Assessment of chemicals for their potential to induce respiratory allergy in guinea pigs: A comparison of different routes of induction and confounding effects due to pulmonary hyperreactivity.
Guinea pigs were sensitized either to selected low molecular weight chemicals known to induce respiratory allergy in humans, trimellitic anhydride (TMA), toluene diisocyanate (TDI), or diphenylmethane-4,4'-diisocyanate (MDI), or to ovalbumin (OA) as a positive control. In most instances, sensitization was induced either by repeated intradermal injections or by a single brief (15-min) high-concentration inhalation exposure. For TMA the repeated high dose intradermal injection regimen was compared with a single low dose intradermal injection regimen. Additionally, the effectiveness of the single 15-min induction protocol was compared with that of five consecutive inhalation exposures each of 3 hr/day. Animals were challenged 2-3 wk later by exposure to the substance used for induction, either as the free chemical or as a hapten-protein conjugate, and with increasing concentrations of acetylcholine (ACh). Challenge with the parental or conjugated hapten was used to assess compound-specific immediate-onset respiratory hyperreactivity, while ACh challenges were used to identify non-specific airway hyperreactivity. After intradermal sensitization with either MDI or TMA guinea pigs challenged with the corresponding hapten-protein conjugate showed a moderate incidence of immediate-type respiratory responses. However, the highest incidence of unequivocal allergic responses was evident from challenge with the hapten rather than with the protein conjugate, although these responses were only elicited with slightly irritant concentrations. After challenge with irritant concentrations of TDI, animals sensitized intradermally did not experience characteristic changes in respiratory patterns. On challenge with Ach and the TDI-protein conjugate these same animals showed an increased airway hyperresponsiveness although characteristic stereotypic breathing patterns, as observed in sensitized animals challenged with TMA, TMA-protein conjugate, or OA, were not detected. Comparison of the intradermal and inhalation induction regimens indicated that prior encounters with irritant haptens by inhalation reduces the concentration required to elicit airway hyperresponsiveness. This finding supports the conclusion that in animals sensitized and challenged by inhalation, irritant respiratory responses may be misconstrued as immediate-onset allergic responses. It appeared that the low dose single intradermal injection protocol is more effective in sensitizing guinea pigs than the high dose repeated injection protocol.
Pauluhn
J
J
Institute of Toxicology, Bayer AG, Building No. 514, 42096 Wuppertal, Germany.