United States
Environmental Protection
Agency
Health Effects Research
Laboratory
Cincinnati OH 45268
EPA-600 ' 79-04'
October ' ^lri
Research and Development
Causes
Anes
from
Deat
Chloroform
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RESEARCH REPORTING SERIES
Research reports of the Office of Research and Development, U.S. Environmental
Protection Agency, have been grouped into nine series. These nine broad cate-
gories were established to facilitate further development and application of en-
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The nine series are:
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This report has been assigned to the ENVIRONMENTAL HEALTH EFFECTS RE-
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This document is available to the public through the National Technical Informa-
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EPA-600/1-79-043
October 1979
CAUSES OF DEATH OF
ANESTHESIOLOGISTS FROM THE
CHLOROFORM ERA
by
Harry W. Linde
and
Paul S. Mesnick
Northwestern University
Chicago, Illinois 60611
Grant No. R805473-01
Project Officer
James B. Lucas
Health Effects Research Laboratory
Cincinnati, Ohio 45268
HEALTH EFFECTS RESEARCH LABORATORY
OFFICE OF RESEARCH AND DEVELOPMENT
U.S. ENVIRONMENTAL PROTECTION AGENCY
CINCINNATI, OHIO 45268
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DISCLAIMER
This report has been reviewed by the Health Effects Research Labora-
tory, U.S. Environmental Protection Agency, and approved for publication.
Approval does not signify that the contents necessarily reflect the views
and policies of the U.S. Environmental Protection Agency, nor does mention
of trade names or commercial products constitute endorsement or recommenda-
tion for use.
ii
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FOREWORD
The U.S. Environmental Protection Agency was created because of in-
creasing public and government concern about the dangers of pollution to
the health and welfare of the American people. Noxious air, foul water,
and spoiled land are tragic testimony to the deterioration of our national
environment. The complexity of that environment and the interplay between
its components require a concentrated and integrated attack on the problem.
Research and development is that necessary first step in problem
solutions. The primary mission of the Health Effects Research Laboratory
in Cincinnati (HERL) is to provide a sound health effects data base in
support of the regulatory activities of the EPA. To this end, HERL con-
ducts a research program to identify, characterize, and quantitate harmful
effects of pollutants that may result from exposure to chemical, physical,
or biological agents found in the environment. In addition to tne valuable
health information generated by these activities, new research techniques
and methods are being developed that contribute to a better understanding
of human biochemical and physiological functions, and how these functions
are altered by low-level insults.
This report is one in a series undertaken to assess the potential
health impact of chloroform, the major by-product of chlorine disinfection
of water supplies. Such research provides a basis for decisions by the
Administrator regarding the necessity for modifying current drinking water
treatment practices. Through a better understanding of health effects,
measures can be taken to reduce exposures to potentially harmful substances.
Garner
Director
Health Effects Research Laboratory
iii
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ABSTRACT
This investigation was undertaken to determine if there were an excess
of cancer deaths occurring in anesthesiologists who practiced in an era
when chloroform was in use and to estimate the degree of chloroform usage
during that era. Causes of death of anesthesiologists dying between 1930
and 1946 were determined. They were presumed to have been in practice as
early as 1880-1890 when chloroform was one of the two most widely used
anesthetic vapors.
Names of white male anesthesiologists listed in directories for 1930-
1946 were searched in the death files of the American Medical Association.
A total of 274 deaths occurred among those listed. Copies of death certif-
icates were obtained from vital statistics offices to ascertain the cause
of death. Death from cancer occurred in 31 cases (11.3% of deaths), from
cardiovascular diseases, 173 (63.1%), from accidents and suicides, 20
(7.3%), from infection, 20 (7.3%) and from all other causes 30 (10.9%). It
was not possible to find a cause of death in 5 cases.
Death rates in this group of anesthesiologists were compared to rates
for U.S. white males, male physicians, anesthesiologists in later decades,
and life insurance policyholders. Combined death rates were lower among
anesthesiologists than the U.S. male population but exceeded them for some
cardiovascular diseases. Death rates for combined malignant neoplasms were
low, with digestive organ neoplasms being the most common. Death rates from
malignancies of the respiratory tract were unusually low. The cardiovascu-
lar disease death rate was similar to that for anesthesiologists in the next
decade although there were fewer deaths from cerebrovascular accidents and
more from heart disease. Death rates for all malignant neoplasms dropped by
about one-fifth over the subsequent two decades.
Review of the literature suggests that chloroform was used for about
two-thirds of all anesthetics in England in 1890, dropping to about one-half
by 1920 and to about zero by 1950. Overall use of chloroform in the United
States appears to have been similar at first then lower, especially in the
later years, although there was considerable regional variation in its use
with some hospitals having rates similar to those in England.
Anesthesiologists in the United States in the late 19th and early 20th
centuries appear to have been occupationally-exposed to chloroform vapor.
Their death rates from all malignant neoplasms and from those of the diges-
tive organs are somewhat greater than for anesthesiologists several decades
later. No firm conclusions on carcinogenesis can be drawn, however, because
of the small population and small number of deaths involved and the different
age distributions of the groups of anesthesiologists.
iv
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This report was submitted in fulfillment of grant R805473-01 by
Northwestern University under the sponsorship of the U.S. Environmental
Protection Agency. This report covers a period from January 1, 1930 to
December 31, 1946, and work was completed as of March 31, 1979.
