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 ch emicals known to induce respiratory allergy in humans, trimellitic anh ydride (TMA), toluene diisocyanate (TDI), or diphenylmethane-4,4'-diis ocyanate (MDI), or to ovalbumin (OA) as a positive control. In most in stances, sensitization was induced either by repeated intradermal inje ctions or by a single brief (IS-min) high-concentration inhalation exp osure. For TMA the repeated high dose intradermal injection regimen wa s compared with a single low dose intradermal injection regimen. Addit ionally, 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 subst ance used for induction, either as the free chemical or as a hapten-pr otein conjugate, and with increasing concentrations of acetylcholine ( ACh). Challenge with the parental or conjugated hapten was used to ass ess compound-specific immediate onset respiratory hyperreactivity, whi le ACh challenges were used to identify non-specific airway hyperreact ivity. After intradermal sensitization with either MDI or TMA guinea p igs 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 f rom challenge with the hapten rather than with the protein conjugate, although these responses were only elicited with slightly irritant con centrations. After challenge with irritant concentrations of TDI, anim als sensitized intradermally did not experience characteristic changes in respiratory patterns. On challenge with Ach and the TDI-protein co njugate these same animals showed an increased airway hyperresponsiven ess although characteristic stereotypic breathing patterns, as observe d in sensitized animals challenged with TMA, TMA-protein conjugate, or OA, were not detected. Comparison of the intradermal and inhalation i nduction regimens indicated that prior encounters with irritant hapten s by inhalation reduces the concentration required to elicit airway hy perresponsiveness. This finding supports the conclusion that in animal s sensitized and challenged by inhalation, irritant respiratory respon ses may be misconstrued as immediate-onset allergic responses. It appe ared that the low dose single intradermal injection protocol is more e ffective in sensitizing guinea pigs than the high dose repeated inject ion protocol.