Comparison of target organs of carcinogenicity for mutagenic and non-mutagenic chemicals

Abstract

A comparison of target organs for mutagens and non-mutagens is presented for 351 rodent carcinogens in the Carcinogenic Potency Database (CPDB) with mutagenicity evaluations in Salmonella. Results are consistent with the hypotheses that in high-dose rodent tests mitogenesis is important in the carcinogenic response for mutagens and non-mutagens alike, and that mutagens have a multiplicative interaction for carcinogenicity because they can both damage DNA directly and cause cell division at high doses. These hypotheses would lead one to expect several results that are found in the analysis: First, a high proportion of both mutagens and non-mutagens induce tumors in rodent bioassays at the MTD. Second, mutagens compared to non-mutagens are: (a) more likely to be carcinogenic; (b) more likely to induce tumors at multiple target sites; and (c) more likely to be carcinogenic in two species. Among carcinogens that induce tumors at multiple sites in both rats and mice, 81% are mutagens; in comparison, among carcinogens that are positive at only a single target site in one species and are negative in the other, 42% are mutagens. Since tissue distribution and pharmacokinetics would not be expected to differ systematically between mutagens and non-mutagens, one would not expect systematic differences in the particular organs in which tumors are induced. Results do not support the idea that mutagens and non-mutagens induce tumors in different target organs. Both mutagens and non-mutagens induce tumors in a wide variety of sites, and most organs are target sites for both. Moreover, the same sites tend to be the most common sites for both: 79% or more of both mutagenic and non-mutagenic carcinogens are positive in each species in at least one of the 8 most frequent target sites: liver, lung, mammary gland, stomach, vascular system, kidney, hematopoietic system and urinary bladder. Species differences are discussed as well as results for particular target organs: liver, Zymbal's gland and kidney.