Evidence that toxic injury is not always associated with induction of chemical carcinogenesis

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Abstract
Long‐term rodent bioassays with chemicals administered at maximum tolerated doses identify noncarcinogens as well as carcinogens. Thirty‐one chemicals recently evaluated for carcinogenic potential by the National Toxicology Program provide unique data on the relationships between mutagenicity, toxicity, and carcinogenicity. Twenty‐two substances were classified as carcinogens, and nine showed no evidence of carcinogenicity. Although cellular proliferation does play an intrinsic role in neoplastic processes, the responses associated with chronic toxicity in these studies were not always sufficient to induce neoplasia. Regardless of their mutagenic potential, 19 carcinogens induced toxic effects at sites that did not show neoplastic changes; similar toxic lesions were also seen among the mutagenic and nonmutagenic noncarcinogens. Although many nonmutagens induced neoplasia at sites that showed toxic effects, some of the same chemicals also exhibited toxicity at other sites that showed no neoplastic effect. These results suggest that for some chemicals, properties other than mutagenicity or toxicity may be responsible for their carcinogenic potential.