ENVIRONMENTAL
RESEARCH
9, 211-214
(1975)
EDITORIAL Inhalation
Anesthetics-More THOMAS
H.
Vinyl
Chloride?
CORBETT
Epidemiologic observations first drew attention to anesthetic gases as possible environmental hazards to operating room personnel in 1967, when Vaisman (1) reported an unusually high incidence of headache, fatigability, nausea, and pruritus among 354 Russian anesthetists. He also noted that 18 of 31 pregnancies reported ended in spontaneous abortion. In addition, two of the pregnancies ended in premature delivery and one in a congenital malformation. In 1968, Bruce et al. (2) published a study of the cause of death among 441 members of the American Society of Anesthesiologists who had died between 1947 and 1966. In addition to an inordinately high suicide rate, there was a high incidence of reticuloendothelial and lymphoid malignancies. An arguably germane study by Li et al. (3) in 1969, found a significantly higher rate of cancer among chemists compared to professional men in general. Nearly half the excess cancer deaths were due to malignant lymphomas and cancer of the pancreas. The relevance, if any, is that both chemists and anesthesiologists are exposed chronically to low concentrations of volatile chemicals and gases in the course of their work. Further studies from Denmark (4), California (5), and Great Britain (6) all demonstrated a high incidence of spontaneous miscarriage of pregnancy among operating room nurses. In 1972, we conducted our own survey of the 621 female nurse-anesthetists in the state of Michigan (7,8), obtaining a response rate of 85%. A total of 33 malignancies in 31 nurse-anesthetists was reported. Several unusual types were noted, including hepatocellular carcinoma, malignant thymoma, malignant melanoma, and leiomyosarcoma. Ten malignancies including skin cancers, were diagnosed during 1971. Excluding skin cancers, the expected incidence adjusted for age distribution, based on statistics from the Connecticut Tumor Registry, was 403/100,000. The age-adjusted incidence among the Michigan nurse-anesthetists was 1333/100,000, or three times the expected rate. This difference was significant at the 3.1% level. Analysis of the data from this survey regarding cogenital abnormalities among children born to nurse-anesthetists revealed a significantly higher incidence of anomalies in children born to mothers who administered anesthesia during the pregnancy as opposed to children born to mothers who did not administer anesthesia during the pregnancy. In the same study, exploring the possibility of transplacental carcinogenesis, we found that three neoplasms had occurred in two of the 434 children whose mothers had practiced during pregnancy. One had a neuroblastoma at birth and later developed a thyroid malignancy at puberty. Another child developed a 211 Copyright 0 1975 by Academic Press, Inc. All rights of reproduction in any form reserved.
212
THOMAS
H.
CORBETT
parotid tumor at 22. Among the 261 children whose mothers did not work while pregnant, there was one neoplasm and an acute leukemia at age three. The figures are not statistically significant, but neither are they reassuring. All the above studies were of small population groups and the need for a nation-wide study of large numbers of operating room personnel became apparent. This study (9) was undertaken by the American Society of Anesthesiologists with the financial support of the National Institute for Occupational Safety and Health (NIOSH). Fifty thousand operating room professionals were surveyed, with 24,000 unexposed medical and nursing professionals serving as controls. The study found 1.3-2 times the incidence of spontaneous abortion in exposed, compared with unexposed, female personnel. Women physician-anesthetists suffered the highest risk, followed by nurse-anesthetists. The