Methylated arsenicals: The implications of metabolism and carcinogenicity studies in rodents to human risk assessment

Samuel Monroe Cohen, Lora L Arnold, Michal Eldan, Ari S. Lewis, Barbara D. Beck

Research output: Contribution to journalReview article

229 Citations (Scopus)

Abstract

Monomethylarsonic acid (MMAV) and dimethylarsinic acid (DMA V) are active ingredients in pesticidal products used mainly for weed control. MMAV and DMAV are also metabolites of inorganic arsenic, formed intracellularly, primarily in liver cells in a metabolic process of repeated reductions and oxidative methylations. Inorganic arsenic is a known human carcinogen, inducing tumors of the skin, urinary bladder, and lung. However, a good animal model has not yet been found. Although the metabolic process of inorganic arsenic appears to enhance the excretion of arsenic from the body, it also involves formation of methylated compounds of trivalent arsenic as intermediates. Trivalent arsenicals (whether inorganic or organic) are highly reactive compounds that can cause cytotoxicity and indirect genotoxicity in vitro. DMAV was found to be a bladder carcinogen only in rats and only when administered in the diet or drinking water at high doses. It was negative in a two-year bioassay in mice. MMAV was negative in 2-year bioassays in rats and mice. The mode of action for DMA V-induced bladder cancer in rats appears to not involve DNA reactivity, but rather involves cytotoxicity with consequent regenerative proliferation, ultimately leading to the formation of carcinoma. This critical review responds to the question of whether DMAV-induced bladder cancer in rats can be extrapolated to humans, based on detailed comparisons between inorganic and organic arsenicals, including their metabolism and disposition in various animal species. The further metabolism and disposition of MMAV and DMAV formed endogenously during the metabolism of inorganic arsenic is different from the metabolism and disposition of MMAV and DMAV from exogenous exposure. The trivalent arsenicals that are cytotoxic and indirectly genotoxic in vitro are hardly formed in an organism exposed to MMAV or DMAV because of poor cellular uptake and limited metabolism of the ingested compounds. Furthermore, the evidence strongly supports a nonlinear dose-response relationship for the biologic processes involved in the carcinogenicity of arsenicals. Based on an overall review of the evidence, using a margin-of-exposure approach for MMAV and DMAV risk assessment is appropriate. At anticipated environmental exposures to MMA V and DMAV, there is not likely to be a carcinogenic risk to humans.

Original languageEnglish (US)
Pages (from-to)99-133
Number of pages35
JournalCritical reviews in toxicology
Volume36
Issue number2
DOIs
StatePublished - Mar 1 2006

Fingerprint

Arsenicals
Arsenic
Metabolism
Risk assessment
Rodentia
Rats
Bioassay
Dynamic mechanical analysis
Cytotoxicity
Carcinogens
Urinary Bladder Neoplasms
Biological Assay
Animals
Weed control
Cacodylic Acid
Urinary Bladder
Weed Control
Methylation
Nutrition
Metabolites

Keywords

  • Arsenic Metabolism
  • Bladder Carcinogenesis
  • Cell Proliferation
  • Cytotoxicity
  • Methylated Arsenicals
  • Risk Assessment

ASJC Scopus subject areas

  • Toxicology

Cite this

Methylated arsenicals : The implications of metabolism and carcinogenicity studies in rodents to human risk assessment. / Cohen, Samuel Monroe; Arnold, Lora L; Eldan, Michal; Lewis, Ari S.; Beck, Barbara D.

In: Critical reviews in toxicology, Vol. 36, No. 2, 01.03.2006, p. 99-133.

Research output: Contribution to journalReview article

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N2 - Monomethylarsonic acid (MMAV) and dimethylarsinic acid (DMA V) are active ingredients in pesticidal products used mainly for weed control. MMAV and DMAV are also metabolites of inorganic arsenic, formed intracellularly, primarily in liver cells in a metabolic process of repeated reductions and oxidative methylations. Inorganic arsenic is a known human carcinogen, inducing tumors of the skin, urinary bladder, and lung. However, a good animal model has not yet been found. Although the metabolic process of inorganic arsenic appears to enhance the excretion of arsenic from the body, it also involves formation of methylated compounds of trivalent arsenic as intermediates. Trivalent arsenicals (whether inorganic or organic) are highly reactive compounds that can cause cytotoxicity and indirect genotoxicity in vitro. DMAV was found to be a bladder carcinogen only in rats and only when administered in the diet or drinking water at high doses. It was negative in a two-year bioassay in mice. MMAV was negative in 2-year bioassays in rats and mice. The mode of action for DMA V-induced bladder cancer in rats appears to not involve DNA reactivity, but rather involves cytotoxicity with consequent regenerative proliferation, ultimately leading to the formation of carcinoma. This critical review responds to the question of whether DMAV-induced bladder cancer in rats can be extrapolated to humans, based on detailed comparisons between inorganic and organic arsenicals, including their metabolism and disposition in various animal species. The further metabolism and disposition of MMAV and DMAV formed endogenously during the metabolism of inorganic arsenic is different from the metabolism and disposition of MMAV and DMAV from exogenous exposure. The trivalent arsenicals that are cytotoxic and indirectly genotoxic in vitro are hardly formed in an organism exposed to MMAV or DMAV because of poor cellular uptake and limited metabolism of the ingested compounds. Furthermore, the evidence strongly supports a nonlinear dose-response relationship for the biologic processes involved in the carcinogenicity of arsenicals. Based on an overall review of the evidence, using a margin-of-exposure approach for MMAV and DMAV risk assessment is appropriate. At anticipated environmental exposures to MMA V and DMAV, there is not likely to be a carcinogenic risk to humans.

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