EPA-450/5-80-004
Carcinogen Assessment Group's
Final Report on Population
Risk to Ambient Benzene Exposures
by
Dr. Roy E. Albert, Chairman
Carcinogen Assessment Group
U.S. ENVIRONMENTAL PROTECTION AGENCY
Office of Air, Noise, and Radiation
Office of Air Quality Planning and Standards
Research Triangle Park, North Carolina 27711
January 10, 1979
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DISCLAIMER
This report has been reviewed by the Strategies and Air Standards
Division of the Office of Air Quality Planning and Standards, EPA,
and approved for publication. Mention of trade names or commercial
products is not intended to constitute endorsement or recommen-
dation for use. Copies of this report are available through the
Library Services Office (MD-35), U.S. Environmental Protection
Agency, Research Triangle Park, N.C. 27711, or from National;
Technical Information Services, 5285 Port Royal Road, Springfield,
Virginia 22161.
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CONTENTS
I Summary 1
II Introduction 3
III General Approach to Utilizing Epidemiological Studies
to Predict Lifetime Probability of Cancer Deaths Due
to Benzene 4
A. Mathematical Model„Employed 4
B. Estimation of Lifetime Probability of Death Due to
Various Forms of Leukemia for a Member of the U.S.
Population 6
IV Epidemiological Studies Utilized 7
A. Infante (1977) 3
B. Askoy (1974, 1976, 1977) ... 13
C. Ott, et al. (1977) 17
V Estimation of Expected Number of Leukemia Deaths Due
to Environmental Exposure to Benzene 21
VI
Bibliography 30
VII APPENDIX - Mutagenic Risks of Benzene Exposure
31
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TABLES
1.
2.
3.
4.
5.
6.
Data Utilized to Estimate Lifetime Probability of
Death Due to Various Forms of Leukemia
24
Lifetime Probability of Death in U.S. Population
Due to Leukemia Type Upon Which Relative Risk in
Each of the Epidemiological Studies is Based . .
Summary of Data Used to Estimate Lifetime
Probability of a Leukemia Death Per ppm Benzene
Lifetime Exposure
. 25
26
Source Specific Benzene Caused Leukemia Deaths/Year
Based on Table 1-1 of SRI Benzene Exposure Document.
Total Exposure of People Residing in Various
Locations, and Resulting Estimated Benzene Caused
Leukemia Deaths/Year - Based on Table 1-2 of SRI
Benzene Exposure Document .... .
. 27
Confidence Limits on Total Benzene Caused Leukemia
Deaths/Year (Assumes "One-Hit" Model is the True
Dose Response Relationship)
27
29
IV
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CARCINOGEN ASSESSMENT GROUP'S FINAL REPORT ON POPULATION RISK
TO AMBIENT BENZENE EXPOSURES
I. Summary
There 1s substantial epidemiological evidence that
benzene is a human leukemogen. However, no validated animal
model has yet been developed for benzene as a carcinogen.
There are several large series of case reports indicating a
high risk of leukemia in individuals who developed aplastic
anemia consequent to benzene exposure. In addition there
are a number of epidemiological studies in the rubber,
chemical and shoe industries that demonstrate an excess risk
of leukemia associated with benzene exposure.
Three of these epidemiological studies provide enough.
information about exposure to benzene and the occurrence of
leukemia to allow us to make crude quantitative estimates of
the leukemia risk associated with current general population
exposures to benzene in the United States. .These studies
were conducted by Infante et al, (1977), Ott, et al ,, (1977)
and Askoy et al.,. (1977, 1976, 1974). ".
The Infante study, which showed an excess incidence of
leukemia, is not yet completely analyzed by the au.thors.
Hence, some assumptions made about the average duration and
magnitude of exposures are necessary. The Ott study
indicated a marginal excess myelogenous leukemia risk with
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relatively well-documented exposures. The Askoy studies
indicated a marked increase in non-lymphatic leukemia to
individuals using benzene based adhesives in small shoe
making shops, however, the exposure data in this situation
was difficult t6 evaluate.
A linear non-threshold model was used to estimate the
leukemia risk to the low average levels of about one part
per billion to which the general population is exposed. The
slope parameter of this model was taken as the geometric
mean of the slope parameter estimates obtained from the
three epidemiological studies. Using this extrapolation
model, we estimated, that the number of cases of leukemia per
year in the general population clue to ambient atmospheric
benzene is about 90 with a 952 confidence interval from 34
to 235 assuming a precision of within two fold in the
exposure estimate. This is from .23% to 1.62% of the total
leukemia deaths in the United States based upon 1973 vital
statistics. .
The purpose of this calculation is to obtain a rough
estimate of the carcinogenic hazard to benzene in the entire
United States population. To do this lifetime averages of
benzene exposure were estimated and these were combined with
the non-threshold linear model of risk as a function of
lifetime average exposure. In this report no attempt has
been made to estimate the' risks to selected sub-populations
who may have greater or less than average exposure or
sensitivity to benzene although it is certain that such
groups exist.
