Arsenic

Overview#

Arsenic exists in two primary inorganic oxidation states: trivalent arsenite (As(III)) and pentavalent arsenate (As(vanadium (V))). As(III) is the more toxic form due to greater chemical reactivity and easier cellular entry.^{[6]Su 2023 — Arsenic in brown rice: do the benefits outweigh the risks?Lihchyun Joseph Su, Tung-Chin Chiang, Sarah N. O'Connor · 2023Open reference 6 ↓}

Organic arsenic species (arsenobetaine, arsenosugars) found primarily in seafood are considered relatively non-toxic.^{[7]Arsenic concentration and speciation in infant formulas and first foodsJackson BP, Taylor VF, Punshon T et al. · 2012Open reference 7 ↓}

The metabolic pathway follows: inorganic As --> MMA (monomethylarsonic acid) --> DMA (dimethylarsinic acid), with methylation consuming S-adenosylmethionine (SAM) as the methyl donor.^{[4]Genetic and Epigenetic Mechanisms in Metal Carcinogenesis and Cocarcinogenesis: Nickel, Arsenic, and ChromiumKonstantin Salnikov, Anatoly Zhitkovich · 2008Open reference 4 ↓}

This SAM depletion reduces the availability of methyl groups for DNA and histone methylation, creating a direct link between arsenic metabolism and epigenetic disruption.^{[4]Genetic and Epigenetic Mechanisms in Metal Carcinogenesis and Cocarcinogenesis: Nickel, Arsenic, and ChromiumKonstantin Salnikov, Anatoly Zhitkovich · 2008Open reference 4 ↓}

Arsenic shares toxicity pathways with Lead, Cadmium, Chromium, and Mercury—all five metals converge on ROS generation, antioxidant defense weakening, enzyme inactivation, and Oxidative Stress.^{[8]Toxic Mechanisms of Five Heavy Metals: Mercury, Lead, Chromium, Cadmium, and ArsenicBalali-Mood M, Naseri K, Tahergorabi Z et al. · 2021Open reference 8 ↓}

However, arsenic has distinctive mechanisms: it inhibits pyruvate dehydrogenase (blocking the TCA cycle by binding vicinal dithiols), and arsenate mimics phosphate to uncouple substrate-level phosphorylation (arsenolysis).^{[5]Toxicity, Mechanism and Health Effects of Some Heavy MetalsMonisha Jaishankar, Tenzin Tseten, Naresh Anbalagan et al. · 2014Open reference 5 ↓}

Biological Roles#

Arsenic has no known essential biological function in humans. Its toxicity operates through several convergent mechanisms:

Glutathione Depletion#

Arsenite binds directly to thiol groups on Glutathione (GSH) (As-SG conjugation) and inhibits glutathione reductase, collapsing the GSH/GSSG ratio.^{[5]Toxicity, Mechanism and Health Effects of Some Heavy MetalsMonisha Jaishankar, Tenzin Tseten, Naresh Anbalagan et al. · 2014Open reference 5 ↓}

This is one of the earliest events in arsenic toxicity and explains why individuals with genetically lower GSH synthetic capacity are more susceptible.^{[5]Toxicity, Mechanism and Health Effects of Some Heavy MetalsMonisha Jaishankar, Tenzin Tseten, Naresh Anbalagan et al. · 2014Open reference 5 ↓}

GSH depletion is a mechanism shared across nearly every toxic heavy metal, but arsenic's direct thiol-binding affinity makes it particularly potent.^{[8]Toxic Mechanisms of Five Heavy Metals: Mercury, Lead, Chromium, Cadmium, and ArsenicBalali-Mood M, Naseri K, Tahergorabi Z et al. · 2021Open reference 8 ↓}

