TR 085 – Recognition of, and Differentiation between, Adverse and Non-adverse Effects in Toxicology Studies

TR 085 : Recognition of, and Differentiation between, Adverse and Non-adverse Effects in Toxicology Studies | December 2002

This report proposes a structured approach to assist the toxicologist in arriving at consistent study interpretation. There are two main steps to the approach, and for each step, criteria are described that form the basis of consistent judgements:

First a decision has to be made on whether differences from control values are treatment-related effects, or occur by chance. This involves consideration of such parameters as 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.

Those differences judged to be treatment-related effects are then evaluated further, to differentiate between those that are adverse and those that are not. This second step involves consideration of 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.

To arrive at an overall judgement in the interpretation of complex studies, it is important to apply a 'weight of evidence' approach that takes into account the criteria proposed in this report. The use of the structured scheme will contribute to improved consistency of individual study interpretation that is the foundation of reliable prediction of chemical hazard and risk.

Finally, a standard set of definitions is proposed for the key terms such as NOEL and NOAEL that are frequently used to describe the overall outcome of a toxicity study.