Skip to main content
NCBI home page
Environmental Health Perspectives logoLink to Environmental Health Perspectives
. 1977 Dec;21:195–210. doi: 10.1289/ehp.7721195

Pathologic changes following chronic exposures to halothane: a review.

L W Chang
PMCID: PMC1475332  PMID: 612446

Abstract

The toxic effects of halothane on the liver, kidney, and brain are reviewed. Increasing evidence has indicated that hepatic degeneration can be induced in several animal speices after exposure to halothane. Recent electron microscopic investigations have also revealed cytological degeneration of the liver cells after chronic exposure to subclinical levels of halothane. Degeneration of the kidney and the nervous system after halothane exposure have also been reported. The pathological effects of halothane on the neonatal (developing) liver, kidney, and brain are also demonstrated by electron microscopy. Although the full significance of these observations on experimental animals in relationship to human exposure is still not known, the indication of the toxic potential of halothane on the biological system is strong and deserves further investigation.

Full text

PDF
195

Images in this article

196FIGURE 1.
on p.196
197FIGURE 2.
on p.197
198FIGURE 3.
on p.198
198FIGURE 4.
on p.198
199FIGURE 5.
on p.199
200FIGURE 6.
on p.200
201FIGURE 7.
on p.201
201FIGURE 8.
on p.201
202FIGURE 9.
on p.202
202FIGURE 10.
on p.202
203FIGURE 11.
on p.203
203FIGURE 12.
on p.203
204FIGURE 13.
on p.204
205FIGURE 14.
on p.205
205FIGURE 15.
on p.205
206FIGURE 16.
on p.206
206FIGURE 17.
on p.206
207FIGURE 18.
on p.207
207FIGURE 19.
on p.207
208FIGURE 20.
on p.208

