Application of a new approach method (NAM) for inhalation risk assessment.

The US Environmental Protection Agency (USEPA) and other regulatory authorities have been working to utilize in vitro studies with human cells and in silico modelling to reduce the use of vertebrate animals for evaluating chemical risk. Using the Source-to-Outcome framework, a novel mathematical procedure was developed to estimate the human equivalent concentration (HEC) for inhalation risk assessment based upon the relevant aerosol characterization, respiratory dosimetry modelling, and endpoints derived from an in vitro assay using human respiratory epithelial tissue. The procedure used the retained doses at the various areas of the inhalation tract estimated from a computational fluid-particle dynamics (CFPD) model coupled with a simple clearance model. The effect of exposure was derived from an in vitro assay. The magnitude of exposure and the particle size distributions (PSDs) of the external aerosol droplets were obtained from Unit Exposure values published by the USEPA and published monitoring studies, respectively. The Source-to-Outcome approach incorporates external and internal exposure metrics with the toxicity pathway. The information was then integrated to conduct a risk assessment for agricultural operators exposed to products containing chlorothalonil (CTN), a broad-spectrum fungicide. The HECs for three different PSDs considered in this work ranged from 0.043 to 0.112 mg-CTN/L for nasal and oral breathing. These were compared with the estimated average daily exposure concentration for six representative application scenarios. The resulting margins of exposure (MOEs) ranged from 230 to 70,000 depending on the application scenario. This New Assessment Method (NAM) that combined human in silico and human in vitro methods, eliminated the typical uncertainties associated with extrapolation from rodent studies, with their associated interspecies toxicokinetics and toxicodynamics differences. The intraspecies toxicodynamics and toxicokinetics, are still relevant and may need to be used in an inhalation risk assessment. The NAM presented in this work is not chemical-specific and may be applied to conduct an inhalation risk assessment for workers as well as bystanders who could be exposed to aerosol particles of any cytotoxic respiratory irritant.