Rodents carcinogenicity studies

There has been extensive debate and consideration on the relevance and value of the traditional long-term rodent bioassays. The FDA looked at rat and mouse studies for 282 human pharmaceuticals, resulting in the conclusion that sufficient evidence is now available for some alternative in vivo carcinogenicity models to support their application as complimentary studies in combination with a single two-year carcinogenicity study [emphasis added] to identify trans-species tumorigens (Contrera et al., 1997). 

Lack of consistency throughout a study is likely when a pathologist has only recently become involved with rodent carcinogenicity. Training is often in a clinical situation (especially in Europe), where each animal or person is unique and there is in a rodent carcinogenicity study consisting of 500 inbred animals. 

Food and Drug Administration (FDA) (2001). Guidance for Industry Statistical Aspects of the Design, Analysis and Interpretation of Chronic Rodent Carcinogenicity Studies of Pharmaceuticals. USDHEW, Washington, D.C. 

Haseman, J.K., Huff, J. and Boorman, G.A. (1984b). Use of historical control data in carcinogenicity studies in rodents. Toxicol. Pathol. 12 126-135. 

ICH. (1996). The Need for Long-Term Rodent Carcinogenicity Studies of Pharmaceuticals. 

We do not know for sure whether either mirex or chlordecone causes cancer in humans. The Department of Health and Human Services (DHHS) has determined that mirex and chlordecone may reasonably be expected to be carcinogens. The International Agency for Research on Cancer (IARC) has determined that mirex and chlordecone are possibly carcinogenic to humans. The EPA has not classified mirex or chlordecone as to carcinogenicity. In rodents, mirex causes liver, adrenal, and blood cancer. Chlordecone also causes liver cancer in rodents, but because of problems with these animal studies, more information is necessary to be sure. 

Carcinogenicity studies are a time-consuming (up to 3 years to complete) and expensive (can be in excess of 1 million dollars each) proposition and are typically carried out in rats and mice. Their purpose is to determine if the drug possesses the capability to initiate or promote the development of tumors. The application of the results of these studies to the human safety has been debated for many years. In many instances over the past two decades, mechanistic studies have shown that positive responses in these rodent models do not have specific relevance for humans, and drugs have been approved on the basis of these explanations. While the scientific debate about relevance of these studies continues, they remain required by regulations. Positive responses without adequate explanation or safety margin can result in nonapproval of the product. 

Not all of the biochemical events in this complex pathway from PPAR-alpha activation to tumors are completely understood, but much is known. It seems that at least some peroxisome-proliferating chemicals that also produce tumors in rodent livers do so through this pathway. If it can be demonstrated that such a mechanism is at work, then it seems that the risk of tumorigenicity for such compounds would be limited to doses that are sufficient to activate PPAK-alpha sufficiently to initiate the dangerous cascade of events within the cell. Experts have developed a number of experimental criteria that should be met if a compound is to be put in this class of carcinogens. Study of P PAR-alpha activation as a route of carcinogensis is an extremely active area of research. 

ANTU was not carcinogenic in rodent feeding studies. Cases of bladder tumors among rat catchers exposed to ANTU have been attributed to P-naphthylamine, a manufacturing impurity of ANTU. In bacterial assays ANTU induced mutations. 

Two-year animal inhalation studies have shown nickel oxide and nickel subsulfide to be carcinogenic in rats, resulting in alveolar/bron-chiolar adenomas and tumors of the adrenal medulla nickel subsulfide was not carcinogenic to mice, whereas nickel oxide caused equivocal evidence of carcinogenicity in mice based on alveolar/bronchiolar adenomas and carcinomas.Nickel sulfate was not carcinogenic in rodent assays but did cause an inflammatory response in the lungs of animals. 

Cohen, S.M., Arnold, L.L., Eldan, M. et al. (2006) Methylated arsenicals the implications of metabolism and carcinogenicity studies in rodents to human risk assessment. Critical Reviews in Toxicology, 36(2), 99-133. 

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