title: Respiratory hypersensitivity to trimellitic anhydride in Brown Norway rats: analysis of dose-response following topical induction and time course following repeated inhalation challenge.
abstract: Trimellitic anhydride (TMA) is a low-molecular-weight chemical known to cause occupational asthma. The dose-response study was designed to determine whether respiratory responses during a single inhalation challenge with TMA (25-30 mg/m3 for 30 min, 3 weeks after the initial induction), the ensuing non-specific airway hyperresponsiveness (AH) to methacholine (MCh) aerosol, and infiltration of eosinophilic granulocytes into the lungs of sensitized Brown Norway (BN) rats are associated and dependent on the concentration of TMA used for topical induction. The initial topical exposure concentrations were 1, 5, and 25% TMA in acetone:olive oil (AOO) followed by a booster induction 1 week later. In the time course study BN rats received AOO alone or were sensitized to the minimal sensitizing topical concentration of TMA (5%) and were the subsequently challenged with TMA on Days 17, 24, 41, 47, 55, and 66, followed by a MCh challenge 1 day later. One additional group of rats was sensitized to 5% TMA but were repeatedly challenged with MCh without prior TMA challenge. In the dose-response study the rats sensitized topically to TMA (5 and 25% in AOO) displayed unequivocal changes in breathing patterns upon challenge with TMA, including an increased responsiveness to MCh aerosol. These findings were associated with a sustained pulmonary eosinophilic inflammation. All endpoints demonstrated consistently that 5% TMA in AOO constitutes the minimal sensitizing concentration. When rats were topically sensitized with this concentration and repeatedly challenged with TMA over a time period of 7 weeks, it became apparent that challenge exposures in BN rats may be false negative when performed at time periods less than 3 weeks after the initial induction. Despite the time-related increased responsiveness elicited by the repeated TMA challenge exposures, the MCh challenge revealed increased non-specific airway hyperreactivity exclusively on Day 17. After the sixth TMA-challenge, the respiratory response and lung weights of rats sensitized topically were essentially similar to those observed in the repetitively re-challenged control group (induction: vehicle only; repeated booster challenge exposures with TMA). Thus, it appears, that in this animal model the effective concentration for successful topical sensitization must be at least approximately 5%. The repeated low-dose re-challenge with TMA in topically sensitized rats resulted in similar or slightly aggravated time-related responses over a period of 7 weeks. An over-proportionally increased susceptibility of rats receiving a topical priming dose prior to repeated inhalation challenge exposures was not observed. In summary, this study shows that the analysis of functional changes in breathing patterns is suitable to identify respiratory allergy. Repeated short-term inhalation exposures to mildly irritant concentrations (but low doses) of chemical asthmagens may be of higher concern than topical exposures.
authors.affiliation: Institute of Toxicology, BAYER HealthCare, Building No 514, 42096 Wuppertal, Germany. juergen.pauluhn.jp@bayer-ag.de
authors.forename: Jürgen
authors.initials: J
authors.lastname: Pauluhn
mesh_terms: D000287:Administration, Topical; D000336:Aerosols; D000485:Allergens / Q000276:immunology / Q000633:toxicity*; D000818:Animals; D016085:Bronchoconstrictor Agents / Q000276:immunology / Q000633:toxicity; D004306:Dose-Response Relationship, Immunologic; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008297:Male; D016210:Methacholine Chloride / Q000276:immunology / Q000633:toxicity; D009929:Organ Size / Q000187:drug effects; D010796:Phthalic Anhydrides / Q000276:immunology / Q000633:toxicity*; D051381:Rats; D011914:Rats, Inbred BN; D012130:Respiratory Hypersensitivity / Q000139:chemically induced* / Q000276:immunology / Q000473:pathology; D015656:Respiratory Mechanics / Q000187:drug effects / Q000276:immunology; D013997:Time Factors
chemical_list: D000336:Aerosols; D000485:Allergens; D016085:Bronchoconstrictor Agents; D010796:Phthalic Anhydrides; D016210:Methacholine Chloride; C015559:trimellitic anhydride