Rodent toxicity and nongenotoxic carcinogenesis: knowledge-based human risk assessment based on molecular mechanisms

Area of Science:

• Toxicology
• Carcinogenesis
• Risk Assessment

Background:

• Assessing chemical threats to human health is crucial.
• Short-term assays detect DNA-damaging chemicals, but nongenotoxic carcinogens require animal bioassays.
• Rodent models present challenges for human risk assessment due to species differences.

Purpose of the Study:

• To examine rodent nongenotoxic carcinogenesis mechanisms.
• To evaluate the relevance of rodent data for human health risk assessment.
• To discuss incorporating mechanistic data into regulatory risk assessment.

Main Methods:

• Review of background issues in rodent carcinogenesis.
• Focus on specific toxicants: peroxisome proliferators, chloroform, and dioxins.
• Analysis of rodent-specific mechanisms like oxidative stress, cell proliferation, and apoptosis suppression.

Main Results:

• Peroxisome proliferators and dioxins trigger receptor-mediated responses in rodents.
• These toxicants induce rodent-specific oxidative stress, cell proliferation, and suppressed apoptosis.
• Evidence suggests rodent carcinogenic mechanisms differ from human responses for some toxicants.

Conclusions:

• Rodent models may not accurately reflect human risk for certain nongenotoxic carcinogens.
• Molecular mechanisms underlying rodent carcinogenesis may not operate in humans.
• Mechanism-based data integration is vital for accurate human health risk assessment and regulation.