Chemical toxicity and chemical carcinogenesis. Is there a causal connection? A comparative morphological evaluation of 1500 experiments.

Chemicals cause toxic and carcinogenic effects as well as beneficial and other adverse effects in animals and in humans. The purpose of this paper is to assess whether there is a direct, uniform causal relationship between toxicity and carcinogenicity. Within this context, specific issues receive attention: the influence of exposure concentrations on carcinogenesis; kidney cancer and alpha 2 mu-globulin; urinary calculi and tumours; and cell turnover or proliferation and cancer. The data used to evaluate histopathological site-specific correspondence between these two end-points comes from 130 studies of chemical carcinogenesis designed and conducted by the US National Toxicology Program (NTP). Nearly 1500 sex-species-exposure group experiments were evaluated for morphological evidence of toxicity and/or carcinogenicity, for dose-response relationships, and for site-specific correlations of toxicity and carcinogenicity. The major conclusions are that chemicals evaluated for long-term toxicity and carcinogenicity in experimental animals can be divided into three categories: (1) those that cause organ toxicity without cancer, (2) those that cause site-specific cancer with no associated toxicity and (3) those that cause toxicity and cancer in the same organ. Examples are given to illustrate each category. On the basis of this comparative analysis, in the great majority of cases the available data do not support a correlation between chemically induced toxicity and carcinogenicity. Moreover, until considerably more scientific knowledge about molecular mechanisms of carcinogenesis becomes available and accepted, attempts to use findings on toxicity to modify the risk assessment process will be fraught with uncertainty and might even have a negative impact on public health.