Scientific and Regulatory Policy Committee

Abstract

Recommendations (best practices) are provided by the Society of Toxicologic Pathology's Adversity Working Group for making consistent interpretations of test article-related effects as "adverse" and assigning a "no observed adverse effect level" (NOAEL) in nonclinical toxicity studies. Adverse is a term indicating "harm" to the test animal, while nonadverse indicates lack of harm. Adverse findings in the study reports should be defined in relation to effects on the test species used and within the context of the given study. Test article-related effects should be described on their own merits, and decisions to consider them as adverse or nonadverse should be justified. Related effects may be discussed together; in particular, markers of toxicity that are not in and of themselves adverse ideally should be discussed in conjunction with the causal toxicity to determine adversity. Adverse findings should be identified in subreports (clinical data, pathology data, etc.) if sufficient information is available, and/or in the final study report as individual or grouped findings, but study NOAELs should be established at the level of the overall study report. Interpretations such as "not biologically relevant" or "not toxicologically important" should be avoided unless defined and supported by scientific rationale. Decisions defining adverse findings and the NOAEL in final study reports should combine the expertise of all contributing scientific disciplines. Where possible, use of NOAELs in data tables should be linked to explanatory text that places them in context. Ideally, in nonclinical summary documents, NOAELs from multiple studies are considered together in defining the most important adverse responses in the most sensitive species. These responses are then considered along with an understanding of their likely mechanisms, as well as other information such as variability in species sensitivity, comparative pathology, reversibility and progression, kinetics, and metabolism of the test substance to help assess human risk.

Derivation of an occupational exposure limit for diacetyl using dose‐response data from a chronic animal inhalation exposure study

“…The response rate of 8% for the 25 ppm-exposed animals for this endpoint was also reasonably close to the chosen BMR of 10%, which was ideal for modeling, as this required less extrapolation between concentration groups to estimate the BMC 10 and BMCL 10 . Adaptive responses, such as hyperplasia, are not implicitly adverse effects (Kerlin et al, 2016;US EPA, 1994). However, adaptive responses such as hyperplasia can progress to neoplasia and other effects if a physiological stressor persists; thus, an OEL based on hyperplasia would be protective of more serious adverse endpoints via this mode of action (Kerlin et al, 2016;US EPA, 1994).…”

“…Adaptive responses, such as hyperplasia, are not implicitly adverse effects (Kerlin et al, 2016;US EPA, 1994). However, adaptive responses such as hyperplasia can progress to neoplasia and other effects if a physiological stressor persists; thus, an OEL based on hyperplasia would be protective of more serious adverse endpoints via this mode of action (Kerlin et al, 2016;US EPA, 1994).…”

“…The OELs based on bronchiolar epithelial hyperplasia were the lowest values generated in this analysis: 0.36 ppm for Scenario 1, and 0.16 ppm for Scenario 2. As previously discussed, hyperplasia is not considered an adverse effect without the presence of coincident adverse health effects (Kerlin et al, 2016;US EPA, 1994); however, because hyperplasia can potentially lead to adverse health effects, this effect was selected as the basis of the diacetyl OEL. Additionally, the more health-protective breathing scenario (Scenario 2), was also selected for the OEL derivation.…”

Is It Adverse, Nonadverse, Adaptive, or Artifact?

“…Several recent publications aimed to provide guidance in determining adversity in preclinical toxicology studies (ECETOC, 2002, Lewis et al ., 2002, Dorato and Engelhardt, 2005, Keller et al ., 2012, Kerlin et al ., 2016, Palazzi et al ., 2016). The readers are encouraged to refer to these publications for more in depth information on adversity in toxicology studies.…”

“…The readers are encouraged to refer to these publications for more in depth information on adversity in toxicology studies. Due to the increased interest in the topic of adverse versus adaptive responses in toxicology studies, several recent workshops, and symposia were organized by the American College of Toxicology (Cavagnaro and Beilke, 2014, Kiorpes and Pandiri, 2014), the Society of Toxicologic Pathology (Kerlin et al ., 2016), and the European Society of Toxicologic Pathology (Palazzi et al ., 2016). This continuing education course at the 2016 STP annual meeting in San Diego, CA, aims to provide a forum to disseminate information and to enable discussion within the STP membership.…”