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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

Measurement of Penh (enhanced pause) in whole body barometric plethysmographs after escalation challenge I – step I (see Figure 1) in naïve but challenged (vehicle/HDI) and skin-sensitized and challenged (HDI/HDI) Brown Norway rats. Data represent records from individual rats (four rats/subgroup) after challenge over a duration of approximately 20 h (Penh-AUC20 h). Note: Due to the limited number of plethysmographs available, only four out of eight rats/subgroup were examined to allow the simultaneous measurement of four naïve and four sensitized rats.
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Figure 0007: Measurement of Penh (enhanced pause) in whole body barometric plethysmographs after escalation challenge I – step I (see Figure 1) in naïve but challenged (vehicle/HDI) and skin-sensitized and challenged (HDI/HDI) Brown Norway rats. Data represent records from individual rats (four rats/subgroup) after challenge over a duration of approximately 20 h (Penh-AUC20 h). Note: Due to the limited number of plethysmographs available, only four out of eight rats/subgroup were examined to allow the simultaneous measurement of four naïve and four sensitized rats.

Mentions: Groups of rats dermally induced with 2%-HDI were subjected to a terminal dose–escalation challenge of about 70–120 mg HDI/m3 without (Figure 1, step I) and with lung-priming challenges (days 20, 35, and 50) (Figure 1, step II) as conceptualized in Figures 1 and 2. At the first escalation challenge using a concentration of 110 mg/m3 for 6, 13, 35, and 50 min, irritation-related changes in respiration occurred at challenge durations of 35 and 50 min in both the control and sensitized groups over a time-period of about 10 h (Figure 7). The escalation challenge executed after three prior priming inhalation encounters at a concentration at 75 mg/m3 for 6, 13, 35, and 75 min showed inconclusive responses at a challenge duration of 35 min (Figure 8) with minimal irritation-related changes in breathing patterns at 75 min for about 6 h post-challenge (Figure 8). Collectively, lung function measurements did not reveal typical delayed-onset responses. Irritant inhalation doses produced changes in respiration in both naïve and sensitized rats (Figure 7) at concentrations close to the vapor saturation concentration of HDI. One rat of group 4b (step II, 13-min challenge duration) succumbed 7 h post-challenge with unclear etiopathology. Gross necropsy showed a red-discolorated liver and ascites without any macroscopic changes of the respiratory tract. These findings appear to be supportive of an incidental causality rather than any allergic etiopathology.Figure 7.


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)

Measurement of Penh (enhanced pause) in whole body barometric plethysmographs after escalation challenge I – step I (see Figure 1) in naïve but challenged (vehicle/HDI) and skin-sensitized and challenged (HDI/HDI) Brown Norway rats. Data represent records from individual rats (four rats/subgroup) after challenge over a duration of approximately 20 h (Penh-AUC20 h). Note: Due to the limited number of plethysmographs available, only four out of eight rats/subgroup were examined to allow the simultaneous measurement of four naïve and four sensitized rats.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 0007: Measurement of Penh (enhanced pause) in whole body barometric plethysmographs after escalation challenge I – step I (see Figure 1) in naïve but challenged (vehicle/HDI) and skin-sensitized and challenged (HDI/HDI) Brown Norway rats. Data represent records from individual rats (four rats/subgroup) after challenge over a duration of approximately 20 h (Penh-AUC20 h). Note: Due to the limited number of plethysmographs available, only four out of eight rats/subgroup were examined to allow the simultaneous measurement of four naïve and four sensitized rats.
Mentions: Groups of rats dermally induced with 2%-HDI were subjected to a terminal dose–escalation challenge of about 70–120 mg HDI/m3 without (Figure 1, step I) and with lung-priming challenges (days 20, 35, and 50) (Figure 1, step II) as conceptualized in Figures 1 and 2. At the first escalation challenge using a concentration of 110 mg/m3 for 6, 13, 35, and 50 min, irritation-related changes in respiration occurred at challenge durations of 35 and 50 min in both the control and sensitized groups over a time-period of about 10 h (Figure 7). The escalation challenge executed after three prior priming inhalation encounters at a concentration at 75 mg/m3 for 6, 13, 35, and 75 min showed inconclusive responses at a challenge duration of 35 min (Figure 8) with minimal irritation-related changes in breathing patterns at 75 min for about 6 h post-challenge (Figure 8). Collectively, lung function measurements did not reveal typical delayed-onset responses. Irritant inhalation doses produced changes in respiration in both naïve and sensitized rats (Figure 7) at concentrations close to the vapor saturation concentration of HDI. One rat of group 4b (step II, 13-min challenge duration) succumbed 7 h post-challenge with unclear etiopathology. Gross necropsy showed a red-discolorated liver and ascites without any macroscopic changes of the respiratory tract. These findings appear to be supportive of an incidental causality rather than any allergic etiopathology.Figure 7.

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