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Genetic toxicology: impact on the next generation of toxicology
1FDA/National Center for Toxicological Research, Jefferson, Arkansas 72079-9502, USA.
Abstract:
In the early 1970s, we overestimated the range of applicability of the hypothesis that mutations were highly predictive of rodent cancer. Many substances that are nonmutagenesis in current screens are carcinogenic; some genotoxicants are not carcinogenic. Methods of quantitative risk assessment that were based on the 1970s' hypothesis of cancer induction are thus inherently limited. Current methods of classifying carcinogens and calculation of human risk must reflect recent understanding of the diversity of mechanisms of carcinogenicity. Screening for genotoxic potential has clearly helped to prevent highly toxic and high risk chemicals from being introduced into commerce. Additional attention, however, must now be focused on assessment and management of risk of those carcinogens and other toxicants that cause damage through mechanisms other than direct damage to DNA. While in the past we depended on the knowledge of chemists and genetic toxicologists to predict carcinogenic potential, on whom do we depend today? With the increasing complexity of our knowledge of the processes of carcinogenicity, it is likely that there will not be any single discipline that can meet the challenge. The more we learn, the more we will come to depend on a profile of information that encompasses the known mechanisms of cancer.
Insights
Early cancer risk assessment models based on mutation prediction are limited. Modern approaches must consider diverse carcinogenicity mechanisms beyond direct DNA damage for accurate risk evaluation.
Area of Science:
- Toxicology
- Carcinogenesis
- Risk Assessment
Background:
- The 1970s hypothesis overestimated mutations as predictors of rodent cancer.
- Many non-mutagenic substances are carcinogenic, and some genotoxicants are not.
- This highlights limitations in early quantitative risk assessment methods.
Purpose of the Study:
- To emphasize the need for updated carcinogen classification and human risk assessment.
- To advocate for incorporating a broader understanding of carcinogenicity mechanisms.
- To address the limitations of solely relying on genotoxic screening.
Main Methods:
- Review of historical and current understanding of carcinogenesis.
- Analysis of discrepancies between mutagenicity and carcinogenicity.
- Discussion of the evolution of risk assessment methodologies.
Main Results:
- Early models based on mutation prediction are insufficient for accurate risk assessment.
- Current screening for genotoxic potential has successfully reduced exposure to high-risk chemicals.
- A significant number of carcinogens operate through mechanisms independent of direct DNA damage.
Conclusions:
- Modern carcinogen classification and human risk assessment must account for the diversity of carcinogenic mechanisms.
- Future risk management requires a comprehensive profile of information encompassing various cancer-causing processes.
- Interdisciplinary collaboration is essential to address the complexity of carcinogenicity.