Chemical respiratory allergens pose a significant human health hazard for many industries, yet there are currently no approved test methods to identify respiratory sensitizers. Attempts to model the processes of sensitization and elicitation in response to exposure to low molecular weight chemical allergens in animals have been unsuccessful, potentially due to insurmountable interspecies differences in the respiratory tract and/or immune system. However, the use of Adverse Outcome Pathways (AOPs) provide an avenue to establish novel approaches that can accurately identify human respiratory sensitization hazards using chemical characterization and <i>in vitro</i> activity profiles.<br/>An AOP describes the etiology of a disease, disorder, or other adverse outcome (AO) as it develops from exposure to a stressor. In order to assist method developers and regulators understanding of how perturbations can be used to infer relative risks and hazards for human health, the etiology of the AO is separated into key events corresponding to measurable perturbations, starting from the first molecular interaction with the stressor, termed the Molecular Initiating Event. In this way, AOPs are used to map physiologically relevant stages in the mechanism of toxicity to available, or potential, bioassays and test methods that measure key events upstream of the adverse outcome. These assays can then be used, often in combination, to inform on the hazards associated with chemical stressors, such as reactive electrophiles. <br/>In recent years, a variety of efforts to characterize the MIE for skin and/or respiratory sensitizers have been developed. For sensitization, protein binding is well understood to be necessary for low molecular weight chemicals to induce immune responses, but much remains to be understood regarding the specific amino acid(s) and/or protein(s) that are involved in dermal and/or respiratory sensitization. To establish the most relevant evidence for human hazard identification, we have used the information on the essentiality of key events to perform a retrospective literature evaluation to identify a list of clinical respiratory sensitizers. This output will be incorporated with other available data in a weight-of-evidence approach to establish a reference chemical list of respiratory sensitizers, irritants, and non-sensitizers to use as the basis for evaluating the accuracy of test methods that characterize the MIE.

Adverse outcome pathway for low molecular weight respiratory sensitizers and weight of evidence approaches

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ACS Fall 2022

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