In Reply We thank Waugh for the interest he has shown in our article1 and the Editor for the opportunity to reply to his comments. It is true that serum fluoride levels are elevated during anesthesia with sevoflurane, which occurs as a result of its metabolism by hepatic cytochrome P450 enzymes to yield hexafluoroisopropanol and inorganic fluoride. Indeed, there were well-documented concerns about the potential toxicity of these metabolites when sevoflurane first came into clinical use in the 1990s, although it rapidly transpired that reported cases of nephrotoxicity in rats were actually caused by compound A (fluoromethyl 2,2-difluoro-1-[trifluoromethyl]vinyl ether), a degradation product formed by the interaction of sevoflurane with carbon dioxide absorbers under specific conditions within the anesthetic breathing circuit.2 Since then, studies of sevoflurane biotransformation and degradation toxicity in humans have yielded minimal evidence of harm,3 and it continues to be used routinely and safely in millions of patients each year. Notwithstanding this or the equivocal data connecting chronic fluoride exposure with tumorigenesis, to our knowledge, the specific contribution of inorganic fluoride to the observed signaling activities and phenotype of cancer cells has not yet been directly assessed. This may transpire to be a topic of interest for future research, particularly as extrahepatic expression of cytochrome p450 enzymes has been identified in numerous human cancers.4 However, it should be noted that there are significant differences in the molecular stability of the various fluorinated anesthetics in clinical use today, which directly influences their susceptibility to biotransformation and, hence, the liberation of inorganic fluoride. Biotransformation of sevoflurane has been measured at 2% to 5%, while that of isoflurane and desflurane stand at 1% and less than 0.1% respectively.5 Thus, if inorganic fluoride were to be driving the signaling changes and more aggressive phenotypes seen in cancer cells exposed to inhalational agents, one might anticipate observing significant differences in the way these cancer cells respond to each of these agents. From the available data, this does not appear to be the case. In fact, a side-by-side comparison of the effects of sevoflurane, isoflurane, and desflurane on the messenger RNA levels of metastasis-associated genes revealed that the greatest changes were observed following exposure to desflurane, the most resistant of the 3 to oxidative defluoridation.6 Therefore, while we cannot categorically discount a role of inorganic fluoride, it seems that the influences exerted by these agents on cancer biology and the host are more likely to be explained by an alternative process. Concerted efforts in our laboratories and others are directed toward elucidating a unifying molecular mechanism, which we hope will serve to inform the design of clinical trials or, ultimately, lend biological plausibility to their outcomes.
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Perry NJS, Ma D. Cancer and Other Outcomes After Surgery With Fluoridated Anesthesia—Reply. JAMA Surg. Published online June 26, 2019. doi:10.1001/jamasurg.2019.1748
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