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CONTENTS
Foreword iii
Abstract iv
Tables vii
Acknowledgements viii
1. Introduction 1
2. Conclusions 1
3. Materials and Methods 2
4. Results and Discussion 3
References 16
Appendix 19
vii
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TABLES
Number Page
1 White Male Anesthesiologist Population and
Age Distribution 4
2 Deaths of Anesthesiologists 1930-1946 5
3 Deaths from Malignant Neoplasms 6
4 Proportional Mortality Rates 7
5 Mortality Ratios Anesthesiologists and Physicians
to White Males 9
6 Mortality Ratios Anesthesiologists to Life Insurance
Policyholders 10
7 Comparison of Ether and Chloroform Administration in
the Late 1860' s 11
viii
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ACKNOWLEDGEMENTS
The authors gratefully acknowledge the assistance of the following:
Norbert J. Smith, Research Associate, Statistical Bureau, Metropolitan
Life Insurance Company for providing statistical advice and consultation
and mortality tables.
The American Society of Anesthesiologists and the Wood Library and
Museum for making available old records and minutes of the society, and
Patrick Sim, Librarian.
The American Medical Association for making available their death records
for study and Ms. Victoria Bigelow, Research Associate, Division of Library
and Archival Services.
David L. Bruce, M.D. for assistance in design of the study, access to
his unpublished data from previous studies and consultation.
Thomas H. Seldon, M.D. for providing old directories of the Inter-
national Anesthesia Research Society.
The Offices of Vital Statistics of the states and New York City.
Mrs. Karen McGary, Mrs. Shelia Brown and Ms. Rita Schwimmer who as-
sisted in collecting and collating data.
ix
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INTRODUCTION
Chloroform has been implicated as an animal carcinogen (1). The effect
of chloroform on man is of interest since it has been found in small quanti-
ties in some drinking water supplies and is used as a solvent in industry and
in the laboratory. Chloroform was introduced in 1847 as an inhalation anes-
thetic agent and was used for this purpose during the latter half of the 19th
century and into the 20th century. With the recognition of its side effects,
and with the introduction of newer and safer drugs, the use of chloroform de-
clined, so that by the mid 20th century, it was rarely used for this purpose.
Anesthesiologists who administered chloroform were inevitably exposed to its
vapors in sub-anesthetic concentration while the drug was being used. If we
consider anesthesiologists dying between 1930 and 1946 at an average age of
65 years and after 40 years of practice, they would have given anesthetics
between 1890 and 1946, during much of the chloroform era. If chloroform did
exert long-term toxic effects, e.g. carcinogenesis, then it would seem likely
that mortality statistics for a group of anesthesiologists would reflect this
toxicity.
This study was undertaken to identify a population of anesthesiologists
who were likely to have used chloroform, to determine the causes of death of
those who died during the years 1930 to 1946 and to examine these mortality
statistics by comparison with other groups. An additional objective was to
assess the relative usage of chloroform for anesthesia in the late 19th and
early 20th centuries.
CONCLUSIONS
Anesthesiologists who practiced during the era when chloroform was in
use as an anesthetic agent exhibited a low death rate for malignant neoplasms
in general and for any specific category of neoplasm in particular. Their
death rate for respiratory malignancies was particularly low.
The evidence from this study does not suggest that chloroform is carcin-
ogenic in man. Since it is impossible to quantitate chloroform exposures
retrospectively, neither can data from this investigation definitely refute
human carcinogenicity of this agent.
The word anesthesiologist came into use in the 1940's to describe
physicians (M.D.) who gave anesthesia to distinguish them from nonmedical
anesthetists such as nurses. It is used here to describe all physician-
anesthetists regardless of their period of practice.
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MATERIALS AND METHODS
White male anesthesiologists listed in the Directories of Anesthetists
of the International Anesthesia Research Society were chosen as the popula-
tion to be studied (2-6). The population was limited to white males by
eliminating those with a given name of the female gender, those who were
listed as female or nonwhite in the American Medical Association death file
or on the death certificate. Chloroform usage was assessed by a review of
the literature subsequent to 1870. Additional information was gathered from
discussion with manufacturers of anesthetic agents who were in business in
the early 20th century.
The total population of male anesthesiologists was obtained by counting
names that appeared in the Directories for 1930, 1935, 1938, 1941, and 1948.
The age distribution of the population for these years was obtained by se-
lecting, at random, a five percent sample of names from each of these di-
rectories. The year of birth for each individual was obtained from an Ameri-
can Medical Directory (7-10). Ages were calculated and the percentage fall-
ing within each ten-year age group, starting at age 25, was determined.
Numbers of anesthesiologists in each age group were calculated for each
calendar year. The population and age distribution for intermediate years
were obtained by linear interpolation. The names of male anesthesiologists
appearing in the Directories for the years 1930, 1935, 1938, and 1941 were
searched in the death files of the American Medical Association.
The names of all individuals found to have died between January 1, 1930
and December 31, 1946 were recorded on cards along with the date and place of
death, date of birth, age, cause of death and last known address, when these
were available. Copies of death certificates were requested from the regis-
trars of vital statistics of the various states and the City of New York to
verify or ascertain the cause of death. These data make up the observed
causes of death of male anesthesiologists, 1930-1946.