incidence of congenital abnormalities among live-born offspring of exposed female-physiciananesthetists was double that among offspring of unexposed female physicians. Among exposed nurse-anesthetists, the risk of fetal abnormalities was 1.6 times that of their unexposed counterparts. There was also a 25% increase in the risk of congenital abnormalities in children of unexposed wives of male anesthesiologists. The frequency of cancer was 1.3-2 times greater among exposed women, the highest risk again among the women physician-anesthetists, followed by nurseanesthetists. Liver disease, excluding serum hepatitis, was found from 1.3-2.2 times more frequently among exposed women than among unexposed counterparts, the highest incidence being among the anesthesia personnel. A similar increase in liver disease was seen among male physician-anesthetists compared with male pediatricians. None of the above studies have established a cause-and-effect relationship. It has been argued that causative factors could include long hours and tension of the operating room, exposure to radiation from X-rays and radium implant procedures, and exposure to patients with transmissible viruses. However, it would require an extraordinarily recalcitrant bias not to consider the chronic exposure to low concentrations of anesthetic gases to be responsible for the excess incidence of cancer and birth defects seen among operating room personnel. Once the possibility of teratogenicity and carcinogenicity of anesthetic agents is entertained, it becomes strengthened theoretically by comparing the chemical structures of several anesthetic agents with the structures of several known human carcinogens (Table 1). The a-chloro ether structures of bis (chloromethyl) ether and chloromethyl methyl ether are thought to be responsible for the carcinogenicity of these agents (10). The anesthetic isoflurane (Forane) has this same cr-chloro ether structure. The a-fluoro ethers methoxyflurane (Penthrane) and enflurane (Ethrane) must also be considered as possible carcinogens, especially since they are also p-chloro ethers. One P-chloro ether, bis (chloroethyl) ether, has recently been shown to induce hepatomas when fed to rats. It is both interesting and disconcerting to know that vinyl chloride. a known human carcinogen, was once considered for use as an anesthetic agent, but was discarded because of its myocardial irritant properties. Perhaps even more
INHALATION
ANESTHETICS-MORE
VINYL
TABLE
213
CHLORIDE?
1
COMPARISON OF THE CHEMICAL STRUCTURES OF SEVERAL KNOWN HUMAN CARCINOGENS WITH CERTAIN INHALATION ANESTHETIC AGENTS INHALATION
HUMAN CARCINOGEZNS
Cl I H-C-O-C-H I H Bis
I II
Ii I
Methyl
I F (Forane)
Cl F I 1 H-C-C-O-C-H
II I
II Cl
I II
A
H
F I
Isoflurane
Ether
Cl I H-C-O-C-H I Chloromethyl
F Cl I I F-C-C-O-C-H I I F H
Cl I
(chloromethyl)
ANESTHETICS
F
Methoxyflurane
Ether
F I
(Penthrane)
F I
F
I
H-C-C-O-C-H I
I
Cl
F
Enflurane
II
Cl \
Cl \
c-c \ H
Ii Vinyl
F (Ethrane)
Cl
/
/
I
H
Chloride
c-c
/
/ \
Cl
Trichloroethylene
disquieting, however, is the structural similarity between the anesthetic trichloroethylene and vinyl chloride. TCE has enjoyed popularity among anesthesiologists in the past, but is used only occasionally at the present time. The occupational exposure to anesthetic gases can be reduced considerably with existing scavenging devices. Operating room pollution with anesthetic gases arises from the need to deliver the gases to the patient under high-flow circumstances. Thus, anesthetic gases in excess of patient requirements escape from TABLE
RANGE
OF CONCENTRATIONS OPERATING
Agent Halothane Methoxyflurane Trichloroethylene Nitrous oxide
2
OF ANESTHETIC AGENTS ROOM ENVIRONMENT
ppm Near
anesthesiologist l-10 2-10 l-103 330-9700
FOUND
IN THE
ppm Near l-2 l-2 l-l.5 310-550
surgeon
214
THOMAS
H.
