Absence of morphologic correlation between chemical toxicity and chemical carcinogenesis

The experimental data set used to evaluate site-specific histopathologic correspondence between the morphologic end points of toxicity and carcinogenicity comprises 130 chemical carcinogenesis studies. Nearly 1500 sex-species-exposure-group experiments were evaluated for a) evidence of toxicity or/and carcinogenicity, b) dose-response relationships, c) site-specific correlations of toxicity and carcinogenicity, and d) correspondence with Salmonella mutagenicity. The major conclusions are that chemicals evaluated for long-term toxicity and carcinogenicity in experimental animals divide typically and consistently into three categories: a) chemicals causing organ toxicity without cancer, b) chemicals causing site-specific cancer with no associated toxicity, and c) chemicals causing both toxicity and cancer in the same organ. Few chemicals overall (and none in this data set) fit the remaining group that cause neither toxicity nor carcinogenicity under these protocol conditions. Mutagenicity exhibited no consistent pattern with any of these groupings. Only 7 of 53 "positive" chemicals had target organ toxicity at all sites of carcinogenicity. Just three chemicals showed carcinogenic effects at the highest exposure concentrations without supporting evidence of tumors at the lower levels. From these comparative morphological analyses, and for almost all cases, available data do not support a correlation between chemically induced toxicity or regenerative phenomena and carcinogenicity. Consequently, until scientific knowledge about molecular mechanisms of chemical carcinogenesis becomes better understood and generally accepted, attempts to use toxicity findings to modify risk assessment processes will be fraught with uncertainty and thus could have a negative impact on public health.