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An evaluation of the mode of action framework for mutagenic carcinogens: Chromium (VI): SOT.
Citation:
KLIGERMAN, A. D. An evaluation of the mode of action framework for mutagenic carcinogens: Chromium (VI): SOT. Presented at Society of Toxicology , Baltimore, MD, March 15 - 19, 2009.
Impact/Purpose:
Determining the mode of action (MOA) of a chemical is important in risk assessment because it determines whether or not supplementary guidance comes into effect. This work shows how the scientific literature on chromium can be used in EPA's MOA framework for determining if chromium has a mutagenic MOA.
Description:
In response to the 2005 revised U.S Environmental Protection Agency’s (EPA) Cancer Guidelines, a strategy is being developed 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 Pesticides’ Health Effects Division (HED) using the data from the National Toxicology Program (NTP) 2-year drinking water studies in rats and mice. 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 in numerous in vitro assays, in animals and in humans 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. Mechanistic evidence was also found for oxidative damage and DNA adduct formation contributing to the tumor response. Within the timeframe and tumorigenic dose range for early events, genetic changes in mice (single/double-stranded DNA breaks) commence. Overall, the weight of evidence supports Cr (VI) acting through a mutagenic MOA. Therefore, the Cancer Guidelines recommend a linear extrapolation for the oral exposure risk assessment. Data also exist showing that germ cells, developing embryos and older children are at risk for Cr (VI)-induced mutations; thus, it is recommended that the ADAFs be applied.