CORBETT
the anesthesia machine through a “pop-off’ valve, usually located about 18 in. from the nose of the anesthetists. Operating room levels of the various gases under usual working conditions are shown in Table 2. With installation of the proper scavenging equipment, exhausting the gas through the operating room ventilation system outlet, these concentrations can be reduced to as low as 2%: of the unscavenged level. The data presented here raise enough serious questions to justify regulations enforcing the installation and employment of gas scavenging devices in the operating room. Future research must be directed toward identification of those anesthetics which are embryolethal, teratogenic, mutagenic, or carcinogenic, with subsequent removal of these chemicals from the anesthesiologists’ arsenal. REFERENCES 1. Vaisman, A. I. (1967). Working conditions in surgery and their effect on the health of anesthesiologists. Eksp. Khir. Anest. 3, 44-49. 2. Bruce, D. L., Eide, K. A., Linde, H. W., and Eckenhoff, J. (1968). Causes of death among anesthesiologists: A 20 year survey. Anesthesiology 29, 565-569. 3. Li, F. P., Fraumeni, J. F., Mantel, M. A., and Miller, R. W. (1969). Cancer Mortality among chemists. J. Nut. Cancer Inst. 43, 1159-1164. 4. Askrog, V., and Harvald, B. (1970). Teratogen effeck af inhalations-anestetika. Nord. Med. 83, 490-500. 5. Cohen, E. N., Belville, H. W., and Brown, B. W. (1971). Anesthesia, pregnancy and miscarriage: A study of operating room nurses and anesthetists. Anesthesiology 35, 343-347. 6. Knill-Jones, R. P., Moir, D. B., Rodrigues, L. V., and Spence, A. A. (1972). Anesthetic practice and pregnancy: A controlled study of women anesthetists in the United Kingdom. Lancer 2, 1326-1328. 7. Corbett. T. H., Cornell. R. G., Lieding, K., and Endres, J. L. (1973). Incidence of cancer among Michigan nurse-anesthetists. Anesthesiology 38, 260-263. 8. Corbett, T. H., Cornell, R. G., Endres, J. L.. and Lieding, K. (1974). Birth defects among children of nurse-anesthetists. Anesthesiology 41, 341-344. 9. Cohen, E. N., Bruce, D. L., Cascorbi, H. F., Corbett, T. H., Jones, T. W., and Whitcher, C. E. (1974). Occupational diseases among operating room personnel: A national study. Anesthesiology 41. 10. Van Duuren, B. L., Katz, C., Goldschmidt, B. M., Frenkel, K., Sivak, A. (1972). Carcinogenicity of halo-ethers: II. Structure-activity relationships of analogs of bis (chloromethyl) ether. J. Nat. Cancer Inst. 48, 1431-1439.
RESEARCH
9, 211-214
(1975)
EDITORIAL Inhalation
Anesthetics-More THOMAS
H.
Vinyl
Chloride?
CORBETT
Epidemiologic observations first drew attention to anesthetic gases as possible environmental hazards to operating room personnel in 1967, when Vaisman (1) reported an unusually high incidence of headache, fatigability, nausea, and pruritus among 354 Russian anesthetists. He also noted that 18 of 31 pregnancies reported ended in spontaneous abortion. In addition, two of the pregnancies ended in premature delivery and one in a congenital malformation. In 1968, Bruce et al. (2) published a study of the cause of death among 441 members of the American Society of Anesthesiologists who had died between 1947 and 1966. In addition to an inordinately high suicide rate, there was a high incidence of reticuloendothelial and lymphoid malignancies. An arguably germane study by Li et al. (3) in 1969, found a significantly higher rate of cancer among chemists compared to professional men in general. Nearly half the excess cancer deaths were due to malignant lymphomas and cancer of the pancreas. The relevance, if any, is that both chemists and anesthesiologists are exposed chronically to low concentrations of volatile chemicals and gases in the course of their work. Further studies from Denmark (4), California (5), and Great Britain (6) all demonstrated a high incidence of spontaneous miscarriage of pregnancy among operating room nurses. In 1972, we conducted our own survey of the 621 female nurse-anesthetists in the state of Michigan (7,8), obtaining a response rate of 85%. A total of 33 malignancies in 31 nurse-anesthetists was reported. Several unusual types were noted, including hepatocellular carcinoma, malignant thymoma, malignant melanoma, and leiomyosarcoma. Ten malignancies including skin cancers, were diagnosed during 1971. Excluding skin cancers, the expected incidence adjusted for age distribution, based on statistics from the Connecticut Tumor Registry, was 403/100,000. The age-adjusted incidence among the Michigan nurse-anesthetists was 1333/100,000, or three times the expected rate. This difference was significant at the 3.1% level. Analysis of the data from this survey regarding cogenital abnormalities among children born to nurse-anesthetists revealed a significantly higher incidence of anomalies in children born to mothers who administered anesthesia during the pregnancy as opposed to children born to mothers who did not administer anesthesia during the pregnancy. In the same study, exploring the possibility of transplacental carcinogenesis, we found that three neoplasms had occurred in two of the 434 children whose mothers had practiced during pregnancy. One had a neuroblastoma at birth and later developed a thyroid malignancy at puberty. Another child developed a 211 Copyright 0 1975 by Academic Press, Inc. All rights of reproduction in any form reserved.