Epigenetic Disruption#

Arsenic produces both hypo- and hypermethylation of DNA depending on dose, duration, and tissue.^{[4]Genetic and Epigenetic Mechanisms in Metal Carcinogenesis and Cocarcinogenesis: Nickel, Arsenic, and ChromiumKonstantin Salnikov, Anatoly Zhitkovich · 2008Open reference 4 ↓} The mechanism is SAM depletion: because arsenic methylation consumes SAM, less is available for normal DNA and histone methylation. Low dietary methionine or folate exacerbates these effects.^{[4]Genetic and Epigenetic Mechanisms in Metal Carcinogenesis and Cocarcinogenesis: Nickel, Arsenic, and ChromiumKonstantin Salnikov, Anatoly Zhitkovich · 2008Open reference 4 ↓}

Arsenic also suppresses GLUT4 expression and upregulates IL-6, linking exposure to insulin resistance and obesity.^{[6]Su 2023 — Arsenic in brown rice: do the benefits outweigh the risks?Lihchyun Joseph Su, Tung-Chin Chiang, Sarah N. O'Connor · 2023Open reference 6 ↓}

Dietary and Environmental Sources#

Drinking Water#

Drinking water contamination is the primary exposure route globally. Bangladesh and West Bengal (India) represent the largest affected populations, while Chilean northern regions provide some of the clearest epidemiological exposure-cancer data.^{[4]Genetic and Epigenetic Mechanisms in Metal Carcinogenesis and Cocarcinogenesis: Nickel, Arsenic, and ChromiumKonstantin Salnikov, Anatoly Zhitkovich · 2008Open reference 4 ↓}

Surface water use is independently associated with chronic kidney disease of unknown cause (CKDu) (OR 3.178, p=0.045).^{[10]Heavy Metal Association with Chronic Kidney Disease of Unknown Cause in Central India - Results from a Case-Control StudyMahendra Atlani, Ashok Kumar, Rajesh Ahirwar et al. · 2024Open reference 10 ↓}

In Sri Lanka's CKDu-endemic regions, household well water contains variable levels of heavy metals including arsenic alongside cyanotoxin-producing Microcystis, suggesting multiple interacting environmental exposures drive kidney damage.^{[11]McDonough et al. 2020 — Water Chemistry and Microbiome of Household Wells in CKDu-Endemic Sri LankaLiza K. McDonough, Karina T. Meredith, Chandima Nikagolla et al. · 2020Open reference 11 ↓}

Rice and Grain Products#

Rice rivals drinking water as a source of inorganic arsenic exposure in U.S. and Asian populations.^{[6]Su 2023 — Arsenic in brown rice: do the benefits outweigh the risks?Lihchyun Joseph Su, Tung-Chin Chiang, Sarah N. O'Connor · 2023Open reference 6 ↓}

Brown rice contains approximately 80% more inorganic arsenic than white rice because the metalloid concentrates in the bran and germ layers removed during refining—FDA averages: white rice 92 ppb, brown rice 154 ppb.^{[6]Su 2023 — Arsenic in brown rice: do the benefits outweigh the risks?Lihchyun Joseph Su, Tung-Chin Chiang, Sarah N. O'Connor · 2023Open reference 6 ↓}

This creates a counterintuitive risk: the "healthier" whole grain carries the greater metal burden.

Arsenic speciation analysis of commercial rice confirms that AsIII dominates, followed by DMA then AsV—meaning the most bioactive and toxic species is the predominant form in rice.^{[12]Navaretnam 2025 — Arsenic speciation using HPLC-ICP-MS in white and brown rice and health risk assessmentRaneesha Navaretnam, Ahmad Zaharin Aris, Muhammad Faizan A. Shukor et al. · 2025Open reference 12 ↓}

All 30 rice samples tested in one Malaysian study exceeded the target hazard quotient (THQ > 1) and the 10^-3 lifetime cancer risk threshold.^{[12]Navaretnam 2025 — Arsenic speciation using HPLC-ICP-MS in white and brown rice and health risk assessmentRaneesha Navaretnam, Ahmad Zaharin Aris, Muhammad Faizan A. Shukor et al. · 2025Open reference 12 ↓}

