Mechanistic Applicability Domains for Nonanimal-Based Prediction of Toxicological End Points: General Principles and Application to Reactive Toxicity

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摘要：

In light of new legislation (e.g., the REACH program in the European Union), several initiatives haverecently emerged to increase acceptance of (quantitative) structure−activity relationships [(Q)SARs] toreduce reliance on animal (in vivo) testing. Among the principles for assessing the validity of (Q)SARsis the need for a defined domain of applicability, i.e., identification of the range of compounds for whichthe (Q)SAR can confidently be applied for purposes of toxicity prediction. Here, we attempt to developa "natural" classification into applicability domains based on considering how a compound and the targetorganism between them "decide" on the nature and extent of the toxic effect. With particular emphasison reactive toxicity, we present rules, based on organic reaction mechanistic principles, for classifyingreactive toxicants into their appropriate mechanistic applicability domains.

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关键词：

Endpoint Determination Predictive Value of Tests Toxicity Tests Quantitative Structure-Activity Relationship Molecular Structure Models, Theoretical Organic Chemicals Animal Testing Alternatives Skin