from HSDB http://toxnet.nlm.nih.gov/cgi-bin/sis/search/f?./temp/~AAA1GaGSU:1
Human Health Effects:
Evidence for Carcinogenicity:
A2; Suspected human carcinogen.
Evaluation: There is limited evidence in humans for the carcinogenicity of ethylene
oxide. There is sufficient evidence in experimental animals for
the carcinogenicity of ethylene oxide. In
making the overall evaluation, the Working Group took into consideration the
following supporting evidence. Ethylene oxide is
a directly acting alkylating agent that: (1) induces a sensitive, persistent
dose-related increase in the frequency of chromosomal aberrations and sister
chromatid exchange in peripheral lymphocytes and micronuclei in bone marrow
cells of exposed workers; (2) has been associated with malignancies of the
lymphatic and hematopoietic system in both humans and experimental animals; (3)
induces a dose related increase in the frequency of hemoglobin adducts in
exposed humans and dose related increases in the numbers of adducts in DNA and
hemoglobin in exposed rodents; (4) induces gene mutations and heritable
translocations in germ cells of exposed rodents; and (5) is a powerful mutagen
and clastogen at all phylogenetic levels. Overall evaluation: Ethylene
oxide is carcinogenic to humans (Group 1).
Human Toxicity Excerpts:
INHALATION CAUSES NAUSEA, VOMITING, NEUROLOGICAL DISORDERS, & EVEN DEATH.
TRACES OF GAS IN GLOVES OR CLOTHING MAY CAUSE BURNS. ... RESIDUES IN VASCULAR
CATHETERS CAN CAUSE THROMBOPHLEBITIS; IN ENDOTRACHEAL TUBES, TRACHEITIS.
... A pulmonary irritant if inhaled
... MAY BE DESCRIBED AS A CENTRAL DEPRESSANT, AN IRRITANT ... CONTACT WITH
... DILUTE SOLN MAY CAUSE IRRITATION & NECROSIS OF EYES ... BLISTERING ...
& NECROSIS OF SKIN. EXCESSIVE EXPOSURE MAY CAUSE IRRITATION OF ... LUNGS,
& CENTRAL DEPRESSION.
Conjunctivitis, dyspnea, cough, vertigo, nausea and vomiting, abdominal pain,
parasystole, arrhythmia, pulmonary edema, and paralysis.
The incidence of spontaneous abortions among hospital staff who used ethylene
oxide, glutaral (glutaraldehyde) and formaldehyde for the
chemical sterilization of instruments was studied using data from a
questionnaire and a hospital discharge register. Results showed that the
frequency of spontaneous abortions was 11.3% for the sterilizing staff and 10.6%
for the nursing auxiliaries (controls). When the staff were concerned in
sterilizing during their pregnancy the frequency was 16.7% compared with 5.6%
for the nonexposed pregnancies. The incr frequency ... correlated with exposure
to ethylene oxide but not with
exposure to glutaral or formaldehyde.
Accidental exposure of a person to an estimated concn of 500 ppm in air for
2-3 min was enough to cause temporary unconsciousness and seizures, but
apparently did not produce ocular symptoms.
A report of 1st to 3rd degree burns occurring postoperatively or postpartum
in 19 women. The gowns and sheets used were found to contain 16-50 times the
safe residual concn of ethylene oxide.
Workers who had been employed for more than one year by a company producing ethylene
oxide had been studied from 1960-1961. No significant
differences had been found between workers permanently working in the ethylene
oxide manufacturing area, those who had previously worked in
this area, those working there intermittently and a further group who had never
worked in ethylene oxide production.
However, a subgroup of individuals with high exposure had decreased hemoglobin
concn and signficant lymphocytosis. When workers were followed up from
1961-1977, those who had been exposed full-time to ethylene
oxide production showed a considerably excess mortality, this
being mainly due to an increased incidence of leukemia, stomach cancer and
diseases of the circulatory system. Although malignancies could not be linked to
any particular chemical associated with ethylene oxide
production it was considered that ethylene
oxide and ethylene dichloride, possibly together with ethylene
chlorohydrin or ethylene, were the causative agents.
The permeation of ethylene oxide through
human skin was determined in vitro. Permeation studies were performed with
excised skin in diffusion cells. Ethylene oxide shows
that it permeated quickly. The health hazard involved in the use of ethylene
oxide in sterilization of medical goods is discussed.
Chronic ethylene oxide poisoning
occurred collectively in four sterilizing workers of a factory manufacturing
medical appliances in Izumo, Japan. All the patients presented with symptoms of
multiple neuropathy, of which the chief complaints were sensory disturbance of
the lower limbs and gait disturbance. One of the patients presented with
delirium and visual hallucinations. ... Clinical observations of the poisoning
/were analyzed/ and the causal factors from the standpoint of industrial
epidemiology and safety measures for the future /were discussed/.
Chromosome aberration frequencies in 61 employees potentially exposed to ethylene
oxide were compared with those in unexposed control groups.
Three worksites /were studied/ with differing historical ambient levels of ethylene
oxide. Within worksites, groups were classified as high
potential exposed, low potential exposed, or controls. Further control groups
including an off-site community control group were added to give a total of 304
control individuals. Blood samples were drawn several times over a 24-month
period. Aberrations were analyzed in 100 cells per sample after culture for
48-51 hours. Worksites I, II, and III respectively represented increasing levels
of potential ethylene oxide exposure.
At worksites I and II, no consistent differences in aberration frequencies were
found among groups. At worksite III aberration frequencies in potentially
exposed individuals were significantly increased compared with controls. The
frequencies of cells with aberrations were 5.6% for the 2 individuals in the
high potential exposure category and 2.6% for 23 persons in the low potential
exposure group. The overall frequency of cells with aberrations in the matched
control individuals was 1.4%. In the total control group of 304 individuals, ...
significant increases in aberrations associated with smoking and increasing age
/were found/.
A retrospective cohort study was performed on a group of 664 male workers
employed for at least one month during the period 1942-1979 in a chemical
factory. Both established and suspected carcinogens had been handled in the
plant, primarily piperazine, but also urethane, ethylene
oxide, formaldehyde, and organic solvents. A significantly
increased mortality, compared with the regional death rate, was observed in the
cohort. The increase was mainly due to violent deaths and cardiovascular
diseases. A statistically significant increase in cancer morbidity was observed
for malignant lymphoma/myelomatosis when an induction latency time /minimum/ of
10 years was used. Furthermore, an increase in bronchial cancer was noted, but
it was statistically significant only when an induction-latency time /minimum
of/ 15 years was used.
Samples of blood were collected from a group of plant workers engaged in the
manufacture of ethylene oxide for
periods of up to 14 yr, and also from a group of control personnel matched by
age and smoking habits. Peripheral blood lymphocytes were cultured for
cytogenetic analysis. Selected immune and hematological parameters were also
investigated. The results of these studies showed no statistically significant
difference between the group of plant workers and the control group in respect
to any of the biological parameters investigated in this study. Nevertheless,
duration of employment in ethylene oxide manufacturing
was positively correlated (p< 0.05) with the frequency of chromosome breaks
and with the percentage of neutrophils in a differential white blood cell count,
and negatively correlated (p< 0.05) with the percentage of lymphocytes. As
the values of these parameters remained within the normal limits of control
populations, the correlations were considered to have no significance for
health. The amount of alkylation (2-hydroxyethyl groups) of the Nt atom of
histidinyl residues in hemoglobin was also measured in an attempt to gauge
recent individual exposures to ethylene oxide. Variable
but, in most instances, readily measurable amounts of Nt- (2'-hydroxyethyl)-L-histidine
(Nt represents the N3 atom of histidine) were found in the hemoglobin of plant
workers and in the control group who had not knowingly been exposed to an
exogenous source of ethylene oxide. There
was no statistically significant difference between the results obtained in the
control group and in the group of plant workers.
A study was made of the effects of ethylene oxide on
the health of sterilizer workers and other personnel exposed while using ethylene
oxide for sterilization of disposable medical devices. The only
significant findings were obtained by chromosomal analysis of cultured
lymphocytes harvested from the workers. There were significant differences in
the numbers and types of chromosomal aberrations between the exposed workers and
the nonexposed controls. Quadriradial and triradial chromosomal forms, which
were rarely found in nonexposed populations, were increased in exposed workers.
Increased numbers of sister chromatid exchanges was found in the cultured
lymphocytes of some, but not all, exposed persons during the 2 yr of study.
Workers (13) were removed from exposure in 1979 because of increased numbers of
aberrant cells. Follow-up over 4 yr did not show a significant improvement,
except for a moderate reduction in sister chromatid exchanges. Recommendations
were given for a surveillance of persons working with or exposed to ethylene
oxide.
... Dialyzer hypersensitivity syndrome presents as an acute anaphylactoid
reaction, the symptoms of which may range from mild to life threatening in
severity. The cause of this syndrome is unknown, but affected patients appear to
have a high incidence of positive radioallergosorbent tests to a conjugate of
human serum albumin and ethylene oxide, suggesting
that ethylene oxide, a substance used
to dry sterilize artificial kidneys, may be an offending allergen.
Samples of peripheral blood were collected from 33 men who were employed in
the manufacture of ethylene oxide for
between 1 and 14 yr, and from 32 men from other parts of the same plant who were
used as controls. Their lymphocytes were analyzed for chromosome damage. There
were low frequencies of polyploidy, chromatid aberrations and chromosome breaks
in the cells of the 65 men. A slightly higher frequency of chromatid aberrations
was observed in the cells of the ethylene oxide workers
than in those of the controls. There was a positive correlation between length
of employment in the ethylene oxide group
and the numbers of aberrations in the cultures of each individual. This trend
was not solely attributable to the age of the men. The levels of chromatid and
chromosome damage observed in this study are consistent with those in humans who
were not recently exposed to known chromosome-breaking agents.
EXPOSURE TO LOW VAPOR CONCN OFTEN RESULTS IN DELAYED NAUSEA AND VOMITING.
HIGHER CONCN PRODUCE IRRITATION OF EYES, NOSE, AND THROAT; HIGH CONCN MAY CAUSE
EDEMA OF LUNGS. CONTACT WITH SKIN CAUSES BLISTERING AND BURNS.
Concern about the possible adverse influence of the workplace environemnt on
reproduction now extends to women health professionals. ... A postal survey of
all women who graduated from US veterinary schools during the period 1970-1980
(n = 2,997; response rate = 90.2%) /was conducted/. Occupational and
reproductive histories were obtained, and spontaneous abortion risks were
estimated with respect to self-reported exposure to radiation, ethylene
oxide, halothane and other anesthetic gases, and pesticides. Of
the 2,174 pregnancies among cohort members who had one veterinary job at the
time of conception, 83.3% of the conceptions occurred while the veterinarian
held a job that involved exposure to pesticides, 63.2% involved exposure to
radiation, 61.9% to anesthetic gases other than halothane, 50.7% to halothane,
and 14.0% to ethylene oxide. Agent-specific
spontaneous abortion risks were estimated for the exposed/unexposed pregnancies,
and risk ratios adjusted for gravidity, history of spontaneous abortion, age and
alcohol and tobacco use were derived by means of logistic regression. Estimated
risk ratios were close to 1.0, and no effect was seen for hours worked per week,
a measure of exposure intensity. Despite no apparent influence of the exposures
on spontaneous abortion risk, caution must be exercised in interpretation of
these results because of potential exposure misclassification. Importantly, the
results emphasize the extent to which women veterinarians may be exposed to
reproductive hazards while pregnant.
Eight hospital workers with chronic ethylene oxide exposure
were age-sex matched with eight nonexposed controls with no significant
differences in educational backgrounds and vocabulary scores. The exposed group
performed more poorly on all eight measures of cognition, memory, attention, and
coordination, with 71.3% less accuracy on the Hand-Eye Coordination Test. There
was a dose-response relationship between exposure and the following: Continuous
Performance Test and sural velocity. These findings suggest that neurologic
dysfunction may result from long-term low-dose exposure to ethylene
oxide, and that these effects may occur at exposure levels
common in hosptial sterilizer operations.
Ethylene oxide is an alkylating
agent and a model direct-acting mutagen and carcinogen. This study has evaluated
a panel of biologic markers including ethylene oxide-hemoglobin
adducts, sister-chromatid exchanges, micronuclei, chromosomal aberrations, DNA
single-strand breaks and an index of DNA repair (ratio of unscheduled DNA
synthesis to NA-AF-DNA binding) in the peripheral blood cells of 34 workers at a
sterilization unit of a large university hospital and 23 controls working in the
univer library. Comprehensive environmental histories were obtained on each
subject including detailed occupational and smoking histories. Industrial
hygiene data obtained prior to the study and personal monitoring during the 8
years preceding the study showed that workers were subject to low level exposure
near or below the current Occupational Safety and Health Administration (OSHA)
standard of 1 ppm (TWA). Personal monitoring data obtained during 2 weeks prior
to blood sampling were uniformly less than 0.3 ppm (TWA). After adjusting for
smoking, ethylene oxide workplace
exposure was significantly (p< 0.001) associated with ethylene
oxide hemoglobin (a carcinogen protein adduct) and 2 measures of
sister chromatid (the average number of sister chromatid exchanges/cell (SCE50)
and the number of high frequency cells (SCEHFC). There was an apparent
suppression of DNA repair capacity in ethylene oxide exposed
individuals as measured by the DNA repair index; ie, the ratio of unscheduled
DNA synthesis and NA-AAF-DNA binding (p< 0.01). No association of DNA repair
index with smoking was found. Another important finding of this study is the
highly significant correlation between ethylene oxide-hemoglobin
adduct levels and SCEHFC (p< 0.01) and sister-chromatid exchanges (p<
0.02) which provides evidence of a direct link between a marker of biologically
effective dose and markers of genotoxic response. In contrast, micronuclei,
chromosomal aberrations and single-strand breaks were not significantly elevated
in the workers. The activity of the u-isoenzyme of glutathione-S-transferase was
measured as a possible genetic marker of susceptibility and a modulator of
biomarker formation. However, possibly because of confounding by age, no
significant relationships were found between glutathione-S-transferase and any
of the exposure-related markers by ANOVA or among other independent variables by
regression.
A multicenter cohort study was carried out to study the possible association
between exposure to ethylene oxide and
cancer mortality. The cohort consisted of 2658 men from eight chemical plants of
six chemical companies in the Federal Republic of Germany who had been exposed
to ethylene oxide for at least one
year between 1928 and 1981. The number of subjects in the separate plants varied
from 98 to 604. By the closing date of the study (31 December 1982) 268 had
died, 68 from malignant neoplasms. For 63 employees who had left the plant
(2.4%) the vital status remained unknown. The standardized mortality ratio for
all causes of death was 0.87 and for all malignancies 0.97 compared with
national rates. When local state rates were used the standardized mortality
ratio were slightly lower. Two deaths from leukemia were observed compared with
2.35 expected standardized = 0.85). Standardized mortality ratios for carcinoma
of the esophagus (2.0) and carcinoma of the stomach (1.38) were raised but not
significantly. In one plant an internal "control group" was selected
matched for age, sex, and date of entry into the factory and compared with the
exposed group. In both groups a "healthy worker effect" was observed.
The total mortality and mortality from malignant neoplasms was higher in the
exposed than in the control group; the differences were not statistically
significant. There were no deaths from leukemia in the exposed group and one in
the control group.