Rice grown in Southern U.S. states (>47% of the U.S. market) has the highest arsenic content compared to California or Asian imports.^{[6]Su 2023 — Arsenic in brown rice: do the benefits outweigh the risks?Lihchyun Joseph Su, Tung-Chin Chiang, Sarah N. O'Connor · 2023Open reference 6 ↓}

Arsenic contamination in paddy soils is itself a driver of antibiotic resistance gene (ARG) proliferation: in heavily polluted Chinese paddy soils, arsenic was the predominant factor shaping ARG distribution, exerting a stronger effect than cadmium, with 119 unique ARGs detected.^{[13]Arsenic and cadmium as predominant factors shaping the distribution patterns of antibiotic resistance genes in polluted paddy soilsZhao X, Shen JP, Zhang LM et al. · 2020Open reference 13 ↓}

This means arsenic-contaminated rice production environments are simultaneously generating antibiotic-resistant microbes that can enter the food chain.

Infant Foods#

Infants face disproportionate exposure due to low body weight. Arsenic is detectable in all infant formulas tested, with total As ranging from 2.2 to 12.6 ng/g; non-dairy formulas contain significantly more than dairy-based formulas.^{[7]Arsenic concentration and speciation in infant formulas and first foodsJackson BP, Taylor VF, Punshon T et al. · 2012Open reference 7 ↓}

Arsenic in formula is almost exclusively inorganic—the more toxic form.^{[7]Arsenic concentration and speciation in infant formulas and first foodsJackson BP, Taylor VF, Punshon T et al. · 2012Open reference 7 ↓}

A 3.5-month-old consuming standard daily formula volumes could be exposed to 0.036-0.21 ug arsenic (As)/kg/day, with the upper range exceeding the adult safe drinking water limit.^{[7]Arsenic concentration and speciation in infant formulas and first foodsJackson BP, Taylor VF, Punshon T et al. · 2012Open reference 7 ↓}

Weaning to solid foods triggers a dramatic increase in arsenic exposure: paired urine samples from 15 New Hampshire Birth Cohort infants showed a 3.8-fold increase in urinary arsenic species between 4 and 6 months of age, with rice cereal consumption showing the strongest correlation (rho=0.90, p=0.03 for inorganic arsenic).^{[14]Signes-Pastor 2018 — Infants' dietary arsenic exposure during transition to solid foodAntonio J. Signes-Pastor, Kathryn L. Cottingham, Manus Carey et al. · 2018Open reference 14 ↓}

Breastfeeding is inversely associated with urinary arsenic species (rho=-0.71, p=0.003).^{[14]Signes-Pastor 2018 — Infants' dietary arsenic exposure during transition to solid foodAntonio J. Signes-Pastor, Kathryn L. Cottingham, Manus Carey et al. · 2018Open reference 14 ↓}

Microbiome Interactions#

The relationship between arsenic and the gut microbiome is bidirectional: arsenic reshapes microbial communities while the microbiome determines arsenic's fate, mobility, and toxicity in the body.^{[2]Arsenic and the gastrointestinal tract microbiomeMcDermott TR, Stolz JF, Oremland RS · 2020Open reference 2 ↓[3]Gut Microbiota: A Target for Heavy Metal Toxicity and a Probiotic Protective StrategyHui Duan, Leilei Yu, Fengwei Tian et al. · 2020Open reference 3 ↓}

This section covers what is arguably the most important aspect of arsenic biology missing from conventional toxicology—and entirely absent from Wikipedia.

