: treatment effects of supplementation on arsenic methylation indices and metabolite concentrations in blood in a bangladeshi population. Environmental Health Perspectives, Mar 2023. URL: https://doi.org/10.1289/ehp11270, doi:10.1289/ehp11270. This article has 16 citations and is from a highest quality peer-reviewed journal.
(mitchell2023acomprehensivesurvey pages 6-8): Erika J. Mitchell and Seth H. Frisbie. A comprehensive survey and analysis of international drinking water regulations for inorganic chemicals with comparisons to the world health organization’s drinking-water guidelines. PLOS ONE, 18:e0287937, Nov 2023. URL: https://doi.org/10.1371/journal.pone.0287937, doi:10.1371/journal.pone.0287937. This article has 33 citations and is from a peer-reviewed journal.
(mitchell2023acomprehensivesurvey pages 2-4): Erika J. Mitchell and Seth H. Frisbie. A comprehensive survey and analysis of international drinking water regulations for inorganic chemicals with comparisons to the world health organization’s drinking-water guidelines. PLOS ONE, 18:e0287937, Nov 2023. URL: https://doi.org/10.1371/journal.pone.0287937, doi:10.1371/journal.pone.0287937. This article has 33 citations and is from a peer-reviewed journal.
(pullella2024elucidatingtherelationship pages 41-44): K Pullella. Elucidating the relationship between arsenic exposure and cancer risk in canada. Unknown journal, 2024.
(o’connor2024unravelingthegenetics pages 2-3): Callan O’Connor, Gregory R. Keele, Whitney Martin, Timothy Stodola, Daniel Gatti, Brian R. Hoffman, Ron Korstanje, Gary A. Churchill, and Laura G. Reinholdt. Unraveling the genetics of arsenic toxicity with cellular morphology qtl. PLOS Genetics, 20:e1011248, Apr 2024. URL: https://doi.org/10.1371/journal.pgen.1011248, doi:10.1371/journal.pgen.1011248. This article has 6 citations and is from a domain leading peer-reviewed journal.