We have applied the micronucleus assay to exfoliated cells of buccal and
nasal cavities to monitor the genotoxic risk in a group of workers exposed to
chromic acid and in another group exposed to ethylene
oxide. The first group comprised 16 subjects working in a hard
type chrome plating factory showing increased chromium absorption and chromium
induced rhinopathy. The second group comprised 9 subjects working in a
sterilization unit, exposed to ethylene oxide concentrations
lower than 0.38 ppm as timed weighted average for a working shift; 3 of them
were involved in a acute exposure too. The frequency of micronucleus in buccal
mucosa was within the norm for exposure both to chromium and to ethylene
oxide. The micronucleus frequency in nasal mucosa was not
altered in chromium platers, whereas a significant increase (p less than 0.01)
in micronucleus was found in 2 out of 3 subjects involved in the accidental ethylene
oxide leakage and a non-significant increase in micronucleus was
found in the group chronically exposed to ethylene
oxide.
Work practices as well as personal and environmental exposure levels were
reported among ethylene oxide sterilizer
operators in health care facilities in the province of Alberta, Canada. A survey
was undertaken between October of 1985 and September of 1986 concerning the use
of and exposure to ethylene oxide in
174 hospitals. The first part of the survey considered all hospitals with ethylene
oxide sterilizers, inquiring about their use at the facility.
The second part of the survey queries workers (14 men and 151 women) concerning
their work history and health status. While no detectable levels of ethylene
oxide were found in environmental samples, over half of the
respondents stated they could smell ethylene oxide at
work. While sampling results never indicated concentrations above the provincial
15 minute time weighted average short term exposure limit of 50 ppm, personal
exposure concentrations and the use of portable sterilizers were positively
associated with short term symptoms such as irritations of the mucous membranes
and skin. Life style behavior and exposure to other chemical irritants were not
considered in the course of this study.
A retrospective cohort study was conducted to examine the mortality
experience of 2174 men employed between 1940 and 1978 by a large chemical
company and who had been assigned to a chemical production department that used
or produced ethylene oxide. Comparisons
were made with the general United States population, the regional population,
and with a group of 26,965 unexposed men from the same plants. Comparisons with
general United States death rates showed fewer deaths than expected in the ethylene
oxide group due to all causes and for total cancers. There was
no statistically significant excess of deaths due to any cause. Seven deaths
each due to leukemia and pancreatic cancer were observed with 3.0 and 4.1 deaths
expected. Among the subcohort of men who worked where both average and peak
exposure levels were probably highest, however, one death due to pancreatic
cancer (0.9 expected) and no deaths due to leukemia were observed. Four of the
seven who died from leukemia and six of the seven died from pancreatic cancer
had been assigned to the chlorohydrin department where the potential for
exposure to ethylene oxide is judged
to have been low. The relative risk of death due to each disease was strongly
related to duration of assignments to that department. When men who worked in
the chlorohydrin department were excluded, there was no evidence for an
association of exposure to ethylene oxide with
pancreatic cancer or leukemia. Together with the failure to show independent ethylene
oxide associations, the chlorohydrin department results suggest
that leukemia and pancreatic cancer may have been associated primarily with
production of ethylene chlorohydrin or propylene chlorohydrin, or both. These
results emphasize the importance of examing additional concurrent asynchronous
exposures among human populations exposed to ethylene
oxide.
An epidemiological study was conducted in 55 subjects (mean age: 41) in
hospitals to determine the prevalence of lens opacities and cataracts in workers
exposed to ethylene oxide in six
sterilization units. The relation between occupational exposure to ethylene
oxide and white blood cell concentrations was also investigated.
Lens opacities were observed in 19 of the 55 exposed. No link was found between
the characteristics of the lens opacities and the characteristics of exposure.
For cataracts, their prevalence differed significantly between the exposed (six
of 21) and the non-exposed (0 of 16); there was no relation between their
existence and overexposures. The risk of lens opacifications by ethylene
oxide could also exist during chronic exposure to low
concentrations. Linear relations were found between the logarithm of the
cumulative exposure index and the logarithms of blood concentrations of
polymorphoneutrophils.
A cohort study was carried out of mortality among 2876 men and women exposed
to ethylene oxide during its
manufacture and use in England and Wales. The study cohort included employees
from three companies producing ethylene oxide and
derivative compounds such as polyethylene glycols and ethoxylates, from one
company that manufactured alkoxides from ethylene
oxide and from eight hospitals with ethylene
oxide sterilizing units. While industrial hygiene data were not
available before 1977, since then the time weighted average exposures have been
less than 5 ppm in almost all jobs and less than 1 ppm in many. Past exposures
were probably somewhat higher. In contrast to other studies, no clear excess of
leukemia was noted (three deaths occurred versus 2.09 expected), and no increase
in the incidence of stomach cancer (five deaths occurred versus 5.95 expected)
was observed. This lack of consistency with the results of earlier studies may
be due to differences in exposure levels. Total cancer mortality was similar to
that expected from national and local death rates from this disease. Small
excesses were noted in some specific cancers, but their relevance to ethylene
oxide exposure was doubtful. No excess of cardiovascular disease
was found. While the results of this study did not exclude the possibility that ethylene
oxide is a human carcinogen, they suggested that any risk of
cancer from currently permitted occupational exposures is small.
Ethylene oxide is widely used to
sterilize heat-sensitive materials. Acute and chronic neurogenic effects to the
central and peripheral nervous system in man and animals have been described. A
cross-sectional study of 25 hospital central supply workers exposed to low
levels of ethylene oxide and 24
unexposed control workers was conducted. Subjects were tested with a
neuropsychological screening battery by examiners blinded to exposure status.