The death rates for selected diseases occurring in this population of
male anesthesiologists were compared to several other populations to examine
the differences in the causes of death. Two forms of comparison of death
rates were used, the proportional mortality rate, that is, the percentage of
the total deaths attributable to a given cause, and the observed-to-expected
mortality ratio. The populations chosen for comparison were U.S. white
males, 1930-1946 (11,12), U.S. white male physicians, 1938-1942 (13,14),
Metropolitan Life Insurance Company standard ordinary life insurance policy-
holders 1966 and members of the American Society of Anesthesiologists 1947-
1956, 1957-1966, and 1967-1972 (15,16 and unpublished data of Bruce et.
al.). Proportional mortality rate comparisons were made with anesthesiolo-
gists in later periods (1947-1972) as well as medical doctors in 1935-1942.
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Expected death rates for U.S. white males 1930-1946 were determined from
U.S. vital statistics rates (11) by averaging death rates for the years 1930,
1933, 1937, 1940, 1943, 1946 and for each ten-year age group between 25 and
84. Expected death rates for digestive and respiratory tract neoplasms and
leukemia and aleukemia were only available for 1940 (12) . These expected
death rates were adjusted to the age distribution of the anesthesiologist
population. For each ten-year age group, the number of anesthesiologists ex-
posed to the risk of death was multiplied by the expected U.S. white male
death rate to give the expected deaths of anesthesiologists. These expected
deaths were summed for ages 25-84 and compared with the observed number of
deaths. Expected death rates for male physicians (13,14) and for standard
policyholders of the Metropolitan Life Insurance Company were also age ad-
justed to the 1930-1946 anesthesiologist population. These policyholder
death rates were those used by Bruce et. al. in their studies of causes of
death of anesthesiologists (15,16). Observed-to-expected mortality ratios
for anesthesiologists as compared to contemporaneous white males for 1947-
1956 and 1957-1966 were obtained from unpublished data of Bruce, et. al.
Causes of death were classified according to 5th revision of the Internation-
al List of Causes of Death *(17) for comparison with contemporaneous vital
statistics rates and according to the 7th revision (18) for comparison with
rates for life insurance policyholders and the data of Bruce et. al. (15,16).
Deaths coded according to the fifth and earlier revisions of the Internation-
al List of Causes of Death did not include- Hodgkin's disease or leukemia as
malignant neoplasms and available vital statistics rates do not include these
diseases with malignancies.
In order to assess the validity of the mortality ratios, 95% confidence
limits were computed for the major causes of death (19).
This investigation was reviewed and approved by the Institutional Review
Board of Northwestern University.
*
See Appendix
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RESULTS AND DISCUSSION
RESULTS
Anesthesiologist Population and Deaths
The names of 274 white male anesthesiologists, who were listed in the
Directories of Anesthetists of the International Anesthesia Research Society,
and who died between January 1, 1930 and December 31, 1946, were located.
Copies of death certificates were obtained for 261 of these deaths. In 11
instances death records were not located by vital statistics offices and one
state would not release the 2 records requested without permission of next of
kin. Two certificates listed only "Natural Causes" and no further information
was available. Overall, 259 causes of death were obtained from copies of
death certificates, 10 from the American Medical Association files and 5
remain unknown.
The size and age distribution of the population of anesthesiologists who
were the subject of this study are shown in Table 1.
TABLE 1. WHITE MALE ANESTHESIOLOGIST POPULATION AND AGE DISTRIBUTION
Year 1930 1935 1938 1941 1948
Population 1119 1099 1418 1634 1972
Age Distribution % in Age Range
Ages 25-34 10.4 11.5 11.8 16.5 9.4
35-44 32.3 34.4 32.9 28.2 33.0
45-54 31.8 29.5 28.9 21.2 31.1
55-64 20.9 21.3 15.8 22.4 21.7
65-74 4.5 3.3 10.5 10.6 3.8
75 0.0 0.0 0.0 1.2 0.9
The deaths occurring among these anesthesiologists over the period 1930-1946
are given by cause and age at death (Table 2). Each death from a malignant
neoplasm is listed by diagnosis and age at death in Table 3. In Table 4,
the proportional mortality rates of this group of anesthesiologists are com-
pared to U.S. physicians 1938-1942 (13,14). In Table 5, the age-adjusted
ratios of deaths observed in the study population to those expected among
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TABLE 2. DEATHS OF ANESTHESIOLOGISTS 1930-1946
BY AGE AND CAUSE, WHITE MALES
Cause of Death* Age 25-34 35-44 45-54 55-64 65-74 75-up Total
ALL CAUSES 9 36 52 93 64 30 274
CARDIOVASCULAR RENAL 1 10 29 62 51 20 173
Vascular lesions of
the central nervous
system 0 2 7 10 13 3 35
Diseases of the heart 1 7 19 47 34 11 119
Chronic & unspecified
nephritis 0 0 2 4 1 3 10
MALIGNANT NEOPLASMS 4 1 4 11 8 3 31
Digestive 2 1 1 8 5 1 18
Respiratory 0 001001