Category	Item	What it indicates/when used	Key quantitative thresholds or notes	Evidence
Diagnostic	Urine total arsenic (24-hour)	Main biomarker for recent arsenic exposure; used in suspected acute or ongoing exposure	24-hour urinary arsenic >100 µg/L reported as elevated/toxic in retrieved evidence; chelation follow-up target <50 µg/L in 24-hour urine; seafood can confound total urinary arsenic unless speciation is done (pullella2024elucidatingtherelationship pages 37-41, balalimood2025recentadvancesin pages 13-14, pullella2024elucidatingtherelationship pages 41-44)	(pullella2024elucidatingtherelationship pages 37-41, balalimood2025recentadvancesin pages 13-14, pullella2024elucidatingtherelationship pages 41-44)
Diagnostic	Spot urine arsenic	Practical alternative to 24-hour collection for recent exposure assessment	Spot urine >50 µg/L reported as elevated in retrieved evidence; should be interpreted with hydration correction (e.g., creatinine adjustment) and ideally with speciation (balalimood2025recentadvancesin pages 12-13, pullella2024elucidatingtherelationship pages 37-41, pullella2024elucidatingtherelationship pages 41-44)	(balalimood2025recentadvancesin pages 12-13, pullella2024elucidatingtherelationship pages 37-41, pullella2024elucidatingtherelationship pages 41-44)
Diagnostic	Urine arsenic speciation (iAs, MMA, DMA)	Best test to distinguish toxic inorganic exposure from seafood-derived organic arsenic; also used to assess methylation phenotype and susceptibility	Requires seafood avoidance before testing; elevated urinary MMA or higher MMA/DMA ratio suggests less complete methylation and potentially higher cancer susceptibility; recent exposure window roughly several days because biologic half-life is about 2-4 days (chakif2026heavymetaltoxicity pages 12-13, pullella2024elucidatingtherelationship pages 37-41)	(chakif2026heavymetaltoxicity pages 12-13, pullella2024elucidatingtherelationship pages 37-41)
Diagnostic	Blood arsenic	Reflects very recent exposure and acute poisoning; less useful after rapid clearance	Blood arsenic >130 nmol/L reported as elevated/toxic in retrieved evidence; blood half-life about 2-6 h, so sensitivity falls quickly after exposure (pullella2024elucidatingtherelationship pages 37-41, pullella2024elucidatingtherelationship pages 41-44)	(pullella2024elucidatingtherelationship pages 37-41, pullella2024elucidatingtherelationship pages 41-44)
Diagnostic	Serum arsenic	Limited clinical utility because arsenic clears rapidly from blood	Not considered reliable for diagnosis once time has elapsed after exposure (balalimood2025recentadvancesin pages 12-13)	(balalimood2025recentadvancesin pages 12-13)
Diagnostic	Hair arsenic	Marker of longer-term past exposure	Can become positive about 30 h after exposure; reflects longer-term exposure but is nondiscriminatory for source/species and is not ideal for acute decision-making (balalimood2025recentadvancesin pages 12-13, pullella2024elucidatingtherelationship pages 37-41)	(balalimood2025recentadvancesin pages 12-13, pullella2024elucidatingtherelationship pages 37-41)
Diagnostic	Nail arsenic (especially toenail)	Marker of chronic exposure over prior months	Toenail arsenic >0.5 µg/g reported as elevated in retrieved evidence; nails reflect long-term exposure over about 3-6 months (pullella2024elucidatingtherelationship pages 37-41, pullella2024elucidatingtherelationship pages 41-44)	(pullella2024elucidatingtherelationship pages 37-41, pullella2024elucidatingtherelationship pages 41-44)
Diagnostic	Imaging (abdominal/chest X-ray)	Supportive test in acute poisoning to identify radiopaque ingested arsenic material or evaluate complications	Used selectively in acute ingestion; not a biomarker of body burden (balalimood2025recentadvancesin pages 12-13)	(balalimood2025recentadvancesin pages 12-13)
Diagnostic	ECG monitoring	Detects cardiotoxicity in acute poisoning	Important because acute arsenic can prolong QT/QRS and trigger torsades/arrhythmias (balalimood2025recentadvancesin pages 12-13, chakif2026heavymetaltoxicity pages 12-13)	(balalimood2025recentadvancesin pages 12-13, chakif2026heavymetaltoxicity pages 12-13)
Treatment	Exposure cessation/source removal	First-line intervention in all cases, especially chronic/subacute arsenicosis	Removal from contaminated water/food/occupational source is the primary treatment for chronic poisoning (balalimood2025recentadvancesin pages 13-14)	(balalimood2025recentadvancesin pages 13-14)
Treatment	Succimer / DMSA	Oral chelator used for arsenic poisoning, especially when prolonged treatment is needed or less invasive therapy is preferred	Named as a key chelator; preferred for prolonged chronic/subacute cases in retrieved evidence; most effective when started minutes to hours after exposure (balalimood2025recentadvancesin pages 13-14)	(balalimood2025recentadvancesin pages 13-14)
Treatment	DMPS	Water-soluble chelator used in arsenic poisoning	Named as a key arsenic chelator; most useful early after exposure; use varies by region/regulatory approval (balalimood2025recentadvancesin pages 13-14)	(balalimood2025recentadvancesin pages 13-14)
Treatment	Dimercaprol / BAL	Traditional parenteral chelator for severe acute arsenic poisoning	Named as a key chelator; most effective when given soon after exposure, typically minutes to hours (balalimood2025recentadvancesin pages 13-14)	(balalimood2025recentadvancesin pages 13-14)
Treatment	IV fluids and electrolyte replacement	Core supportive therapy for acute poisoning with severe vomiting/diarrhea and shock	Critical because deaths often result from hypovolemia, renal failure, or cardiac complications (balalimood2025recentadvancesin pages 12-13, balalimood2025recentadvancesin pages 13-14)	(balalimood2025recentadvancesin pages 12-13, balalimood2025recentadvancesin pages 13-14)
Treatment	GI decontamination / bowel irrigation / NG suction	Used in selected acute ingestions, especially if arsenic is still in the GI tract or radiopaque material is seen	Activated charcoal adsorbs arsenic poorly; whole-bowel irrigation or continued NG suction may be considered in severe ingestion (balalimood2025recentadvancesin pages 13-14)	(balalimood2025recentadvancesin pages 13-14)
Treatment	Antiarrhythmic management and magnesium	Supportive management for QT prolongation/torsades and other arrhythmias	Magnesium sulfate, amiodarone, or lidocaine reported as options; avoid class IA/IC/III antiarrhythmics in this context per retrieved review (balalimood2025recentadvancesin pages 13-14)	(balalimood2025recentadvancesin pages 13-14)
Treatment	Benzodiazepines for seizures	Symptom-directed treatment in acute neurotoxicity	Used when seizures occur during severe intoxication (balalimood2025recentadvancesin pages 13-14)	(balalimood2025recentadvancesin pages 13-14)
Treatment	Hemodialysis	Adjunctive/supportive therapy in severe poisoning with kidney failure or oliguria	Recommended in acute kidney injury/oliguria; supportive rather than stand-alone antidotal therapy (balalimood2025recentadvancesin pages 13-14)	(balalimood2025recentadvancesin pages 13-14)
Treatment	Exchange transfusion	Special situation therapy for arsine gas poisoning with massive hemolysis	Can help remove arsine-related toxic burden in severe hemolytic presentations (balalimood2025recentadvancesin pages 13-14)	(balalimood2025recentadvancesin pages 13-14)
Treatment	Antioxidant/nutritional adjuncts	Investigational or supportive approaches to mitigate toxicity or improve methylation/detoxification	Selenium, zinc, folate, vitamins A/C/E, and phytochemicals have been proposed; clinical evidence remains limited (balalimood2025recentadvancesin pages 13-14, abuawad2023thefolicacid pages 6-7, abuawad2023thefolicacid pages 7-8, abuawad2023thefolicacid pages 1-2)	(balalimood2025recentadvancesin pages 13-14, abuawad2023thefolicacid pages 6-7, abuawad2023thefolicacid pages 7-8, abuawad2023thefolicacid pages 1-2)

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1. Disease Information

1.1 Concise overview

1.2 Synonyms and alternative names

1.3 Key identifiers (ontology/terminology)

1.4 Evidence provenance

2. Etiology

2.1 Causal factors

2.2 Risk factors

Environmental/occupational

Host and contextual risk modifiers

2.3 Protective factors

2.4 Gene–environment interactions

3. Phenotypes (clinical manifestations)

4. Genetic/Molecular Information

4.1 Causal genes

4.2 Pathogenic variants

4.3 Epigenetic information

5. Environmental Information

5.1 Environmental factors

5.2 Lifestyle factors

6. Mechanism / Pathophysiology

6.1 Current mechanistic understanding (high-level causal chain)

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

9.1 Epidemiology and exposure burden

9.2 Regulatory coverage and inequity

10. Diagnostics

11. Outcome / Prognosis

11.1 Acute poisoning outcomes

11.2 Long-term complications and quantitative cancer risks

12. Treatment

12.1 Acute management (real-world implementation)

12.2 Nutritional intervention evidence (human trial)

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Recent developments and expert analysis (2023–2024 emphasis)

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