Toxicity of compound A in rats. Effect of increasing duration of administration.
BACKGROUND
An olefin called compound A (CF2 = C(CF3)OCH2F) results from the action of soda lime or Baralyme on sevoflurane. We have demonstrated that rats exposed to the olefin for 3 h died at or were injured by olefin concentrations lower than those previously reported to produce these effects. The present report examines the impact of duration of 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, and specimens of brain, kidney, lung, liver, and small intestine were obtained from all rats for examination by microscopy using hematoxylin and eosin stain and a stain (proliferating cell nuclear antigen) for cell growth (regeneration).


RESULTS
The lethal concentrations in 50% of rats equaled 203 +/- 4 ppm (mean +/- SE) for a 6-h exposure period and 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 exposure period. Compared with results from control rats (those breathing oxygen for 6 h or 12 h), only renal and pulmonary injury were found. Pulmonary injury only occurred at near-lethal concentrations. Renal injury (defined as necrosis of the outer stripe of the outer medullary layer or corticomedullary junction necrosis) occurred at and above 25-50 ppm for 6-h and 12-h exposures, respectively, a result similar to that previously obtained with a 3-h exposure. Exposure to 25-50 ppm stimulated cell regeneration in a dose-related manner.


CONCLUSIONS
In rats, lethal concentrations of the olefin and concentrations producing severe renal injury are inversely related to the duration of exposure to the olefin, exceeding by two- to fourfold peak concentrations that can be obtained in clinical practice. The threshold concentrations for nephrotoxicity (i.e., minimal toxicity) equal concentrations that can be produced in clinical practice. However, even if these threshold effects in rats apply to humans, they probably would not alter renal function. Although dose-related, neither the lethal nor the toxic effects are simply a function of cumulative dose (concentration-time).
Gonsowski
C T
CT
Department of Anesthesia, University of California, San Francisco 94143-0464.
Laster
M J
MJ
Eger
E I
EI
Ferrell
L D
LD
Kerschmann
R L
RL
D000777:Anesthetics / Q000378:metabolism* / Q000633:toxicity*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004987:Ethers / Q000378:metabolism* / Q000633:toxicity*; D006845:Hydrocarbons, Fluorinated / Q000633:toxicity*; D007150:Immunohistochemistry; D007674:Kidney Diseases / Q000139:chemically induced; D007928:Lethal Dose 50; D008171:Lung Diseases / Q000139:chemically induced; D008297:Male; D008738:Methyl Ethers; D009687:Nuclear Proteins / Q000032:analysis; D018809:Proliferating Cell Nuclear Antigen; D011654:Pulmonary Edema / Q000139:chemically induced; D051381:Rats; D017208:Rats, Wistar; D012038:Regeneration / Q000187:drug effects; D000077149:Sevoflurane; D013997:Time Factors
D000777:Anesthetics; D004987:Ethers; D006845:Hydrocarbons, Fluorinated; D008738:Methyl Ethers; D009687:Nuclear Proteins; D018809:Proliferating Cell Nuclear Antigen; D000077149:Sevoflurane; C078742:fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether