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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

Ancillary pre-study showing the time and concentration dependence of respiratory changes in naïve Wistar rats (5–6 animals/concentration) that were simultaneously exposed for 15-min to air, 30-min to either HDI-vapor (up to 27 mg/m3) or aerosol (at and above 109 mg/m3) followed by a 30-min recovery period. Changes in tidal volumes, minute volumes (MV), and the concentration dependence of ventilation (MV) are given in the top, middle, and lower panels, respectively. Measurements were made in head-out volume–displacement plethysmographs attached to a directed-flow nose-only inhalation chamber (Pauluhn & Thiel, 2007). The solid lines were derived using a sigmoid model fitted to measurements from the pre-exposure and exposure periods to estimate the degree of respiratory depression. All data were normalized to the pre-exposure period (=100%). The concentration dependence of the maximum stable depression of the respiratory minute volume is depicted in the lower panel. Depressed tidal volumes increased at concentrations with stable aerosol (Figure 3).
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Figure 0004: Ancillary pre-study showing the time and concentration dependence of respiratory changes in naïve Wistar rats (5–6 animals/concentration) that were simultaneously exposed for 15-min to air, 30-min to either HDI-vapor (up to 27 mg/m3) or aerosol (at and above 109 mg/m3) followed by a 30-min recovery period. Changes in tidal volumes, minute volumes (MV), and the concentration dependence of ventilation (MV) are given in the top, middle, and lower panels, respectively. Measurements were made in head-out volume–displacement plethysmographs attached to a directed-flow nose-only inhalation chamber (Pauluhn & Thiel, 2007). The solid lines were derived using a sigmoid model fitted to measurements from the pre-exposure and exposure periods to estimate the degree of respiratory depression. All data were normalized to the pre-exposure period (=100%). The concentration dependence of the maximum stable depression of the respiratory minute volume is depicted in the lower panel. Depressed tidal volumes increased at concentrations with stable aerosol (Figure 3).

Mentions: Naïve Wistar rats that were nose-only exposed to HDI vapor/aerosol for 30 min displayed an instant concentration-dependent decrease of the respiratory minute volume as shown in Figure 4. A maximum depression in ventilation occurred at exposure concentrations exceeding 70 mg/m3. Decreased tidal volumes were observed at exposures to the vapor phase with reversal towards increased tidal volumes at concentrations (Figure 4) high enough to stabilize the aerosol phase (Figure 3). This is taken as evidence that the HDI-aerosol gained access to the lower airways when present in concentrations in the range or above the vapor saturation concentration. This interpretation was empirically verified in Wistar rats exposed at 112 and 190 mg HDI-vapor/aerosol/m3 × 30 min (Figure 5). Transient, minimally increased extravasated protein and PMN were observed at 112 mg/m3 on postexposure day 1 with reversibility on postexposure day 3. Definite pulmonary irritation was evidenced at 190 mg/m3; however, without gaining statistically increased lung weights or increased cell counts (Figure 5). Increased γ-glutamyl transpeptidase (γ-GT) is taken as evidence of lower airway exposure and injury (Pauluhn, 2000).Figure 4.


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)

Ancillary pre-study showing the time and concentration dependence of respiratory changes in naïve Wistar rats (5–6 animals/concentration) that were simultaneously exposed for 15-min to air, 30-min to either HDI-vapor (up to 27 mg/m3) or aerosol (at and above 109 mg/m3) followed by a 30-min recovery period. Changes in tidal volumes, minute volumes (MV), and the concentration dependence of ventilation (MV) are given in the top, middle, and lower panels, respectively. Measurements were made in head-out volume–displacement plethysmographs attached to a directed-flow nose-only inhalation chamber (Pauluhn & Thiel, 2007). The solid lines were derived using a sigmoid model fitted to measurements from the pre-exposure and exposure periods to estimate the degree of respiratory depression. All data were normalized to the pre-exposure period (=100%). The concentration dependence of the maximum stable depression of the respiratory minute volume is depicted in the lower panel. Depressed tidal volumes increased at concentrations with stable aerosol (Figure 3).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 0004: Ancillary pre-study showing the time and concentration dependence of respiratory changes in naïve Wistar rats (5–6 animals/concentration) that were simultaneously exposed for 15-min to air, 30-min to either HDI-vapor (up to 27 mg/m3) or aerosol (at and above 109 mg/m3) followed by a 30-min recovery period. Changes in tidal volumes, minute volumes (MV), and the concentration dependence of ventilation (MV) are given in the top, middle, and lower panels, respectively. Measurements were made in head-out volume–displacement plethysmographs attached to a directed-flow nose-only inhalation chamber (Pauluhn & Thiel, 2007). The solid lines were derived using a sigmoid model fitted to measurements from the pre-exposure and exposure periods to estimate the degree of respiratory depression. All data were normalized to the pre-exposure period (=100%). The concentration dependence of the maximum stable depression of the respiratory minute volume is depicted in the lower panel. Depressed tidal volumes increased at concentrations with stable aerosol (Figure 3).
Mentions: Naïve Wistar rats that were nose-only exposed to HDI vapor/aerosol for 30 min displayed an instant concentration-dependent decrease of the respiratory minute volume as shown in Figure 4. A maximum depression in ventilation occurred at exposure concentrations exceeding 70 mg/m3. Decreased tidal volumes were observed at exposures to the vapor phase with reversal towards increased tidal volumes at concentrations (Figure 4) high enough to stabilize the aerosol phase (Figure 3). This is taken as evidence that the HDI-aerosol gained access to the lower airways when present in concentrations in the range or above the vapor saturation concentration. This interpretation was empirically verified in Wistar rats exposed at 112 and 190 mg HDI-vapor/aerosol/m3 × 30 min (Figure 5). Transient, minimally increased extravasated protein and PMN were observed at 112 mg/m3 on postexposure day 1 with reversibility on postexposure day 3. Definite pulmonary irritation was evidenced at 190 mg/m3; however, without gaining statistically increased lung weights or increased cell counts (Figure 5). Increased γ-glutamyl transpeptidase (γ-GT) is taken as evidence of lower airway exposure and injury (Pauluhn, 2000).Figure 4.

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