Related Experiment Videos
How useful are chronic (life-span) toxicology studies in rodents in identifying pharmaceuticals that pose a
1Drug Safety Unit, Pfizer Inc, Groton, CT 06340.
Abstract:
After 20 years' experience of the chronic rodent bioassay and in the light of our current understanding of the mechanisms of carcinogenesis, there is now a wide recognition that the present strategies for assessing carcinogenic risk of pharmaceuticals are in need of urgent revision. The few pharmaceuticals known to cause cancer in humans each possess at least one of four properties: genotoxicity, immunosuppression, hormonal activity or chronic irritation. These properties can be identified by genotoxicity studies in vivo and well-designed toxicology studies of up to 6 months duration in rats. About 50% of all chemicals evaluated in the bioassay are positive. The findings from non-genotoxic compounds can often be shown to lack relevance for humans because either the exposure (daily dose and duration) is excessive when compared with actual human exposure or the response to a carcinogenic challenge is qualitatively different in rodents from that in humans. Many studies of the mechanisms of carcinogenesis in rats have elucidated why the data generated in rat bioassays are often not relevant to humans. However, the relative paucity of pharmacological data in mice means that similar studies of mechanism cannot be carried out so effectively in mice. The results of mouse bioassays are dominated by the frequency with which the liver (and, to a lesser extent, the lung) is a target organ. Molecular biology is now providing evidence of why chemically induced tumours in this organ cannot be extrapolated to human risk. Examination of the pattern of results in the NTP and IARC bioassay databases and the rodent data for 18 chemicals which appear thus far not to be carcinogenic in humans, indicates that data generated in mouse bioassays do not contribute to human carcinogenic risk assessment. It is argued that, for pharmaceuticals, only compounds with a novel mode of action need be studied for longer than 6 months. For such compounds, a study in rats at pharmacodynamically relevant dose levels for 12-18 months will, in general, provide adequate information for carcinogenic risk assessment in humans.
Insights
Current pharmaceutical cancer risk assessment strategies need revision. Identifying genotoxicity, immunosuppression, hormonal activity, or irritation in short-term rat studies can predict human carcinogenicity, making mouse bioassays largely irrelevant.
Area of Science:
- Toxicology
- Pharmacology
- Carcinogenesis
Background:
- Chronic rodent bioassays for pharmaceutical cancer risk assessment require urgent revision based on current knowledge of carcinogenesis mechanisms.
- Pharmaceuticals causing human cancer exhibit genotoxicity, immunosuppression, hormonal activity, or chronic irritation, detectable in shorter studies.
Purpose of the Study:
- To evaluate the relevance of current pharmaceutical cancer risk assessment strategies, particularly rodent bioassays.
- To determine the utility of mouse bioassays in human carcinogenic risk assessment for pharmaceuticals.
Main Methods:
- Analysis of genotoxicity studies in vivo and toxicology studies (up to 6 months) in rats.
- Examination of rodent bioassay data, including NTP and IARC databases, and data for chemicals not carcinogenic in humans.
- Review of mechanistic studies on carcinogenesis in rats and mice, considering pharmacological data limitations in mice.
Main Results:
- Genotoxicity, immunosuppression, hormonal activity, or chronic irritation predict human carcinogenicity and can be identified in short-term rat studies.
- Mouse bioassay data, particularly liver and lung tumors, show limited relevance for human carcinogenic risk assessment.
- Rat bioassay data often lacks human relevance due to excessive exposure levels or qualitative differences in carcinogenic response.
Conclusions:
- Pharmaceutical cancer risk assessment should prioritize genotoxicity testing and short-term rat toxicology studies.
- Mouse bioassays are not essential for human carcinogenic risk assessment of pharmaceuticals.
- For novel compounds, 12-18 month rat studies at pharmacodynamically relevant doses are generally sufficient for risk assessment.