Current Status and Emerging Opportunities in Replacement of the Lifetime Mouse Cancer Bioassay
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Drug Informotion Journal, Vol. 36, pp. 64-657, 2002 Printed in !he USA. All rights reserved.
Copyright 0 2002 Drug Information Association Inc.
CURRENT STATUS AND EMERGING OPPORTUNITIES IN REPLACEMENT OF THE LIFETIME MOUSE CANCER BIOASSAY* BEATRIZSILVA-LIMA Professor of Pharmacology, Unit of Pharmacology and Pharmacotoxicology, the University of Lisboa, and Preclinical Assessment Group, INFARMED, Lisboa, Portugal
JAN WILLEM
VAN DER
LAAN
Preclinical Assessment Group, The Medicines Evaluation Board, Laboratory for Medicines and Medical Devices. National Institute of Public Health and the Environment, Bilthoven, The Netherlands
The approach to evaluating the carcinogenic potential of pharmaceuticals is a matter of debate and has undergone important changes related to increasing knowledge of the mechanisms of carcinogenesis, accumulated data from carcinogenicity studies, and technological progress. The discussions held during the International Conference of Harmonization (ICH) led to the proposal of a basic principle for carcinogenicity testing: one rodent lifespan study plus an additional short-term study carrying mechanistic insight to the carcinogenicity endpoints. Alternatively, a second lifespan study is acceptable. This approach is in line with the development of alternative models, primarily geneticallymodified mice that are conceived on the basis of known mechanisms of carcinogenesis. Such models have been evaluated through studies sponsored by the International Life Sciences Institute. These studies are in their final stage. Important data have already been presented. This paper includes a critical analysis of the results available from the models and thinking in Europe about their contribution to risk assessment. It provides “a” European view, rather than “the” European view, of the problem, since the latter is dependent upon ongoing analysis of the available data being performed by the Committee for Proprietary Medicinal Products’ Safety Working Party. Key Words: Carcinogenicity testing; Transgenic mice; Knockout mice
INTRODUCTION DURING THE LAST THREE decades, concepts of carcinogenesis have been modified in important ways, in response to increased knowledge of the mechanisms involved and
increased data from rodent carcinogenity studies performed. In the 1970s, when the policies for cancer risk assessment began to be developed in the United States, it was assumed that carcinogenesis produced by chemical exposure involved staged irrevers-
Presented at the DIA 37th Annual Meeting, July 7-1 I , 2001, Denver, Colorado. Reprint address: Beatriz Silva-Lima, University of Lisboa Faculty of Pharmacy, Av. das Forqas Armadas 1600 Lisboa, Portugal (e-mail: [email protected]). *The views presented in this paper are those of the authors and should not be understood or quoted as being made on behalf of the European Medicines Evaluation Agency or its scientific committees.
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