Role of nitrous acid in the association between nitrogen dioxide and asthma symptoms: effect of nitrous acid exposure on specific airway resistance in guinea pigs

Epidemiological evidence regarding the effects of nitrogen dioxide (NO2) on asthma and chronic obstructive pulmonary disease (COPD) is inconclusive because NO2 assays measure nitrous acid (HONO) as NO2. Epidemiological study using separate measurements of indoor HONO and NO2 suggests that indoor HONO levels are associated with decrease in lung function, and HONO exposure experiment in rats suggests that HONO adversely affects respiratory function more than NO2. Effects of NO2 on respiratory tract resistance have not been observed in rats but have been observed in guinea pigs, including baseline specific airway resistance (sRaw). The present study aimed to investigate the effects of HONO exposure on baseline sRaw in guinea pigs. Eighteen male Hartley guinea pigs were divided into Groups C, M, and H (n = 6 per group) and exposed to HONO at three concentrations, respectively, 24 h/d for 7 weeks. Double-flow plethysmography was used to measure the sRaw once a week and grade respiratory waveforms, indicating increased airway resistance. The experiment was performed twice. Mean HONO concentrations of two experiments in Groups C, M, and H were 0.02, 0.66, and 3.43 parts per million (ppm). The sRaw increased significantly in Groups H and M compared with sRaw in Group C, and in a concentration-dependent manner after the 4th week of HONO exposure. Increased airway resistance was observed in 50% of animals in Group M and 100% of animals in Group H in some weeks. However, in some animals from Group M, increased airway resistance was observed earlier than the airway resistance increases observed in all animals in Group H. These sRaw results suggest that HONO affects asthma symptoms or COPD, at a lowest observed adverse effect level (LOAEL) of < 0.66 ppm. HONO may affect baseline sRaw after shorter exposure periods and at lower concentrations compared with the reported effects of NO2. The present results suggest that HONO is the most important nitrogen oxide affecting asthma and COPD indoors, and that HONO may be the causative agent in the association between NO2 and asthma symptoms in epidemiological studies.