Evaluation of animal toxicity studies with diisocyanates regarding presence of thresholds for induction and elicitation of respiratory allergy by quantitative weight of evidence

Abstract

Animal toxicity studies on diisocyanates were evaluated using quantitative weight of evidence (QWoE) to test the hypothesis that the dose-response curve shows a threshold for the induction and/or elicitation of respiratory sensitization. A literature search identified 59 references that included at least two concentration groups of the diisocyanate and a vehicle-exposed concurrent control in the study design. These studies were subjected to a QWoE-assessment applying scoring criteria for quality and relevance/strength of effects relevant to the selected endpoint of respiratory sensitization. Overall, the studies assessing dose/concentration-response for diisocyanates with the endpoint, respiratory sensitization, were heterogenous regarding study design, animal models used, endpoints assessed, and quality. Only a limited number of the studies subjected to the QWoE-assessment allowed drawing conclusions about possible thresholds for respiratory sensitization. Highest quality and relevance/strength of effects scores were obtained by a series of studies specifically designed to investigate a potential threshold for elicitation of respiratory sensitization in the Brown Norway (BN) rat. These studies applied an elaborate study design to optimize induction of respiratory sensitization and reduce interference by respiratory tract irritation. In summary, the available studies provided moderate to good support for the existence of a threshold for elicitation and limited to moderate support for a threshold regarding induction of respiratory allergy by diisocyanates in experimental animals. However, a quantitative extrapolation of threshold values established in rodents to humans remains complex.