Leukemia and aleukemia 1 000001
Lymphosarcoma 0 030003
ACCIDENTS 0 2 4 2 0 2 10
SUICIDES 0 2 4 4 0 0 10
ALL OTHER CAUSES 4 11 11 14 5 5 50
Infection, infectious
diseases 4 6 5 2 2 1 20
Causes unknown 0 021115
*See appendix
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TABLE 3. DEATHS FROM MALIGNANT NEOPLASMS
WHITE MALE ANESTHESIOLOGISTS, 1930-1946
Cause Age at Death
Carcinoma, tongue 63
Carcinoma, esophagus 69 74
Carcinoma, stomach 43 60 62 80
Carcinoma, colon 56 58
Carcinoma, rectum, rectosigmoid 33 33 53 66
Carcinoma, liver 63
Carcinoma, ampulla of Vater 55
Carcinoma, gall bladder 64
Carcinoma, pancreas 59 69
Carcinomatosis, abdominal viscera 62
Carcinoma, lung 57
Carcinoma, prostate 71 78 81
Carcinoma, kidney 62
Carcinoma, bladder 73
Seminoma, testicle 33
Melanotic sarcoma, eye 70
Lymphosarcoma retroperitoneal 53 53
Lymphosarcoma, spleen 54
Aleukemia 30
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TABLE 4. PROPORTIONAL MORTALITY RATES OF
ANESTHESIOLOGISTS AND OTHER PHYSICIANS
CARDIOVAS CULAR-RENAL
Vascular lesion of the
central nervous system
Diseases of the heart
Chronic and unspecified
nephritis
MALIGNANT NEOPLASMS
Digestive
Respiratory
Leukemia, aleukemia
Lymphoid, recticuloendo-
thelial system
ACCIDENTS
SUICIDES
ALL OTHER CAUSES
Infection, infectious
diseases
Causes unknown
DA
1930-1946*
Percent
63.1
12.8
43.4
3.6
11.3
6.6
0.4
0.4
1.1
3.6
3.6
18.2
7.3
1.8
MD
1938-1942**
Percent
60.0
10.8
40.7
5.9
10.3
4.3
1.0
0.6
***
4.6
1.9
23.9
***
1.2
* Director of Anesthetists listings, 1930-1946 (this study).
** U.S-. white male physicians, 1938-1942 (13,14).
*** A dash indicates data not available.
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contemporaneous U.S. white males are shown. Ninety-five percent confidence
limits are given for the major causes of death. For comparison, similar
mortality ratios are shown for anesthesiologists in the subsequent two dec-
ades (Bruce, et. al., unpublished data) and for U.S. physicians, 1938-1942
(13,14).
Mortality ratios were also derived by comparing the subjects of this
study to a single population, male standard ordinary policyholders of the
Metropolitan Life Insurance Company (Table 6).
The leading causes of death among anesthesiologists 1930-1946 were the
cardiovascular-renal diseases and malignant neoplasms. The same was true for
all physicians of the same era. The comparatively high rates for suicides and
the low rates for respiratory malignancies are notable. Infection and infec-
tious diseases claimed a high proportion of lives as well.
The death rate for anesthesiologists in this study is lower than that
for U.S. white males for most causes. Overall mortality from malignant neo-
plasms, as well as those of individual systems, is lower than that among the
white male population, especially for respiratory malignancies.
The death rate for all causes in the study population is similar to that
for life insurance policyholders, however, rates for certain causes do differ.
Death rates from suicides and vascular lesions of the central nervous system
are more than twice that of the policyholders. Cancer death rates are low,
with the exception of those of the digestive organs. Respiratory cancer
ratios are especially low.
Chloroform Usage
Quantitative information about the relative use of chloroform and ether
as inhalation anesthetic agents is not readily available since the literature
of the late 19th and early 20th centuries was generally descriptive.
Chloroform was first used clinically in 1847. Statistics given by Sykes
suggest that chloroform was used for about two-thirds of all anesthetics in
England in 1890, about one-half in 1920 and was rarely used by 1950 (20). In
the United States, chloroform usage varied from region to region, but was
apparently similar to England until the latter part of the 19th century, when
its use decreased more rapidly. An article by Andrews (21) on the dangers of
the two agents does contain information on the use of ether and chloroform in
the 1860's (Table 7). An editorial in 1880 (22) indicated that there was a
great deal of regional variation in the popularity of chloroform as an anes-
thetic agent in the United States and stated that "chloroform is pleasant,
rapid and sure, but dangerous, therefore we hesitate and many discard it.
Ether is slow, unpleasant, although vastly less dangerous, therefore, many
prefer chloroform.
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TABLE 5. MORTALITY RATIOS ANESTHESIOLOGISTS AND
PHYSICIANS TO U.S. WHITE MALES*
ANESTHESIOLOGISTS M.D.'s
1930-1946** 1947-1956+ 1957-1966+ 1938-1942+
CAUSE OF DEATH
ALL CAUSES 0.76 + 0.92 0.74 0.51 1.02
CARDIOVASCULAR-RENAL 1.01 + .201 1.07 0.54 1.12
Vascular lesions of the
central nervous system 1.25 0.75 0.65 1.20
Diseases of the heart 1.06 + .194 1.39 0.60 1.18
Chronic and unspecified
nephritis 0.40 1.03 2.16 — ++
MALIGNANT NEOPLASMS 0.69 0.59 0.54 0.84
Digestive 0.74ft — ++ 0.68 — ++
Respiratory 0.18+t — ++ 0.32 — ++
Leukemia and aleukemia 0.67+t 1.18 0.83 1.75
ACCIDENTS 0.34 0.22 0.49 0.71
SUICIDES 1.03 1.22 1.44 1.04
ALL OTHER 0.46 0.34 0.22 — ++
* Age-adjusted ratios of observed deaths among anesthesiologists
and other physicians to number expected among contemporaneous U.S.
white males, + 95% confidence limits where appropriate.
