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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

Concentration dependence of HDI-aerosol relative to the total concentration of HDI.
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Figure 0003: Concentration dependence of HDI-aerosol relative to the total concentration of HDI.

Mentions: BN-rats were exposed in directed-flow nose-only restraining tubes (for details, see Pauluhn & Thiel, 2007). Animals were sensitized topically (contralateral flanks) on days 0 and 7 to HDI dissolved in the vehicle acetone:olive oil (4:1 mixture, 100 μl vehicle/administration; 2% w/v). This induction regimen was similar to that used for TDI (Pauluhn, 2014). Based on the potency comparison of HDI and TDI in mice after topical administration, HDI was found to be markedly more potent than TDI (Thorne et al., 1987). Animals were exposed “open epicutaneously” for 24 h. Naive control and sensitized rats were simultaneously primed/challenged by inhalation (for details, see Figures 1 and 2). Each sub-group per stepped challenge consisted of eight male rats. When executing step II (Figure 1), the first inhalation priming encounter was to the vapor saturation concentration of HDI (approximately 120 mg/m3, see Figures 2 and 3). At this concentration, a precipitous increase of pulmonary irritation occurred. Accordingly, inhalation exposures were continued at lower concentrations in the range of 72–87 mg/m3. Ramped inhalation challenges, including terminal examinations, were executed on target days 20 (step I) and 65 (step II). In the step II study, animals were re-challenged on days 20, 35, and 50 prior to the dose–response analysis on day 65 (grace period ± 2 d). The time spacing between each priming exposure was long enough to minimize acute irritation-related carry-over effects. Nitric oxide in exhaled air (eNO) was determined shortly after each terminal provocation challenge and 20 h later. This endpoint provided supportive evidence in the BN-rat TDI-study (Pauluhn, 2014) and was judged to indicate increased airway inflammation in atopic, non-smokers exposed to higher levels of isocyanates (Jonaid et al., 2014). eNO has also been shown to be a sensitive, non-invasive biomarker of airway inflammation of rats (Liu et al., 2013) and is generally considered as a diagnostic biomarker in occupational asthma (Ewald-Kleimeier et al., 2013).Figure 3.


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)

Concentration dependence of HDI-aerosol relative to the total concentration of HDI.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 0003: Concentration dependence of HDI-aerosol relative to the total concentration of HDI.
Mentions: BN-rats were exposed in directed-flow nose-only restraining tubes (for details, see Pauluhn & Thiel, 2007). Animals were sensitized topically (contralateral flanks) on days 0 and 7 to HDI dissolved in the vehicle acetone:olive oil (4:1 mixture, 100 μl vehicle/administration; 2% w/v). This induction regimen was similar to that used for TDI (Pauluhn, 2014). Based on the potency comparison of HDI and TDI in mice after topical administration, HDI was found to be markedly more potent than TDI (Thorne et al., 1987). Animals were exposed “open epicutaneously” for 24 h. Naive control and sensitized rats were simultaneously primed/challenged by inhalation (for details, see Figures 1 and 2). Each sub-group per stepped challenge consisted of eight male rats. When executing step II (Figure 1), the first inhalation priming encounter was to the vapor saturation concentration of HDI (approximately 120 mg/m3, see Figures 2 and 3). At this concentration, a precipitous increase of pulmonary irritation occurred. Accordingly, inhalation exposures were continued at lower concentrations in the range of 72–87 mg/m3. Ramped inhalation challenges, including terminal examinations, were executed on target days 20 (step I) and 65 (step II). In the step II study, animals were re-challenged on days 20, 35, and 50 prior to the dose–response analysis on day 65 (grace period ± 2 d). The time spacing between each priming exposure was long enough to minimize acute irritation-related carry-over effects. Nitric oxide in exhaled air (eNO) was determined shortly after each terminal provocation challenge and 20 h later. This endpoint provided supportive evidence in the BN-rat TDI-study (Pauluhn, 2014) and was judged to indicate increased airway inflammation in atopic, non-smokers exposed to higher levels of isocyanates (Jonaid et al., 2014). eNO has also been shown to be a sensitive, non-invasive biomarker of airway inflammation of rats (Liu et al., 2013) and is generally considered as a diagnostic biomarker in occupational asthma (Ewald-Kleimeier et al., 2013).Figure 3.

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