CORRELATIONS BETWEEN CHEMICALLY RELATED SITE-SPECIFIC CARCINOGENIC EFFECTS IN LONG-TERM STUDIES IN RATS AND MICE

We examined a database of 379 long-term carcinogenicity studies in rats and mice to evaluate sex and species correlations in site-specific carcinogenic responses. Within a species, most target sites showed a strong correlation between males and females. For example, chemicals producing forestomach or liver tumors in males were likely to produce these same types of tumors in females. There was also a significant correlation between species for certain site-specific carcinogenic effects, most notably tumors of the forestomach, liver, and thyroid gland. In contrast, adrenal pheochromocytoma, preputial/clitoral gland neoplasms, and lung tumors showed no significant interspecies correlation. Many chemicals produced a syndrome of carcinogenic effects involving tumors of the skin, Zymbal gland, preputial/clitoral gland, mammary gland, and/or oral cavity. Regarding different target sites, there appeared to be a correlation between thyroid and liver tumors both within and between species. Further, all chemicals producing mesotheliomas in male rats also produced mammary gland neoplasms in female rats. In contrast, kidney and urinary bladder tumors showed no significant association with any other tumor type in rats or mice. If a chemical produced a site-specific carcinogenic effect in female rats or mice, there was approximately a 65% probability that the chemical would also bc carcinogenic at that same site in males. The interspecies correlation was somewhat lower: approximately 36% of the site-specific carcinogenic effects ob-served in one species (rats or mice) were also observed in the other species. The high correlation between males and females suggests that in some instances it may be appropriate to consider a reduced protocol such as male rats and female mice. This would result in substantial cost savings, and an examination of NCI/NTP studies suggests that while there will bc some sensitivity loss associated with this approach, the rodent carcinogens not detected by this reduced protocol are not those most likely to pose a carcinogenic threat to humans. Nevertheless, the decision of whether to use a reduced protocol is best made on a case-by-case basis.