Gut Barrier Disruption#

Arsenic directly disrupts the intestinal epithelial barrier. Chronic exposure disrupts colonic epithelial structure, increases paracellular transport, and induces proinflammatory cytokines (IL-6, IL-8, TNF-alpha).^{[1]Effects of Heavy Metals on Gut Barrier Integrity and Gut MicrobiotaSweta Ghosh, Syam P. Nukavarpu, Venkatakrishna Rao Jala · 2024Open reference 1 ↓}

Approximately 60% of ingested heavy metals are absorbed in the intestine, causing oxidative stress and intestinal barrier damage.^{[23]Heavy Metal-Gut Microbiota Interactions: Probiotics Modulation and Biosensors DetectionLiliana Anchidin-Norocel, Oana C. Iatcu, Andrei Lobiuc et al. · 2025Open reference 23 ↓} Arsenic exposure increases pathogenic bacteria and decreases Firmicutes, compounding barrier damage through loss of SCFA-producing commensals.^{[23]Heavy Metal-Gut Microbiota Interactions: Probiotics Modulation and Biosensors DetectionLiliana Anchidin-Norocel, Oana C. Iatcu, Andrei Lobiuc et al. · 2025Open reference 23 ↓}

Notably, Urolithin A (UroA), a gut microbial metabolite of polyphenols, has been shown to protect colon epithelial cells against arsenic-induced oxidative stress and barrier dysfunction^{[1]Effects of Heavy Metals on Gut Barrier Integrity and Gut MicrobiotaSweta Ghosh, Syam P. Nukavarpu, Venkatakrishna Rao Jala · 2024Open reference 1 ↓}—another illustration of how microbial metabolic capacity modulates arsenic's impact.

Co-selection of Antibiotic Resistance#

Arsenic drives proliferation of antibiotic resistance through co-selection—three molecular mechanisms by which metal exposure selects for antibiotic-resistant organisms:^{[26]Baker-Austin 2006 — Co-selection of Antibiotic and Metal ResistanceBaker-Austin C, Wright MS, Stepanauskas R et al. · 2006Open reference 26 ↓}

1. cobalt (Co)-resistance: arsenic resistance genes (arsC, arsB) and antibiotic resistance genes physically linked on the same mobile genetic element
2. Cross-resistance: shared efflux pumps that expel both arsenic and antibiotics (arsenic is listed among metals conferring resistance via reduced membrane permeability)^{[26]Baker-Austin 2006 — Co-selection of Antibiotic and Metal ResistanceBaker-Austin C, Wright MS, Stepanauskas R et al. · 2006Open reference 26 ↓}
3. cobalt-regulatory mechanisms: exposure to arsenic transcriptionally activates resistance to unrelated toxicants

In CKD patients, lead and arsenic resistance were the most prevalent metal resistance phenotypes among culturable gut bacteria, with co-resistance to antibiotics detected in the same isolates—meaning arsenic exposure may inadvertently select for antibiotic-resistant organisms in the gut.^{[27]Miranda 2022 — Metal(loid) and Antibiotic Resistance in CKD Gut BacteriaMiranda, Rojas, Geisse et al. · 2022Open reference 27 ↓}

The arsC (arsenic reduction) gene was detected across isolates from CKD patients.^{[27]Miranda 2022 — Metal(loid) and Antibiotic Resistance in CKD Gut BacteriaMiranda, Rojas, Geisse et al. · 2022Open reference 27 ↓}

Unlike antibiotics, metals are not subject to degradation and represent a long-term selection pressure that persists indefinitely in the environment.^{[26]Baker-Austin 2006 — Co-selection of Antibiotic and Metal ResistanceBaker-Austin C, Wright MS, Stepanauskas R et al. · 2006Open reference 26 ↓} This makes arsenic-contaminated environments—including agricultural soils and the human gut—reservoirs of antibiotic resistance.

Conditions Associated#

Cancer#

Chronic arsenic exposure is linked to cancers of the skin, lung, bladder, kidney, liver, pancreas, prostate, and digestive tract.^{[6]Su 2023 — Arsenic in brown rice: do the benefits outweigh the risks?Lihchyun Joseph Su, Tung-Chin Chiang, Sarah N. O'Connor · 2023Open reference 6 ↓[4]Genetic and Epigenetic Mechanisms in Metal Carcinogenesis and Cocarcinogenesis: Nickel, Arsenic, and ChromiumKonstantin Salnikov, Anatoly Zhitkovich · 2008Open reference 4 ↓[5]Toxicity, Mechanism and Health Effects of Some Heavy MetalsMonisha Jaishankar, Tenzin Tseten, Naresh Anbalagan et al. · 2014Open reference 5 ↓}

