Alveolar and Airway Cell Kinetics in the Lungs of Rats Exposed to Nitrogen Dioxide, Ozone, and a Combination of the Two Gases

Rats carrying minipumps filled with 5-bromo-2′deoxyuridine were exposed to ozone, NO₂, or a mixture of the two gases using four different protocols: (A) ozone 0.2 ppm, NO₂ 3.6 ppm, or their mixture for 24 hr a day; (B) ozone 0.4 ppm, NO₂ 7.2 ppm, or their mixture for 12 hr per night; (C) ozone 0.6 ppm, NO₂ 10.8 ppm, or their mixture for 8 hr per night; and (D) ozone 0.8 ppm, NO₂ 14.4 ppm, or their mixture for 6 hr per night. After three consecutive daily exposures, the animals were returned to filtered air and killed 7 days after implantation of the mini-pump. Alveolar labeling indices were comparable to control values except in the group of animals exposed for 6 hr nightly to a combination of 0.8 ppm of ozone and 14.4 ppm of NO₂. Labeling indices in the peripheral airways were the most sensitive exposure index since they were significantly increased over control values in all animals exposed to ozone, NO₂, or a mixture of the two gases, regardless of concentration or exposure duration. Labeling indices increased with elevated dose rate, i.e., concentration of the gases in the inspired air. The response to the combined gases was greater than the calculated sum of the responses to the two individual gases for the three higher dose rates in the large airways and for the highest dose rate in the peripheral airways. The results led to the following conclusions: (1) By the criterion of analysis of cell kinetics in rat large and peripheral airways, neither ozone, NO₂, nor their mixture follows Haber′s law (c × t = k) over the concentration ranges studied; and (2) at the higher dose rates studied, there is a more than additive (synergistic) airway response to the combination of ozone and NO₂.