Arsenic Research in NHEERL s Environmental Carcinogenesis Division Research Triangle Park NC

Arsenic Research in NHEERL’s Environmental Carcinogenesis Division, Research Triangle Park, NC Authors: Kirk Kitchin, Sarfaraz Ahmad, Jim Allen, Elena McDorman, Kathleen Wallace, Barbara Roop, Stephen Nesnow, Guy Lambert, Alan Tennant, Don Delker, Marc Mass1, Andrew Kligerman, Anuradha Mudipalli Key Words: arsenic, computational toxicology Arsenic is a human carcinogen in skin, lung, liver, urinary bladder and kidney. Exposures to arsenic can occur via drinking water (the main route), food and the respiratory and dermal routes. The states with the highest ground water concentrations of arsenic are Arizona, New Mexico, Nevada, Idaho, Utah, California, Wisconsin, Michigan, New Hampshire and Maine. There are tens of millions of humans exposed to greater than 50 ug/L of arsenic in their drinking water in Bangladesh, India, PRC China, Taiwan, Viet Nam, Nepal, Thailand, Chile, Argentina and Mexico. The Environmental Carcinogenesis Division’s health effects arsenic research is centered on (1) the carcinogenic and toxic mode (mechanism) of action of arsenic, (2) individual and subpopulation susceptibility to arsenic, (3) the dose (concentration)-response relationship (linear, sublinear, supra linear), (4) data useful for extrapolating risk to low doses (concentrations) of arsenic, (5) animal models of arsenic carcinogenesis and (6) structure-activity relationships and computational toxicology of arsenicals. With respect to mode of action research, the proposed modes/mechanisms of action for arsenic carcinogenesis include but are not limited to clastogenesis, mutation, oxidative stress, gene amplification, altered DNA methylation, cell proliferation, promotion, effects on the progression stage, inhibition of DNA repair and interaction with important cellular proteins. Based on recent experimental findings from ECD, methylation and subsequent reduction of inorganic arsenic to DMA(III) may be a “toxification” or “activation” pathway of carcinogenesis. Research on susceptibility to arsenic has shown that dietary deficiency of folate [a precursor of the methyl donor S-adenosylmethionine (SAM)] can increase the frequency of micronuclei in polychromatic erythrocytes in mice. Dose response studies of arsenic have shown a sublinear relationship between administered dose of arsenite and rat hepatic heme oxygenase induction. Animal models of arsenic carcinogenesis have used the transgenic K6/ODC mouse. To date, mouse skin tumors have been produced by short-term exposure to three different arsenicals arsenite, DMA(V) and MMA(III). Other research activities include arsenic binding to peptides and proteins, reactive oxygen species as a cause of carcinogenesis, genotoxicity and mutation caused by arsenicals, cell proliferation and DNA microarray studies of the effect of arsenic on gene expression. (Disclaimer: This is an abstract of a proposed presentation and does not necessarily reflect EPA policy.) Contact Information: Kirk Kitchin ORD/NHEERL 919/541-7502 Kitchin.Kirk@epa.gov 1 Deceased