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Arsenic Poisoning

Environmental 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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Mappings
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Definitions
0
Inheritance
17
Pathophysiology
0
Histopathology
11
Phenotypes
4
Genes
5
Treatments
2
Subtypes
4
Differentials
4
Datasets
4
Trials
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Subtypes

2
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

17
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 link ⚠ ABNORMAL
small intestine link
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 link
arsenic methylation link ↑ INCREASED
liver link
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 link ↓ DECREASED
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 link ⚠ ABNORMAL
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 link ↑ INCREASED
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 link ⚠ ABNORMAL
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 link ↓ DECREASED
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 Computational
"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 link ⚠ ABNORMAL
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 link ↕ DYSREGULATED
Show evidence (1 reference)
PMID:20514360 PARTIAL 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."
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 link ↑ INCREASED
Show evidence (1 reference)
PMID:20514360 PARTIAL 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."
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 link ↕ 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 link
neuron projection development link ⚠ ABNORMAL
peripheral nerve link
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 link
hepatocyte apoptotic process link ↑ INCREASED
liver link
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 link
hepatic stellate cell activation link ↑ INCREASED
liver link
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 link ↑ INCREASED
liver link
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."
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 link
nitric oxide mediated signal transduction link ↓ DECREASED
blood vessel link
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
"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..."
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 link
proximal tubule link
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.
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Causal Graph

graph LR
    Peripheral_Nerve_Axonopathy["Peripheral Nerve Axonopathy"]
    Renal_Tubular_Injury["Renal Tubular Injury"]
    Cardiovascular_Endothelial_Dysfunction["Cardiovascular Endothelial Dysfunction"]
    Gastrointestinal_Absorption_and_Transport["Gastrointestinal Absorption and Transport"]
    Oxidative_Stress_and_ROS_Generation["Oxidative Stress and ROS Generation"]
    SAM_Depletion["SAM Depletion"]
    DNA_Repair_Inhibition_via_Zinc_Finger_Protein_Disruption["DNA Repair Inhibition via Zinc Finger Protein Disruption"]
    Arsenolysis["Arsenolysis"]
    Hepatic_Methylation_and_Biotransformation["Hepatic Methylation and Biotransformation"]
    Hepatic_Stellate_Cell_Activation["Hepatic Stellate Cell Activation"]
    Inhibition_of_Sulfhydryl_Dependent_Enzymes["Inhibition of Sulfhydryl-Dependent Enzymes"]
    Tumor_Suppressor_Gene_Silencing["Tumor Suppressor Gene Silencing"]
    Arsenic_Induced_Carcinogenesis["Arsenic-Induced Carcinogenesis"]
    Hepatic_Fibrosis["Hepatic Fibrosis"]
    Mitochondrial_Dysfunction["Mitochondrial Dysfunction"]
    Hepatocellular_Oxidative_Injury["Hepatocellular Oxidative Injury"]
    Global_DNA_Hypomethylation["Global DNA Hypomethylation"]