Results were reviewed independently by 2 neuropsychologists without knowledge of
exposure. Subject status was categorized as normal, impaired, or disagreement
(between the two neuropsychologists). There were more subjects concordantly
judged as impaired in the exposed group than in the control group. Although
limited by the cross-sectional study design and the global categorization, these
findings suggest that central nervous system dysfunction and cognitive
impairment may result from chronic ethylene oxide exposure
in hospital central supply units.
Ethylene oxide is used to
chemically sterilize heat-sensitive materials in hospitals. Neurotoxic effects
of ethylene oxide have been described
in animals and humans; cognitive deficits may be associated with chronic low
level ethylene oxide exposure. In this
study, hospital workers with chronic ethylene oxide exposure
were compared with a non-exposed control group to detect neurological and
neuropsychological abnormalities. Ethylene oxide breathing
zone levels of up to 250 ppm in exposed subjects were reported. The exposed
group had lower P300 amplitude in electroencephalographic (EEG) tests,
bilaterally hypoactive distal deep tendon reflexes and poorer performance on
neuropsychological tests involving psychomotor speed. Exposed subjects
acknowledge more symptoms and higher levels of depression and anxiety. Nerve
conduction velocities and EEG spectral analysis were simialr in both exposed and
control groups as were scores on most psychological tests.
A 43 yr old female licensed practical nurse, while sterilizing heat sensitive
medical items, accidentally dropped and broke an ampule containing 17 gm epoxyethane.
While disposing of the broken ampule, she began to experience nausea and stomach
spasms. The exposure was estimated to have been of 2-3 min duration and not to
have exceeded 500 ppm. Upon leaving the contaminated room, she became pale,
lightheaded, and passed out for approximately 3-4 min. Convulsive movements of
her arms and legs were noted during a 1-min period of apnea. She was given
oxygen, began breathing, and awoke instantly without confusion or nausea.
Approximately 3 min later she again felt nausea, stomach spasms, and
lightheadedness and became apneic and passed out. Twitching of the extremities
occurred and she was given oxygen again. Arterial blood gases, chest X rays, and
routine laboratory measurements performed at that time were normal. During the
24 hr following discharge she continued to complain of random muscle twitches,
nausea, and malaise.
The presence of ethylene oxide in
dialysis tubing has been suggested as a possible cause of allergic reactions in
some patients. Ethylene oxide also is
a pulmonary irritant when inhaled. It is too toxic to be applied topically as an
antiseptic.
Three cases of hematopoietic cancer that had occurred been 1972 and 1977
/were reported/ in workers at a Swedish factory where 50% ethylene
oxide and 50% methyl formate had been used since 1968 to
sterilize hospital equipment. Attention had been drawn to the case cluster by
the factory safety committee. One woman with chronic myeloid leukaemia and
another with acute myelogenous leukaemia had worked in a storage hall where they
were exposed for 8 hr per day to an estimated 20 plus or minus 10 (SD) ppm (36
plus or minus 18 mg/cu m) ethylene oxide. The
third case was that of a man with primary macroglobulinemia (morbus Waldenstrom)
who had been manager of the plant since 1965 and had been exposed to ethylene
oxide for an estimated 3 hr per week. (The Working Group noted
that Waldenstrom's macroglobulinemia is classified in ICD /International
Classification of Diseases codes/ 10 as a malignant immunoproliferative
disease.)
Two hundred and three workers employed for at least one year at /a Swedish
factory where 50% ethylene oxide and
50% methyl formate had been used since 1968 to sterilize hospital equipment/
were subsequently followed up for mortality. During 1978-82, five deaths
occurred (4.9 expected), of which four were from cancer (1.6 expected). Two of
the deaths were from lymphatic and hematopoietic cancer (0.13 expected), but one
of these decedents had been part of the original case cluster that had prompted
the study.
A retrospective cohort study /was reported/ of 767 men employed at a chemical
plant in eastern Texas, USA, between 1955 and 1977 where ethylene
oxide was produced. All of the men had worked at the factory for
at least five years and were potentially exposed to the compound. Potential
exposure to ethylene oxide was
determined by personnel at the company on the basis of work histories. In an
industrial hygiene survey in all samples taken in the ethylene
oxide production area contained less than 10 ppm (18 mg/cu m).
Vital status was ascertained for more than 95% of cohort members from a
combination of plant records, personal knowledge and telephone follow-up.
Altogether, 46 deaths were recorded, whereas 80 were expected on the basis of US
vital statistics. Death certificates were obtained for 42 of the 46 deceased
subjects. Eleven deaths were from cancer (15.2 expected), and nonsignificant
excesses were seen of cancers of the pancreas (3/0.8) and brain and central
nervous system (2/0.7) and of Hodgkin's disease (2/0.4); no death from leukaemia
was found.
18,254 employees at 14 US industrial plants where ethylene
oxide had been used to sterilize medical supplies or spices or
in the testing sterilizing equipment /were followed/. The plants were selected
because they held adequate records on personnel and exposure and their workers
had accumulated at least 400 person-years at risk before 1978. Only workers with
at least three months of exposure to ethylene oxide were
included in the cohort. Forty five percent of the cohort were male, 79% were
white, 1,222 were sterilizer operators and 15,750 were employed before 1978.
