Human risk assessment of inhaled irritants: Role of sensory stimulations from spatially separated nociceptors. (October 2021)

• Record Type: Journal Article
• Authors: Pauluhn, Juergen; Whalan, John E.
• Is Part Of: Toxicology. Volume 462(2021)
• Publication Date: 2021-10
• Subjects: Ammonia -- Toluene diisocyanate -- Phosgene -- Inhalation dosimetry -- Metric of exposure -- Nociceptive sensitization; Toxicology -- Periodicals; Chemicals -- Physiological effect -- Periodicals; 615.9005
• DOI: 10.1016/j.tox.2021.152929
• Languages: English
• ISSNs: 0300-483X

Abstract

Highlights: Understanding of chemosensory nociception and neuro-immune interactions. Breathing patterns in rats exposed to upper, bronchial, and pulmonary irritants. Alternative approach for estimating PODs from respiratory function data. Hazard characterization and assessment for irritants causing nociceptor sensitization. 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 % (RD50 ) assay with focus on the Log-linear extrapolation of the non-sensory irritant threshold (RD0 or RD10 ) 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.