When Is There Enough Evidence to Perform a Nonlinear Cancer Assessment?
Under U.S. EPA's Proposed Guidelines for Carcinogen Risk Assessment (FR 61:179670-18011, 199996), departure from the default linear cancer assessment may be made for carcinogens for which there is sufficient evidence of a nonlinear mechanism. DCP, and agricultural fumigant that protects against crop damage by nematodes, is metabolized largely by glutathione conjugation with subsequent mercapturic acid excretion in the urine. DCP has been tested extensively for mutagenicity and carcinogenicity in both in vivo systems. In vitro assays show positive mutagenicity, which is prevented by physiological levels of glutathione, in the presence of a metabolozing system. In vivo genotoxicity assays are equivocal. Mutagenic epoxide metabolites have been identified at - LD50 doses in mouse liver. In vitro studies with mouse liver show that glutathione decreases epoxide formation. A two-year inhalation assay yielded benign tumors in mice and no increase in tumors in rats. A gavage assay yielded largely benign tumors in rats and mice with the exception of a rare urinary bladder carcinoma in mice. A feeding assay confirmed the liver tumors in rats observed in the gavage study, but no increase in tumors was observed in mice. Mechanistic studies, such as DNA replication, rate of apoptosis, and DNA adduct formation were unable to verify or rule out a genotoxic mechanism of tumor formation. Because the mode of tumor formation was uncertain, a genotoxic mechanism was assumed and a linear cancer assessment was performed.