Analysis of 627 8 hr personal samples indicated that average exposure during
1976-85 was 4.3 ppm (7.7 mg/cu m) for sterilizer operators; the average level
for other exposed workers, on the basis of 1,888 personal samples, was 2.0 ppm
(3.6 mg/cu m). Many companies began to install engineering controls in 1978, and
exposures before that year were thought to have been higher. There was no
evidence of confounding exposure to other occupational carcinogens. The cohort
was followed to 1987 through the national death index and records of the Social
Security Administration, the Internal Revenue Service and the US Postal Service,
and 95.5% were traced successfully. The expected numbers of deaths were
calculated from rates in the US population, stratified according to age, race,
sex and calendar year. In total, 1,177 cohort members had died (1,454.3
expected), including 40 for whom no death certificate was available. There were
343 deaths from cancer (380.3 expected). The observed and expect numbers of
deaths were 36/33.8 from all lymphatic and hematopoietic cancer, including 8/5.3
from lymphosarcoma-reticulosarcoma (ICD9 200), 4/3.5 from Hodgkin's disease,
13/13.5 from leukaemia, 8/6.7 from non-Hodgkin's lymphoma (ICD9 202) and 3/5.1
from myeloma; 6/11.6 from cancer of the brain and nervous system; 11/11.6 from
cancer of the stomach; 16/16-9 from cancer of the pancreas; 8/7.7 from cancer of
the oesophagus; and 13/7.2 from cancer of the kidney. Mortality ratios for
subjects first exposed before 1978 were virtually identical to those for the
full cohort. No significant trend in mortality was observed in relation to
duration of exposure, but the mortality ratios for leukaemia (1.79 based on five
deaths) and non-Hodgkin's Lymphoma (1.92 based on five deaths) were higher after
allowance for a latency of more than 20 years. Among the sterilizer operators,
mortality ratios (and observed numbers of deaths) were 2.78 (two) for leukaemia
and 6.68 (two) for lymphosarcoma/reticulosarcoma; no death from stomach cancer
was seen.
Repeat plasma donors were studied to determine whether there was a
relationship between allergic-type reactions during plasmapheresis and IgE-dependent
sensitization to ethylene oxide gas
used for sterilization of disposable fluid administration sets. Serums from 32
donors with allergic-type reactions and 84 donors who had no reactions but were
exposed to the same materials and served as controls were tested for IgE
antibodies to ethylene oxide. The
results, expressed as an IgE ethylene oxide index,
were greater than 2 in 78% of serums from donors with allergic and 12% of serums
from controls. This association was significant (p< 0.0001). Reactivity of
the antibodies was directed against an ethylene oxide-human
serum albumin conjugate and not against human serum albumin carrier protein. IgG
antibodies with ethylene oxide specificity
also were present in the serums of repeat plasmapheresis donors. Each of seven
rabbits immunized with an ethylene oxide-protein
conjugate responded with a high serum level of antibody with ethylene
oxide specificity. It was concluded that the residual ethylene
oxide in fluid administration sets is immunogenic and may cause
allergic reactions in plasma donors.
Chromosomal aberrations and micronuclei in lymphocytes were measured in
workers exposed to propylene oxide in a factory producing alkylated starch, and
in workers exposed to ethylene oxide in
connection with sterilization of medical equipment. Adduct levels in hemoglobin
were determined as a measure of in vivo doses of the two compounds. The levels
of hydroxypropylvaline in propylene oxide exposed workers were correlated in
estimated exposure doses. The levels of this adduct in the unexposed group were
close to the detection limit of the method. The levels of hydroxyethylvaline,
recorded in the propylene oxide-exposed group were consistent with earlier data
on hemoglobin alkylation in occupationally unexposed subjects. The adduct
measurements revealed increased levels of hydroxyethylvaline in the two
subgroups of ethylene oxide-exposed
workers, ie, assemblers with a low and sterilizers with a high exposure.
According to expectation the subgroups differed in adduct levels. The results of
the cytogenetic study showed that the clastogenic potency of propylene oxide was
lower than that of ethylene oxide, since
the propylene oxide-exposed individuals had lower frequencies of micronuclei and
chromosomal breaks compared to the assemblers despite a lower adduct level in
the last group.
Cases of human ethylene oxide (EtO)
neuropathy were reviewed and the clinical features characterized. ... The 12
patients with EtO toxicity selected for review were each engaged ln sterilizing
work with EtO in the factory or hospital. Sensorimotor neuropathy developed in
two patients within 3 and 5 months of exposure. They had been repeatedly exposed
to EtO for up to several hundred ppm. Complaints included muscle weakness
hypesthesia and a tingling sensation in distal lower limbs although distal upper
limbs were also sometimes involved. Ten of the 12 demonstrated muscle weakness
in neurological examinations. Needle EMG revealed neurogenic changes in eight.
Histological studies of the sural nerve biopsied in three patients demonstrated
mild abnormalities. Cerebrospinal fluid studies showed elevated protein in two
of six patients. ...
Mortality from cancer among workers exposed to ethylene
oxide (EtO) has been studied in 10 distinct cohorts that include
about 29800 workers and 2540 deaths. This paper presents a review and
meta-analysis of these studies, primarily for leukemia, nonHodgkin's lymphoma,
stomach cancer, pancreatic cancer, and cancer of the brain and nervous system.