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II. Introduction
The Carcinogen Assessment Group (CAG) has been asked by
the Office of Air Quality Planning and Standards (OAQPS) to
estimate the carcinogenic risk to the United States
population of ambien.t benzene concentrations. This type of
information is useful in judging the overall contribution of
benzene emissions to the national rates of cancer mortality,
and will be used by OAQPS in the decision whether to
regulate benzene.
As the basis for this estimation, the CAG is using three
epidemiological studies that show a relationship between
excess mortality due to leukemia and benzene'-exposure. Each
of these studies have strengths and weaknesses that will be
discussed, but taken together they represent convincing
evidence that benzene is a -human carcinogen.
To date, no clear evidence exists implicating benzene as
a carcinogen from animal experiments. A study is in
progress at New York University that appears to suggest that
inhaled benzene is causing leukemia in rats. At the present
time it is felt that it would be premature to base a risk
extrapolation on this preliminary data. However, at the
completion of this study the CAG will update the present
risk analysis to take account of this new information.
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III. General Approach to Utilizing Epidemiologfcal Studies
to Predict Lifetime Probability'of Cancer Deaths Due
to Benzene
As was noted in the benzene health document (Goldstein,
et al., 1977), very little information exists that can be
utilized to obtain a dose response relationship between
benzene and leukemia in humans or animals.
However, if a number of simplifying assumptions are
made, it is possible to construct crude dose response models
*
whose parameters can be estimated using vital statistics,
epidemiological studies, historical workplace benzene
".standards and-monitoring data, and a recent environmental
benzene exposure study (.Mara and Lee, 1978).
A- Mathematical Model Employed
We assume that for low exposures the lifetime
probability of death from leukemia may be represented by the
linear equation
P * A+Bx
where A is the rate in the absence of benzene- exposure and x
is the average lifetime exposure to atmospheric benzene
expressed in ppm. The term Bis the change in the leukemia
rate for each Increase of one ppm of benzene in the air.
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If we make the assumption that, "R", the relative risk
of leukemia for benzene exposed workers compared to the
genera] population Is independent of the length or age of
exposure but depends only upon the total exposure, it
follows that
R s £2 -A * B {XT -±-£21
P1 A + Bxi
Rpl - A + B (xi + x2)
Or
P! » A + Bxj
so that B = Pi(R-l)/x2
where: xj. = ambient level exposure to benzene
xe «• industrial level exposure to benzene
P! * the lifetime probability of dying of
leukemia with no or negligible benzene
exposure
To use this model estimates of R and x2 must be obtained
from the epidemiological studies. The exposure values Xl
are derived in the exposure study conducted by SRI dated May
1978 and will be discussed where they are utilized.
The estimate of the lifetime probability of death due to
different types of leukemia, Plf is discussed in detail in
the next section.
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B. Estimation of Lifetime Probability of Death Due to
Various Forms of Leukemia for a Member of the U.S.
Population
The data utilized to estimate the lifetime probability
of death due to various forms of leukemia is shown in Table
1, which was taken from "Vital Statistics of the United
States 1973 Volume II - Mortality Part A." The second and
third columns (total deaths and total death rate in 1973)
were taken from page 1-184 and 1-8, respectively and
uti.lized to derive column four, total U.S. population in
each of the age classes.
The total number of deaths in 1973 due to each of the
types of leukemia listed by the 8th ICD code
204 - lymphatic
205 - rayeloid
206 - monocytic
207 - other and unspecified
are shown in columns five through eight.
The age specific death rates for each type of leukemia
are estimated by dividing the total number of deaths due to
that type by the total number of people in that age class.
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In the appendix of a 1978 CAG document on population
risk due to coke ovens a method referred to as the "constant
segmented model11 is derived that allows one to estimate the
lifetime probability of death due to a disease given the
age-specific incidence rates for the disease and all sources
of death. This model was employed-using the data in Table 1
to obtain the lifetime probabilities of leukemia that
approximate as closely as possible the type of leukemia that
the relative risk estimates were based upon in each
epidemiological study. These lifetime probabilities are
shown in Table 2, and will be used subsequently to estimate
lifetime probabilities of leukemia death for each unit of
exposure to the general population for each of the
epidemiological studies.
IV. Epidemiological Studies Utilized
Each of the epidemiological studies is discussed in
general. The relative risks are modified in each of the
studies to represent a most likely rather than a
conservative lower limit as usually is the case where the
primary aim of epidemiological workers is to establish with
little doubt a "statistically significant" elevated relative
risk. Estimates of the average lifetime exposure are also
made using as much data as is available. This information
is then utilized employing the previously discussed
mathematical model to estimate the lifetime probability of
leukemia for each unit of exposure.
