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Alternatives models in carcinogenicity testing--a European perspective.
JanWillem van der Laan1, Beatriz Silva Lima, David Snodin
1Laboratory for Medicines and Medical Devices, National Institute of Public Health and the Environment, Bilthoven, The Netherlands. jan-willem.van.der.laan@rivm.nl
Toxicologic Pathology
|March 14, 2002
Summary
Transgenic mouse models show promise for carcinogenicity testing but require cautious interpretation due to potential false positives/negatives. Regulatory authorities are evaluating their use in pharmaceutical risk assessment.
Area of Science:
- Toxicology
- Genotoxicity Testing
- Carcinogenesis Research
Background:
- Transgenic mouse strains are being considered for in vivo carcinogenicity assessment.
- European regulatory authorities support their inclusion in International Conference on Harmonization (ICH) guidelines.
- Concerns exist regarding the premature, systematic use of these models in pharmaceutical development.
Purpose of the Study:
- To evaluate the current status and regulatory implications of transgenic mouse models for carcinogenicity assessment.
- To determine the reliability and differentiation capabilities of these models for hazard identification and risk assessment.
Main Methods:
- Review of International Life Sciences Institute (ILSI) project data on transgenic models.
- Analysis of sensitivity to genotoxic pharmaceuticals.
- Assessment of false positive and false negative rates.
Main Results:
- Current transgenic models exhibit similar sensitivity to genotoxic pharmaceuticals.
- The models show potential for both false negatives and false positives.
- Differentiation between models for regulatory purposes is not yet feasible.
Conclusions:
- The evaluation of transgenic mouse models is at an equivocal stage.
- Regulatory authorities must cautiously interpret data from these models.
- Further refinement is needed before widespread application in pharmaceutical risk assessment.