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.

Inorganic arsenic (iAs) at high exposures is a human carcinogen, affecting mainly the urinary bladder, lung and skin. We present an assessment of the mode of action (MOA) of iAs’s carcinogenicity based on the United States Environmental Protection Agency/International Programme on Chemical Safety (USEPA/IPCS) framework, focusing primarily on bladder cancer. Evidence is presented for a MOA involving formation of reactive trivalent metabolites interacting with critical cellular sulfhydryl groups, leading to cytotoxicity and regenerative cell proliferation. Metabolism, kinetics, cell transport, and reaction with specific proteins play a critical role in producing the effects at the cellular level, regardless of cell type, whether urothelium, lung epithelium or epidermis. The cytotoxicity induced by iAs results in non-cancer toxicities, and the regenerative cell proliferation enhances development of epithelial cancers. In other tissues, such as vascular endothelium, different toxicities develop, not cancer. Evidence supporting this MOA comes from in vitro investigations on animal and human cells, from animal models, and from epidemiological studies. This MOA implies a non-linear, threshold dose-response relationship for both non-cancer and cancer end points. The no effect levels in animal models (approximately 1 ppm of water or diet) and in vitro (>0.1 µM trivalent arsenicals) are strikingly consistent. Cancer effects of iAs in humans generally are not observed below exposures of 100–150 ppb in drinking water: below these exposures, human urine concentrations of trivalent metabolites are generally below 0.1 µM, a concentration not associated with bladder cell cytotoxicity in in vitro or animal models. Environmental exposures to iAs in most of the United States do not approach this threshold.

Defining the mode(s) of action by which chemicals induce tumors in laboratory animals has become a key to judgments about the relevance of such tumor data for human risk assessment. Frameworks for analyzing mode of action information appear in recent U.S. EPA and IPCS publications relating to cancer risk assessment. This FORUM paper emphasizes that mode of action analytical frameworks depend on both qualitative and quantitative evaluations of relevant data and information: (1) presenting key events in the animal mode of action, (2) developing a “concordance” table for side-by-side comparison of key events as defined in animal studies with comparable information from human systems, and (3) using data and information from mode of action analyses, as well as information on relative sensitivity and exposure, to make weight-of-evidence judgments about the relevance of animal tumors for human cancer assessments. The paper features a systematic analysis for using mode of action information from animal and human studies, based in part on case examples involving environmental chemicals and pharmaceuticals.

Understanding the relationship of chemicals to carcinogenesis has progressed significantly since the initial observations of Hill and Pott in the 1700’s. Distinguishing between DNA-reactive chemicals and those which increase cancer risk by increasing cell proliferation has been a major breakthrough in delineating overall mechanisms. Competing processes for activation versus inactivation of chemicals occur at many levels, including metabolism, DNA repair, and cellular repair processes. These processes can be affected by other agents to decrease carcinogenesis (chemoprevention). Increasing knowledge of the multiple steps of carcinogenesis is leading to improved methods for screening chemicals for carcinogenic activity and for regulatory decision making. Improvements in assessment of modes of action involved in animal and in vitro models have led to more rational approaches to assessing relevance to humans. The advent of genomics and high-throughput technologies have contributed to investigations of mechanisms and is beginning to impact development of better methods for screening chemicals. Based on developments in basic research, epidemiology, and astute clinical observations, the major risk factors and etiologic agents have been identified for a majority of cancers, which is beginning to lead to methods to decrease cancer incidence overall and identify targets for early detection and treatment.

An approach to the evaluation of carcinogenic risk resulting from exposure to a given chemical is presented in place of a reliance on two-year rodent bioassays. An emphasis is placed on evaluation of the potential DNA reactivity or increased cell proliferation that can be produced by a chemical. The special cases of immunosuppressive and estrogenic chemicals are considered. These evaluations are proposed to involve a combination of in vitro assays, computerized models, and short-term (up to 13 weeks) bioassays in rodents. The emphasis is on mechanistic understanding and evaluation of the dose response and relevance to humans.