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

Carbon dioxide absorbents degrade both halothane and sevoflurane to to xic unsaturated compounds (CF2=CBrCl and CH2FO-C[=CF2][CF2][i.e., Comp ound A], respectively). Given the long history of safe administration of halothane, comparable toxicities of these degradation products woul d imply a similar safety of sevoflurane. We therefore examined CF2=CBr Cl in the context of four issues relevant to previous studies of the t oxicity of Compound A: 1) reactivity of the degradation product ill vi tro; 2) rate of its production ill 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, degradi ng 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 Ba ralyme(R) (Allied Healthcare Products, Inc., St. Louis, MO) produces 3 0 times as much Compound A from a minimum alveolar anesthetic concentr ation (MAC) concentration of sevoflurane as CF2=CBrCl from a MAC conce ntration of halothane; with soda lime, the difference is 60-fold. Corr ecting for differences in uptake of halothane versus sevoflurane decre ases the differences to 20-40 times. 3) For a 3-h administration to ra ts, the partial pressure of Compound A causing minimal renal injury or necrosis of half the affected tubule cells exceeds the partial pressu re of CF2=CBrCl causing minimal injury or necrosis of half the affecte d tubule cells by a factor of approximately 4-6. Thus, the ratio of pr oduction (Item 2 above) to the partial pressure causing injury with CF 2=CBrCl is approximately a quarter of that ratio for Compound A. 4) Co mpounds that block the beta-lyase pathway either do not change (acivic in) or decrease (aminooxyacetic acid; AOAA) renal injury from CF2=CBrC l in rats, whereas these compounds increase (acivicin) or do not chang e (AOAA) injury from Compound A. We conclude that the safety of haloth ane cannot be used to support the safety of sevoflurane. Implications: Carbon dioxide absorbents degrade halothane and sevoflurane to unsatu rated compounds nephrotoxic to rats. Relative to sevoflurane's degrada tion product, halothane's degradation product has less toxicity relati ve to production, less reactivity, and a different mechanism of injury . The clinical absence of halothane nephrotoxicity does not necessaril y indicate a similar absence for sevoflurane.