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

Abstract

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/m3 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, nonspecific 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 At necropsy on the same day, blood was withdrawn for measuring total serum immunoglobulin E (IgE) and organs were weighed.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.

Intranasal challenge with increasing ovalbumin doses differently affects airway hyperresponsiveness and inflammatory cell accumulation in mouse model of asthma

“…Moreover, the accumulation of inflammatory cells appears to be a more sensitive indicator of the allergen dose used for challenge than AHR: intranasal challenge with 10 lg of ovalbumin induced significant accumulation of inflammatory cells, whereas AHR to methacholine in this group was not detected. Similar to our results, inflammatory cell accumulation was also shown to be more sensitive than AHR to antigen dose used for challenge in two other animal models, allergic responses to an extract of Penicillium chrysogenum in BALB/c mice [24], and to trimellitic anhydride in Brown Norway rats [25]. The described model, therefore, closely resembles clinical observations and represents an elegant experimental system that could provide insights in the mechanisms by which inflammation transiently enhances AHR after allergen challenge.…”

Molecular Characterization of Trimellitic Anhydride–induced Respiratory Allergy in Brown Norway Rats

“…In confirmation with previous studies, TMA-induced apneas and allergic laryngitis, increased inflammatory cell numbers in BAL, altered breathing frequency, and elevated IgE levels in serum and lung (Arts et al 1998;Arts et al 2004;Valstar et al 2006).…”

“…The acetone concentration was kept between 3,000 and 5,000 ppm (~7-12 g/m 3 ), which levels are far below the level inducing sensory irritation (Alarie 1973;De Ceaurriz et al 1981;Schaper and Brost 1991) and which indeed did not induce changes in breathing pattern in either sensitized or unsensitized rats (Arts et al 1998). The challenge concentration of TMA was based on a previous study performed in BN rats (Arts et al 2004). Atmospheric concentrations of TMA were determined gravimetrically by filter sampling, and those of acetone, by calculations based on the nominal concentration, assuming the usual 100% generation efficiency for this vapor.…”

Validation of a mouse model of chemical-induced asthma using trimellitic anhydride, a respiratory sensitizer, and dinitrochlorobenzene, a dermal sensitizer

“…13 Recently it has also been shown that Brown Norway rats dermally sensitized to TMA had asthma-like early and late changes in breathing pattern after airway exposure to TMA. 12,14,15 DNCB is a typical dermal sensitizer that elicits contact hypersensitivity mediated by T H 1 cytokines, such as IFN-g and IL-12, 16 and it does not appear to cause occupational asthma or allergic rhinitis. 17 The primary objective of this study was to examine the capability of our previously described mouse model of chemical-induced asthma 18,19 to discriminate between a respiratory sensitizer (TMA) and a dermal sensitizer (DNCB).…”

“…10 TMA is a respiratory sensitizer in human subjects, 11 but it is also capable of inducing airway irritation in animals. 12 It has been shown that high doses of TMA, when applied to the skin, preferentially induce a T H 2 response, with increased levels of IL-4, IL-10, and IL-13 and relatively low amounts of the T H 1 cytokine IFN-g in draining lymph nodes. 13 Recently it has also been shown that Brown Norway rats dermally sensitized to TMA had asthma-like early and late changes in breathing pattern after airway exposure to TMA.…”