Chemicals Associated with Site-Specific Neoplasia in 1394 Long-Term Carcinogenesis Experiments in Laboratory Rodents

Abstract

The carcinogenicity data base used for this paper originated in the late 1960s by the National Cancer Institute and since 1978 has been continued and made more comprehensive by the National Toxicology Program. The extensive files contain among other sets of information detailed pathology data on more than 400 long-term (most often 24 month) chemical carcinogenesis studies, comprised of nearly 1600 individual experiments having at least 10 million tissue sections that have been evaluated for toxicity and carcinogenicity. Using the current data set of 379 studies made up of 1394 experiments, we have compiled listings of chemicals having like carcinogenic target sites for each of the 34 organs or systems for which histopathology diagnoses have been recorded routinely. The most common tumor site is the liver (15% of all experiments), followed in rank order by: lung, hematopoietic system and kidneys, mammary glands, forestomach, thyroid glands, Zymbal glands, urinary bladder, skin and uterus/cervix, and circulatory system and adrenal glands. These compilations are most useful for maintaining a historic perspective when evaluating the carcinogenicity of contemporary experiments. Equally important, the chemicaltumor-organ connection permits an evaluation of how well chemically induced cancers in a particular organ in one sex or species will predict or correlate with the other sex or species. Using liver cancers as an example, the overall interspecies concordance is 80%. Likewise target site predictions can be made for chemicals selected for study that may be similar to those already evaluated; thereby experimental protocols could be adjusted to allow, for example, more extensive pathology on preselected target organs (i.e., serial sections of the kidney). Further from these observations, one could decide to use two strains of mice to evaluate a short-chain chlorinated aliphatic compound or to study a human carcinogen in a sex-species known to develop chemically induced tumors in the same site observed in humans. Structural classes of chemicals having a propensity for certain organs can be easily identified from these data. Sex-species responders to particular induced cancers become clearly evident, such as in the ovary of female mice or in the kidney of male rats.

Correlations between Chemically Related Site-Specific Carcinogenic Effects in Long-Term Studies in Rats and Mice

“…Among the liver carcinogens in the database, 70% (16/23) of the chemicals that produced these neoplasms in both species were mutagenic in Salmonella compared to only 30% (7/23) for those chemicals whose only carcinogenic effect was liver tumors in mice (2,12). This difference in Salmonella mutagenicity (70% versus 30%) is statistically significant (p<0.05).…”

Mouse models in liver cancer research: A review of current literature

“…Because of the high incidence of altered (or preneoplastic) hepatocytes in certain mouse strains (especially C3H and B6C3F1 mice, the latter corresponding to the progeny of C3H mice coupled to C57BL/6 mice), epigenetic carcinogens alone can be used to induce HCC-formation in these mice [8,11] . Many chemicals have been shown to induce HCCs in the mouse liver [10,14] . To date, the most frequently used hepatocarcinogens in mice are diethylnitrosamine (DEN) and phenobarbital (PB), although the carcinogenic effect of PB is controversial [8] .…”

“…For this purpose, chemicals are either administered to newborn mice in order to determine genotoxicity, or compounds are administered for longer periods (usually 2 years) to assess epigenetic carcinogenity [6,14] . However, because of the significant inconsistencies between mouse and human carcinogens, extrapolating the results of these mouse studies to the human situation remains difficult [18] .…”

Prevalidation of a Rat Liver Foci Bioassay (RLFB) Based on Results from 1600 Rats: A Study Report

“…Several medium-term carcinogenesis assays using FAH as an endpoint have been proposed (32,37,42,62,66), and have been suggested to become part of a general testing strategy taking its place between in vitro mutagenicity tests and the chronic rodent bioassay (CRB) (19,66). The limitation of these in vivo test systems to the liver is an obvious disadvantage for the identification of cancer risk factors in general, but the liver is the prevailing target organ of chemical carcinogens in rodents (1), being affected by ∼30% of all chemicals positively tested in long-term carcinogenesis bioassays in the National Toxicology Program (29).…”