Predicting the carcinogenicity of chemicals in humans from rodent bioassay data.

Abstract

Regulatory agencies currently rely on rodent carcinogenicity bioassay data to predict whether or not a given chemical poses a carcinogenic threat to humans. We argue that it is always more useful to know a chemical's carcinogenic potency (with confidence limits) than to be able to say only qualitatively that it has been found to be a carcinogen. In a typical bioassay, a chemical is administered to groups of 50 to 100 rodents at the highest feasible level (the maximum tolerated dose) and rarely at less than 1/10 this dose in order to maximize the statistical significance of any increase in tumors that might result. Recently, much experimental work has focused on the mechanisms by which site-specific toxicity arising from chronic administration at the maximum tolerated dose may lead to carcinogenicity. Extrapolation of high-dose results to low doses does not take into consideration the possibility of a threshold dose, below which the carcinogenic potency is much lower or even zero. Threshold dose-response phenomena may be much more relevant to the etiology of cancer in the rodent bioassays than was earlier realized; if so, there is an even greater need for establishing dose-dependent potency estimates. The emphasis of this review is on the interspecies comparison of high-dose potencies. The qualitative and quantitative comparison of carcinogenicities between mice and rats and between rodents and humans is reviewed and discussed. We conclude that there is a good qualitative (yes/no) correlation for both the rat/mouse and the rodent/human comparison. There is also a good correlation of the carcinogenic potencies between rats and mice, and the upper limits on potencies in humans are consistent with rodent potencies for those chemicals for which human exposure data are available. For the rodent/human comparison, the best estimate of the interspecies potency factor is lognormally distributed around 1 when the potencies in both species are measured in units of (mg/kg-day)-1.

Chemical carcinogen safety testing: OECD expert group international consensus on the development of an integrated approach for the testing and assessment of chemical non-genotoxic carcinogens

“…At the moment, the interpretation of histological findings to predict carcinogenicity is currently based on the most conservative approach, of observing benign tumours and carcinomas. However, there are distinct differences in the molecular biology of cancer between rodent and human particularly with respect to timing and control of tumour growth and progression (Goodman and Wilson 1991 ; Holliday 1996 ; Wolf et al 2019 ). Ultimately, the IATA needs to address the complexity of human biological processes of cancer development.…”

Are Raw Brassica Vegetables Healthier Than Cooked Ones? A Randomized, Controlled Crossover Intervention Trial on the Health-Promoting Potential of Ethiopian Kale

“…AFB1 is the most potent naturally occurring chemical liver carcinogen [ 10 , 11 ], potentially causing both acute toxicity (aflatoxicosis) and chronic diseases [ 12 ]. Chronic dietary exposure to AFB1 is a significant risk for the formation of hepatocellular carcinoma (HCC) [ 13 ].…”

The legacy of the F344 rat as a cancer bioassay model (a retrospective summary of three common F344 rat neoplasms)

“…Tissue site concordance between animals and humans exposed to the same xenobiotics has been shown for many chemicals including aflatoxins B1, vinyl chloride, some arsenicals, asbestos, benzene and diethylstilbesterol among others (Tomatis et al. 1989 ; Goodman & Wilson 1991 ). Even though target sites for carcinogenesis are often concordant between animals and humans (Tomatis et al.…”