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

Pauluhn J - Inhal Toxicol (2015)

Bottom Line: 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.PMN were essentially indistinguishable at 900 mg HDI/m(3) × 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.

View Article: PubMed Central - PubMed

Affiliation: Bayer Pharma AG, Experimental Toxicology , Wuppertal , Germany (retired) and.

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/m(3) × min (75 mg/m(3) for 75 min). PMN were essentially indistinguishable at 900 mg HDI/m(3) × 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.

No MeSH data available.


Related in: MedlinePlus

Inhalation exposure of Brown Norway rats to 100 or 200 mg/m3 polyisocyanate aerosol for 30-min with and without supplementation of 8 mg HDI/m3. Respiratory function measurements were made concomitant with exposure (15-min exposure to air for the collection of base-line data, 30 min exposure to the diisocyanate followed by air exposure for 30 min). Rats were subjected to bronchoalveolar lavage fluid (BAL) on postexposure day 1. Data were presented as means ± SD (six rats/group). Asterisks denote significant difference to the equally exposed air time-matched control group (*p < 0.05, **p < 0.01).
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Figure 0006: Inhalation exposure of Brown Norway rats to 100 or 200 mg/m3 polyisocyanate aerosol for 30-min with and without supplementation of 8 mg HDI/m3. Respiratory function measurements were made concomitant with exposure (15-min exposure to air for the collection of base-line data, 30 min exposure to the diisocyanate followed by air exposure for 30 min). Rats were subjected to bronchoalveolar lavage fluid (BAL) on postexposure day 1. Data were presented as means ± SD (six rats/group). Asterisks denote significant difference to the equally exposed air time-matched control group (*p < 0.05, **p < 0.01).

Mentions: Additional groups of rats were exposed for 30-min to the mixture of HDI-vapor (8 mg/m3) and polyisocyanate-aerosol (100 and 200 mg/m3, MMAD/GSD 1.8 µm/1.7) with actually determined total mass concentrations of the polyisocyanate in the range of 100–108 and 191–222 mg/m3, respectively. Lung function measurements provided evidence of marked differences in aerosol-induced changes in respiratory patterns in the presence of HDI-vapor, especially for tidal volumes (Figure 6, upper panel). Bronchoalveolar lavage (1 d postexposure) did not reveal appreciable differences (Figure 6, lower panel) of the neat aerosol or that containing HDI which suggest that, in principle, HDI-vapor can be shuttled into the lower airways by the polyisocyanate aerosol; however, due to the HDI-driven changes in ventilation “inhaled dose”, adjustments become difficult. Based on the findings from these ancillary pre-studies, the conclusion was drawn that the objective of study can only be achieved when using challenge concentration of at least 70–80 mg HDI/m3 (a maximum depression in HDI vapor-induced ventilation). A precipitous increase in alveolar irritation occurred in the range of 120 mg HDI/m3 (Figure 3), that is, a concentration above the vapor saturation of HDI-monomer favoring aerosol formation.Figure 6.


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

Pauluhn J - Inhal Toxicol (2015)

Inhalation exposure of Brown Norway rats to 100 or 200 mg/m3 polyisocyanate aerosol for 30-min with and without supplementation of 8 mg HDI/m3. Respiratory function measurements were made concomitant with exposure (15-min exposure to air for the collection of base-line data, 30 min exposure to the diisocyanate followed by air exposure for 30 min). Rats were subjected to bronchoalveolar lavage fluid (BAL) on postexposure day 1. Data were presented as means ± SD (six rats/group). Asterisks denote significant difference to the equally exposed air time-matched control group (*p < 0.05, **p < 0.01).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496806&req=5

Figure 0006: Inhalation exposure of Brown Norway rats to 100 or 200 mg/m3 polyisocyanate aerosol for 30-min with and without supplementation of 8 mg HDI/m3. Respiratory function measurements were made concomitant with exposure (15-min exposure to air for the collection of base-line data, 30 min exposure to the diisocyanate followed by air exposure for 30 min). Rats were subjected to bronchoalveolar lavage fluid (BAL) on postexposure day 1. Data were presented as means ± SD (six rats/group). Asterisks denote significant difference to the equally exposed air time-matched control group (*p < 0.05, **p < 0.01).
Mentions: Additional groups of rats were exposed for 30-min to the mixture of HDI-vapor (8 mg/m3) and polyisocyanate-aerosol (100 and 200 mg/m3, MMAD/GSD 1.8 µm/1.7) with actually determined total mass concentrations of the polyisocyanate in the range of 100–108 and 191–222 mg/m3, respectively. Lung function measurements provided evidence of marked differences in aerosol-induced changes in respiratory patterns in the presence of HDI-vapor, especially for tidal volumes (Figure 6, upper panel). Bronchoalveolar lavage (1 d postexposure) did not reveal appreciable differences (Figure 6, lower panel) of the neat aerosol or that containing HDI which suggest that, in principle, HDI-vapor can be shuttled into the lower airways by the polyisocyanate aerosol; however, due to the HDI-driven changes in ventilation “inhaled dose”, adjustments become difficult. Based on the findings from these ancillary pre-studies, the conclusion was drawn that the objective of study can only be achieved when using challenge concentration of at least 70–80 mg HDI/m3 (a maximum depression in HDI vapor-induced ventilation). A precipitous increase in alveolar irritation occurred in the range of 120 mg HDI/m3 (Figure 3), that is, a concentration above the vapor saturation of HDI-monomer favoring aerosol formation.Figure 6.

Bottom Line: 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.PMN were essentially indistinguishable at 900 mg HDI/m(3) × 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.

View Article: PubMed Central - PubMed

Affiliation: Bayer Pharma AG, Experimental Toxicology , Wuppertal , Germany (retired) and.

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/m(3) × min (75 mg/m(3) for 75 min). PMN were essentially indistinguishable at 900 mg HDI/m(3) × 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.

No MeSH data available.


Related in: MedlinePlus