The magnitude and consistency of the standardized mortality ratios (SMRs) were
evaluated for the individual and combined studies, as well as trends by
intensity or frequency of exposure, by duration of exposure, and by latency
(time since first exposure). Exposures to other workplace chemicals were
examined as possible confounder variables. Three small studies ... initially
suggested an association between EtO and leukemia, but ln seven subsequent
studies the SMRs for leukemia have been much lower. For the combined studies the
SMR = 1.06 (95% confidence interval (95% CI) 0.73-1.48). There was a slight
suggestion of a trend by duration of exposure (p = 0-19) and a suggested incr
with longer latency (p = 0.07), but there was no overall trend in risk of
leukemia by intensity or frequency of exposure; nor did a cumulative exposure
analysis in the largest study indicate a quantitative association. There was
also an indication that ln two studies with Increased risks the workers had been
exposed to other potential carcinogens. For non-Hodgkin's lymphoma there was a
suggestive risk overall (SMR = 1.35, 95% CI 0.93-1.90). Breakdowns by exposure
intensity or frequency, exposure duration, or latency did not indicate an
association, but a positive trend by cumulative exposure (p = 0.05) was seen In
the largest study. There was a suggested incr ln the overall SMR for stomach
cancer (SMR = 1.28, 95% CI 0.98-1.65 (CI 0.73-2.26 when heterogeneity among the
risk estimates was taken Into account)), but analyses by intensity or duration
of exposure or cumulative exposure did not support a causal association for
stomach cancer. The overall SMRs and exposure-response analyses did not indicate
a risk from EtO for pancreatic cancer (SMR = 0.98), brain and nervous system
cancer (SMR = 0.89), or total cancer (SMR = 0.94). Although the current data do
not provide consistent and convincing evidence that EtO causes leukemia or
non-Hodgkin's lymphoma, the issues are not resolved and await further studies of
exposed populations.
Ethylene oxide (EtO) induced
mutations in the hypoxanthine-guanine phosphoribosyltransferase (HPRT) gene were
characterized in 28 independently derived 6-thioguanine resistant human diploid
fibroblast clones using polymerase chain reaction based techniques and Southern
blot analysis. Sequence analysis revealed one single base pair deletion and 13
base substitutions nine of which were transversions: five AT-TA three GC-TA and
one GC-CG. Four mutants were found to have GC-AT transitions. Seven of the point
mutations caused splicing errors. Six occurred in splice site sequences and one
created a new splice acceptor site 16 bp upstream of exon 9. Three splice
mutations were localized at the same site in the splice donor sequence of intron
8. Fourteen mutants had large HPRT gene deletions. In seven mutants the entire
HPRT gene was deleted. The remaining deletion mutants had a truncated HPRT gene
where one or several exons were lost. These results show that EtO induces many
different kinds of HPRT mutations, among which as many as 50% are large
deletions.
A cohort of 1971 chemical workers licensed to handle ethylene
oxide was followed up retrospectively from 1940 to 1984 and the
vital status of each subject was ascertained. No quantitative information on
exposure was available and therefore cohort members were considered as
presumably exposed to ethylene oxide. The
cohort comprised 637 subjects allowed to handle only ethylene
oxide and 1334 subjects who obtained a license valid for ethylene
oxide as well as other toxic gases. Potential confounding
arising from the exposure to these other chemical agents was taken into
consideration. Causes of death were found from death certificates and
comparisons of mortality were made with the general population of the region
where cohort members were resident. Seventy six deaths were reported whereas
98.8 were expected; the difference was statistically significant. The number of
malignancies for any site exceeded the expected number (standardized mortality
ratio (SMR) = 130; 43 observed deaths; 95% confidence interval (95% CI) 94-175)
and approached statistical significance. For all considered cancer sites the
SMRs were higher than 100 but the excess was only significant p < 0.05, two
sided test for lymphosarcoma and reticulosarcoma ICD-9 = 200; SMR = 682; four
observed deaths; (95% CI 186-1745) The excess of cases for all cancers of
hematopoietic tissue (ICD-9)= 200-208) also approached statistical significance
(SMR = 250; six observed deaths; 95% CI 91-544).
Human Toxicity Values:
No effect level: 5-10 ppm, during 10 yr; severe toxic effects: 60 min 250 ppm=
450 mg/cu m; symptoms of illness: 100 ppm= 180 mg/cu m; unsatisfactory >10
ppm= 18 mg/cu m
Skin, Eye and Respiratory Irritations:
Ethylene oxide is irritating to the
eyes, respiratory tract, and skin.
Aqueous solutions of ethylene oxide or
solutions formed when the anhydrous cmpd comes in contact with moist skin are
irritating and may lead to a severe dermatitis with blisters, blebs and burns.
It is also absorbed by leather and rubber and may produce burns or irritation.
Allergic eczematous dermatitis has also been reported. Exposure to the vapor in
high concn leads to irritation of the eyes. Severe eye damage may result if the
liquid is splashed in the eyes. Large amounts of ethylene
oxide evaporating from the skin may cause frostbite.