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A. Infante (1977)
1. Description of Infante Study (1977)
In a retrospective study of mortality in a cohort of 74-8
white male workers in two Ohio plants manufacturing a
natural rubber cast film product, Infante et al., (1977)
observed a statistically significant higher rate of leukemia
than in either of two control groups. The leukemia
mortality rate was 5.06 times higher than the general U.S.
white male population standardized for age and time period
of the cohort exposure, and 4.74 times higher than a cohort
of 1447 white males employed at an Ohio fibrous-glass
'construction products factory. These results were based on
a 75% follow-up of the vital status of the workers. A total
of 160 deaths were observed and of these there were 7
leukemia deaths, four of which were acute myelogenous, one
chronic myelogenous, and two monocytic leukemia.
As with virtually all epidemiological studies, the
Infante study has various strengths and shortcomings. Among
its strengths are; (1) the worker exposures are said to have
been almost exclusively restricted to benzene, since it is
used throughout the plant as the principal solvent in all
major processes; (2) the individuals in the cohort all
worked before 1950 and were followed until 1975, thus
allowing long latency diseases to be observed, and (3) acute
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myelogenous leukemia was observed, which is the same cell
type of leukemia observed in other studies where workers
have had known benzene exposures. The disadvantages of
relying on this study for determining general population
risks are: (1) the authors essentially give no estimate of
worker exposures except to say that the levels were -less
than the prevailing recommended occupational limits at the
time various monitoring surveys were made; (2) the members
of the cohort study actually worked at two separate plants
(Akron and St. Mary's, Ohio). Air monitoring information in
the .former plant is almost non-existent (Baier, 1977), and
therefore the exposure to half of the members of the cohort
is almost completely unknown. However, it is known (Young
1977) that the crude rates (leukemia cases/total people in
the cohort) are similar in the two locations; (3) Warren et
al., (1977) claimed that over 400 workers known to be
exposed to low benzene levels were deliberately excluded
from the cohort. In spite of these problems, it is felt
that this study is the least flawed of the three utilized.
2. Estimation of the .Relative Risk
In an update, published as a letter to the editor in
Lancet (Benzene and Leukemia. October 14, 1977) Infante et
al., note that:
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(1) Sakol (1977) has supplied additional
Information that at least two more cases of leukemia
known to exist, but not reported on death
certificates, were probably in Infante's cohort;
(2) Due to a more complete follow-up, the expected
number of deaths due to leukemia in their cohort was
reduced from 1.38 to 1.25.
Using this supplemental information, the new relative risk
due to total leukemia is estimated to be
R * (7+2)/1.25 = 7.20
3. Estimation of Average Occupational Exposure
Information about the plant benzene levels is contained
in the Appendix to the testimony of Baler at the OSHA
benzene hearings (Baler, 1977). From the opening of the
factory in 1940 until 1946, no; mom"toring records were
available. Following the installation of new ventilation
equipment in 1946, a survey showed that levels in "most
areas" in the plant ranged from 0 to 15 ppm and that all
areas had less than the maximum safe limit of 100 ppm which
prevailed at that time. From this information, one can
guess that the average exposure to all people in the plant
before 19.46 is probably not much more than 100 ppm, and not
less than 15 ppm.
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Benzene levels were monitored after 1946 at various
plant locations but: they were all instantaneous samples and
no reliable information Is available about how many
man-hours were spent at those locations or whether
protective masks were worn. These are case reports of
exposures to 1000 ppm for short time intervals. Since the
average levels were generally close to the occupational
standard, we will make the assumption that the average
worker exposure was the same as the prevailing recommended
occupational limits. These are tabulated below along with
the time weighted average for the 36 years of the total
exposure period.
Time No. of Average Time-Weighted
Interval Cases Exposure (oom) Averaae ( nnm\
1940-46
1947
1948-56
1957-68
1969-75
(7)
(1)
(9)
(12)
(7)
100-15
50 39.9-23.3
35
25
10
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The actual levels to which the workers were exposed was
a subject of heated debate at the OSHA benzene hearings.
The CAG would like to see a realistic estimate of the
population weighted average exposure and its uncertainty
limits. The time-weighted averages for occupational
exposure must be converted to a continuous exposure lifetime
basis. It will be assumed that the maximum likely lifetime
exposure would result if a worker entered the factory in
1940 and was exposed for 35 years to the occupational limit
of benzene. This exposure would result in a time-weighted
average of 40.36 ppm for 35 years. The least likely
exposure is assumed to occur if a worker .started in 1950
and was exposed to the occupational limit, which results in
a time-weighted average of 23.7 ppm for 25 years. The
equivalent continuous lifetime exposures corresponding to
these work place exposure estimates are:
High estimate: 40.36 x 240 x 1. x 35 = 4.4ppm
Low estimate: 23.7 x 240 x 1 x 25 - l.Sppm
365 3 70
The geometric mean of the high-low exposures,
/4.4xl.8 = 2.81, is taken to be the best estimate of the
lifetime average for workers in the cohort.
