Inhalation dosimetry of hexamethylene diisocyanate vapor in the rat and human respiratory tracts

Abstract

Hexamethylene diisocyanate (HDI) is a reactive chemical used in the commercial production of polyurethanes. Toxic effects in rodents exposed to HDI vapor primarily occur in the nasal passages, yet some individuals exposed occupationally to concentrations exceeding current regulatory limits may experience temporary reduction in lung function and asthma-like symptoms. Knowledge of interspecies differences in respiratory tract dosimetry of inhaled HDI would improve our understanding of human health risks to this compound. HDI uptake was measured in the upper respiratory tract of anesthetized Fischer-344 rats. Nasal uptake of HDI was >90% in rats at unidirectional flow rates of 150 and 300 ml/min and a target air concentration of 200 ppb. Uptake data was used to calibrate nasal and lung dosimetry models of HDI absorption in rats and humans. Computational fluid dynamics (CFD) models of the nasal passages were used to simulate inspiratory airflow and HDI absorption. Transport of HDI through lung airways was simulated using convection-diffusion based mass transport models. HDI nasal uptake of 90% and 78% was predicted using the rat and human nasal CFD models, respectively. Total respiratory tract uptake was estimated to be 99% in rats and 97% in humans under nasal breathing. Predicted human respiratory uptake decreased to 87% under oral breathing conditions. Absorption rates of inhaled HDI in human lung airways were estimated to be higher than the rat due to lower uptake in head airways. Model predictions demonstrated significant penetration of HDI to human bronchial airways, although absorption rates were sensitive to breathing style.

Analysis of the interrelationship of the pulmonary irritation and elicitation thresholds in rats sensitized with 1,6-hexamethylene diisocyanate (HDI)

“…The protocols applied focused on the analysis of the concentration × time ( C × t )–response relationship on elicitation-based endpoints by employing a highly rationalized dose-escalation-like protocol. For the HDI-vapor, a C const × t var regimen was selected with a “ C” high enough to overcome the scrubbing capacity of the nasal passages of the obligate nasal breathing rats (Schroeter et al., 2013 ; Shiotsuka et al., 2006 , 2010 ). Ancillary pre-studies served the purpose of identifying that “ C ” of HDI-vapor gains access to the lower airways at stable breathing conditions.…”

“…The workday and ppmV-adjusted equivalent were estimated to be 23 (mg/m 3 × min) × 1/7 (conversion from mg to ppmV) × 1/480 min −1 = 0.007 ppmV. The derivation of the rat to human conversion factor assumed that bronchial airways of oronasally breathing humans are subjected to a 3-times higher dose as compared with nasally breathing rats (Schroeter et al., 2013 ). Likewise, due to the reflexively-induced depression of ventilation occurring in rats, the inhaled dose of rats exposed to HDI-vapor at concentrations penetrating the lower respiratory tract is likely to be about one-third of normally breathing rats.…”

Optimizing a Test Bed System to Assess Human Respiratory Safety After Exposure to Chemical and Particle Aerosolization

“…An in silico model, such as the Multiple Path Particle Dosimetry Model (MPPD) is a wellestablished, validated, and accepted model that can help identify the location of a particular droplet/particle size is expected to reach and deposit and where lesions of cellular damage may occur. [61][62][63][64][65] A mass per unit surface area can then be applied to both in vivo (which has been done successfully for validation purposes) and in vitro applications for establishing the appropriate droplet/particle size to emulate the intended exposure scenario that investigators wish to assess for potential exposure effects.…”

Reaction products of hexamethylene diisocyanate vapors with “self” molecules in the airways of rabbits exposed via tracheostomy

“…Animal studies of HDI exposure to identify “self” reaction targets in the lower airway have been compromised by inherent species differences with humans; for example, rodents are obligate nose breathers and their upper airways are proportionally larger and possess a scrubbing effect or capacity for absorbing/capturing reactive vapors (Ferguson et al, 1988; Harkema et al, 2006; Kennedy et al, 1993; Morris & Buckpitt, 2009; Schroeter et al, 2013). Prior rat and guinea pig studies with several different radiolabeled monoand di-isocyanates demonstrated limited penetration into the lower airways and higher levels of upper airway and oral absorption (Ferguson et al, 1988; Gledhill et al, 2005; Kennedy et al, 1994; Schroeter et al, 2013).…”

“…Prior rat and guinea pig studies with several different radiolabeled monoand di-isocyanates demonstrated limited penetration into the lower airways and higher levels of upper airway and oral absorption (Ferguson et al, 1988; Gledhill et al, 2005; Kennedy et al, 1994; Schroeter et al, 2013). …”