Carcinogenicity, mechanisms promotion

The key to hexavalent chromium s mutagenicity and possible carcinogenicity is the abiHty of this oxidation state to penetrate the cell membrane. The Cr(VI) Species promotes DNA strand breaks and initiates DNA—DNA and DNA-protein cross-links both in cell cultures and in vivo (105,112,128—130). The mechanism of this genotoxic interaction may be the intercellular reduction of Cr(VI) in close proximity to the nuclear membrane. When in vitro reductions of hexavalent chromium are performed by glutathione, the formation of Cr(V) and glutathione thiyl radicals are observed, and these are beHeved to be responsible for the formation of the DNA cross-links (112). 

Human data as well as studies in animals have provided negative evidence of carcinogenicity for endosulfan (Hack et al. 1995 Hoechst 1988b, 1989a). However, endosulfan promoted the development of altered hepatic foci in rats initiated with nitrosodiethylamine (Fransson-Steen et al. 1992). Although the mechanism of tumor promotion of endosulfan is not known, it has been suggested that it involves inhibition of cellular communication (Kenne et al. 1994). A brief discussion of this topic is provided in Section 2.5 under Cancer Effects. 

Finally, it is important that further research be carried out on the identification and mechanism of action of environmental cocarcinogens and tumor promoters which can enhance the carcinogenicity of PAH. Human exposure to at least trace amounts of PAH is unavoidable. The probability of eventual tumor development may be controlled primarily by repeated exposure to cocarcinogens or promoters. 

Cancer. No studies have been conducted in human populations to determine whether mirex or chlordecone causes cancer. However, studies in mice and rats have demonstrated the ability of mirex to cause liver tumors (Innes et al. 1969 NTP 1990 Ulland et al. 1977a), pheochromocytomas (NTP 1990), and rare renal tumors (NTP 1990). A study in mice and rats also showed the ability of chlordecone to increase liver tumors (NC11976). As indicated above, available data on the genotoxicity of mirex and chlordecone indicate that these chemicals do not cause cancer by a mutagenic mechanism but rather by tumor promotion. Both mirex and chlordecone are considered by the DHHS to be substances that may reasonably be anticipated to be carcinogens and by IARC to be possible human carcinogens. EPA has not classified mirex or chlordecone as to their carcinogenicity. 

The treatment of animals with growth-promoting hormones is a common practice in conventional agriculture outside of the EU. The effects of this practice are still not predictable in an entirely reliable way with respect to the toxic and carcinogenic effects of their residuals on humans (Collins et al. 1989). Although their use was banned in the EU several years ago, satisfactory controlling mechanisms have not been established. 

Positive carcinogenic findings in animals require careful evaluation to determine their relevance to humans. Of key importance is the mechanisms/mode(s) of action of tumor induction. The WHO/IPCS has developed a conceptual framework to provide a strucmred and transparent approach for the assessment of the overall weight of evidence for a posmlated mode of induction for each mmor type observed (Sonich-Mullin et al. 2001). The framework promotes confidence in... 

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