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Chemicals with carcinogenic activity in the rodent liver; mechanistic evaluation of human risk
1American Health Foundation, Valhalla, NY 10595, USA.
Abstract:
A wide variety of chemicals, both naturally occurring and synthetic, have exhibited carcinogenic activity in rodent liver. Some are clearly DNA reactive whereas others produce only epigenetic effects. Hepatocarcinogens are categorized according to these properties and the characteristics of examples of both types are reviewed. DNA-reactive rodent hepatocarcinogens represent human cancer risk even at non-toxic exposures, whereas epigenetic agents pose either no risk because their effects are specific to rodents, or a risk only at high exposures at which they produce the same cellular effects in humans that are the basis for their carcinogenic activity in rodents.
Insights
This study categorizes rodent liver carcinogens based on DNA reactivity or epigenetic effects. DNA-reactive agents pose human cancer risks, while epigenetic agents pose risks only at high exposures.
Area of Science:
- Toxicology
- Hepatocarcinogenesis
- Chemical Carcinogenesis
Background:
- Numerous natural and synthetic chemicals induce liver cancer in rodents.
- Hepatocarcinogens exhibit diverse mechanisms, including direct DNA reactivity and epigenetic modifications.
- Understanding these mechanisms is crucial for assessing human health risks.
Purpose of the Study:
- To categorize rodent liver carcinogens based on their mode of action.
- To review the characteristics of both DNA-reactive and epigenetic hepatocarcinogens.
- To evaluate the human risk associated with different classes of hepatocarcinogens.
Main Methods:
- Review of existing literature on rodent hepatocarcinogens.
- Classification of chemicals based on genotoxicity and epigenetic activity.
- Comparative analysis of rodent and human cellular responses to carcinogens.
Main Results:
- Hepatocarcinogens were divided into DNA-reactive and epigenetic categories.
- DNA-reactive agents showed carcinogenic activity through direct DNA damage.
- Epigenetic agents induced cancer via non-genotoxic pathways, often requiring high exposure levels.
Conclusions:
- DNA-reactive rodent hepatocarcinogens present a risk to humans even at low exposures.
- Epigenetic hepatocarcinogens may pose no risk or risk only at high exposures, depending on species-specific cellular effects.
- Risk assessment requires differentiating carcinogen mechanisms and exposure levels.