IPCS framework for analyzing the relevance of a noncancer mode of action for humans

被引:267
作者
Boobis, Alan R. [8 ]
Doe, John E. [7 ]
Heinrich-Hirsch, Barbara
Meek, M. E. [6 ]
Munn, Sharon [5 ]
Ruchirawat, Mathuros [4 ]
Schlatter, Josef [3 ]
Seed, Jennifer [2 ]
Vickers, Carolyn [1 ]
机构
[1] WHO, Int Programme Chem Safety, CH-1211 Geneva 27, Switzerland
[2] US EPA, Risk Assessment Div, Washington, DC 20460 USA
[3] Swiss Fed Off Publ Hlth, Nutr & Toxicol Risks Sect, Zurich, Switzerland
[4] Chulabhorn Res Inst, Bangkok, Thailand
[5] European Chem Bur, Inst Hlth & Consumer Protect, Joint Res Ctr, Ispra, Italy
[6] Hlth Canada, Existing Subst Div, Safe Environm Programme, Ottawa, ON K1A 0L2, Canada
[7] ECETOC, Brussels, Belgium
[8] Univ London Imperial Coll Sci Technol & Med, Sect Expt Med & Toxicol, Div Med, London, England
关键词
animal-human concordance; dose-response relationships; human relevance framework; key events; mode of action; noncancer endpoints; risk assessment;
D O I
10.1080/10408440701749421
中图分类号
R99 [毒物学(毒理学)];
学科分类号
100405 ;
摘要
Structured frameworks are extremely useful in promoting transparent, harmonized approaches to the risk assessment of chemicals. One area where this has been particularly successful is in the analysis of modes of action (MOAs) for chemical carcinogens in experimental animals and their relevance to humans. The International Programme on Chemical Safety (IPCS) recently published an updated version of its MOA framework in animals to address human relevance (cancer human relevance framework, or HRF). This work has now been extended to noncancer effects, with the eventual objective of harmonizing framework approaches to both cancer and noncancer endpoints. As in the cancer HRF, the first step is to determine whether the weight of evidence based on experimental observations is sufficient to establish a hypothesized MOA. This comprises a series of key events causally related to the toxic effect, identified using an approach based on the Bradford Hill criteria. These events are then compared qualitatively and, next, quantitatively between experimental animals and humans. The output of the analysis is a clear statement of conclusions, together with the confidence, analysis, and implications of the findings. This framework provides a means of ensuring a transparent evaluation of the data, identification of key data gaps and of information that would be of value in the further risk assessment of the compound, such as on dose-response relationships, and recognition of potentially susceptible subgroups, for example, based on life-stage considerations.
引用
收藏
页码:87 / 96
页数:10
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