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An Evaluation of the Mode of Action Framework for MutagenicCarcinogens Case Study II: Chromium (VI).
Citation:
MCCARROLL, N., J. CHEN, G. AKERMAN, N. Keshava, A. D. KLIGERMAN, AND E. RINDE. An Evaluation of the Mode of Action Framework for MutagenicCarcinogens Case Study II: Chromium (VI). ENVIRONMENTAL AND MOLECULAR MUTAGENESIS. John Wiley & Sons, Inc, Hoboken, NJ, 51(2):89-111, (2010).
Impact/Purpose:
EPA’s mode of action forum is developing guidelines to determine if a chemical acts through a mutagenic mode of action to determine whether supplementary guidance is needed. This is a study showing how to use the scientific literature on chromium IV with the framework.
Description:
In response to the 2005 revised U.S Environmental Protection Agency’s (EPA) Cancer Guidelines, a strategy is being developed to include all mutagenicity and other genotoxicity data with any additional information to determine whether a carcinogen operates through a mutagenic mode of action (MOA). This information is necessary for EPA to decide whether age-dependent adjustment factors (ADAFs) should be applied to the cancer risk assessment. Chromium (VI), which is carcinogenic in animals and humans via the inhalation route, was assessed for carcinogenicity by the Cancer Assessment Review Committee (CARC) of the Office of Pesticide Programs, Health Effects Division (HED) using the data from the National Toxicology Program (NTP) 2-year drinking water studies in rats and mice that were finalized in 2008. From these data, CARC classified Cr (VI) as “Likely to be Carcinogenic in Humans” via the oral route, based on oral cavity tumors in male and female rats and tumors of the small intestine in male and female mice. Cr (VI) was also mutagenic, producing consistent positive results for mutagenic activity in numerous in vitro assays, in animals (mice and rats) and in humans (single/double-stranded DNA breaks and micronucleus induction in blood and buccal cells) occupationally exposed to Cr (VI). Accordingly, Cr (VI) was processed through the framework analysis and key steps leading to tumor formation were identified: interaction of cellular components (DNA) with Cr (VI), mutagenesis, cell proliferation (hyperplasia) and tumor formation. Within the timeframe and tumorigenic dose range for early events, genetic changes in mice (single/double-stranded DNA breaks detected by the Comet assay at 0.59 to 9.5 mg/kg orally administered) can commence within 24 hours of treatment. Supporting evidence is also found for cell proliferation, indicating that mutagenicity, associated with oxidative damage, DNA adduct formation and cytotoxicity, leads to a proliferative response, which occurs in the process of tumor induction. Overall, the weight of evidence evaluation supports Cr (VI) acting through a mutagenic MOA. In addition, no data were found that an alternative MOA might be operative. Therefore, the Cancer Guidelines recommend a linear extrapolation for the oral exposure risk assessment. Data also show that Cr (VI) induces mutagenicity in germinal cells, passes through the placental barrier, and causes DNA deletions and teratogenicity in developing embryos. Additionally, there is concern that older children are at risk because of the ability of Cr (VI) to penetrate cellular membranes and interact via intracellular mechanism leading to mutations; thus, it is recommended that the ADAFs be applied.
