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Consideration of both genotoxic and nongenotoxic mechanisms in predicting carcinogenic potential
1Chemical Industry Institute of Toxicology, Research Triangle Park, NC 27709.
Abstract:
Bacterial and cell culture genotoxicity assays have proven to be valuable in the identification of DNA reactive carcinogens because mutational events that alter the activity or expression of growth control genes are a key step in carcinogenesis. The addition of metabolizing enzymes to these assays have expanded the ability to identify agents that require metabolic activation. However, chemical carcinogenesis is a complex process dependent on toxicokinetics and involving at least steps of initiation, promotion and progression. Identification of those carcinogens that are activated in a manner unique to the whole animal, such as 2,6-dinitrotoluene, require in vivo genotoxicity assays. There are many different classes of non-DNA reactive carcinogens ranging from the potent promoter 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) that acts through a specific receptor, to compounds that alter growth control, such as phenobarbital. Many compounds, such as saccharin, appear to exhibit initiating, promotional and/or carcinogenic activity as events secondary to induced cytotoxicity and cell proliferation seen only at the chronic lifetime maximum tolerated doses mandated in rodent bioassays. Simple plus/minus vs. carcinogen/noncarcinogen comparisons used to validate the predictivity of bacterial and cell culture genotoxicity assays have revealed that a more comprehensive analysis will be required to account for the carcinogenicity of so many diverse chemical agents. Predictive assays and risk assessments for the numerous types of nongenotoxic carcinogens will require understanding of their mechanism of action, reasons for target organ and species specificity, and the quantitative dose-response relationships between endpoints such as induced cell proliferation and carcinogenic potential.
Insights
Genotoxicity assays help identify DNA-reactive carcinogens, but predicting non-DNA reactive carcinogens requires understanding complex mechanisms. Further research into toxicokinetics and dose-response relationships is crucial for accurate risk assessment.
Area of Science:
- Toxicology and Carcinogenesis
- Genetics and Molecular Biology
Background:
- Genotoxicity assays are valuable for identifying DNA-reactive carcinogens.
- Metabolizing enzymes enhance assays but cannot fully predict complex chemical carcinogenesis.
- In vivo assays are necessary for carcinogens activated uniquely within the whole animal.
Purpose of the Study:
- To highlight the limitations of current genotoxicity assays in predicting all carcinogen classes.
- To emphasize the need for a comprehensive analysis of diverse chemical agents.
- To underscore the importance of understanding mechanisms for nongenotoxic carcinogens.
Main Methods:
- Review of bacterial and cell culture genotoxicity assays.
- Discussion of in vivo genotoxicity assays.
- Analysis of chemical carcinogenesis processes including toxicokinetics, initiation, promotion, and progression.
Main Results:
- Simple genotoxicity assays are insufficient for predicting the carcinogenicity of many diverse chemical agents.
- Non-DNA reactive carcinogens, like TCDD and phenobarbital, act through various mechanisms.
- Some compounds exhibit carcinogenic activity secondary to cytotoxicity and cell proliferation at high doses.
Conclusions:
- Predictive assays and risk assessments for nongenotoxic carcinogens require a deeper understanding of their mechanisms of action.
- Target organ and species specificity must be considered.
- Quantitative dose-response relationships, particularly concerning induced cell proliferation, are essential for accurate carcinogenicity prediction.