title: Quantitative differences in the production and toxicity of CF2=BrCl versus CH2F-O-C(=CF2)(CF3) (compound A): the safety of halothane does not indicate the safety of sevoflurane.
abstract: Carbon dioxide absorbents degrade both halothane and sevoflurane to toxic unsaturated compounds (CF2=CBrCl and CH2F-O-C[=CF2][CF3] [i.e., Compound A], respectively). Given the long history of safe administration of halothane, comparable toxicities of these degradation products would imply a similar safety of sevoflurane. We therefore examined CF2=CBrCl in the context of four issues relevant to previous studies of the toxicity of Compound A: 1) reactivity of the degradation product in vitro; 2) rate of its production in vitro; 3) its in vivo toxicity; 4) importance of the beta-lyase pathway to the toxicity in vivo. We found the following. 1) CF2=CBrCl is less reactive than Compound A, degrading in human serum albumin at one-fifth the rate of Compound A. 2) Over a 3-h period of "anesthesia," a standard circle system containing Baralyme (Allied Healthcare Products, Inc., St. Louis, MO) produces 30 times as much Compound A from a minimum alveolar anesthetic concentration (MAC) concentration of sevoflurane as CF2=CBrCl from a MAC concentration of halothane; with soda lime, the difference is 60-fold. Correcting for differences in uptake of halothane versus sevoflurane decreases the differences to 20-40 times. 3) For a 3-h administration to rats, the partial pressure of Compound A causing minimal renal injury or necrosis of half the affected tubule cells exceeds the partial pressure of CF2=CBrCl causing minimal injury or necrosis of half the affected tubule cells by a factor of approximately 4-6. Thus, the ratio of production (Item 2 above) to the partial pressure causing injury with CF2=CBrCl is approximately a quarter of that ratio for Compound A. 4) Compounds that block the beta-lyase pathway either do not change (acivicin) or decrease (aminooxyacetic acid; AOAA) renal injury from CF2=CBrCl in rats, whereas these compounds increase (acivicin) or do not change (AOAA) injury from Compound A. We conclude that the safety of halothane cannot be used to support the safety of sevoflurane.
  
  
  CONCLUSIONS
  Carbon dioxide absorbents degrade halothane and sevoflurane to unsaturated compounds nephrotoxic to rats. Relative to sevoflurane's degradation product, halothane's degradation product has less toxicity relative to production, less reactivity, and a different mechanism of injury. The clinical absence of halothane nephrotoxicity does not necessarily indicate a similar absence for sevoflurane.
authors.affiliation: Department of Anesthesia, University of California, San Francisco 94143-0464, USA.
authors.forename: E I
authors.initials: EI
authors.lastname: Eger
authors.forename: P
authors.initials: P
authors.lastname: Ionescu
authors.forename: M J
authors.initials: MJ
authors.lastname: Laster
authors.forename: D
authors.initials: D
authors.lastname: Gong
authors.forename: R B
authors.initials: RB
authors.lastname: Weiskopf
authors.forename: R L
authors.initials: RL
authors.lastname: Kerschmann
mesh_terms: D000042:Absorption; D000625:Aminooxyacetic Acid / Q000494:pharmacology; D018685:Anesthetics, Inhalation / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D000818:Animals; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004987:Ethers / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D006221:Halothane / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D006846:Hydrocarbons, Halogenated / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D007555:Isoxazoles / Q000494:pharmacology; D007674:Kidney Diseases / Q000139:chemically induced; D008190:Lyases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008738:Methyl Ethers; D051381:Rats; D011916:Rats, Inbred F344; D017208:Rats, Wistar; D000077149:Sevoflurane
chemical_list: D018685:Anesthetics, Inhalation; D004791:Enzyme Inhibitors; D004987:Ethers; D006845:Hydrocarbons, Fluorinated; D006846:Hydrocarbons, Halogenated; D007555:Isoxazoles; D008738:Methyl Ethers; D000625:Aminooxyacetic Acid; D000077149:Sevoflurane; C078742:fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether; D008190:Lyases; C006303:acivicin; D006221:Halothane