** This study.
+ Bruce, D.L., et. al., unpublished data.
t U.S. male physicians, data from Dublin and Spiegelman (13,14).
++ A dash indicates data not available.
tt Ratios to U.S. white male rates for 1940 (12).
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TABLE 6. MORTALITY RATIOS
ANESTHESIOLOGISTS TO LIFE INSURANCE POLICYHOLDERS*
1930-1946** 1947-1956*** 1957-1966*** 1967-1972***
CAUSE OF DEATH
ALL CAUSES 1.09 + 0.132 1.04 0.60 0.75
CARDIOVASCULAR-RENAL 1.22+0.186 1.44 0.61 0.81
Vascular lesions of
the central
nervous system
Diseases of the
heart
MALIGNANT NEOPLASMS
Digestive
Respiratory
Leukemia and aleukemia
ACCIDENTS
SUICIDES
ALL OTHER CAUSES
* Age-adjusted ratio of observed deaths among anesthesiologists to number
expected among male standard ordinary policyholders of Metropolitan Life
Insurance Company, 1966, + 95% confidence where appropriate.
** This study.
*** American Society of Anesthesiologists Members (16).
2.16
1.12 + .205
0.59
1.13
0.06
.a 0.45
0.89
2.78
1.20
1.30
1.48
0.60
0.62
0.11
1.33
0.41
2.20
0.58
0.77
0.62
0.56
0.64
0.30
0.91
0.76
2.86
0.30
0.89
0.85
0.64
0.71
0.48
0.40
0.80
2.98
0.36
10
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TABLE 7. COMPARISON OF ETHER AND CHLOROFORM
IN THE LATE 1860's (21)
Source Chloroform Ether
Chicago (Hospital and Private Records 6,726 895
Bellevue Hospital, NY (1867-1869) 600 600
U.S. Army Records 13,956 6,978
In a survey by Lumbard (23) in 1906 with 79 respondents from 23 states,
67 anesthesiologists preferred ether, 7 chloroform, and 5 were noncommittal.
The use of chloroform for major surgical procedures continued to decrease in
the United States after the turn of the century. Its use in short procedures
and particularly in obstetrics remained relatively frequent in the United
States even beyond 1940 (24). A report published by the Polk County (Iowa)
Medical Society Anesthetic Committee (25) reviewed the use of general and
local anesthesia for major surgical procedures performed at three hospitals
for the year 1923. Chloroform was used in 0.25 to 1.0 percent, ether in 62
to 90 percent and nitrous oxide in 7 to 33 percent of all anesthetics admin-
istered. Records of the Iowa Lutheran General Hospital for the years 1921,
1922 and the first six months of 1923 showed that chloroform was used in 1
percent of all anesthetics for surgery.
Chloroform continued to be used to some extent by anesthesiologists
through the 1920's and 1930's and was the focus of new study by Waters and
associates in the 1940's (26). Anesthetic grade chloroform was available
as late as 1959 (personal communication, N. Semenuk, E.R. Squibb & Sons).
11
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DISCUSSION
Sources of Information
Three sets of records form the basis of this investigation. They are
as follows: The Directories of Anesthetists of the International Anesthesia
Research Society, the death files of the American Medical Association and
vital statistics records of the states and New York City. Additionally, the
records of the American Society of Anesthesiologists and predecessor societies
were examined. These latter records, while providing some information on
deaths, are too incomplete during the era of interest to be important to
this study.
The Directories of Anesthetists were not membership lists of the Society,
but rather sought to list all anesthesiologists, regardless of affiliation.
Each directory solicited from its readers names of physicians practicing
anesthesia who were not listed. These directories are the most complete
lists of anesthesiologists available for the period and are thus a sound
basis for selection of a study population.
The American Medical Association published the American Medical Direc-
tory which is, "a Register of Legally Qualified Physicians of the United
States." The Directory was published at 2 or 3 years intervals from 1906
through 1942 and then again in 1950. To prepare this directory, the as-
sociation maintained a file with a card for each physician in the United
States. Medical school graduation lists, information from state boards of
registration in medicine, medical societies, etc. were the sources used to
prepare this file. Physicians were requested, by mail, on a regular basis
to provide information to update their listings. The file cards usually
contained the physician's name, date of birth, sex, race if other than
white, name of medical school, date of graduation, current and previous
addresses and other information such as state and date of licensure, spe-
cialty preference, etc. When notification was received of the death of a
physician, his (her) card was removed from the active file to a dead file.
When removed from the active file, the date, place and often cause of death
as well as the source of this information were added to the card. The
obituary from the Journal of the American Medical Association was often
pasted to the card. Notifications of death were received from state boards,
registrars of vital statistics, medical societies, colleagues and families
of the deceased. These records of the American Medical Association are the
most complete records available on physicians of the period. Short of
searching the vital statistics records of each state and New York City, for
the seventeen-year period, they provide the best source of information
available for this investigation.
