Mutagenicity of chemicals in genetically modified animals 650210002

Mutagenicity of chemicals in genetically modified animals

[ Genotoxiciteit in transgene muizen ]

Willems MI, van Benthem J

47 p in English 2000

RIVM Rapport 650210002, TNO Report no V99.1097

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Toon Nederlands

English Abstract
The strategy for assessing human health risks of chemicals consists of a large number of tests in different research disciplines. Tests include acute and chronic toxicity, genotoxicity, reproduction toxicity and carcinogenicity. Genotoxic properties of chemicals are assessed in short-term in vitro and in vivo genotoxicity tests. There are two main endpoints for genotoxicity: gene mutations and chromosome aberrations. Under in vitro conditions, there are sufficient assays for both endpoints. Testing under in vivo conditions is essential to confirm in vitro data since it is impossible to mimic, in a petri dish, all the complex factors determining whether a chemical will induce mutations in a specific tissue in animals in vivo. Moreover, in a regulatory context, a relevant negative in vivo result from an adequately performed test overrules positive in vitro results. There are appropriate assays in existence to investigate in vivo chromosome aberration; however, problems occur when a compound induces gene mutations in vitro. In the absence of reliable in vivo gene mutation assays, a justified assessment of the genotoxic potential of chemicals may be hampered. Introduced in this report, based open literature data up to August 2000, are several promising new in vivo gene mutation assays. The report is not restricted to assays with the commercially available transgenic models; all assays - whether using transgenes or endogenous genes as reporter genes - are incorporated. In reviewing the current state of the art in evaluating these assays, the advantages and the disadvantages of the assays are discussed. This is to determine the feasibility of the routine use of these new in vivo gene mutation tests for health risk estimation. Gene mutation assays with transgenic animals have already been used on a small scale for legislation of chemicals. However, to allow the routine use of these assays for regulatory purposes, they will have to be validated further and an official OECD guideline prepared.

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