TOXICITY OF COMPOUND-A IN RATS - EFFECT OF INCREASING DURATION OF ADMINISTRATION

Background: An olefin called compound A (CF2 = C(CF3)OCH2F) results fr om the action of soda lime or Baralyme on sevoflurane. We have demonst rated that rats exposed to the olefin for 3 h died at or were injured by olefin concentrations lower than those previously reported to produ ce these effects. The present report examines the impact of duration o f exposure to the olefin on such effects. Methods. Twenty-three groups of ten Wistar rats breathed 0, 12.5, 25, 50, 75, 100, 125, 150, 175, 200, 225, and 250 ppm of the olefin in oxygen for 6 or 12 h. Rats that survived were killed on day 1 or day 4 after breathing the olefin, an d specimens of brain, kidney, lung, liver, and small intestine were ob tained from all rats for examination by microscopy using hematoxylin a nd eosin stain and a stain (proliferating cell nuclear antigen) for ce ll growth (regeneration). Results: The lethal concentrations in 50% of rats equaled 203 +/- 4 ppm (mean +/- SE) for a 6-h exposure period an d 127 +/- 9 ppm for a 12-h exposure period, and both values were less than the previously determined value of 331 +/- 7 ppm for a 3-h exposu re period. Compared with results from control rats (those breathing ox ygen for 6 h or 12 h), only renal and pulmonary injury were found. Pul monary injury only occurred at near-lethal concentrations. Renal injur y (defined as necrosis of the outer stripe of the outer medullary laye r or corticomedullary junction necrosis) occurred at and above 25-50 p pm for 6-h and 12-h exposures, respectively, a result similar to that previously obtained with a 3-h exposure. Exposure to 2 5-50 ppm stimul ated cell regeneration in a dose-related manner. Conclusions: In rats, lethal concentrations of the olefin and concentrations producing seve re renal injury are inversely related to the duration of exposure to t he olefin, exceeding by two- to fourfold peak concentrations that can be obtained in clinical practice. The threshold concentrations for nep hrotoxicity (i.e., minimal toxicity) equal concentrations that can be produced in clinical practice. However, even if these threshold effect s in rats apply to humans, they probably would not alter renal functio n. Although dose-related, neither the lethal nor the toxic effects are simply a function of cumulative dose (concentration-time).