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*• Estimation of Lifetime Probability of Leukemia
Per Unit of Exposure
The change in the leukemia rate per lifetime average ppm
in the atmosphere is derived from the previously discussed
equation:
B = P! (R-U/x2
which gives us an estimate
B = .006732 x (7.20-D/2.81 = .014854
B. Askoy (1974, 1976, 1977)
1. Description of Askoy Studies
Askoy (1977, 1976, 1974) has reported his observations
of the occurrence of leukemia and aplastic anemia cases at
two medical institutions in Istanbul over a period from 1967
to 1975. He has compared the types of leukemia seen in shoe
workers, who work with benzene solvents in small
unventilated shops, with the types of leukemia observed in
people with no known exposure to benzene. He has also
tabulated the exposure duration of patients with different
types of leukemia. He found that in shoe workers there were
34 cases of leukemia observed in the nine years from 1967 to
1975. Based on "official records" which show that in
Istanbul ..there are 28,500 workers in the shoe, slipper and
handbag industry, he calculates that the annual incidence
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rate of leukemia 1s 13 per 100,000, which is significantly
higher than 6 per 100,000, the rate in the general
population. The calculation is based on crude rates with no
age adjustment.
He also found that the types of leukemias occurring in
people exposed to benzene are different than for those with
no known exposure. In a sample of 50 non-exposed leukemia
patients, approximately 50 percent had chronic leukemia, but
in 40 benzene-exposed patients only 5 percent had chronic
leukemia. Also, in the exposed group preleukemia and acute
erythroleukemia accounted for 34 percent of the cases,
whereas in the non-exposed group only 6% of the cases were
of those types.
The concentration of benzene to which the workers were
exposed was estimated only in terms of the maximum
concentrations existing at the times when benzene was being;
used in the shops. At the OSHA benzene hearings in 1977
Dr. Askoy stated that the concentrations outside working
hours ranged between 15 and 30 ppm and reached a maximum of
between 150 and 210 ppm when adhesives containing benzene
were being used.
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2. Estimation of Relative Risk.
A total of 26 patients with leukemia were observed in
the 6 2/3 year period from 1966 to September 1973 in a group
of 28,500 Instanbul shoe workers exposed chronically to
benzene. This was felt to be an underestimate of the true
number of leukemia cases among the shoe workers during the
period with Askoy subsequently being aware of two additional
cases. However, three of the twenty-eight total cases were
lymphoblastic or lymphoid leukemia, not thought to be as-
sociated with benzene exposure. Eliminating these three
cases, an estimate of the yearly incidence rate is
I = (26+2-3) x IPS = 13.15 per 100,000 per year
28,500 x 6..67 -
The total incidence rate of leukemia in Turkey is
thought to be about 2,,5 to 3.0 per 100,000 Askoy (.1977).
However from Askoy*s non-exposed patient group we estimate
that 48% based on 24 out of 50 are non-lymphoblastic or
lymphoid leukemia. In addition, the national rate which is
based on the total population was felt by Cooke (1954) to be
about twice that experienced for the relatively young group
of benzene-exposed shoe workers who had a average age at
diagnosis of 34.2 years. Using this information we estimate
that the yearly incidence rate of non-lymphoblastic or
lymphoid leukemia in the Turkish population of the same age
structure as the benzene exposed shoe workers is
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I 3 (2.5+3.0) x 24 x 1 - .66 per 100,000
2 50 2
An estimate of the relative risk for benzene exposed
shoe workers is thus
R = 13.15 = 19.92
.66
3. Estimation of Lifetime Average Exposure
It was noted that the benzene levels were 15 to 30 ppm
outside working hours and 150 to 210 ppm during working
hours when benzene was in use in the typical small shoe
manufacturing shop. We will assume that the average working
hour exposure to benzene was the geometric mean of the
midpoint of the two intervals or
X7 3 \H5 + 30) x (150 + 210) = 63.6 ppm
sJ 2 ~~ 2
In addition we will assume:
(1) ft ten hour working day
(2) A 300 day working year
(3) An average age at the end of the observation
period of 50 years
(4) An a-verage of 9.7 years of exposure; this is
the average length of exposure for the
leukemia cases in Askoy's series.
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These assumptions lead to a lifetime average exposure
estimate of
X2 = 63.6 x (10) x (300) x (9.7) = 4.22 ppm
2? JBT BIT
4. Estimation of Lifetime Probability of Leukemia
Per Unit of Exposure
The change in the leukemia rate per lifetime average ppm
in the atmosphere is derived from the previously discussed
equation:
B = Pi(R-l)/x2
which gives us an estimate
B * .004517 x (19.92-1)74.22 - .020252
C. Ott, et al., (1977)
1• Description of Qtt Study
The long-term mortality patterns and associated exposure
estimation of a cohort of 594 workers exposed to benzene
were reported by Ott, et al., (1977). The workers were
employed in three production areas of the company, which had
been in operation for varying times since 1920.
