To the Editor I read the article by Perry et al1 with interest. Several other molecular mechanisms and factors may also play a role in how anesthesia may influence cancer outcomes. First, it is important to distinguish the difference between certain fluoridated anesthesia, such as sevoflurane, from their contribution to higher plasma fluoride levels. For example, it is known that sevoflurane can provide 20-fold the total daily dietary fluoride intake from all sources of fluoridated food and water combined,2 resulting in peak ionic fluoride levels in the range of 50 μmol/L.3 Hence, fluoridated anesthesia can result in extremely high plasma fluoride levels. Second, it is important to point out that chronic fluoride exposure has been found to decrease the messenger RNA (mRNA) expression of p16 tumor suppressor gene.4 Interestingly, a review of published literature will show that loss of p16 predisposes humans to cancer, and p16 inactivation is associated with melanoma, acute lymphocytic leukemia, osteosarcoma, and mesothelioma as well as brain, esophageal, lung, pancreas, bladder, head and neck, breast, ovarian, prostate, and renal carcinoma. However, in addition to downregulating p16, chronic fluoride exposure has been found to upregulate high-sensitivity C-reactive protein, core-binding factor α 1, chemokine (C-C motif) ligand 2, calcitonin, Smoothened mRNA, Sonic Hedgehog signaling pathway, osteoprotegerin, DiGeorge syndrome chromosomal region 8, cyclooxygenases, and prostaglandins E2 expression. Importantly, fluoride exposure has also been shown to be a potent inhibitor of paraoxonase 1 and forkhead box protein 3 transcription factor. A further review of literature will elucidate the significance of these molecular mechanisms in cancer progression and disease outcomes. Furthermore, human studies have also found that chronic fluoride exposure resulting in serum ionic fluoride levels of 3 to 14 μmol/L leads to significant inhibition of Na+/K+–adenosine triphosphatase (NKA) activity.5 Here again, a review of literature will show that inhibition of NKA activity is associated with tumor invasiveness, metastasis, and tissue fibrosis as well as kidney, prostate, and bladder cancer. Interestingly, loss of NKA activity is also associated with neurotoxicity, Alzheimer disease, seizures, and mental disorders as well as diabetic nephropathy, cardiomyopathy, and hypertension. Taken together, the molecular mechanisms by which anesthesia may increase the susceptibility to subsequent cancer risk and mortality (in addition to other negative health outcomes) is most likely dependent on the type of inhalation anesthetic used and the effect of excessive fluoride exposure on molecular pathways associated with increased risk of cancer.
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Waugh DT. Cancer and Other Outcomes After Surgery With Fluoridated Anesthesia. JAMA Surg. Published online June 26, 2019. doi:10.1001/jamasurg.2019.1747
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