Recognition of adverse and nonadverse effects in toxicity studies.

One of the most important quantitative outputs from toxicity studies is identification of the highest exposure level (dose or concentration) that does not cause treatment related effects that could be considered relevant to human health risk assessment. A review of regulatory and other scientific literature and of current practices has revealed a lack of consistency in definition and application of frequently used terms such as No Observed Effect Level (NOEL), No Observed Adverse Effect Level (NOAEL), adverse effect, biologically significant effect, or toxicologically significant effect. Moreover, no coherent criteria were found that could be used to guide consistent interpretation of toxicity studies, including the recognition and differentiation between adverse and nonadverse effects. This presentation will address these issues identified first by proposing a standard set of definitions for key terms such as NOEL and NOAEL that are frequently used to describe the overall outcome of a toxicity study. Second, a coherent framework is outlined that can assist the toxicologist in arriving at consistent study interpretation. This structured process involves two main steps. In the first, the toxicologist must decide whether differences from control values are treatment related or if they are chance deviations. In the second step, only those differences judged to be effects are further evaluated in order to discriminate between those that are adverse and those that are not. For each step, criteria are described that can be used to make consistent judgments. In differentiating an effect from a chance finding, consideration is given inter alia to dose response, spurious measurements in individual parameters, the precision of the measurement under evaluation, ranges of natural variation and the overall biological plausibility of the observation. In discriminating between the adverse and the non-adverse effect consideration is given to: whether the effect is an adaptive response, whether it is transient, the magnitude of the effect, its association with effects in other related endpoints, whether it is a precursor to a more significant effect, whether it has an effect on the overall function of the organism. whether it is a specific effect on an organ or organ system or secondary to general toxicity or whether the effect is a predictable consequence of the experimental model. In interpreting complex studies it is recognised that a weight of the evidence approach, combining the criteria outlined here to reach an overall judgment, is the optimal way of applying the process. It is believed that the use of such a scheme will help to improve the consistency of study interpretation that is the foundation of hazard and risk assessment.