212
THOMAS
H.
CORBETT
parotid tumor at 22. Among the 261 children whose mothers did not work while pregnant, there was one neoplasm and an acute leukemia at age three. The figures are not statistically significant, but neither are they reassuring. All the above studies were of small population groups and the need for a nation-wide study of large numbers of operating room personnel became apparent. This study (9) was undertaken by the American Society of Anesthesiologists with the financial support of the National Institute for Occupational Safety and Health (NIOSH). Fifty thousand operating room professionals were surveyed, with 24,000 unexposed medical and nursing professionals serving as controls. The study found 1.3-2 times the incidence of spontaneous abortion in exposed, compared with unexposed, female personnel. Women physician-anesthetists suffered the highest risk, followed by nurse-anesthetists. The incidence of congenital abnormalities among live-born offspring of exposed female-physiciananesthetists was double that among offspring of unexposed female physicians. Among exposed nurse-anesthetists, the risk of fetal abnormalities was 1.6 times that of their unexposed counterparts. There was also a 25% increase in the risk of congenital abnormalities in children of unexposed wives of male anesthesiologists. The frequency of cancer was 1.3-2 times greater among exposed women, the highest risk again among the women physician-anesthetists, followed by nurseanesthetists. Liver disease, excluding serum hepatitis, was found from 1.3-2.2 times more frequently among exposed women than among unexposed counterparts, the highest incidence being among the anesthesia personnel. A similar increase in liver disease was seen among male physician-anesthetists compared with male pediatricians. None of the above studies have established a cause-and-effect relationship. It has been argued that causative factors could include long hours and tension of the operating room, exposure to radiation from X-rays and radium implant procedures, and exposure to patients with transmissible viruses. However, it would require an extraordinarily recalcitrant bias not to consider the chronic exposure to low concentrations of anesthetic gases to be responsible for the excess incidence of cancer and birth defects seen among operating room personnel. Once the possibility of teratogenicity and carcinogenicity of anesthetic agents is entertained, it becomes strengthened theoretically by comparing the chemical structures of several anesthetic agents with the structures of several known human carcinogens (Table 1). The a-chloro ether structures of bis (chloromethyl) ether and chloromethyl methyl ether are thought to be responsible for the carcinogenicity of these agents (10). The anesthetic isoflurane (Forane) has this same cr-chloro ether structure. The a-fluoro ethers methoxyflurane (Penthrane) and enflurane (Ethrane) must also be considered as possible carcinogens, especially since they are also p-chloro ethers. One P-chloro ether, bis (chloroethyl) ether, has recently been shown to induce hepatomas when fed to rats. It is both interesting and disconcerting to know that vinyl chloride. a known human carcinogen, was once considered for use as an anesthetic agent, but was discarded because of its myocardial irritant properties. Perhaps even more
INHALATION
ANESTHETICS-MORE
VINYL
TABLE
213
CHLORIDE?
