Repeated Exposure to Isoprene Oxidation Products Causes Enhanced Respiratory Tract Effects in Multiple Murine Strains

Abstract

Ozone reacts with terpenes, common hydrocarbons in cleaning and consumer products as well as the ambient environment, to form particle- and gas-phase products; these have been shown to cause sensory irritation and airflow limitation in mice during single exposures. Isoprene, a hemiterpene emitted from both plants and animals as a bioeffluent, induces the largest effects. This study evaluated the effects of repeated exposures to isoprene oxidation products (OPs) on airway irritation, airflow limitation, and airway responsiveness. A secondary objective was to evaluate a genetic influence by examining multiple murine strains. Six strains (A/J, AKR/J, BALB/c, Swiss Webster, C57Bl/6, and C3H/HeN; total n = 35) were exposed to isoprene oxidation products (1080 ± 155 ppb isoprene + 3227 ± 157 ppb ozone at admixing) for 3 h/day for 4 consecutive days. Respiratory parameters were monitored on days 1 and 4 via head-out plethysmography, and airway responsiveness to aerosolized methacholine was evaluated 24 h before the first exposure and immediately after the fourth exposure. Sensory irritation was observed during exposure, as evidenced by a reduction in respiratory frequency (f). A reduction in peak expiratory flow normalized for tidal volume (PEF/VT) also occurred, indicating an airflow limitation effect. Marked enhancement of the effects on f and PEF/VT was observed with repeated exposures, suggesting a cumulative effect. Frequency was reduced from 46.0 ± 2.3% of baseline during exposure 1 to 34.2 ± 2.1% during exposure 4 (p = .00002; pooled values for all strains). Similarly, PEF/VT decreased from 75.6 ± 3.9% of baseline during exposure 1 to 53.1 ± 3.7% during exposure 4 (p < .00001). A significant reduction in airway responsiveness was observed following repeated exposures in most strains. Interstrain differences in responses were noted, indicating a genetic component. These findings have important implications for indoor environments, where isoprene concentrations can be high in buildings with high occupant densities. The findings are also relevant to outdoor environments, where isoprene emissions from vegetation lead to the formation of isoprene OPs, which may partition onto existing particulate matter (PM) in the atmosphere to contribute to secondary organic aerosol. Further, the genetic variability observed in the mouse strains examined suggests that interindividual differences in response may also exist in human populations, which may help to explain the high variability in symptom reporting in indoor environments.