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Adam N. Effects of general anesthetics on memory functions in man. J Comp Physiol Psychol. 1973 May;83(2):294–305. doi: 10.1037/h0034406. [DOI] [PubMed] [Google Scholar]
  2. Andersen N. B., Amaranath L. Anesthetic effects on transport across cell membranes. Anesthesiology. 1973 Aug;39(2):126–152. doi: 10.1097/00000542-197308000-00005. [DOI] [PubMed] [Google Scholar]
  3. Askrog V., Petersen R. Forurening af operationsstuer med luftformige anaestetika og røntgenbestråling (sikkerhedsforanstaltninger) Nord Med. 1970 Apr 16;83(16):501–504. [PubMed] [Google Scholar]
  4. BRODY G. L., SWEET R. B. Halothane anesthesia as a possible cause of massive hepatic necrosis. Anesthesiology. 1963 Jan-Feb;24:29–37. doi: 10.1097/00000542-196301000-00005. [DOI] [PubMed] [Google Scholar]
  5. Bruce D. L., Eide K. A., Linde H. W., Eckenhoff J. E. Causes of death among anesthesiologists: a 20-year survey. Anesthesiology. 1968 May-Jun;29(3):565–569. doi: 10.1097/00000542-196805000-00039. [DOI] [PubMed] [Google Scholar]
  6. Bruce D. L. What is a "safe" interval between halothane exposures? JAMA. 1972 Sep 4;221(10):1140–1143. [PubMed] [Google Scholar]
  7. Burkholder P. M., Hyman L. R., Barber T. A. Extracellular clusters of spherical microparticles in glomeruli in human renal glomerular diseases. Lab Invest. 1973 Apr;28(4):415–425. [PubMed] [Google Scholar]
  8. Carney F. M., Van Dyke R. A. Halothane hepatitis: a critical review. Anesth Analg. 1972 Jan-Feb;51(1):135–160. [PubMed] [Google Scholar]
  9. Chang L. W., Dudley A. W., Jr, Katz J. Pathological changes in the nervous system following in utero exposure to halothane. Environ Res. 1976 Feb;11(1):40–51. doi: 10.1016/0013-9351(76)90109-2. [DOI] [PubMed] [Google Scholar]
  10. Chang L. W., Dudley A. W., Jr, Lee Y. K., Katz J. Ultrastructural changes in the nervous system after chronic exposure to halothane. Exp Neurol. 1974 Nov;45(2):209–219. doi: 10.1016/0014-4886(74)90113-7. [DOI] [PubMed] [Google Scholar]
  11. Chang L. W., Dudley A. W., Jr, Lee Y. K., Katz J. Ultrastructural studies of the hepatocytes after chronic exposure to low levels of halothane. Exp Mol Pathol. 1975 Aug;23(1):35–42. doi: 10.1016/0014-4800(75)90004-0. [DOI] [PubMed] [Google Scholar]
  12. Chang L. W., Dudley A. W., Lee Y. K., Katz J. Ultrastructural changes in the kidney following chronic exposure to low levels of halothane. Am J Pathol. 1975 Feb;78(2):225–242. [PMC free article] [PubMed] [Google Scholar]
  13. Chang L. W., Lee Y. K., Dudley A. W., Jr, Katz J. Ultrastructural evidence of the hepatotoxic effect of halothane in rats following in-utero exposure. Can Anaesth Soc J. 1975 May;22(3):330–338. doi: 10.1007/BF03004842. [DOI] [PubMed] [Google Scholar]
  14. Chang L. W., Sprecher J. A. Degenerative changes in the neonatal kidney following in-utero exposure to methylmercury. Environ Res. 1976 Jun;11(3):392–406. doi: 10.1016/0013-9351(76)90101-8. [DOI] [PubMed] [Google Scholar]
  15. Cohen E. N., Bellville J. W., Brown B. W., Jr Anesthesia, pregnancy, and miscarriage: a study of operating room nurses and anesthetists. Anesthesiology. 1971 Oct;35(4):343–347. doi: 10.1097/00000542-197110000-00005. [DOI] [PubMed] [Google Scholar]
  16. Cohen E. N., Hood N. Application of low-temperature autoradiography to studies of the uptake and metabolism of volatile anesthetics in the mouse. I. Chloroform. Anesthesiology. 1969 Mar;30(3):306–314. doi: 10.1097/00000542-196903000-00014. [DOI] [PubMed] [Google Scholar]
  17. Cohen E. N., Hood N. Application of low-temperature autoradiography to studies of the uptake and metabolism of volatile anesthetics in the mouse: II. Diethyl ether. Anesthesiology. 1969 Jul;31(1):61–68. doi: 10.1097/00000542-196907000-00018. [DOI] [PubMed] [Google Scholar]
  18. Corbett T. H. Anesthetics as a cause of abortion. Fertil Steril. 1972 Nov;23(11):866–869. doi: 10.1016/s0015-0282(16)39319-0. [DOI] [PubMed] [Google Scholar]
  19. Corbett T. H., Ball G. L. Chronic exposure to methoxyflurane: a possible occupational hazard to anesthesiologists. Anesthesiology. 1971 Jun;34(6):532–537. doi: 10.1097/00000542-197106000-00012. [DOI] [PubMed] [Google Scholar]
  20. Corbett T. H. Retention of anesthetic agents following occupational exposure. Anesth Analg. 1973 Jul-Aug;52(4):614–618. [PubMed] [Google Scholar]
