Carcinogen identification, determining

There are three principal ways for a chemical to be added to the Proposition 65 list. A chemical can be listed if either of two independent committees of scientists and health professionals finds that the chemical has been clearly shown to cause cancer or birth defects or other reproductive harm. These two committees are the Carcinogen Identification Committee (CIC) and the Developmental and Reproductive Toxicant (DART) Identification Committee, and both are part of OEHHA s Science Advisory Board. The committee members are appointed by the Governor and are designated as the State s Qualified Experts for evaluating chemicals under Proposition 65. When determining whether a chemical should be placed on the list, the committees base their decisions on the most current scientific information available. OEH-HA staff scientists compile all relevant scientific evidence on various chemicals for the committees to review. The committees also consider comments from the public before making their decisions. 

Research in PAH carcinogenesis has made major advances in the past decade. Most notable has been identification of diol epoxide metabolites as the active forms of benzo[a]pyrene, 7,12-dimethylbenz[tf]anthracene, and other carcinogenic PAH. This finding has stimulated enormous research activity and opened the way to determination of the detailed molecular mechanism of action of this important class of carcinogenic molecules. 

The importance of the role of DNA in the genetic code has focused research on the structure of the active compound and the overall conformation of DNA as a receptor. In addition the identification of benzola]pyrene as an important carcinogen (27) has stimulated extensive research to determine the origin and its activity. 

In the hazard identification process for chemicals that cause stochastic effects described above (EPA, 1987a), the weight-of-evidence classification is determined primarily by observations of tumors in animals or humans. Other information about the properties of a chemical, structure-activity relationships for other chemicals that cause stochastic effects, and the influence of a chemical on the carcinogenic process often is limited and plays only a modulating role in the weight-of-evidence classification based on tumor findings. 

Overall, cancer risk assessment involves the four steps of hazard identification, dose-response, exposure assessment, and risk characterization. The dose-response curve established for cancer potency derivation for a chemical is based on evaluation of data on the carcinogenicity and dose-response characteristics of the chemical. The pharmacokinetics and mechanistic data evaluation (e.g., genotoxic or nongenotoxic) and a dose-response review of all adequate bioassays are conducted to determine, if target dose estimates or a dose-response model different from the default may be suggested. 

It is now widely accepted that the identification and quantitation of the products of interactions between DNA and electrophilic chemicals (or their metabolites) is of key importance in the understanding of the mutagenic and carcinogenic processes. In particular, qualitative and quantitative determinations of DNA adducts formed during low-level exposures to chemicals are essential for rational prospective risk assessments (5). 

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