Medical Surveillance:
Biological monitoring of ethylene oxide exposure
by analysis of alveolar air and blood was studied in 10 workers employed in a
hospital sterilizer unit. Environmemtal air, alveolar air, and venous blood were
sampled during and at the end of an 8 hr workshift. The mean environmental
concentration of ethylene oxide was
5.4 mg/cu m air and the mean alveolar ethylene oxide concentration
was 1.2 mg/cu m alveolar air. Regression analysis showed that blood ethylene
oxide concentrations were higher than environmental ethylene
oxide concentrations by a mean ratio of 3 and higher than
alveolar ethylene oxide concentrations
by a mean ratio of 12.
PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is
indicated, in particular when exposure to a carcinogen has occurred, ad hoc
decisions should be taken concerning ... /cytogenetic and/or other/ tests that
might become useful or mandatory. /Chemical Carcinogens/
The 1984 OSHA standard for ethylene oxide (EtO)
mandates medical surveillance under various circumstances. When performed
medical surveillance for EtO must include a complete blood count (CBC) with
differential leukocyte count. This requirement is based on reports of EtO
associated absolute lymphocytosis and other hematologic effects. This paper
describes experiences in providing EtO medical surveillance for a 300 bed
hospital over a 6 year period. An apparent relative lymphocytosis which
persisted over 3-4 years in sterilization workers with documented TWA personal
EtO exposures averaging 0.07 ppm /was observed/. In addition three workers had a
history of acutely toxic overexposure to EtO as a result of a sterilizer
malfunction. These workers became symptomatic following the high accidental
overexposure but did not show absolute lymphocytosis or altered patterns in the
relative lymphocytosis. Finally a cross-sectional comparison of the CBC data
from the EtO exposed workers to data from non-EtO exposed hospital workers
showed no significant differences ruling out an association of the relative
lymphocytosis with EtO exposure. These observations led us to review the basis
for the inclusion of the CBC in routine EtO medical surveillance. /Such/
experience, review of the literature on EtO associated lymphocytosis and anemia,
and review of the literature on the use of the CBC with differential as
screening test suggest that the leukocyte differential may not be useful in
routine medical surveillance for EtO exposure.
In a study on workers in a chemical plant where ethylene
oxide (EtO) is manufactured and partly used for ethylene glycol
production, exposure to EtO was monitored during annual periodic health
assessments In January 1988, December 1988, and March 1990 by the determination
of the level of 2-hydroxyethylvaline in hemoglobin. The 2-hydroxyethylvaline
levels in workers corresponded with the potential EtO exposures. The highest
level was found in December 1988, in blood samples collected 1-2 months after a
shut down, maintenance, and start up program. The range of adduct levels found
in the three examinations indicated that average EtO exposures during the 4
months preceding blood sampling were below 0.5 ppm. It was demonstrated that the
method allows for the accurate monitoring of low levels of EtO exposure and
provides personalized time integrated exposure data with great discriminative
power. In addition, the method may serve to identify unexpected personal
exposures, which may lead to targeted exposure control measures.
Populations at Special Risk:
Ethylene oxide is a suspected
occupational toxicant of the male reproductive system indigenous to the
occupation of hospital sterilizers. /From table/
Industrial and occupational exposure is generally the result of inhalation of
ethylene oxide vapor released from
leaking or faulty equipment, valves, or fittings.
/Hospital workers/ operating a defective ethylene
oxide sterilizer.
Probable Routes of Human Exposure:
Exposure to ethylene oxide is
primarily occupational via inhalation. (SRC)
OSHA estimates that approximately 80,000 and 144,000 workers are directly and
indirectly exposed to ethylene oxide in
ethylene oxide production, chemical
synthesis by ethoxylation, health care facilities (sterilization), medical
products (sterilization) and miscellaneous manufacturers (e.g., spice
sterilization)(1). The number of workers exposed directly (indirectly) in the
various industries are: production and synthesis 3676; sterilization - health
care facilities 62,370 (25,000); sterilization - medical products manufacture
14,000 (116,900); sterilization - spice manufacturers 160(1). Typical exposures
are usually high during short periods in which sterilizer doors are opened,
typically 5-10 ppm for 20 minutes(1). Some typical survey results are: Medical
products manufactures 0.1.1-2.0 ppm 8 hr TWA; Hospital sterilizer chamber
operators 2.5 ppm TWA; 121 use sites in Southern California <5 ppm (TWA) in
114/121 sites; 2 hospitals 3-6 ppm and <5 ppm resp; survey of 27 hospitals
TWA exposures less than or equal to 1, <4 and >10 ppm in 9/27, 16/27 and
5/27, respectively(1). Union Carbide production plant in Texas City 5-33 ppm and
7.25 and 10.25 ppm avg in 2 control rooms and 0-56 ppm, 11.6 ppm avg throughout
plant(2). In-depth survey of 2 Union Carbide production facilities in West
Virginia- 2 of 48 and 4 of 41 samples positive, TWA exposure of positive samples
1.5-82 ppm(4,5). Production and maintenance workers in the 1960's avg exposure
levels 0.6-60 ppm(3).
NIOSH (NOES Survey 1981-1983) has statistically estimated that 50,132 workers
are exposed to ethylene oxide in the
USA(2). The personal 8-hr TWA exposure in 12 hospitals ranged from ND to 6.3 ppm
for sterilizer operators and ND to 6.7 ppm for folders and packers. Short term
(2 to 30 min) exposure levels for sterilizer operators ranged from ND to 103
ppm(1). Lower exposure levels were correlated with effective engineering
controls and good work practices, rather than with the size of the hospital, or
number or location of sterilizers.