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Particular emphasis was placed on the study of route\u2010of\u2010induction\u2010dependent effects and their progression upon inhalation challenge with TMA (\u223c23 mg m<jats:sup>\u22123<\/jats:sup> for a duration of 30 min), which included analysis of specific and non\u2010specific airway hyperreactivity and pulmonary inflammation initiated and sustained by immunological processes. Refinement of the bioassay focused on procedures to probe changes occurring upon challenge with TMA or methacholine aerosols using physiological, biochemical and immunological procedures. Following challenge with TMA, the rats sensitized to TMA showed marked changes in peak inspiratory and expiratory air flows and respiratory minute volume. In these animals, a sustained pulmonary inflammation occurred, characterized by specific endpoints determined in bronchoalveolar lavage (lactate dehydrogenase, protein, nitrite, eosinophil peroxidase, myeloperoxidase). When compared with the naive controls, lung weights were increased significantly, as were the weights of lung\u2010associated lymph nodes following inhalation induction and auricular lymph nodes following topical induction. The extent of changes observed was equal or more pronounced in animals sensitized epicutaneously (day 0 : 150 \u00b5l vehicle\/50% TMA on each flank, day 7; booster administration to the skin of the dorsum of both ears using half the concentration and volume used on day 0) when compared with rats sensitized by 5 \u00d7 3 h day<jats:sup>\u22121<\/jats:sup> inhalation exposures (low dose: 25 mg TMA m<jats:sup>\u22123<\/jats:sup>, high dose: 120 mg TMA m<jats:sup>\u22123<\/jats:sup>). In summary, the findings support the conclusion that the Brown Norway rat model is suitable for identifying TMA as an agent that causes both an immediate\u2010type change of breathing patterns and a delayed\u2010type sustained pulmonary inflammatory response. However, it remains unresolved whether the marked effects observed in the topically sensitized rats are more related to a route\u2010of\u2010induction or dose\u2010dependent phenomenon. Copyright \u00a9 2002 John Wiley &amp; Sons, Ltd.<\/jats:p>","DOI":"10.1002\/jat.831","type":"journal-article","created":{"date-parts":[[2002,8,25]],"date-time":"2002-08-25T19:42:44Z","timestamp":1030304564000},"page":"89-97","source":"Crossref","is-referenced-by-count":28,"title":["Respiratory hypersensitivity to trimellitic anhydride in Brown Norway Rats: a comparison of endpoints"],"prefix":"10.1002","volume":"22","author":[{"given":"J\u00fcrgen","family":"Pauluhn","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Petra","family":"Eidmann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexius","family":"Freyberger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Grazyna","family":"Wasinska\u2010Kempka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hans\u2010Werner","family":"Vohr","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2002,3,13]]},"reference":[{"key":"e_1_2_1_2_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF00381052"},{"key":"e_1_2_1_3_2","doi-asserted-by":"publisher","DOI":"10.1159\/000234247"},{"key":"e_1_2_1_4_2","first-page":"1259","article-title":"Antihapten antibodies in workers exposed to trimellitic anhydride fumes: a potential immunopathogenic mechanism for the trimellitic anhydride pulmonary disease\u2013anemia syndrome","volume":"120","author":"Patterson R","year":"1979","journal-title":"Am. 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