Comparison between Carcinogenicity and Mutagenicity Based on Chemicals Evaluated in the IARC Monographs

Abstract

The qualitative relationship between carcinogenicity and mutagenicity (DNA-damaging activity), based on chemicals which are known to be or suspected of being carcinogenic to man and/or to experimental animals, is analyzed using 532 chemicals evaluated in Volumes 1-25 of the IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. About 40 compounds (industrial processes) were found to be either definitely or probably carcinogenic to man, and 130 chemicals have been adequately tested in rodents and most of them also in various short-term assays. For a comparison between the carcinogenicity of a chemical and its behavior in short-term tests, systems were selected that have a value for predicting carcinogenicity. These were divided into mutagenicity in (A) the S. typhimurium/microsome assay, (B) other submammalian systems and (C) cultured mammalian cells; (D) chromosomal abnormalities in mammalian cells; (E) DNA damage and repair; (F) cell transformation (or altered growth properties) in vitro.The following conclusions can be drawn. In the absence of studies in man, long-term animal tests are still today the only ones capable of providing evidence of the carcinogenic effect of a chemical. The development and application of an appropriate combination of short-term tests (despite current limitations) can significantly contribute to the prediction/confirmation of the carcinogenic effects of chemicals in animals/man. Confidence in positive tests results is increased when they are confirmed in multiple short-term tests using nonrepetitive end points and different activation systems. Assays to detect carcinogens which do not act via electrophiles (promoters) need to be developed. The results of a given short-term test should be interpreted in the context of other toxicological data. Increasing demand for quantitative carcinogenicity data requires further examination of whether or not there is a quantitative relationship between the potency of a carcinogen in experimental animals/man, and its genotoxic activity in short-term tests. At present, such a relationship is not sufficiently established for it to be used for the prediction of the carcinogenic potency of new compounds.There is increasing evidence to suggest that DNA damage (expressed mainly as mutations) is involved in the induction of many cancers; however, the relevance of the various biological end points used in short-term assays to mechanisms of tumor induction is not known precisely. All test procedures must therefore be validated before they can be used to predict the carcinogenicity of chemicals. Ideally, such validations would be based on correlations between responses in short-term tests and data from epidemiological studies in humans.

Comparison of multiple parameters of rodent carcinogenicity and in vitro genetic toxicity

“…Numerous evaluations have considered the relationship between the capability of chemicals to induce tumors in rodents and to induce mutation or other types of genetic toxicity [eg, Bartsch and Tomatis, 1983;Bridges, 1976;McCann et al, 1975;Hollstein et al, 1979;Rinkus and Legator, 1979;Butterworth, 1979;Purchase et al, 1978;Reitz et al, 19821. It is clear that this relationship is complex, and at this time there are a number of discordant results that preclude the use of in vitro genetic toxicity results to predict all potential in vivo carcinogens in a reliable manner.…”

Consensus report: mutagenicity and carcinogenicity of car exhausts and coal combustion emissions.

“…The high qualitative correlation between bacterial mutagenicity and animal carcinogenicity justifies the use ofthese short-term tests for the identification of potentially carcinogenic organic chemicals. Although reasonably good correlation between mutagenic and carcinogenic potency is found for certain classes of chemicals a general correlation cannot be expected for all chemicals (96,97). Within a series of extractable organics from motor vehicle particle emissions a good correlation was observed between bacterial mutagenic activity, mammalian cell mutagenic and transforming activity, and skin tumor initiating activity.…”

Use of short-term test systems for the prediction of the hazard represented by potential chemical carcinogens

“…Attempts have also been made to develop a quantitative correlation between in vitro and/n vivo data (Tomatis et al, 1982;Bartsch, 1983). The implication of such a correlation is that it is possible to detect potent carcinogens as the result of a strong positive response in mutagenicity test systems.…”