  21. Cousins M. J., Mazze R. I., Barr G. A., Kosek J. C. A comparison of the renal effects of isoflurane and methoxyflurane in Fischer 344 rats. Anesthesiology. 1973 Jun;38(6):557–563. doi: 10.1097/00000542-197306000-00010. [DOI] [PubMed] [Google Scholar]
  22. Doniach D. Cell-mediated immunity in halothane hypersensitivity. N Engl J Med. 1970 Aug 6;283(6):315–316. doi: 10.1056/NEJM197008062830611. [DOI] [PubMed] [Google Scholar]
  23. Gall E. A. Report of the pathology panel. National halothane study. Anesthesiology. 1968 Mar-Apr;29(2):233–248. doi: 10.1097/00000542-196803000-00002. [DOI] [PubMed] [Google Scholar]
  24. Hetrick W. D., Wolfson B., Garcia D. A., Siker E. S. Renal responses to "light" methoxyflurane anesthesia. Anesthesiology. 1973 Jan;38(1):30–37. doi: 10.1097/00000542-197301000-00009. [DOI] [PubMed] [Google Scholar]
  25. Hughes H. C., Jr, Lang C. M. Hepatic necrosis produced by repeated administration of halothane to guinea pigs. Anesthesiology. 1972 May;36(5):466–471. doi: 10.1097/00000542-197205000-00010. [DOI] [PubMed] [Google Scholar]
  26. JONES W. M., MARGOLIS G., STEPHEN C. R. Hepatotoxicity of inhalation anesthetic drugs. Anesthesiology. 1958 Nov-Dec;19(6):715–723. doi: 10.1097/00000542-195811000-00001. [DOI] [PubMed] [Google Scholar]
  27. Jenkins L. C. Chronic exposure to anaesthetics: a toxicity problem? Can Anaesth Soc J. 1973 Jan;20(1):104–120. doi: 10.1007/BF03025569. [DOI] [PubMed] [Google Scholar]
  28. Klion F. M., Schaffner F., Popper H. Hepatitis after exposure to halothane. Ann Intern Med. 1969 Sep;71(3):467–477. doi: 10.7326/0003-4819-71-3-467. [DOI] [PubMed] [Google Scholar]
  29. Kosek J. C., Mazze R. I., Cousins M. J. The morphology and pathogenesis of nephrotoxicity following methoxyflurane (penthrane) anesthesia. An experimental model in rats. Lab Invest. 1972 Dec;27(6):575–580. [PubMed] [Google Scholar]
  30. Kuzucu E. Y. Methoxyflurane, tetracycline, and renal failure. JAMA. 1970 Feb 16;211(7):1162–1164. [PubMed] [Google Scholar]
  31. Linde H. W., Bruce D. L. Occupational exposure of anesthetists to halothane, nitrous oxide and radiation. Anesthesiology. 1969 Apr;30(4):363–368. doi: 10.1097/00000542-196904000-00002. [DOI] [PubMed] [Google Scholar]
  32. Mathieu A., DiPadua D., Mills J., Kahan B. Experimental immunity to a metabolite of halothane and fluroxene: cutaneous delayed-type hypersensitivity. Anesthesiology. 1974 Apr;40(4):385–390. doi: 10.1097/00000542-197404000-00015. [DOI] [PubMed] [Google Scholar]
  33. Mazze R. I., Cousins M. J., Kosek J. C. Dose-related methoxyflurane nephrotoxicity in rats: a biochemical and pathologic correlation. Anesthesiology. 1972 Jun;36(6):571–587. doi: 10.1097/00000542-197206000-00010. [DOI] [PubMed] [Google Scholar]
  34. Mazze R. I., Cousins M. J. Renal toxicity of anaesthetics: with specific reference to the nephrotoxicity of methoxyflurane. Can Anaesth Soc J. 1973 Jan;20(1):64–80. doi: 10.1007/BF03025566. [DOI] [PubMed] [Google Scholar]
  35. Mazze R. I., Trudell J. R., Cousins M. J. Methoxyflurane metabolism and renal dysfunction: clinical correlation in man. Anesthesiology. 1971 Sep;35(3):247–252. doi: 10.1097/00000542-197109000-00004. [DOI] [PubMed] [Google Scholar]
  36. Newberne P. M., Bresnahan M. R., Kula N. Effects of two synthetic antioxidants, vitamin E, and ascorbic acid on the choline-deficient rat. J Nutr. 1969 Feb;97(2):219–231. doi: 10.1093/jn/97.2.219. [DOI] [PubMed] [Google Scholar]
  37. PITTINGER C. B., FEATHERSTONE R. M., STICKLEY E., LEVY L., CULLEN S. C. Observations on the kinetics of transfer of xenon and chloroform between blood and brain in the dog. Anesthesiology. 1956 Jul-Aug;17(4):523–530. doi: 10.1097/00000542-195607000-00002. [DOI] [PubMed] [Google Scholar]
  38. Paronetto F., Popper H. Lymphocyte stimulation induced by halothane in patients with hepatitis following exposure to halothane. N Engl J Med. 1970 Aug 6;283(6):277–280. doi: 10.1056/NEJM197008062830602. [DOI] [PubMed] [Google Scholar]
  39. Porter A. L. An analytical review of the effects of non-hydrogen-bonding anesthetics on memory processing. Behav Biol. 1972 Jun;7(3):291–309. doi: 10.1016/s0091-6773(72)80102-0. [DOI] [PubMed] [Google Scholar]
  40. Prieur D. J., Davis W. C., Padgett G. A. Defective function of renal lysosomes in mice with the Chediak-Higashi syndrome. Am J Pathol. 1972 May;67(2):227–236. [PMC free article] [PubMed] [Google Scholar]