The FDA expert panel estimated cancer cases would increase 148.6% if rice consumption rose from <1 serving/day to precisely 1 serving/day.^{[6]Su 2023 — Arsenic in brown rice: do the benefits outweigh the risks?Lihchyun Joseph Su, Tung-Chin Chiang, Sarah N. O'Connor · 2023Open reference 6 ↓} Arsenic is elevated alongside other metals in thyroid cancer tissue.^{[9]Recent advances in the application of metallomics in diagnosis and prognosis of human cancerYan Zhang, Jie He, Jiao Jin et al. · 2022Open reference 9 ↓}

Chronic Kidney Disease#

Blood arsenic is independently associated with CKDu (chronic kidney disease of unknown cause) in central India (OR 1.013, 95% CI 1.003-1.024, p=0.014), with surface water use as a key risk factor.^{[10]Heavy Metal Association with Chronic Kidney Disease of Unknown Cause in Central India - Results from a Case-Control StudyMahendra Atlani, Ashok Kumar, Rajesh Ahirwar et al. · 2024Open reference 10 ↓}

Parallel CKDu epidemics in Sri Lankan rice-farming regions involve multi-metal exposure through groundwater.^{[11]McDonough et al. 2020 — Water Chemistry and Microbiome of Household Wells in CKDu-Endemic Sri LankaLiza K. McDonough, Karina T. Meredith, Chandima Nikagolla et al. · 2020Open reference 11 ↓} In CKD patients, arsenic-resistant bacteria dominate the gut resistome.^{[27]Miranda 2022 — Metal(loid) and Antibiotic Resistance in CKD Gut BacteriaMiranda, Rojas, Geisse et al. · 2022Open reference 27 ↓}

Metabolic Disease#

Arsenic exposure is associated with type-2 diabetes, metabolic syndrome, and obesity.^{[6]Su 2023 — Arsenic in brown rice: do the benefits outweigh the risks?Lihchyun Joseph Su, Tung-Chin Chiang, Sarah N. O'Connor · 2023Open reference 6 ↓} The metabolic consequences may be partly microbiome-mediated: arsenic perturbs bile acid metabolism and affects metabolic health-associated gut microbiota, with changes linked to T2DM pathways.^{[22]Heavy Metal Exposure Causes Changes in the Metabolic Health-Associated Gut Microbiome and MetabolitesXuanji Li, Asker Daniel Brejnrod, Madeleine Ernst et al. · 2019Open reference 22 ↓}

Prenatal exposure programs offspring microbiome shifts in insulin signaling and NAFLD pathways.^{[24]Shukla et al. 2023 — Analysis of Gut Bacteriome of In Utero Arsenic-Exposed MiceShukla S, Srivastava A, Verma D et al. · 2023Open reference 24 ↓}

Neurodevelopmental Effects#

Arsenic and/or fluoride exposure from intrauterine to adult periods in rats reduces neurobehavioral performance and causes hippocampal CA1 lesions, mediated through altered gut microbiome composition and disrupted tryptophan, GABA, and arachidonic acid metabolism.^{[28]Zhang 2023 — Mechanism of Learning and Memory Impairment in Rats Exposed to Arsenic and/or Fluoride Based on Microbiome and MetabolomeZhang Xiao Li, Yu Sheng Nan, Qu Ruo Di et al. · 2023Open reference 28 ↓}

In children, urinary arsenic shows the strongest negative correlation with social behavior (r=-0.43, p<0.001) and is associated with disrupted microbiome-associated catecholamine precursor metabolites.^{[29]Krajewski 2025 -- Heavy metals, noradrenaline/adrenaline ratio, and microbiome-associated hormone precursor metabolites: biomarkers for social behaviour, ADHD symptoms, and executive function in childrenKristin Krajewski · 2025Open reference 29 ↓}

