Limits...
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

Dependence of PMN in bronchoalveolar lavage on the escalation C × t-dose of HDI at escalation challenges I (step I) and IV (step II) (for details, see Figure 1). Data were presented as means ± SD (eight animals/subgroup). Equally challenged naïve and HDI-sensitized Brown Norway rats were considered indistinguishable at 600 and 900 mg HDI/m3 × min in rats without and with additional inhalation priming exposures.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4496806&req=5

Figure 0012: Dependence of PMN in bronchoalveolar lavage on the escalation C × t-dose of HDI at escalation challenges I (step I) and IV (step II) (for details, see Figure 1). Data were presented as means ± SD (eight animals/subgroup). Equally challenged naïve and HDI-sensitized Brown Norway rats were considered indistinguishable at 600 and 900 mg HDI/m3 × min in rats without and with additional inhalation priming exposures.

Mentions: Rats from the naive control not receiving repeated priming inhalation exposures did not elaborate any escalation dose-dependent increase in BAL-PMN whereas those repeatedly primed showed increased susceptibility (Figure 12). Despite this circumstance, sensitized rats without (step I)/with (step II) inhalation priming exposures elaborated comparable levels of BAL-PMN. Differences in PMN between equally challenged controls and sensitized groups were not observed at the 6- and 13-min challenges whereas distinct differences occurred at longer escalation challenge durations and three preceding priming-challenges. Based on the analyses given in Figure 12, 900 mg HDI/m3 × min is considered to be the NOAEL for elicitation. Notably, sensitivity to inhalation challenge is generally assumed to increase with repeated exposure to the sensitizing agent. The POD of step I was slightly lower than that from step II. This apparent difference is conceived to be caused by the more irritant and variable challenge concentrations used at step I compared with step II. Accounting for these experimental factors, the outcome from either step is believed to be equivalent in this experimental model. The less irritant challenge dose used in step II is considered to deliver the most robust NOAEL.Figure 12.


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)

Dependence of PMN in bronchoalveolar lavage on the escalation C × t-dose of HDI at escalation challenges I (step I) and IV (step II) (for details, see Figure 1). Data were presented as means ± SD (eight animals/subgroup). Equally challenged naïve and HDI-sensitized Brown Norway rats were considered indistinguishable at 600 and 900 mg HDI/m3 × min in rats without and with additional inhalation priming exposures.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 0012: Dependence of PMN in bronchoalveolar lavage on the escalation C × t-dose of HDI at escalation challenges I (step I) and IV (step II) (for details, see Figure 1). Data were presented as means ± SD (eight animals/subgroup). Equally challenged naïve and HDI-sensitized Brown Norway rats were considered indistinguishable at 600 and 900 mg HDI/m3 × min in rats without and with additional inhalation priming exposures.
Mentions: Rats from the naive control not receiving repeated priming inhalation exposures did not elaborate any escalation dose-dependent increase in BAL-PMN whereas those repeatedly primed showed increased susceptibility (Figure 12). Despite this circumstance, sensitized rats without (step I)/with (step II) inhalation priming exposures elaborated comparable levels of BAL-PMN. Differences in PMN between equally challenged controls and sensitized groups were not observed at the 6- and 13-min challenges whereas distinct differences occurred at longer escalation challenge durations and three preceding priming-challenges. Based on the analyses given in Figure 12, 900 mg HDI/m3 × min is considered to be the NOAEL for elicitation. Notably, sensitivity to inhalation challenge is generally assumed to increase with repeated exposure to the sensitizing agent. The POD of step I was slightly lower than that from step II. This apparent difference is conceived to be caused by the more irritant and variable challenge concentrations used at step I compared with step II. Accounting for these experimental factors, the outcome from either step is believed to be equivalent in this experimental model. The less irritant challenge dose used in step II is considered to deliver the most robust NOAEL.Figure 12.

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