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

Abstract

This paper summarizes a range of experimental data central for developing a science-based approach for hazard identification of monomeric and polymeric aliphatic 1,6-hexamethylene diisocyanate (HDI). The dose–response curve of HDI-induced pulmonary responses in naïve or dermally sensitized rats after one or several inhalation priming exposures was examined in the Brown Norway (BN) rat asthma model. Emphasis was directed to demonstrate the need and the difficulty in selecting an appropriate pulmonary dose when much of the inhaled chemically reactive vapor may concentration dependently be retained in the upper airways of obligate nose-breathing rats. The course taken acknowledges the experimental challenges in identifying an elicitation threshold for HDI-monomer near or above the saturated vapor concentration or in the presence of a HDI-polymer aerosol. The inhalation threshold dose on elicitation was determined based on a fixed concentration (C) × variable exposure duration (t) protocol for improving inhalation dosimetry of the lower airways. Neutrophilic granulocytes (PMN) in bronchoalveolar lavage (BAL) fluid in equally inhalation primed naïve and dermally sensitized rats were used to define the inhalation elicitation threshold C × t. Sensitized rats elaborated markedly increased PMN challenged sensitized rats relative to equally challenged naïve rats at 5625 mg HDI/m3 × min (75 mg/m3 for 75 min). PMN were essentially indistinguishable at 900 mg HDI/m3 × min. By applying adjustment factors accounting for both inter-species differences in inhalation dosimetry and intra-species susceptibility, the workplace human-equivalent threshold C × t was estimated to be in the range of the current ACGIH TLV® of HDI. Thus, this rat “asthma” model was suitable to demonstrate elicitation thresholds for HDI-vapor after one or several inhalation priming exposures and seems to be suitable to derive occupational exposure values (OELs) for diisocyanates in general.

Evaluation of animal toxicity studies with diisocyanates regarding presence of thresholds for induction and elicitation of respiratory allergy by quantitative weight of evidence

“…A plot for the studies that assessed dose-response for the elicitation of respiratory allergy (Figure 5) shows that several high quality studies provide moderate to good support for the presence of thresholds. Highest quality and relevance/strength of effects scores were obtained by studies specifically designed to enable identification of a threshold for elicitation of respiratory allergy in a specific animal model, the BN rat (Pauluhn, 2008a(Pauluhn, , 2014(Pauluhn, , 2015Pauluhn and Poole, 2011). These studies used an elaborate study design to optimize induction of respiratory allergy and reduce interference in the response by respiratory tract irritation.…”

“…From the studies selected for scoring, only seven studies reached sufficient relevance/strength of effect scores (≥ 27) or overall scores (≥ 45), respectively, to provide moderate to good support for the hypothesis that a threshold for the induction or elicitation of respiratory allergy by diisocyanates exists. Of these studies, three studies performed in the 1980-1990 timeframe used guinea pigs (Huang et al, 1993a;Karol, 1983;Pauluhn and Eben, 1991) and four studies performed after 2008 used the BN rat as model systems (Pauluhn, 2008a(Pauluhn, , 2014(Pauluhn, , 2015Pauluhn and Poole, 2011). Detailed descriptions of the design and results of these studies are provided in supplement 3.…”