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

被引:64
作者
Combes, R
Barratt, M
Balls, M
机构
[1] FRAME, Nottingham NG1 4EE, England
[2] Marlin Consultancy, Bedford MK43 7LW, England
来源
ATLA-ALTERNATIVES TO LABORATORY ANIMALS | 2003年 / 31卷 / 01期
关键词
biokinetic modelling; decision-trees; ECVAM; EU chemicals policy; non-animal testing scheme; (Q)SAR and expert systems; read-across; risk assessment; threshold of regulation;
D O I
10.1177/026119290303100103
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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 physicochemical 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 predictivity 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 computer-based methods for biokinetic modelling, since these offer the most realistic and most economical solution to the need to test large numbers of chemicals.
引用
收藏
页码:7 / 19
页数:13
相关论文
共 31 条
[1]   In vitro preclinical lead optimisation technologies (PLOTs) in pharmaceutical development [J].
Atterwill, CK ;
Wing, MG .
TOXICOLOGY LETTERS, 2002, 127 (1-3) :143-151
[2]  
Balls M., 2002, ATLA S1, V30, P1
[3]  
BARRATT MD, 1995, ATLA-ALTERN LAB ANIM, V23, P410
[4]  
Barratt MD, 2000, DEV AN VET, V31, P449
[5]   The applicability of in vitro-derived data in hazard identification and characterisation of chemicals [J].
Blaauboer, BJ .
ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY, 2002, 11 (3-4) :213-225
[6]   The integrated use of alternative methods in toxicological risk evaluation - ECVAM Integrated Testing Strategies task force report 1 [J].
Blaauboer, BJ ;
Barratt, MD ;
Houston, JB .
ATLA-ALTERNATIVES TO LABORATORY ANIMALS, 1999, 27 (02) :229-237
[7]  
Bottrill K, 1998, ATLA-ALTERN LAB ANIM, V26, P421
[8]   A tiered approach to threshold of regulation [J].
Cheeseman, MA ;
Machuga, EJ ;
Bailey, AB .
FOOD AND CHEMICAL TOXICOLOGY, 1999, 37 (04) :387-412
[9]   The use of genetically engineered cells for assessing CYP2D6-related polymorphic effects [J].
Coecke, S ;
Bogni, A ;
Langezaal, I ;
Worth, A ;
Hartung, T ;
Monshouwer, M .
TOXICOLOGY IN VITRO, 2001, 15 (4-5) :553-556
[10]   The use of long-term hepatocyte cultures for detecting induction of drug metabolising enzymes: The current status - ECVAM hepatocytes and metabolically competent systems task force report 1 [J].
Coecke, S ;
Rogiers, V ;
Bayliss, M ;
Castell, J ;
Doehmer, J ;
Fabre, G ;
Fry, J ;
Kern, A ;
Westmoreland, C .
ATLA-ALTERNATIVES TO LABORATORY ANIMALS, 1999, 27 (04) :579-638