Each job category was assigned an average exposure range
as accurately as the historical air monitoring data
permitted. The concentrations ranged from less than 2 ppm
(8-hour time weighted average) to greater than 25 ppm. ^The
analysis covered employees with known benzene exposure who
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worked from January 1, 1940 through 1973. A total of 53
employees with known exposure to arsenicals, vinyl chloride
and asbestos in addition to their benzene exposure was omit-
ted from the formal cohort of people exposed to benzene.
The benzene exposure of each person was evaluated and
ex-pressed as the product of parts per million times months
of exposure. For the 91 deceased people with exposure to
benzene alone, 45% of them had exposures between 0 and 499
ppm-months and 35% had exposures greater than 1000 ppm-
months. The results of the analysis of mortality by cause
of death showed no statistically significant excess of
mortality compared to the U.S. white male age-specific
mortality rates. Three cases of leukemia were observed
where 0.8 cases were expected, a situation of borderline
statistical significance (p<0.047). All three were my-
elocytic leukemia, two of them acute, which latter is the
type associated with benzene exposure of shoe workers
(Askoy, 1976) and other occupations (Yigliani, 1976).
2. Estimation of Relative Risk
In Ott's cohort 3 deaths due to non-lymphocytic non-
monocytic leukemia were observed with only .8 expected. An
estimation of the relative risk of non-lymphocytic -
monocytic leukemia is thus
R 3 3/.8 = 3.75
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3. Estimation of Lifetime Average Exposure
Ott estimated the ppm-months of exposure of each
individual in his cohort from work history data and plant
hygiene benzene measurement surveys. The most complete
presentation of this data is given in Ott1s (1977) table 7
#
which is used to estimate the average level of exposure.
It is assumed that the average exposure in each of the
exposure intervals is equal to the midpoint of the first two
intervals and is equal to the lower limit plus 1/2 of the
interval width for the open or third classification. The
total average ppnfi-months is obtained by taking the average
of the three classifications weighted by the expected value
of the number of deaths in each classification giving the
value
(250 x 65.1 + 750 x 16.2 + 1250 x 32.8)/{65.1 + 16.2 + 32.8}
= 608.46 ppm x months
The average lifetime exposure is obtained by using the
following assumptions:
(1) An'eight hour working day
(2) A 240 day working year
(3) An average age at the end of the observation
period of 65 years
which gives the lifetime estimate of
(608.46) x (8 ) x (240) x (1 ) = .171 ppm
( 12 ) (14) (365) (65)
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4. Estimation of Lifetime Probability of Leukemia
Per Unit of Exposure
The change in the leukemia rate per lifetime average ppm
in the atmosphere is derived from the previously discussed
equation:
B * Pi(R-l)/X2
which gives us an estimate
B » .002884 x (3.75-U)/.17 = .04638
D. Summary of Results
The total leukemic response has been based on different
classifications of leukemia for the three studies. A
summary of the type of response utilized is given in Table
3. It would have been preferable to have applied a uniform
method of classification for all the studies. However, due
to the lack of specific detail in the presented papers this
was not possible.
Even with this added source of variability the resulting
slope estimates B, which have the physical meaning of the
total probability of deaths due to 1 ppm of benzene in the
air breathed over an individual lifetime, were remarkably
consistent between studies. The geometric mean of the three
estimates ic
. B =3J.014854x.020252x»046380 = .024074
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The estimated log mean Is
log-jQB = -1.618453, with the estimated variance
of this mean being 0"log B = .021785
V. Estimation of Expected Number of Leukemia Deaths Due to
Environmental Exposure to Benzene
The SRI in their exposure document expressed exposure to
the U.S.' population in two ways.
The first method assumed a static population living
around the point sources and gave total ppb-person years for
each of the point source classifications in Table 1-1.
If exposure units fn 106 ppb-person years are denoted
as D, the expected number of leukemia deaths per year may be
estimated approximately by the relationship
ND =» .024074 x 0x103/70.96 = .3392620
where .024074 is the geometric mean of the slope parameter
taken from the three studies, and 70.96 is the average
expected life of a randomly drawn person living in the
United States based on 1973 vital statistics.
Using Table I-rl and the above equation the number of
leukemia deaths per year are estimated for the various point
sources .and are shown in Table 4.
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The second method employed to estimate exposure did not
make the over-simplified assumption that the human
population was static. Instead an attempt was made to
follow a typical individual through a typical day in order
to obtain his average exposure. The exposure estimates
derived on this basis are shown in Table 1-2 of the SRI
document and were utilized in conjunction with the above
equation to derive the estimated number of leukemia deaths
per year shown in Table 5.
We note that approximately a total of 90 cases of
leukemia per year could be expected due to benzene exposure.
In a recent CAG document on ROM's, a method was developed to
obtain confidence intervals for estimates based upon the
assumptions that each .epidemic!ogical study gave an unbiased
estimate of the true slope parameter and the estimates were
distributed log normally. Adding the additional assumption
that the exposure estimates are also log-normally
distributed we derive the relationship that the 35%
confidence interval for the log of the number of leukemia
deaths per year is ^
1.953289 + F.083689 + Iog2u
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where we are 95% confident that the true exposure is between
(u-1) x 100% and (u-l)-l x 100% of the exposure estimate.
The confidence limits derived from this relationship for
various assumed values of u are shown in Table.6.
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TABLE 2 - Lifetime Probability of Death in. U.S.
Population Due to Leukemia Type Upon
VThich Relative Risk in Each of the
Epidemiclogical Studies is Based.
Epidemiological
( Study
Infante
Ott
As key
JCD Codes
Utilized
204-207
205
2.0 5-10 7
Type of
Leukemia
Total Leukemia
Myelogenous
Non-Lymphatic
Lifetime Probability
of Death Due to
Type of Leukemia
.006732
.002884
.004517
-25-
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-26-
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TABLE 4 - Source Specific "Benzene Caused Leukemia
• Deaths/Year Based on Table 1-1 of SRI Benzene
Exposure Document9
tource o£
cposure
leraical
inufacturing
Iqke Ovens
?etroleum
lefineries
toitoiaobile
Emissions
Gasoline Ser-
vice Stations
Self Service
Gasoline
A Exposure in
10° 10
' Expected Number of Benzene Cau.
x pp -Person Years Leukemia Deaths/Year
8.5
.2
2.5
150.0
19-. 0
' TOTAL
2.33
.07
.85
5.0.89
6.44
-54
61.67
Mara, Susan J. and Shonh S. Lee. Assessment of-Human Exposures to Atmospheric
Benzene. SRI International for U.S. Environmental Protection Agency, Research
Triangle Park, NC. Publication No. EPA-450/3-78-031. June 1978.
. -27-
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TABLE 5 - Total Exposure of People Residing in Various
Locations, and Resulting Estimated Benzene-
Caused Leukemia Deaths/Year - Based on
Table 1-2 of SRI Benzene Exposure Document9
Vicinity of Residence
Chemical Manufacturing
Coke Ovens
* »
Petroleum Refineries
Urban Areas
TOTAL
Exposure in .
106ppb-Person
Years
10.0
.2
4.5
250.0
264.7
Expected Number of
Benzene-Caused
Leukemia Deaths/Year
3.39
.07
1.53
84.80
89.30
aMara, Susan J. and Shonh S. Lee. Assessment of Human Exposures to Atmospheric
Benzene. SRI International for U.S. Environmental Protection Agency, Research
Triangle Park, NC. Publication No. EPA-450/3-78-031.
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TABLE 6 - Confidence Limits-on Total Benzene
Caused Leukemia Deaths Per Year
(Assumes "One-Hit" Model is the True
Dose Response Relationship)
Level of Precision
Assumed for Exposure
Estimate
C.U-1) x 100%
95% Confidence Limits
Lower Upper
Limit Limit
0%:
10%
50%
100%
1000%
46.1 .
45.8
41.2
34.3
7.5
174.8
176.0
195.9
254.9
1081.7
*Assumes no error in exposure estimate.
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Bib!iography
Cancer Risk of Benzene
Askoy, M. (1977) "Testimony of Mazaffer Askoy, M.D. to
Occupational Safety and Health Administration, U.S.
Department of Labor," July 13, 1977, 13 pp.
Askoy, M. (1976) "Types Leukemia In Chronic Benzene
"Poisoning. A Study in Thirty-Four Parts," Acta Haemat,
5_i, 65-72.
Askoy, M., Erdem, S., and Oincol, G. (1974) "Leukemia in
Shoe-Workers Exposed Chronically to Benzene, Blood, 44 (6),
837-841. '
Askoy. M., Erden, S., Dincol, K., Kepyuksel, T., and Dincol,
G. (1974) "Chronic Exposure to Benzene as a possible
Contributary Etiologic Factor in Hodgkin's Disease, Blut,
28_, 293_-29J3.
Baler, E.J. "Statement of the National Institutes of
Occupational Safety and Health," Exhibit 84A, OSHA Benzene
Hearings, July 19-Aug 10, 1977.
Cooke, J.V. (1954) "The Occurrence of Leukemia," Blood 9,
340.
Goldstein, B.D., Snyder, C.A., Snyder, R., and R. and S. R.
Wolman, "Review of Benzene Toxicity," Prepared for EPA,
August 18, 1977.
Infante, P.F., Rinsky, R.A., Wagoner, J.K., and Young, R.J.
(1977) "Benzene and Leukaemia (Letter to the Editor),
Lancet. 867-869, October 22, 1977.
