OZONE DOSE AND EFFECT IN HUMANS AND RATS - A COMPARISON USING O-18 LABELING AND BRONCHOALVEOLAR LAVAGE

In an effort to improve risk assessments for ozone (O-3) we compared the incorporation of inhaled oxygen-18-labeled O-3 (O-18(3)) into the lungs of humans and laboratory rats. Cells and fluids obtainable through bronchoalveolar lavage (BAL) were examined after exposure to O-18(3) to determine whether excess O-18 concentrations (presumed to be reaction products of O-18(3)) could be detected and equated to the O-3 dose to the lung. Three O-3 effect measurements (increased BAL protein and neutrophils and decreased BAL macrophages) were also made in subjects or animals exposed in parallel to determine whether there was a correspondence between dose and effect measurements. Eight human male volunteers 18 to 35 yr of age were exposed to O-18(3) (0.4 ppm for 2 h) with 15-min alternating periods of heavy treadmill exercise and rest. Rats (F344) were exposed identically, except without exercise. O-18(3) was generated directly from pure O-18(2). BAL cells and centrifugally separable surfactant material were freeze-dried and analyzed by mass spectrometer for excess O-18. Results showed that the exercising humans had four- to fivefold higher O-18 concentrations in all of their BAL constituents than did the rats. The humans also had significant increases in all of the effects markers after 0.4 ppm O-3, whereas the rats did not. Rats that were exposed to higher concentrations of O-18(3) (2.0 ppm) had levels of O-18 in BAL that were more comparable to but still lower than those of exercising humans. Changes in all of the effects markers in these rats were comparable or higher than in exercising humans. Therefore, it appears that O-3 toxicity in resting rats underestimates effects in exercising humans because rats have a lower than expected dose of O-3 to the distal lung. The dose and effect linkage between rats and humans should improve extrapolation of animal toxicity data to humans.