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Respiratory Allergy to Trimellitic Anhydride in Rats: Concentration-Response Relationships during Elicitation

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Author: Arts, J.H.E. · Koning, M.W. de · Bloksma, N. · Kuper, C.F.
Institution: TNO Voeding
Source:Inhalation Toxicology, 5, 16, 259-269
Identifier: 237735
doi: doi:10.1080/08958370490427932
Keywords: Biology · Toxicology and Applied Pharmacology · drug vehicle · immunoglobulin E · methacholine · trimellitic anhydride · airway dynamics · animal experiment · animal model · animal tissue · article · breathing pattern · breathing rate · concentration response · controlled study · female · histopathology · immunoglobulin blood level · inhalation · larynx · larynx injury · lung · lung weight · nonhuman · priority journal · rat · respiratory tract allergy · skin sensitization · squamous cell metaplasia · tidal volume · trachea · Administration, Inhalation · Allergens · Animals · Body Weight · Bronchial Provocation Tests · Dose-Response Relationship, Drug · Female · Immunoglobulin E · Lung · Methacholine Chloride · No-Observed-Adverse-Effect Level · Organ Size · Phthalic Anhydrides · Rats · Rats, Inbred BN · Rats, Wistar · Respiratory Function Tests · Respiratory Hypersensitivity · Animalia · Rattus norvegicus


The present study investigated whether airway responses of sensitized rats to trimellitic anhydride (TMA) were concentration dependent and whether these were related to irritation by TMA. Groups of BN and Wistar rats were sensitized by two dermal applications of TMA (50% w/v, followed by 25% w/v in vehicle). Controls received vehicle (acetone-olive oil 4:1, v/v). All animals were challenged 3 wk after the first sensitization by inhalation of one of a range of concentrations of TMA (0.2-61 mg/m3 for BN rats, 15-250 mg/m 3 for Wistar rats). Breathing pattern, breathing frequency, and tidal volume were measured before, during, and after challenge to assess allergic and irritative airway responses. One day after challenge, non-specific airway responsiveness to a range of concentrations of methacholine was measured. At necropsy on the same day, blood was withdrawn for measuring total serum immunoglobulin E (IgE) and organs were weighed. Larynx, trachea and lungs were examined histopathologically. In BN rats, TMA sensitization elevated total IgE levels; subsequent inhalation challenge with 2 mg/m3 of TMA and higher caused laryngeal inflammation with squamous epithelial metaplasia, and pulmonary hemorrhages. Concentration-related decreases in breathing frequency and alterations in breathing pattern, which differed from the irritation-induced pattern, were also observed at these levels. Inhalation challenge with TMA concentrations of 12 mg/m3 and higher increased lung weight. Increased nonspecific airway responsiveness was observed at the 2 next higher tested concentrations of 46 and 61 mg/m3. In unsensitized BN rats, only laryngeal squamous metaplasia was observed, albeit at higher challenge concentrations of TMA, and decreased breathing frequency, a typical breathing pattern characteristic of irritation. Identically sensitized Wistar rats showed airway inflammation and pulmonary hemorrhages upon challenge with TMA, but no functional changes, even at distinctly irritating concentrations of TMA up to 250 mg/m3. In conclusion, TMA challenge of sensitized BN rats caused challenge concentration-related allergic airway inflammation, asthmalike changes in breathing pattern, and increased nonspecific airway responsiveness. The lowest no-observed-effect level (NOEL) based on the most sensitive endpoint investigated was 0.2 mg/m3, a value that is well below the irritation concentration. The presence of a NOEL in the sensitized BN rat suggests that assessment of safe human exposure levels is feasible.