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 umol/L.4 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 a 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 umol/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.
Corresponding Author: Declan T. Waugh, BSc, CEnv, MCIWEM, MIEMA, EnviroManagement Services,
- Perry NJS, Buggy D, Ma D. Can anesthesia influence cancer outcomes after surgery? JAMA Surg. 2019;154(4):279-280. doi:10.1001/jamasurg.2018.4619 ArticlePubMedGoogle ScholarCrossref
- Perbet S, Salavert M, Amarger S, Constantin JM, D’Incan M, Bazin JE. Fluoroderma after exposure to sevoflurane. Br J Anaesth. 2011;107(1):106-107. doi:10.1093/bja/aer180PubMedGoogle ScholarCrossref
- Goldberg ME, Cantillo J, Larijani GE, Torjman M, Vekeman D, Schieren H. Sevoflurane versus isoflurane for maintenance of anesthesia: are serum inorganic fluoride ion concentrations of concern? Anesth Analg. 1996;82(6):1268-1272. doi:10.1097/00000539-199606000-00029PubMedGoogle Scholar
- Ming J, Wu S, You T, et al. Histone deacetylation in the promoter of p16 is involved in fluoride-induced human osteoblast activation via the inhibition of Sp1 binding. Biol Trace Elem Res. 2019;188(2):373-383. doi:10.1007/s12011-018-1413-zPubMedGoogle ScholarCrossref
- Waugh DT. Fluoride exposure induces inhibition of sodium-and potassium-activated adenosine triphosphatase (Na+, K+-ATPase) enzyme activity: molecular mechanisms and implications for public health. Int J Environ Res Public Health. 2019;16(8):E1427. doi:10.3390/ijerph16081427PubMedGoogle ScholarCrossref