Carcinogen Testing: Current Problems and New Approaches

Weisburger, John H.; Williams, Gary M.

doi:10.1126/science.7291981

Cited by 240 publications

(67 citation statements)

References 55 publications

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“…It is clear that the linear model fits most of the data (327/390) and that all three models fit much ofit. If we look at the model that best fits the experimental data without regard to the adequacy ofthis fit ( (28)(29)(30)(31) and that nongenotoxic compounds will result in threshold or nonlinear dose response. The belief that genotoxic agents induce linear dose response stems from theoretical arguments about one molecule of a genotoxic compound interacting with DNA resulting in a "single hit."…”

Section: Resultsmentioning

confidence: 99%

Nonlinearity of dose-response functions for carcinogenicity.

Hoel

Portier

1994

Environ Health Perspect

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Carcinogenesis data for 315 chemicals were obtained from the National Cancer Institute-National Toxicology Program (NCI-NTP) bioassay programs and were analyzed to examine the shape ofcarcinogenesis dose-response curves. Tumor site data were more often consistent with a quadratic response than with a linear response, suggesting that the routine use of linear dose-response models will often overestimate risk. Information from in vivo short-term mutagenicity and genotoxicity assays was also obtained for most ofthese rodent biossanys. It was found that there were no clear relationships between the shape ofthe carcinogenesis dose-response curve and the result ofthe short-term test. These observations argue against the concept that carcinogens that are positive in a short-term assay be regulated usinga linear dose-response curve and those that are negative be regulated using a sublinear dose-response curve or a safety factor approach.

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Section: Resultsmentioning

confidence: 99%

Nonlinearity of dose-response functions for carcinogenicity.

Hoel

Portier

1994

Environ Health Perspect

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“…This effect on DNA was the basis for the Ames' assay utilizing Salmonella mutagenicity assays along with a variety of other in vitro and in vivo assays that have been developed for evaluation of genotoxicity (Haseman, Hailey, and Morris 1998;Kirkland, Aardema, et al 2005;Kirkland et al 2006;Zeiger 2004). However, it became evident as more and more chemicals were tested that several of these were not positive in the genotoxicity assays and yet produced cancer in two-year bioassays in rodents (Weisburger and Williams 1981).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Possible Carcinogenic Risk to Humans Based on Liver Tumors in Rodent Assays

2010

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The two-year rodent bioassay remains the mainstay for carcinogenicity testing, although numerous difficulties have been identified. Fundamentally, a chemical can increase the risk of cancer (1) by damaging DNA directly (DNA reactive) or (2) indirectly by increasing the number of DNA replications (non-DNA reactive). Mechanistic research has identified numerous precursor lesions in the sequence of key events necessary for neoplasia development. Based on these concepts, the author has proposed a short-term (thirteen-week) assay for screening for carcinogenic potential based on a mode of action analysis and on readily available, identifiable preneoplastic changes. A screening assay that detects all potential rodent hepatocarcinogens has been previously identified (Toxicol Pathol 32 [2004], 393-401) including increased liver weight, hepatocellular necrosis, hypertrophy, and cytomegaly. Labeling index for DNA replication might supply additional support. These markers have high sensitivity but low specificity. However, most chemicals can be appropriately classified as to their mode(s) of action for hepatocarcinogenesis with follow-up mechanistic studies, and a rational evaluation of their relevance to humans can be made. A similar process can be envisioned for other tissues for evaluation for carcinogenic potential.

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“…Based on the mechanism of action, chemical carcinogens are divided into genotoxic and non-genotoxic chemicals (Weisburger & Williams, 1981;. The genotoxic chemicals covalently react with DNA, leading to somatic mutation resulting in the development of initiated cells.…”

Section: Discussionmentioning

confidence: 99%

Induction of peroxisome proliferation and hepatic tumours in C57BL/6N mice by ciprofibrate, a hypolipidaemic compound

Rao

Dwivedi²,

Subbarao³

et al. 1988

Br J Cancer

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Summary The hepatic effects of ciprofibrate, a potent peroxisome proliferator, were evaluated in male C57BL/6N mice, a mouse strain with very low incidence of spontaneous liver tumour development. Dietary feeding of ciprofibrate (0.0125% or 0.025% w/w) for 2 weeks resulted in a marked proliferation of peroxisomes (9-fold increase) and several-fold increase (8-to 10-fold) in the activity of peroxisomal /3-oxidation enzymes. Feeding ciprofibrate at 0.025% concentration for 15 months followed by a 0.0125% for 6 months led to the development of hepatic adenomas in 8/14 (57%) and hepatocellular carcinomas (HCC) in 3/14 (21%) mice. In mice given 0.0125% ciprofibrate for 18 months 5 of 8 (62%) and 3 of 8 (37%) developed adenomas and HCC respectively. Similar to the findings observed in rats, both the adenomas and HCC were negative for y-glutamyltranspeptidase. These results in C57BL/6N mice of hepatocarcinogenic effect of ciprofibrate, a non-genotoxic chemical, indicate that peroxisome proliferation can be used as a reliable parameter to evaluate the carcinogenicity of hypolipidaemic compounds.

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Carcinogen Testing: Current Problems and New Approaches

Cited by 240 publications

References 55 publications

Nonlinearity of dose-response functions for carcinogenicity.

Nonlinearity of dose-response functions for carcinogenicity.

Evaluation of Possible Carcinogenic Risk to Humans Based on Liver Tumors in Rodent Assays

Induction of peroxisome proliferation and hepatic tumours in C57BL/6N mice by ciprofibrate, a hypolipidaemic compound

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