Infante, P.F., Rinsky, R.A., Wagoner, J.K., and Young, R.J.
(1977) "Leukemia in Benzene Workers,' " Lancet, 76-78, July
9, 1977.
Ott, M.G., Townsend, J.C., Fishback, W.A., and Langer, R.A.
(1977) "Mortality Among Individuals Occupationally Exposed
to Benzene," Exhibit 154, OSHA Benzene Hearings, July 9-
August 10, 1977.
Sakol, M.J. (1977) "Testimony of Marvin J. Sakol, M.D., to
Occupational Safety and Health Administration, U.S.
Department of Labor".
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VII. APPENDIX
Mutagenlc Risks of Benzene Exposure
Summary
In addition to the risk from.leukemia, benzene exposure
is also likely to induce inherited mutations. The magnitude
of this risk can not be estimated because of the uncertain
quantitative relationship between heritable mutations and
chromosome aberrations which have been consistently observed
in exposed workers.
Review of Experimental Results
Benzene was found to be non-mutagenic in the Ames' test
for point rautational effects (Simmon et al., 1977; Shahin,
1977; and Lyon, 1975). However, it is possible that a human
metabolic activation enzyme system or a mammalian body fluid
activation system would cause it to be mutagenic.
Somatic chromosomal aberrations have been demonstrated
in animals and humans. In rabbits, Kiss! ing and Speck, 1971
reported the induction of cytogenetic damage vn vivo by
subcutaneous injection of 0,2 ng/kg day benzene. The
frequency of metaphase spreads showing aberrations (mostly
gaps and breaks) increased from 5.9% to 57.8% after an
average exposure interval of 18 weeks. Two months after
discontinuance of the benzene treatment, cytogenetic damage
was still observed.
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Dobrokhotov (1972) exposed rats to 0.2 g/kg day benzene and
0.8 g/kg day toluene, and found similar rates of chromosomal
aberrations in the two chemicals given separately, and an
additive effect when given together. Chromatic deletions in
metaphase chromosomes of bone-marrow cells have been found
in rats given single doses of benzene subcutaneously at 2
ml/kg (Philip and Jensen, 1970). Deletions have also been
observed in rats given benzene at Ig/kg day, subcutaneously,
for 12 days.
A dominant lethal and j_n vivo cytogenetics combined
test has been performed with rats dosed intraperitoneally
with 0.5 ml/kg benzene (Lyon; 1975). . No dominant lethality
was found but increases were found in chromatic and
chromosomal aberrations. Lyon (1975) also found increased
micronuclei counts 6 hours after the final dosing of rats at
0.05 and 0.25 ml/kg/day after two days of dosing
intraperitoneally.
In patients with benzene-induced aplastic anemia,
lymphocyte chromosome damage has been found (Pollini and
Colombi, 1964). Polini et a!., (1964) later found a 70%
incidence of heteroploid chromosomal patterns in the blood
lymphocytes and bone marrow parenchyma cells of each of four
subjects with benzene-induced blood dyscrasias. Similar
patient studies of benzene exposed individuals with
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persistent chromosomal alterations associated with blood
dyscrasias have also been reported by others (Forni and
Moreo, 1967, 1969; Hartwich et al., 1969; Khan and Khan,
1973; Sellzel and Kelemen, 1971; Forni et aU, (1971); Tough
and Court Brown, 1965}.
Vigiliani and Forni (1969) found a significant increase
of chromosomal aberrations in pheripheral lymphocytes of
workers exposed to benzene, but not in those exposed to
xylene and toluene. Some of these aberrations persisted for
several years after recovery from benzene hemopathy. They
suggested that toxicity to the bone marrow might result in
cells with an abnormal number of chromosomes and that
proliferation of these cells could then give rise to an
advantaged leukemic clone. Forni et aK, (1971) examined
chromosomal aberrations in 34 workers in a rotogravure plant
and.compared these to 24 matched controls, and found a
significantly higher number of both stable and unstable
aberrations in 10 benzene-exposed workers but a number
comparable to controls in all of the 24 toluene-exposed
workers.
A recent report (Kilian and Daniels, 1978) on.52 workers
exposed to benzene for one month to 26 years (mean of 56.6
months) found chromosomal aberrations (chromosome breaks,
dicentric chromosomes, trans!ocations and exchange figures)
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in peripheral lymphocytes at 2-3 times the rates found in
controls. In this study, the 8 hour average time-weighted
benzene exposure was 2-3 ppm, the average concentration
determined by 15 minute sampling was 25 ppm and the peak
concentration was 50 ppm.
The same laboratory reported on the monitoring of 471
peripheral lymphocyte cultures from 290 Texas Division
benzene workers between 1965 and 1978 {Benge et a!.,.1978).
