Gold, L. S., and Slone, T. H. The mouse liver in perpsective: Comparison of target organs of carcinogenicity for mutagens and non-mutagens in chronic bioassay. Fifth Workshop on Mouse Liver Tumors: Summary Report. Washington, DC: International Life Sciences Institute, 1995.
In chronic, long-term carcinogenesis bioassays conducted at the MTD with ad libitum feeding, the liver is the most frequent target site in rats and in mice, and among mutagenic and non-mutagenic carcinogens in each species. In the Carcinogenic Potency Database, 174 chemicals have been evaluated as liver carcinogens in rats (20% of chemicals tested), and 192 in mice (24% of chemicals tested). In mice, about half of the chemicals that induce liver tumors also induce tumors at another site. In our Carcinogenic Potency Database (CPDB) more mutagens (in Salmonella) than non-mutagens have been identified as liver carcinogens in each species: in mice 84 mutagens and 70 non-mutagens are liver carcinogens; in rats the respective numbers are 75 mutagens and 32 non-mutagens. Liver is also the most frequent target site in monkeys in recently completed bioassays at the National Cancer Institute: the liver was a target site for 8 of the 10 chemicals that induced tumors in monkeys.
The purpose of a focus on a specific target site in long term bioassays of chemical carcinogenicity, e.g. liver, is not expected to provide information about specific chemicals that will increase human cancer rates at that same site. Our analyses of bioassays in rats, mice, hamsters, as well as comparisons involving known human carcinogens, indicate that if a chemical induces tumors at a given site in one species, it induces tumors at the same site in a second species no more than 50% of the time.
This workshop's focus on mouse liver tumors reflects recent work on mechanism of carcinogenesis and efforts to improve human risk assessment at low dose, as well as a controversy surrounding the validity of results in mouse liver due to the large number of non-mutagens that induce such tumors and the high and variable spontaneous tumor rates in some strains. Examination of this issue requires comparisons between rats and mice as well as between mutagens and non-mutagens, in order to put the mouse liver in perspective.
Results of our comparison of target organs for mutagens and non-mutagens are 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.
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. Our 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.
Our analysis indicates a species difference in the predominance of the liver in mice compared to rats. Among chemicals with positive results in the mouse, 55% (84/154) of mutagens compared to 71% (70/99) of non-mutagens induce liver tumors, while the proportions among positive chemicals in the rat are 39% (75/194) and 33% (32/98). Thus, while the proportion of rat carcinogens that are positive in the liver is similar for mutagens and non-mutagens, in mice a higher proportion of non-mutagenic than mutagenic carcinogens are positive in the liver. This finding in mice reflects the fact that chlorinated compounds (composed solely of chlorine, carbon, hydrogen and optionally oxygen) are frequently positive in the mouse liver and not mutagenic in Salmonella. Excluding the chlorinated compounds, results in mice are more similar for mutagenic and non-mutagenic carcinogens: 56% (79/142) of mutagens and 59% (40/68) of non-mutagens are mouse liver carcinogens.
Few rodent carcinogens are positive only in mouse liver when tested in both rats and mice, and these are not exclusively non-mutagens. In the CPDB, 261 rodent carcinogens with mutagenicity evaluations have been tested in both rats and mice, and 82 of these (31%) induce tumors in only one target site of one species. Thirty-five of these are mutagens. Investigation of the specific target sites for these 82 chemicals does not suggest differences in the responses of mutagens and non-mutagens. The mouse liver is the most common single-site, single-species target organ for both mutagens (12 chemicals) and non-mutagens (19 chemicals). Many of the non-mutagens in this group are chlorinated compounds Excluding chlorinated compounds, 9 mutagens and 8 non-mutagens are single-species carcinogens positive only in the mouse liver. Among the single-site, single-species carcinogens that do not induce mouse liver tumors, mutagens and non-mutagens are similar: several different sites are target organs and only a few chemicals are uniquely positive at each site.
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