1
COMPARISON OF THE CHEMICAL STRUCTURES OF SEVERAL KNOWN HUMAN CARCINOGENS WITH CERTAIN INHALATION ANESTHETIC AGENTS INHALATION
HUMAN CARCINOGEZNS
Cl I H-C-O-C-H I H Bis
I II
Ii I
Methyl
I F (Forane)
Cl F I 1 H-C-C-O-C-H
II I
II Cl
I II
A
H
F I
Isoflurane
Ether
Cl I H-C-O-C-H I Chloromethyl
F Cl I I F-C-C-O-C-H I I F H
Cl I
(chloromethyl)
ANESTHETICS
F
Methoxyflurane
Ether
F I
(Penthrane)
F I
F
I
H-C-C-O-C-H I
I
Cl
F
Enflurane
II
Cl \
Cl \
c-c \ H
Ii Vinyl
F (Ethrane)
Cl
/
/
I
H
Chloride
c-c
/
/ \
Cl
Trichloroethylene
disquieting, however, is the structural similarity between the anesthetic trichloroethylene and vinyl chloride. TCE has enjoyed popularity among anesthesiologists in the past, but is used only occasionally at the present time. The occupational exposure to anesthetic gases can be reduced considerably with existing scavenging devices. Operating room pollution with anesthetic gases arises from the need to deliver the gases to the patient under high-flow circumstances. Thus, anesthetic gases in excess of patient requirements escape from TABLE
RANGE
OF CONCENTRATIONS OPERATING
Agent Halothane Methoxyflurane Trichloroethylene Nitrous oxide
2
OF ANESTHETIC AGENTS ROOM ENVIRONMENT
ppm Near
anesthesiologist l-10 2-10 l-103 330-9700
FOUND
IN THE
ppm Near l-2 l-2 l-l.5 310-550
surgeon
214
THOMAS
H.
CORBETT
the anesthesia machine through a “pop-off’ valve, usually located about 18 in. from the nose of the anesthetists. Operating room levels of the various gases under usual working conditions are shown in Table 2. With installation of the proper scavenging equipment, exhausting the gas through the operating room ventilation system outlet, these concentrations can be reduced to as low as 2%: of the unscavenged level. The data presented here raise enough serious questions to justify regulations enforcing the installation and employment of gas scavenging devices in the operating room. Future research must be directed toward identification of those anesthetics which are embryolethal, teratogenic, mutagenic, or carcinogenic, with subsequent removal of these chemicals from the anesthesiologists’ arsenal. REFERENCES 1. Vaisman, A. I. (1967). Working conditions in surgery and their effect on the health of anesthesiologists. Eksp. Khir. Anest. 3, 44-49. 2. Bruce, D. L., Eide, K. A., Linde, H. W., and Eckenhoff, J. (1968). Causes of death among anesthesiologists: A 20 year survey. Anesthesiology 29, 565-569. 3. Li, F. P., Fraumeni, J. F., Mantel, M. A., and Miller, R. W. (1969). Cancer Mortality among chemists. J. Nut. Cancer Inst. 43, 1159-1164. 4. Askrog, V., and Harvald, B. (1970). Teratogen effeck af inhalations-anestetika. Nord. Med. 83, 490-500. 5. Cohen, E. N., Belville, H. W., and Brown, B. W. (1971). Anesthesia, pregnancy and miscarriage: A study of operating room nurses and anesthetists. Anesthesiology 35, 343-347. 6. Knill-Jones, R. P., Moir, D. B., Rodrigues, L. V., and Spence, A. A. (1972). Anesthetic practice and pregnancy: A controlled study of women anesthetists in the United Kingdom. Lancer 2, 1326-1328. 7. Corbett. T. H., Cornell. R. G., Lieding, K., and Endres, J. L. (1973). Incidence of cancer among Michigan nurse-anesthetists. Anesthesiology 38, 260-263. 8. Corbett, T. H., Cornell, R. G., Endres, J. L.. and Lieding, K. (1974). Birth defects among children of nurse-anesthetists. Anesthesiology 41, 341-344. 9. Cohen, E. N., Bruce, D. L., Cascorbi, H. F., Corbett, T. H., Jones, T. W., and Whitcher, C. E. (1974). Occupational diseases among operating room personnel: A national study. Anesthesiology 41. 10. Van Duuren, B. L., Katz, C., Goldschmidt, B. M., Frenkel, K., Sivak, A. (1972). Carcinogenicity of halo-ethers: II. Structure-activity relationships of analogs of bis (chloromethyl) ether. J. Nat. Cancer Inst. 48, 1431-1439.