    Gastrointestinal_Absorption_and_Transport --> Hepatic_Methylation_and_Biotransformation
    Gastrointestinal_Absorption_and_Transport --> Inhibition_of_Sulfhydryl_Dependent_Enzymes
    Gastrointestinal_Absorption_and_Transport --> Arsenolysis
    Hepatic_Methylation_and_Biotransformation --> Oxidative_Stress_and_ROS_Generation
    Hepatic_Methylation_and_Biotransformation --> SAM_Depletion
    Inhibition_of_Sulfhydryl_Dependent_Enzymes --> Mitochondrial_Dysfunction
    Arsenolysis --> Mitochondrial_Dysfunction
    Oxidative_Stress_and_ROS_Generation --> DNA_Repair_Inhibition_via_Zinc_Finger_Protein_Disruption
    Oxidative_Stress_and_ROS_Generation --> Peripheral_Nerve_Axonopathy
    Oxidative_Stress_and_ROS_Generation --> Hepatocellular_Oxidative_Injury
    Oxidative_Stress_and_ROS_Generation --> Cardiovascular_Endothelial_Dysfunction
    Oxidative_Stress_and_ROS_Generation --> Renal_Tubular_Injury
    Mitochondrial_Dysfunction --> Oxidative_Stress_and_ROS_Generation
    Mitochondrial_Dysfunction --> Hepatocellular_Oxidative_Injury
    Mitochondrial_Dysfunction --> Renal_Tubular_Injury
    DNA_Repair_Inhibition_via_Zinc_Finger_Protein_Disruption --> Arsenic_Induced_Carcinogenesis
    SAM_Depletion --> Global_DNA_Hypomethylation
    SAM_Depletion --> Tumor_Suppressor_Gene_Silencing
    Global_DNA_Hypomethylation --> Arsenic_Induced_Carcinogenesis
    Tumor_Suppressor_Gene_Silencing --> Arsenic_Induced_Carcinogenesis
    Hepatocellular_Oxidative_Injury --> Hepatic_Stellate_Cell_Activation
    Hepatic_Stellate_Cell_Activation --> Hepatic_Fibrosis

    style Peripheral_Nerve_Axonopathy fill:#dbeafe
    style Renal_Tubular_Injury fill:#dbeafe
    style Cardiovascular_Endothelial_Dysfunction fill:#dbeafe
    style Gastrointestinal_Absorption_and_Transport fill:#dbeafe
    style Oxidative_Stress_and_ROS_Generation fill:#dbeafe
    style SAM_Depletion fill:#dbeafe
    style DNA_Repair_Inhibition_via_Zinc_Finger_Protein_Disruption fill:#dbeafe
    style Arsenolysis fill:#dbeafe
    style Hepatic_Methylation_and_Biotransformation fill:#dbeafe
    style Hepatic_Stellate_Cell_Activation fill:#dbeafe
    style Inhibition_of_Sulfhydryl_Dependent_Enzymes fill:#dbeafe
    style Tumor_Suppressor_Gene_Silencing fill:#dbeafe
    style Arsenic_Induced_Carcinogenesis fill:#dbeafe
    style Hepatic_Fibrosis fill:#dbeafe
    style Mitochondrial_Dysfunction fill:#dbeafe
    style Hepatocellular_Oxidative_Injury fill:#dbeafe
    style Global_DNA_Hypomethylation fill:#dbeafe
●

Phenotypes

11
Blood(2) Cardiovascular(2) Digestive(1) Endocrine(1) Integument(3) Nervous System(2)
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
"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 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)
🧬

Genetic Associations

4
AS3MT Polymorphisms (Associated)
Show evidence (1 reference)
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 methylation pathway that AS3MT polymorphisms modulate.
GSTT1/GSTM1 Polymorphisms (Associated)
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)
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)
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.
💊

Treatments

5
Chelation Therapy with Dimercaprol (BAL) 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) 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) 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 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 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

4
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

7
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

4

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

Lead Poisoning Not Yet Curated 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 Not Yet Curated 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

4
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 link
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 link
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 link
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 link
Clinically relevant study linking arsenic exposure to epigenetic changes in target tissue (urothelium) relevant to arsenic-induced bladder cancer risk.
🔬

Clinical Trials

4
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 ↗
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 ↗
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: '2026-02-12T02:07:17Z'
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 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 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
    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
    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
    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:0030791
      label: arsenite methyltransferase activity
  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
    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
    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
    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
    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
    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
    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.
- 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
    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
    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
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    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
    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
    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
    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
    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
    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:0002125
      label: peripheral nerve
  evidence:
  - reference: PMID:31336801
    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
    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."
- 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
    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.
- 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
    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
    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
    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
    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."
- 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
    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."
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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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 Arsenicosis (Groundwater Exposure)
  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
    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."
- subtype: General
  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
    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.