Citation

Pauluhn J, Whalan JE. Toxicology 2021; ePub(ePub): ePub.

Copyright

(Copyright © 2021, Elsevier Publishing)

DOI

10.1016/j.tox.2021.152929

PMID

unavailable

Abstract

Contemporary approaches to human health risk assessment for respiratory tract irritants are variable and controversial. This manuscript provides an in-depth analysis and assessment of the applicability of the classical respiratory depression 50% (RD(50)) assay with focus on the Log-linear extrapolation of the non-sensory irritant threshold (RD(0) or RD(10)) relative to the contemporary Point of Departure (POD) U.S.-EPA benchmark approach. Three prototypic volatile chemically reactive irritants are used to exemplify the pros and cons of this alternative approach. These irritants differ in physicochemical properties affecting water-solubility and lipophilicity. Depending on these variables, a vapor may preferentially be retained in the extrathoracic region (ET), the tracheobronchial region (TB), and the pulmonary region (PU); although a smooth transition between these regions occurs at increasingly high concentrations. Each region has its specific nociceptors sensing irritants and regional-specific response to injury. The alternative approach using rats identified the chemical-specific critical region of respiratory tract injury. Statistically derived PODs on ET-TB related sensory irritation provide important information for ET-TB irritants but not for PU irritants. The POD of ET-TB irritants from acute and repeated studies decreased substantially. In summary, statistically derived PODs improve the risk assessment of respiratory tract irritants; however, those from repeated exposures should be given preference to those from acute exposures.

Language: en

Keywords

Ammonia; inhalation dosimetry; metric of exposure; nociceptive sensitization; phosgene; toluene diisocyanate