Dietary heavy metals including arsenic are implicated in neurodegeneration through gut-brain axis disruption.^{[30]Editorial: Risk of dietary hazardous substances and impact on human microbiota: possible role in several dysbiosis phenotypesAguilera M, Lamas B, Van Pamel E et al. · 2021Open reference 30 ↓}

Cardiovascular Disease#

Arsenic exposure is linked to cardiovascular disease and hypertension.^{[6]Su 2023 — Arsenic in brown rice: do the benefits outweigh the risks?Lihchyun Joseph Su, Tung-Chin Chiang, Sarah N. O'Connor · 2023Open reference 6 ↓} The metabolic perturbations induced by arsenic in the gut—particularly bile acid disruption—may contribute to cardiovascular risk through the microbiome-metabolome axis.^{[21]Toxic and Essential Metals: Metabolic Interactions with the Gut Microbiota and Health ImplicationsQinheng Zhu, Boyan Chen, Fu Zhang et al. · 2024Open reference 21 ↓}

Key Studies#

Cross-References#

• Nickel, Chromium—co-reviewed carcinogenic metals^{[4]Genetic and Epigenetic Mechanisms in Metal Carcinogenesis and Cocarcinogenesis: Nickel, Arsenic, and ChromiumKonstantin Salnikov, Anatoly Zhitkovich · 2008Open reference 4 ↓}
• Lead, Cadmium, Mercury—shared ROS/GSH depletion mechanisms^{[8]Toxic Mechanisms of Five Heavy Metals: Mercury, Lead, Chromium, Cadmium, and ArsenicBalali-Mood M, Naseri K, Tahergorabi Z et al. · 2021Open reference 8 ↓}
• Epigenetic Modifications—SAM depletion and methylation paradox
• oxidative stress—convergent toxicity pathway across metals
• Glutathione (GSH)—universal target of arsenic-induced depletion
• Faecalibacterium prausnitzii—protective against arsenic toxicity^{[15]The gut microbiome is required for full protection against acute arsenic toxicity in mouse modelsCoryell M, McAlpine M, Pinkham NV et al. · 2018Open reference 15 ↓}
• Desulfovibrio—thiolation of arsenic compounds; enriched under metal exposure^{[2]Arsenic and the gastrointestinal tract microbiomeMcDermott TR, Stolz JF, Oremland RS · 2020Open reference 2 ↓[19]Rezazadegan et al. 2025 — Heavy Metals and Gut Microbiota: A Systematic ReviewFatemeh Rezazadegan, Maryam Mahmoudi, Seyed Mohammad Mousavi · 2025Open reference 19 ↓}
• Co-Selection—arsenic as driver of antibiotic resistance^{[26]Baker-Austin 2006 — Co-selection of Antibiotic and Metal ResistanceBaker-Austin C, Wright MS, Stepanauskas R et al. · 2006Open reference 26 ↓}
• Antimicrobial Resistance—arsenic in paddy soils shapes ARG distribution^{[13]Arsenic and cadmium as predominant factors shaping the distribution patterns of antibiotic resistance genes in polluted paddy soilsZhao X, Shen JP, Zhang LM et al. · 2020Open reference 13 ↓}
• Gut-Metal-Microbiome Interactions—bidirectional arsenic-microbiome relationship
• Developmental Metal Vulnerability: Critical Windows of Susceptibility—prenatal arsenic exposure programs offspring microbiome
• Iron—shared intestinal transporters; iron-importing genes upregulated under arsenic stress^{[17]Exposure to toxic metals triggers unique responses from the rat gut microbiotaRichardson JB, Dancy BCR, Horton CL et al. · 2018Open reference 17 ↓}
• Heavy Metals—arsenic as metalloid classified among toxic heavy metals
• Environmental Metal Exposure—arsenic in groundwater, rice, and infant foods
• Metal Carcinogenesis—overarching framework for arsenic carcinogenesis