Exposure to variable hyperoxia has recently been shown to be much more effective at producing proliferative retinopathy in the newborn rat than exposure to constant hyperoxia. To incorporate a more clinically relevant oxygen-exposure paradigm in our studies, we have now used a cycle between 50 and 10% oxygen and have compared its effects with those found using new exposures to the previously used 80140% cycle. Starting at birth and continuing for 14 d, rats were exposed to environments that cycled between 50 and 10% oxygen or 80 and 40% oxygen every 24 h. After exposure, some rats were killed for assessment of retinal vascular development. Others were removed to room air for 4 d before killing and evaluation for the presence of abnormal neovascularization-a clinical consequence believed to be promoted by termination of oxygen therapy. The 50110% cycle resulted in greater retardation of retinal blood vessel development during oxygen than that found in the 80140% exposure group. After 4 d postexposure in room air, the incidence of preretinal neovascularization was 97% in the 50110% rats and 72% in the 80140% group. Clearly, the overall amount of oxygen the subject receives is less critical than other parameters of its administration in producing proliferative retinopathy. Also, the range of variation (40% in both cases) is not the controlling characteristic. Our results suggest that consistency of oxygen level and avoidance of hypoxic levels should be important concerns in neonatal oxygen therapy. ROP is a complex disease involving multiple factors. Oxygen was first recognized as a critical factor in the early 1950s (1-3), but the potential for prolonged hyperoxia alone to cause or exacerbate ROP is still not clearly defined. The disease persists despite the attention now placed on careful monitoring and limited oxygen delivery. Additional doubt about the role of hyperoxia in the pathogenesis of ROP has been raised with the finding that cyanotic premature infants can develop ROP in the absence of oxygen therapy (4). The theory (5) that the developing retina is highly sensitive to any disruption of its oxygen supply, whether hyperoxemic or hypoxemic, warrants consideration. Recent studies in animals (6, 7) have addressed this issue.Exposure to variable hyperoxia has been shown to be a much more effective stimulus of proliferative retinopathy in the newborn rat than exposure to constant hyperoxia (6). This previous study compared the effect of a cyclic variation of oxygen between 80 and 40% with that of a constant 80% exposure. An exposure paradigm that incorporates fluctuations in oxygen level is clearly more representative of the neonatal setting than the constant exposures typical of animal studies. Still, variations in inspired oxygen (FiO,) between 80 and 40% do not accu- rately reflect the therapeutic levels received by prema-

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