Application of AOP networks in human health risk assessment: Increasing confidence in rodent olfactory nasal lesions as the point of departure for hydrogen sulfide exposure limits

Acute exposure to hydrogen sulfide initiates a series of hallmark biological effects that occur progressively at increasing exposure levels: odor perception, conjunctivitis, olfactory paralysis, “knockdown”, pulmonary edema, and paralysis of breathing. Although effects of exposure to high concentrations of hydrogen sulfide are clear, effects associated with chronic, low-level exposure in humans is under debate, leading to uncertainty in the critical effect used in regulatory risk assessments addressing low dose exposures. This study integrates experimental animal, observational epidemiology, and occupational exposure evidence by applying a pathway-based approach. A hypothesized adverse outcome pathway (AOP) network was developed from 34 studies, comprised of 5 AOPs sharing 2 molecular initiating events (MIEs) and culminating in 5 adverse outcomes. A comparative assessment of effect levels and weight of evidence identified an AOP leading to a biologically-plausible, low-dose outcome relative to the other outcomes (nasal lesions, 30 ppm vs neurological effects, >80 ppm; pulmonary edema, >80 ppm; cardiovascular related mortality, >400 ppm; mortality via central nervous system depression, >400 ppm). This AOP (i.e., AOP1) consists of the following key events: cytochrome oxidase inhibition (>10 ppm), neuronal cell loss (>30 ppm), and olfactory nasal lesions (defined as both neuronal cell loss and basal cell hyperplasia; >30 ppm) in rodents or olfactory paralysis (>100 ppm) in humans. The key event relationships in this pathway were supported by high empirical evidence and have high biological plausibility due to known mechanistic understanding and consistency in observations for diverse chemicals. Based on assessment using the human relevance framework, this biological pathway (or, mode of action) is qualitatively possible in humans and is likely to share the same set of key event leading to olfactory paralysis in humans. This approach provides a basis to link the known observations in humans with the subchronic animal data, reducing the overall uncertainty of the human health risk assessment of H2S.