  41. Qizilbash A. H. Halothane hepatitis. Can Med Assoc J. 1973 Jan 20;108(2):171–177. [PMC free article] [PubMed] [Google Scholar]
  42. Qizilbash A. H. Halothane hepatitis. Can Med Assoc J. 1973 Jan 20;108(2):171–177. [PMC free article] [PubMed] [Google Scholar]
  43. Quimby K. L., Aschkenase L. J., Bowman R. E., Katz J., Chang L. W. Enduring learning deficits and cerebral synaptic malformation from exposure to 10 parts of halothane per million. Science. 1974 Aug 16;185(4151):625–627. doi: 10.1126/science.185.4151.625. [DOI] [PubMed] [Google Scholar]
  44. RAVENTOS J. The action of fluothane; a new volatile anaesthetic. Br J Pharmacol Chemother. 1956 Dec;11(4):394–410. doi: 10.1111/j.1476-5381.1956.tb00007.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. STEPHEN C. R., MARGOLIS G., FABIAN L. W., BOURGEOIS-GAVARDIN M. Laboratory observations with fluothane. Anesthesiology. 1958 Nov-Dec;19(6):770–781. doi: 10.1097/00000542-195811000-00009. [DOI] [PubMed] [Google Scholar]
  46. Sawyer D. C., Eger E. I., 2nd, Bahlman S. H., Cullen B. F., Impelman D. Concentration dependence of hepatic halothane metabolism. Anesthesiology. 1971 Mar;34(3):230–235. doi: 10.1097/00000542-197103000-00005. [DOI] [PubMed] [Google Scholar]
  47. Schatzki P. F., Kay S., McGavic J. D. Ultrastructural pathology of a case of halothane hepatitis. Am J Dig Dis. 1973 Oct;18(10):905–911. doi: 10.1007/BF01073343. [DOI] [PubMed] [Google Scholar]
  48. Scholler K. L. Electron-microscopic and autoradiographic studies on the effect of halothane and chloroform on liver cells. Acta Anaesthesiol Scand Suppl. 1968;32:1–62. [PubMed] [Google Scholar]
  49. Sherlock S. Halothane hepatitis. Gut. 1971 Apr;12(4):324–329. doi: 10.1136/gut.12.4.324. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Simpson B. R., Strunin L., Walton B. Halothane hepatitis: fact or fallacy. Bull N Y Acad Med. 1973 Aug;49(8):708–721. [PMC free article] [PubMed] [Google Scholar]
  51. Smith A. L., Larson C. P., Jr, Hoff J. T. Effects of halothane on regional cerebral blood flow in experimental focal ischemia. Anesthesiology. 1973 Oct;39(4):377–381. doi: 10.1097/00000542-197310000-00005. [DOI] [PubMed] [Google Scholar]
  52. Smith A. L., Larson C. P., Jr, Hoff J. T. Effects of halothane on regional cerebral blood flow in experimental focal ischemia. Anesthesiology. 1973 Oct;39(4):377–381. doi: 10.1097/00000542-197310000-00005. [DOI] [PubMed] [Google Scholar]
  53. Stevens W. C., Eger E. I., 2nd, White A., Halsey M. J., Munger W., Gibbons R. D., Dolan W., Shargel R. Comparative toxicities of halothane, isoflurane, and diethyl ether at subanesthetic concentrations in laboratory animals. Anesthesiology. 1975 Apr;42(4):408–419. doi: 10.1097/00000542-197504000-00008. [DOI] [PubMed] [Google Scholar]
  54. Taves D. R., Fry B. W., Freeman R. B., Gillies A. J. Toxicity following methoxyflurane anesthesia. II. Fluoride concentrations in nephrotoxicity. JAMA. 1970 Oct 5;214(1):91–95. [PubMed] [Google Scholar]
  55. Tobey R. E., Clubb R. J. Renal function after methoxyflurane and halothane anesthesia. JAMA. 1973 Feb 5;223(6):649–652. [PubMed] [Google Scholar]
  56. Uzunalimoglu B., Yardley J. H., Boitnott J. K. The liver in mild halothane hepatitis. Light and electron microscopic findings with special reference to the mononuclear cell infiltrate. Am J Pathol. 1970 Dec;61(3):457–478. [PMC free article] [PubMed] [Google Scholar]
  57. Van Dyke R. A. Biotransformation of volatile anaesthetics with special emphasis on the role of metabolism in the toxicity of anaesthetics. Can Anaesth Soc J. 1973 Jan;20(1):21–33. doi: 10.1007/BF03025562. [DOI] [PubMed] [Google Scholar]
  58. Ware R. A., Burkholder P. M., Chang L. W. Ultrastructural changes in renal proximal tubules after chronic organic and inorganic mercury intoxication. Environ Res. 1975 Aug;10(1):121–140. doi: 10.1016/0013-9351(75)90078-x. [DOI] [PubMed] [Google Scholar]
  59. Whitcher C. E., Cohen E. N., Trudell J. R. Chronic exposure to anesthetic gases in the operating room. Anesthesiology. 1971 Oct;35(4):348–353. doi: 10.1097/00000542-197110000-00006. [DOI] [PubMed] [Google Scholar]

Articles from Environmental Health Perspectives are provided here courtesy of National Institute of Environmental Health Sciences

RESOURCES