Fig. 3. General approach for assessment of potential human carcinogens.

3. A research program was implemented by several U.S. government agencies to generate an integrated body of mechanistic data from studies on a selected group of prototype dyes derived from benzidine and benzidine congeners (45). The objective of the research program was to apply mechanism-based SAR to predict the carcinogenicity of hundreds of benzidine- and benzidine-con-gener-derived dyes. The results of this program have led to the development of a significant new use rule (SNUR) by EPA under the Toxic Substances Control Act (TSCA), which would require persons to notify EPA at least 90 days before commencing the manufacture, import, or processing of any benzidine-derived dyes (46). A similar SNUR is being developed for azo dyes containing the benzidine congeners o-toluidine and o-dianisidine in the molecules.

4. Although the tumor-promoting activity of organic peroxides is well documented, the carcinogenicity of many of these free radical-forming chemicals has not been adequately tested. Structure-activity relationship and data from a battery of mechanism-based short-term tests specific for peroxides are supported by EPA to be used for predicting the tumor-promoting or carcinogenic activities of organic peroxides (47).

5. On the basis of structural analogy to 2,4,6-trichlorophenol (a known carcinogen) and evidence for formation of semiquinone free radicals and DNA binding activity, 2,4,6-tribromophenol, an existing chemical in a hazardous waste site, was added to the list of hazardous wastes and the list of hazardous constituents regulated under the Resource Conservation and Recovery Act (RCRA) of EPA (48).

6. Since the enactment of the TSCA in 1977, mechanism-based SAR has been used by EPA's Structure Activity Team in the initial hazard assessment of premanufacturing notification (PMN) chemicals with little or no toxicity data (49, 50). Under the PMN program of the TSCA, EPA is required to evaluate each of the approximately 2,000 PMN submissions each year from companies intending to manufacture or import new chemical substances for any unreasonable risk they may pose to human or the environment. Structure-activity relationship analysis of a PMN chemical substance may result in a regulatory decision of either dropping the case from further consideration or triggering testing requirements to obtain data for further assessment while regulating chemical exposure. To further support a regulatory decision based on carcinogenicity, quantitative cancer risk of the PMN chemical is also estimated through use of exposure data and surrogate dose-response data of close structural analogues, if available.

7. To help the industry design and develop safer chemicals, the recently constructed "Pollution Prevention (P2) Framework" of the Office of Pollution and Prevention and Toxics (OPPT)/EPA provides a number of EPA-developed, SAR-based computerized models to assess the potential hazards and risks of chemicals (51). The "OncoLogic" Expert System (34) is one of the P2 models for estimating the carcinogenicity potential of chemical substances.

In addition to data from animal carcinogenicity studies, SAR is also an important element in the weight of evidence approach for hazard identification of potential human carcinogens (52, 53). Structure-activity relationship can be used to strengthen or weaken carcinogenicity concern. For instance, information on reactive metabolites and potential mode of action consistent with that of a chemical class in question would enhance the confidence of conclusions made from animal bioassays. Mechanism-based SAR can also play a crucial role in modifying the weight of evidence when there are conflicting tumor data and gaps from animal bioassays.

In recent years, a number of national and international programs have arisen to evaluate alternative test methods to replace, reduce, and refine the use of animals for hazard identification and risk assessment purposes (41, 54, 55). Despite the many advances that have been made in the last decade, predictive toxicology that relies on SAR has not reached the stage that can replace animal testing under current regulatory statutes. Increasing understanding of the mechanistic basis of chemical carcinogenesis and of the relationship between molecular structure and carcinogenic activity appears to be the key to making SAR predictions compelling enough to warrant their use in regulatory decision-making. The predictive value of SAR models for human carcinogens, like that of empirical models, will probably always be open to question:

Models can be confirmed by the demonstration of agreement between observation and prediction, but confirmation is inherently partial. Complete confirmation is logically precluded by the fallacy of affirming the consequent and by incomplete access to natural phenomena. Models can only be evaluated in relative terms, and their predictive value is always open to question. The primary value of models is heuristic (56).

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