Copies of death certificates were obtained by mail request from vital
statistics offices. In general, cooperation of vital statistics offices was
excellent, although some were slow to respond.
12
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Mortality
Deaths occurring among anesthesiologists were examined by the propor-
tional mortality rate, by the mortality ratios to contemporaneous U.S. white
males, and to life insurance policyholders (1966). These latter comparisons
were made because the desired vital statistics rates were available in ap-
propriate details (i.e., by age, race, sex, and cause) and to allow further
comparison with other physicians and with anesthesiologists in later time
periods.
The proportional mortality rate is a useful tool to examine the relative
importance of different diseases in causing death. The proportional rate
for a given cause, however, is affected not only by changes in the number of
deaths from that cause, but also by changes in numbers of deaths from other
causes.
Two comparison populations were selected for calculation of age-adjusted
observed-to-expected mortality ratios, U.S. white males, 1930-1946, and male
life insurance policyholders (1966). Contemporary white males were exposed
to the same general environment (physical, chemical, social, economic, etc.)
that the anesthesiologists were. AnesthesiologistSjhowever, being of a
higher socioeconomic class probably had better nutrition, health care, and
living conditions than the average white male. This, in turn, may have
contributed to lower death rates. Vital statistics for different socioeco-
nomic classes for that time period are not available. Life insurance policy-
holders were generally employed and of somewhat higher socioeconomic class
but were not contemporaneous.
The three leading causes of death among anesthesiologists, diseases of
the heart, vascular lesions of the central nervous system, and cancer were
the same as those for all physicians living at the same time (13,14). An-
esthesiologists had nearly double the proportion of suicides, however, data
for physicians do include those for anesthesiologists; however, this should
introduce little bias since less than 1% of all U.S. physicians were anes-
thesiologists during the study period (2-6,10).
When compared to the contemporaneous white male population, anesthesiol-
ogists have only three-fourths the expected death rate, although their rate
for cardiovascular-renal diseases are about the same. The rates are lower
for cancer, accidental death, and the residual (all other) causes. The
lower cancer rates may have been due to earlier detection and treatment.
The residual category includes the causes that were more prevalent in lower
socioeconomic classes (e.g. tuberculosis). In contrast to anesthesiolo-
gists, physicians had death rates similar to white male population (13,14).
Their cardiovascular-renal mortality ratios were similar to anesthesiologists.
The cause for this difference in mortality from all causes combined is not
clear from the available data, although cancer and accidental death ratios
are lower for anesthesiologists.
When compared by mortality ratios to white males or policyholders, an-
esthesiologists in this study had similar death rates from all causes as did
anesthesiologists 1947-1956, but were greater than those for 1957-1966 and
13
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1967-1972. This pattern prevails for the cardiovascular-renal diseases
combined, although vascular lesions of the central nervous system are a more
prominent cause, and diseases of the heart less so in the study group than in
the next decade.
Overall cancer death ratios changed little for anesthesiologists over
the years, although digestive neoplasms were greatest during the study
period. The respiratory tract neoplasm ratio increased steadily from 1930-
1946 through 1967-1972, although it never reached one-half of the expected
rate.
Digestive neoplasm mortality ratios for anesthesiologists did decrease
after 1930-1946, especially when compared to expected rates for policyholders.
It is difficult to ascribe significance to this since small numbers of
deaths are involved and also because the mortality ratio to contemporaneous
white males is low. The two types of malignant tumors observed in rodents
fed chloroform, kidney epithelial tumors in male rats and hepatocellular
carcinoma in mice of both sexes, were not a prominent cause of death of
anesthesiologists (1). In the study group of anesthesiologists there was one
death from cancer (carcinoma) in each of these organs, giving a proportional
mortality rate of 0.004% for each. Unfortunately, comparison vital statistics
are not available to calculate mortality ratios. Respiratory tract neoplasm
deaths are, in contrast, remarkably low during 1930-1946 and remain low,
although they do increase, until 1967-1972. The low rate observed by Bruce,
et. al. in the 1947-1966 study (15) led them to investigate the cigarette
smoking habits of anesthesiologists. They found no difference between an-
esthesiologists and the general population in their 1967-1972 study (27).
Since the hazards of cigarette smoking were less well recognized prior to
1946, and since cigarettes were freely advertised in medical journals, it is
unlikely that anesthesiologists smoked less than their white male contempo-
raries.
A possible, but speculative, explanation of the low incidence of res-
piratory cancer lies in the phenomenon of enzyme induction. Enzymes which
metabolize xenobiotics (chemicals foreign to the biologic system) are present
in the lung, liver, and other body tissues. Certain xenobiotics have the
ability to induce the formation of larger quantities of enzyme, which in turn
can metabolize (and often detoxify) the xenobiotic at a more rapid rate.
Many inhalation anesthetics, including chloroform do induce xenobiotic-
metabolizing enzymes in the liver (28) although their ability to do so in the
lung has not been studied. Other xenobiotics have been shown to induce
enzymes in the lung and some lung enzyme systems do metabolize carcinogens
(29). Thus, it is possible that long-term exposure to chloroform or other
anesthetics may speed the detoxification of inhaled carcinogens.
