Recognition of Adverse and Nonadverse Effects in Toxicity Studies

Abstract

One of the most important quantitative outputs from toxicity studies is identi cation 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 scienti c literature and of current practices has revealed a lack of consistency in de nition and application of frequently used terms such as No Observed Effect Level (NOEL), No Observed Adverse Effect Level (NOAEL), adverse effect, biologically signi cant effect, or toxicologically signi cant 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 nonadvers e effects. This presentation will address these issues identi ed rst by proposing a standard set of de nitions 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 rst, 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 nding, consideration is given inter alia to dose response, spurious measurements in individual parameters, the precision of the measuremen t under evaluation, ranges of natural variation and the overall biological plausibility of the observation. In discriminating between the adverse and the non-advers e 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 signi cant effect, whether it has an effect on the overall function of the organism, whether it is a speci c effect on an organ or organ system or secondary to general toxicity or whether the effect is a predictable consequenc e 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 .

Characterizing “Adversity” of Pathology Findings in Nonclinical Toxicity Studies

“…To help address this issue, a European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) initiative, reporting in 2002, organized a task force for addressing adversity in toxicology studies. This effort resulted in a publication by Lewis et al in (2002) that provided the following definitions, which were more specific to findings in toxicologic pathology:…”

“…Conversely, extremely rare or unfamiliar findings may increase uncertainty regarding adversity and result in a higher degree of conservatism. Factors indicating that an intergroup difference is probably not a test item-related effect include lack of a clear dose-response or pairwise differences between groups, high variability or imprecision of the end point, incidence values within the normal range of biological variation, and/or lack of biological plausibility taking into account preexisting knowledge of the test item (adapted from Lewis et al 2002).…”

Liver Hypertrophy

“…. affects the performance of the whole organism's ability to respond to an additional environmental challenge'' (Lewis et al 2002). Another widely accepted definition is that an adverse effect is ''a change in morphology, physiology, growth, reproduction, development, or life span of an organism which results in impairment of functional capacity or impairment of capacity to compensate for additional stress or increased susceptibility to the harmful effects of other environmental influences'' (WHO/IPCS [International Programme on Chemical Safety] 2004).…”

Predictive Toxicology Approaches for Small Molecule Oncology Drugs

“…The standard benchmarks typically used in toxicology studies-including the no-observed-effect level (NOEL), no-observed-adverse-effect level (NOAEL), and lowestobserved-adverse-effect level (LOAEL)-are usually not applicable with cytotoxic oncology molecules (Dorato and Englehardt 2005;Lewis et al 2002). Rather, benchmarking in rat and dog studies with oncology therapeutics includes the dose that results in 10% mortality over the duration of the study (STD 10 ) in rats, and the highest non-severely toxic dose (HNSTD), which is defined as a dose that does not produce death or moribundity during a study in rats or dogs.…”