title: Development of a respiratory sensitization/elicitation protocol of toluene diisocyanate (TDI) in Brown Norway rats to derive an elicitation-based occupational exposure level.
abstract: Toluene diisocyanate (TDI), a known human asthmagen, was investigated in skin-sensitized Brown Norway rats for its concentration×time (C×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×t; one used a variable C (Cvar) and constant t (tconst), the other a constant C (Cconst) and variable t (tvar). The selection of the "minimal 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 Cconst×tvar 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 naïve rats, the related human-equivalent respiratory tract irritant threshold concentration was estimated to be 0.09ppm. The respective 8-h time-adjusted asthma-related human-equivalent threshold C×t-product (dose), in 'asthmatic' rats, was estimated to be 0.003ppm. Both thresholds are in agreement of the current ACGIH TLV(®) 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×t-dependent respiratory tract irritation and eventually asthma.
authors.affiliation: Bayer Pharma AG, Wuppertal, Germany. Electronic address: juergen.pauluhn@bayer.com.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Pauluhn
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D006241:Haptens / Q000008:administration & dosage* / Q000633:toxicity; D006801:Humans; D007509:Irritants / Q000008:administration & dosage* / Q000633:toxicity; D008297:Male; D016273:Occupational Exposure / Q000592:standards; D051381:Rats; D011914:Rats, Inbred BN; D012130:Respiratory Hypersensitivity / Q000139:chemically induced*; D014051:Toluene 2,4-Diisocyanate / Q000008:administration & dosage* / Q000633:toxicity
chemical_list: D006241:Haptens; D007509:Irritants; D014051:Toluene 2,4-Diisocyanate
keywords: Asthma rat bioassay; Diisocyanate asthma; Dose–response; Neutrophilic inflammation; Risk assessment