It was not possible to calculate mortality ratios to U.S. white males
for lymphosarcoma since this cause of death was not considered separately in
vital statistics rates before 1948. Data are not available for this cause of
death among the life insurance policyholders.
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Suicide
In their studies, Bruce, et._ al. found a high incidence of suicide among
anesthesiologists as compared to white males or policyholders. The rate was
also high in comparison with other physicians (except opthalmologists and
psychiatrists) (16). This does not appear to be true for anesthesiologists
1930-1946. Although their suicide rate was high when compared to white males
or policyholders in later years, it was nearly equal to contemporaneous white
males and physicians. During the depression years (1930-1940) the white male
death rate for suicide was high (11).
15
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REFERENCES
1. Report on Carcinogenesis Bioassay of Chloroform. Carcinogenesis Pro-
gram, Division of Cancer Cause and Prevention, National Cancer Insti-
tutes of Health, Bethesda, MD, March 1, 1976, 60 pp.
2. Directory of Anesthetists 1930. International Anesthesia Research
Society, Avon Lake, Ohio, 1930.
3. Directory of Anesthetists 1935. International Anesthesia Research
Society, Rocky River, Ohio, 1935.
4. Directory of Anesthetists 1938. International Anesthesia Research
Society, Rocky River, Ohio, 1938.
5. International Directory of Anesthetists 1941. International Anesthesia
Research Society, Rocky River, Ohio, 1941.
6. International Directory of Anesthetists 1948. International Anesthesia
Research Society, Rocky River, Ohio-, 1948.
7. American Medical Directory, 12th edition, American Medical Association,
Chicago, Illinois, 1931.
8. ibid.: 14th edition, 1936.
9. ibid.: 17th edition, 1942.
10. ibid.: 18th edition, 1950.
11. U.S. Department of Health, Education and Welfare, Public Health Service,
National Office of Vital Statistics: Death Rates by Age, Race, and Sex.
Vital Statistics-Special Reports 43:1956.
1. All Causes
11. Malignant Neoplasms, Including Neoplasms of Lymphatic and Hema-
topoietic Tissues.
13. Major Cardiovascular-renal Diseases
14. Diseases of Cardiovascular System
15. Vascular Lesions Affecting Central Nervous System
17. Diseases of the Heart
16
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20. Chronic and Unspecified Nephritis and Other Renal Sclerosis.
28. Motor Vehicle Accidents
29. Accidents, Except Motor Vehicle
30. Suicides
12. Grove, R.D. and Hetzel, A.M. Vital Statistics Rates in the United
States, 1940-1960. U.S. Department of Health, Education and Welfare,
Public Health Service, National Center for Health Statistics, Washington,
B.C. 1968.
13. Dublin, L.I. and Spiegelman, M. The Longevity and Mortality of American
Physicians. JAMA, 134:1211-1215, 1947.
14. Dublin, L.I., Spiegelman, M. and Leland, R.G. Longevity and Mortality
of Physicians. Postgraduate Medicine, 2:188-202, 1947.
15. Bruce, D.L., Eide, K.A., Linde, H.W. and Eckenhoff, J.E. Causes of
Death Among Anesthesiologists: A 20-year Survey. Anesthesiology, 29:
565-569, 1968.
16. Bruce, D.L., Eide, K.A., Smith, N.J., Seltzer, F. and Dykes, M.H.M. A
Prospective of Survey of Anesthesiologists Mortality. Anesthesiology,
41:71-74, 1974.
17. Manual of the International List of Causes of Death, based on the Fifth
Decennial Revision by the International Commission, Paris, October 1938,
United States Government Printing Office, Washington, D.C. 1940.
18. Manual of the International Statistical Classification of Diseases,
Injuries, and Causes of Death, 7th revision, World Health Organization,
Geneva, 1957.
19. Gershenson, H. Measurement of Mortality, Society of Actuaries, Chicago,
Illinois, 1961, pp. 174-177.
20. Sykes, W.S. Essays on the First Hundred Years of Anesthesia, Vol. II,
E and S Livingston, Ltd., Edinburgh, 1961.
21. Andrews, E. The Relative Dangers of Anesthesia By Chloroform and Ether-
Statistics of 209,893 Cases. Chicago Medical Examiner, 11:257-266, 1870.
22. Anesthetics (Editorial). Toledo Medical and Surgical Journal, 4:413-
419, 1880.
23. Lumbard, J.D. Chloroform vs. Ether, Medical Record, December 1, 1906
cited in Murphy, J.B. ed., Practical Medicine Series, Vol. II General
Surgery, Year Book Publishers, Chicago, Illinois, 1907, pp. 13-14.
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24. Lundy, J.S. Clinical Anesthesia, W.B. Saunders Co., Philadelphia, PA
1942, pp. 414-415.
25. Report of the Anesthesia Committee, Polk County Medical Society,
American Journal of Surgery, 38:59-60, 1923.
26. Waters, R.M. ed. Chloroform: A Study After 100 Years, University of
Wisconsin Press, Madison, WS, 1951.
