Application of Mechanistic Data in Carcinogen Risk Assessment -- Example Chloracetanilides. A. G. E. Wilson and W. F. Heydens, Monsanto Company, St. Louis, Missouri 63167
The provisions of the revised carcinogen risk assessment guidelines emphasize the importance of mechanistic information in the risk assessment process for chemicals. In this paper we will discuss how the extensive mechanistic data for several chloracetanilide herbicides has been used in the cancer risk assessment process and the application to combined risk assessment under FQPA (Food Quality Protection Act). Chronic administration of several chloracetanilide herbicides results in nasal tumors in the rat, but not the mouse. An extensive battery of tests have confirmed that these chloracetanilide herbicides are not genotoxic. Extensive mechanistic studies have provided critical insight into the mechanism of rat specific oncogenicity. In this presentation, the role of nasal tissue metabolism and cell proliferation as critical determinants in the unique susceptibility of the rat to nasal tumor formation will be discussed. The mechanism of rat nasal carcinogenicity has been shown to involve metabolism by the rat nasal turbinates to a putative toxic iminoquinone metabolite (IQ). In vivo studies have demonstrated formation of an IQ protein adduct in rat nasal tissue, whereas this adduct is not found in mouse nasal tissue. In vitro studies have demonstrated the significantly greater ability of rat nasal tissue to form IQ, compared to other species. The metabolic capability of rat nasal tissue to form DEIQ was over 20,000-fold greater than human. The mechanism of nasal tumor formation involves the dose-dependent increase in cell proliferation in rat nasal olfactory epithelium. No increase in cell proliferation is observed in the nasal tissue of mice. These results provide important evidence for a rat specific, threshold-based, non-genotoxic mechanism that involves unique nasal tissue metabolism and the induction of cell proliferation. Furthermore, the scientific data supports the view that the carcinogenicity seen in the rat is not relevant to humans.
These data provide a basis for supporting a cancer risk assessment procedure based on a margin of safety (exposure) approach. In addition, they provide a basis for using the potential for formation of IQ as a basis for conducting combined risk assessment.