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

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.