Development of a respiratory sensitization/elicitation protocol of toluene diisocyanate (TDI) in Brown Norway rats to derive an elicitation-based occupational exposure level

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• 作者：Jü ; rgen Pauluhn ; ^{juergen.pauluhn@bayer.com" class="auth_mail} ; ^{juergen-pauluhn@t-online.de" class="auth_mail}
• 关键词：Asthma rat bioassay ; Diisocyanate asthma ; Neutrophilic inflammation ; Dose&ndash ; response ; Risk assessment
• 刊名：Toxicology
• 出版年：7 May, 2014
• 年：2014
• 卷：319
• 期：Complete
• 页码：10-22
• 全文大小：2944 K

文摘

Toluene diisocyanate (TDI), a known human asthmagen, was investigated in skin-sensitized Brown Norway rats for its concentration 脳 time (C 脳 t)-response relationship on elicitation-based endpoints. The major goal of study was to determine the elicitation inhalation threshold dose in sensitized, re-challenged Brown Norway rats, including the associated variables affecting the dosimetry of inhaled TDI-vapor in rats and as to how these differences can be translated to humans. Attempts were made to duplicate at least some traits of human asthma by using skin-sensitized rats which were subjected to single or multiple inhalation-escalation challenge exposures. Two types of dose-escalation protocols were used to determine the elicitation-threshold C 脳 t; one used a variable C (C_var) and constant t (t_const), the other a constant C (C_const) and variable t (t_var). The selection of the 鈥渕inimal irritant" C was based an ancillary pre-studies. Neutrophilic granulocytes (PMNs) in bronchoalveolar lavage fluid (BAL) were considered as the endpoint of choice to integrate the allergic pulmonary inflammation. These were supplemented by physiological measurements characterizing nocturnal asthma-like responses and increased nitric oxide in exhaled breath (eNO). The C_const 脳 t_var regimen yielded the most conclusive dose-response relationship as long C was high enough to overcome the scrubbing capacity of the upper airways. Based on ancillary pre-studies in na茂ve rats, the related human-equivalent respiratory tract irritant threshold concentration was estimated to be 0.09 ppm. The respective 8-h time-adjusted asthma-related human-equivalent threshold C 脳 t-product (dose), in 鈥榓sthmatic鈥?rats, was estimated to be 0.003 ppm. Both thresholds are in agreement of the current ACGIH TLV^庐 of TDI and published human evidence. In summary, the findings from this animal model suggest that TDI-induced respiratory allergy is likely to be contingent on two interlinked, sequentially occurring mechanisms: first, dermal sensitizing encounters high enough to cause systemic sensitization. Second, when followed by inhalation exposure(s) high enough to initiate and amplify an allergic airway inflammation, then a progression into asthma may occur. This bioassay requires an in-depth knowledge on respiratory tract dosimetry and irritation of the involved test substance to clearly understand the dosimetry causing C- and/or C 脳 t-dependent respiratory tract irritation and eventually asthma.