Tiered toxicity testing: Evaluation of toxicity-based decision triggers for human health hazard characterization

A set of biologically-based toxicity testing decision triggers was developed and analyzed within a tiered testing and decision-making framework for evaluating potential human health hazards and risks associated with chemical exposures. The proposed three-tiered toxicity testing approach starts from a base set of toxicity studies (acute toxicity, in vitro genetic toxicity, in vitro cytogenetics, repeat dose/subchronic toxicity, developmental toxicity, reproductive toxicity) and then uses the toxicity triggers to identify which specific additional tests are needed to adequately characterize a substance's hazard potential. The toxicity triggers were initially evaluated using published information for eight chemicals, representing diverse classes. A retrospective validation study was then conducted using seven chemicals which had completed the USEPA's Voluntary Children's Chemical Evaluation Program (VCCEP). The toxicity triggers were shown to identify appropriate higher tier tests and to be reasonably predictive of the results expected in higher tiered tests. Employing these toxicity triggers within a tiered testing framework could lead to a reduction in the number of laboratory animals without diminishing the degree of scientific certainty necessary for hazard evaluations. The toxicity triggers appear to be suitable for identifying which specific endpoints and tests warrant further evaluation, and which do not, and for documenting the scientific basis for such decisions. (c) 2007 Elsevier Ltd. All rights reserved.