27. Bruce, D.L., Eide, K.A., Smith, N.J., Seltzer, F. and Dykes, M.H.M.
Characteristics of the American Society of Anesthesiologists' Membership,
1967-1971. Anesthesiology, 41:67-70, 1974.
28. Linde, H.W. and Berman, M.L. Nonspecific Stimulation of Drug Metaboli-
zing Enzymes by Inhalation Anesthetics. Anesthesia and Analgesia,
50: 656-667, 1971.
29. Anderson, M.W., Philpot, R.M. and Bend, J.R., et. al. Pulmonary
Uptake and Metabolism of Chemicals by the Lung. In: Duncan, W.A.,
Leonard, B.J. eds., Clinical Toxicology, Excerpta Medica, Amsterdam,
1977, pp. 85-105.
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APPENDIX
SELECTED CATEGORIES FROM INTERNATIONAL LIST OF
CAUSES OF DEATH, 5th REVISION*
Causes of Death Code Numbers
CARDIOVASCULAR AND RENAL DISEASES 58,83,90-103,131-132
Diseases of the heart 90-95
Chronic and unspecified nephritis 131-132
Acute rheumatic fever. ; 58
Vascular lesions of the central nervous system 83
Pericarditis 90
Acute endocarditis 91
Chronic affections of the valves and endocardium 92
Diseases of the myocardium 93
Diseases of the coronary arteries and angina pectoris 94
Other diseases of the heart 95
Aneurysm 96
Arteriosclerosis 97
Gangrene 98
Other diseases of the arteries 99
Diseases of the veins 100
Diseases of the lymphatic system 101
High blood pressure 102
Other diseases of the circulatory system 103
MALIGNANT NEOPLASMS 44b,45-55,74
Lymphogranulomatosis (Hodgkin1 s disease) 44b
Cancer of the buccal cavity and pharynx 45
Cancer of the digestive organs and peritoneum 46
Cancer of the respiratory system1 47
Cancer of the uterus+ 48
Cancer of other female genital organs"1" 49
Cancer of the breast -50
Cancer of the male genital organs 51
Cancer of the urinary organs 52
Cancer of the skin 53
Cancer of the brain and other parts of the central nervous system 54
Cancer of other and unspecified organs 55
Leukemias and aleukamias 74
*Reference (17)
"hiJone observed in this study of males only
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TECHNICAL REPORT DATA
(Please read Instructions on the reverse before completing)
1. REPORT NO.
EPA-600/1-79-Q45
2.
3. RECIPIENT'S ACCESSION NO.
4. TITLE AND SUBTITLE
Causes of Death of Anesthesiologists from the
Chloroform Era
5. REPORT DATE
October 1979 issuing Hate
6. PERFORMING ORGANIZATION CODE
7. AUTHOR(S)
Harry W. Linde and Paul S. Mesnick
8. PERFORMING ORGANIZATION REPORT NO.
9. PERFORMING ORGANIZATION NAME AND ADDRESS
Northwestern University
Chicago, Illinois 60611
10. PROGRAM ELEMENT NO.
11. CONTRACT/GRANT NO.
Grant No. R805473
12. SPONSORING AGENCY NAME AND ADDRESS
Health Effects Research Laboratory- Cinn, OH
Office of Research & Development
U.S. Environmental Protection Agency
Cincinnati, Ohio 45268
13. TYPE OF REPORT AND PERIOD COVERED
Final - 1-1-30 - 12-31-46
14. SPONSORING AGENCY CODE
EPA/600/10
15. SUPPLEMENTARY NOTES
16. ABSTRACT
This investigation was undertaken to determine if there were an excess of
cancer deaths occurring in anesthesiologists who practiced in an era when chloroform
was in use and to estimate the degree of chloroform usage during that era. Causes
of death of anesthesiologists dying between 1930 and 1946 were determined.
Death rates in this group of anesthesiologists were compared to rates for U.S.
white males, male physicians, anesthesiologists in later decades, and life in-
surance policyholders. Combined death rates were lower among anesthesiologists
than the U.S. male population but exceeded them for some cardiovascular diseases.
Death rates for combined malignant neoplasms were low, with digestive organ neo-
plasms being the most common. Death rates from malignancies of the respiratory
tract were unusually low.
Anesthesiologists in the United States in the late 19th and early 20th centuries
appear to have been occupationally-exposed to chloroform vapor. Their death rates
from all malignant neoplasms and from those of the digestive organs are somewhat
greater than for anesthesiologists several decades later. No firm conclusions on
carcinogenesis can be drawn, however, because of the small population and small
number of deaths involved and the different age distributions of the groups of
17.
anescnesioiogists.
KEY WORDS AND DOCUMENT ANALYSIS
DESCRIPTORS
b.lDENTIFIERS/OPEN ENDED TERMS C. COSATI Field/Group
Chloroform, epidemiology, malignant
neoplasms, heart diseases, anesthesiolo-
gy, physicians, mortality
06/J
18. DISTRIBUTION STATEMENT
Release to Public
19. SECURITY CLASS (ThisReport)'
Unclassified
21. NO. OF PAGES
30
20. SECURITY CLASS (Thispage)
Unclassified
22. PRICE
EPA Form 2220-1 (Rev. 4-77)
PREVIOUS EDITION IS OBSOLETE
U.S. GOVERNMENTPRIHTOIGOFFICE: 1979-657-146/5486
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