Carcinogens rodent liver

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. 

Williams, G.M. 1997. Chemicals with carcinogenic activity in the rodent liver mechanistic evaluation of human risk. Cancer Lett. 117 175-188. 

Sasaki, Y. F., Izumiyama, F., Nishidate, E., Matsusaka, N., and Tsuda, S. (1997a). Detection of rodent liver carcinogen genotoxicity by the alkaline single-cell gel electrophoresis (comet) assay in multiple mouse organs (liver, lung, spleen, kidney, and bone marrow). Mutat Res 391, 201-214. 

The mechanism of carcinogenicity of benzidine is thought to involve its metabolic transformations forming reactive intermediates binding to DNA. Such DNA adducts have been identified in rodent liver. It tested positive in most genotoxic tests. Its carcinogenicity may possibly be related to the slow rate of liver detoxification by acetylation allowing activation of benzidine or its metabolites in urine (Whysner et al. 1996). 

Certain phthalate plasticizers such as di-(2-etltylhexyl) phthalate, DEHP, belong to the peroxisome prohferator, PP, family of rodent liver carcinogens. " Here, the evidence for peroxisome proliferator-mediated rodent carcinogenesis in response to PPs will be considered together with an evaluation of the molecular basis for rodent-human species differences in response. Specifically, this chapter will focus on the role and mechanisms of peroxisome proliferator-induced rodent peroxisomal gene expression and the evidence for lack of relevance of this mechanism to humans. 

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. 

Ashby J, Mohammed R. 1988. UDS activity in the rat liver of the human carcinogens benzidine and 4-aminobiphenyl and the rodent carcinogens 3,3 -dichlorobenzidine and Direct Black 38. Mutagenesis 3(1) 69-71. 

In more recent years, efforts have been stepped up to control environmental pollution, with the result that in many areas residues of such compounds in fish and shellfish are decreasing substantially from previous levels. The chlorinated compounds mentioned earlier have the ability at sustained high doses in rodents to promote the development of liver cancer thus, they have been called "carcinogenic." When viewed in terms of projected hazards to human health, however, human exposure is usually low level and sporadic. Most of the detectable levels of chlorinated compounds in various fish and shellfish pose no hazard to human health. 

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