Methylated Arsenicals: The Implications of Metabolism and Carcinogenicity Studies in Rodents to Human Risk Assessment

Abstract

Monomethylarsonic acid (MMA^V) and dimethylarsinic acid (DMA^V) are active ingredients in pesticidal products used mainly for weed control. MMA^V and DMA^V 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. DMA^V 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. MMA^V 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 DMA^V-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 MMA^V and DMA^V formed endogenously during the metabolism of inorganic arsenic is different from the metabolism and disposition of MMA^V and DMA^V from exogenous exposure. The trivalent arsenicals that are cytotoxic and indirectly genotoxic in vitro are hardly formed in an organism exposed to MMA^V or DMA^V 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 MMA^V and DMA^V risk assessment is appropriate. At anticipated environmental exposures to MMA^V and DMA^V, there is not likely to be a carcinogenic risk to humans.

Key words :

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

Notes

*The valence state of arsenic is indicated with a superscript when it is specifically noted in or is obvious from the description in the referenced publication. In the few instances where this cannot be ascertained, the valence is not indicated.

*Due to the analytical methods available at the time, it is unknown if the dimethylated arsenical present in this complex was in the trivalent form (dimethylarsonous acid) or the pentavalent form (dimethylarsinic acid).

*The “Cancer Dietary” daily dose estimate is presented by the U.S. EPA, “Cacodylic Acid and Sodium Salt: The HED Chapter of the Re-registration Eligibility Decision Document.”

^†For the daily dose of DMA from drinking water, we assumed arsenic was present in drinking water at the maximum contaminant level (MCL) (U.S. EPA, 2001a) and that 1% of the arsenic was in the form of DMA (i.e., 0.1 μg/L DMA). Additionally, we used an average water intake of 1.4 L/day for a 70-kg adult as recommend by the U.S. EPA (1997). Our assumption regarding the amount of DMA in drinking water was based on available information indicates that concentrations of DMA in groundwater are negligible and often below method detection limits (Chatterjee et al., 1995; Chen et al., 1994, as cited in NRC, 1999).