Human risk assessment of inhaled irritants: Role of sensory stimulations from spatially separated nociceptors.

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.

The evaluation of inhalation studies for exposure quality: A case study with formaldehyde.

The inherent complexity of generating and monitoring a test article in an inhalation chamber can make inhalation toxicity testing challenging. Poor study design, human error, and electrical and mechanical problems can adversely affect an inhalation exposure and undermine a study's results. We have developed a process for evaluating seven key elements of exposure quality in inhalation chamber studies: 1) test article characterization, 2) generation method, 3) chamber sampling and analytical method, 4) chamber concentrations, 5) particle size characteristics, 6) chamber type, and 7) controls. For each study evaluated, exposure deficiencies are documented, and a study is given an overall rating (Robust, Adequate, or Poor) for the quality of its exposure characterization and documentation. In combination with the systematic consideration of experimental features other than exposure, these ratings can inform the utility of a study for use in hazard identification and/or exposure-response analysis. Exposure quality evaluations of 204 formaldehyde inhalation studies are presented as a case study. Of these, 34% were rated Robust because they had comprehensive exposure documentation and no serious deficiencies in the key elements of exposure quality. Another 19% of studies with minor uncertainties or limitations were rated Adequate. Conversely, 47% of the studies were rated Poor due to multiple serious exposure deficiencies. This formaldehyde case study illustrates the need to carefully consider the exposure quality of inhalation toxicity studies when their results are used to support hazard and risk assessments.