ATLA::Alternatives to Laboratory Animals

Volume 31, Number 1

An overall strategy for the testing of chemicals for human hazard and risk assessment under the EU REACH system.

Robert Combes1, Martin Barratt2 and Michael Balls

FRAME, Russell & Burch House, 96-98 North Sherwood Street, Nottingham, NG1 4EE, UK; 2Marlin Consultancy, 10 Beeby Way, Carlton, Bedford MK43 7LW, UK

SUMMARY

In its White Paper, Strategy for a Future Chemicals Policy, published in 2001, the European Commission (EC) proposed the REACH (Registration, Evaluation and Authorisation of CHemicals) system to deal with both existing and new chemical substances. This system is based on a top-down approach to toxicity testing, in which the degree of toxicity information required is dictated primarily by production volume (tonnage). If testing is to be based on traditional methods, very large numbers of laboratory animals could be needed in response to the REACH system, causing ethical, scientific and logistical problems that would be incompatible with the time-schedule envisaged for testing. The EC has emphasised the need to minimise animal use, but has failed to produce a comprehensive strategy for doing so. The present document provides an overall scheme for predictive toxicity testing, whereby the non-animal methods identified and discussed in a recent and comprehensive ECVAM document, could be used in a tiered approach to provide a rapid and scientifically justified basis for the risk assessment of chemicals for their toxic effects in humans. The scheme starts with a preliminary risk assessment process (involving available information on hazard and exposure), followed by testing, based on physicochernical properties and (Q)SAR approaches, (Q)SAR analyses are used in conjunction with expert system and biokinetic modelling, and information on metabolism and identification of the principal metabolites in humans. The resulting information is then combined with production levels and patterns of use to assess potential human exposure. The nature and extent of any further testing should be based strictly on the need to fill essential information gaps in order to generate adequate risk assessments, and should rely on non-animal methods, as far as possible. The scheme also includes a feedback loop, so that new information is used to improve the preclictivity of computational expert systems. Several recommendations are made, the most important of which is that the European Union (EU) should actively promote the improvement and validation of (Q)SAR models and expert systems, and computerbased methods for biokinetic modelling, since these offer the most realistic and most economical solution to the need to test large numbers of chemicals.

Keywords: biokinetic modelling, decision-trees, ECVAM, EU chemicals policy, non-animal testing scheme, (Q)SAR and expert systems, read-across, risk assessment, threshold of regulation