An Evaluation of the Mode of Action Framework for Mutagenic Carcinogenscase Study: Cyclophosphamide (Journal Article)
In response to the 2005 revised U.S Envrionmental Protection Agency (EPA) Cancer Guidelines, a Risk Assessment Forum’s Technical Panel is devising a strategy in which genetic toxicology data combined with other information are assessed 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. The decision tree that is being developed as part of this approach outlines the critical steps for analyzing a compound for carcinogenicity through mutagenic MOA (e.g., data analysis, determination of mutagenicity in animals and in humans). Agents satisfying the criteria proceed through the Agency’s framework analysis for MOAs. Cyclophosphamide (CP), an antineoplastic agent, which is carcinogenic in animals and humans and mutagenic in vitro and in vivo, was selected as a case study. There were consistent positive results for mutagenic activity in numerous in vitro assays, in animals (mice, rats, and hamsters) and in humans. CP was processed through the framework analysis and key steps leading to tumor formation was identified as: metabolism of the parent compound to alkylating metabolites, DNA damage followed by and induction of multiple adverse genetic events, cell proliferation, and bladder tumors. Genetic changes in rats can commence within 30 minutes and in cancer patients are seen by 1 hour, well within the timeframe and tumorigenic dose range for early events. Supporting evidence is also found for cell proliferation, indicating that mutagenicity, associated with cytotoxicity, leads to a proliferative response, which occurs early in the process of tumor induction. So far, no data were found that an alternative MOA other than mutagenicity might be operative. If the weight of the evidence supports a mutagenic MOA, the Cancer Guidelines recommend a linear extrapolation for the risk assessment; additionally, the ADAFs would be applied.