A group of 972 "preemployment examinees" who were judged, on
the basis of the history taken at the time, to have had
negligible exposure to known chromosome-breaking agents were
used as controls. Rates of chromosomal abnormalities were
found not to be increased in the exposed group over the
control group. The time-weighted average benzene
concentrations were estimated to have been below 50 ppm
prior to 1972 and well below 10 ppm from 1973 to the present
time.
A report by Picciano (1978) which is a further analysis
of the Kilian and Daniel (1978) and Benge (1978) study
comparing the information on benzene exposed individuals to
a 44-person group seen for preemployment examination.
Workers exposed to three different levels of benzene at less
than 10 ppm for several years showed a dose response
relationship. The types of aberrations detected are similar
to those reported for higher benzene exposures by (Tough et
-34-
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al., 1970). The workers were monitored for urinary
excretion of phenol which is a primary metabolite of
benzene. All workers had no detectable phenol which
indicated no recent exposure to benzene. Exposures for the
dose-response relationship were 0, less than 1, 1-2.5 and
greater than 2.5 ppm.
Fredga et al., (1978) performed a study on 65 workers,
occupationally handling motor fuels. A moderate, but
statistically significant, increase in frequency of chro-
mosome aberrations was found in road tanker drivers and
industrial workers, but not in ship tanker crews and gaso-
line station staff. The estimated exposure dose was 60 ppm
or less. The dose absorbed will be reported in a subsequent
study.
Conclusions
Ample evidence exists that benzene causes chromosomal
aberrations in animals and humans exposed to benzene. This
evidence was reviewed above. However, since this is a
somatic cell effect as opposed to a germinal cell effect it
is difficult to estimate the heritable risk to future
generations from such evidence. These chromosomal aber-
rations probably involve breaks in DNA and therefore are
heritable" events if they occur in the germinal cells,
although the experiments to prove that point have not been
decisive.
-35-
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It is generally recognized that rings, dicentrics,
translocatlons and exchange figures are heritable, but
chromosome breaks could be caused from toxicity of somatic
cells and therefore may not be heritable. The former
lesions should be used as indicators that genetic damage to
future generations may have occurred. At the current time
quantitative estimates of heritable genetic damage due to
benzene cannot be made from data on the frequency of somatic
mutations, although this damage may be occurring at
concentrations as low as 1 ppm in air.
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Bibliography
Mutagenicity: Benzene
Benge, M.C., J.R. Venable, D.J. Picciano and D.J..Killian
(1977) "Cytogenetic study of 290 workers exposed to
benzene." Report Dow Chemical U.S.A. 1977.
Dobrokhotov, V.B. (1972) "The mutagenic influence of benzene
and toluene under experimental conditions," Gig. Sanit;
37:36-39.
Forni, A., and L. Moreo (1967) "Cytogenetic studies in a
case of benzene leukaemia," Eur. Jour. Cancer, 3:251-255.
Forni, A., and L. Moreo. 1969. "Chromosome studies in a case
of benzene-induced erythroleukaemia." Cancer, 3:251-255.
Forni, A., et al. (1971a) "Chromosome studies in workers
exposed to benzene or toluene or both," Arch. Environ.
Health, 22:373-378.
Forni, A., et al. (1971b) "Chromosome changes and their
evolution in subjects with past exposure to benzene," Arch.
Environ. Health, 23:385-391.
Fredga, K., Reitalu, J. and Berlin, M. Chromosome studies in
workers exposed to benzene. Report #771018 of the Institute
of Genetics, Univ. of Lund and Department of Env. Health,
University of Lund, Sweden.
Haberlandt, W., and B. Mente 1971 "Deviation on number and
structure of chromosomes in industrial workers exposed to
benzene," Zbl. Arfaeitsmed, 21:338-341.
Hartwich, G., and G. Schwanitz (1972)
"Chromosomenuntersuchungen nach chronischer
Benzol-Exposition." Dtsch. Med. Wschr. 97:45-49.
Hartwich, G., et al. (1969) "Chromsome anomalies in a case
of benzene leukemia." Ger. Med. Monthly, 14:449-450.
Khan, H., and M. H. Khan (1973) "Cytogenetic studies
following chronic exposure to benzene," Arch. Toxikol.,
31:39-49. "™
Kilian, D. J., and R. C. Daniel (1978) "A Cytogenetic study
of workers exposed to benzene in the Texas Division of Dow
Chemical, U.S.A.," Feb. 27, 1978, Dow Chemical, Freeport,
Texas.
Kiss!ing, M., and B. Speck (1971) "Chromosomal aberrations
in experimental benzene intoxication," Helv. Med. Acta,
36:59-66.
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-------
Koizumi, A., et al. (1974) "Cytokinetic and cytogenetic
changes in cultured human leucocytes and HeLa cells induced
by benzene," Ind. Health (Japan), 12:23-29.
Ltapkalo, A.A. (1973) "Genetic activity of benzene and
toluene," Gig Tr. Prof. Zabol„, 17:24-28.
Lyon, J.P. (1975) "Mutagenicity Studies with Benzene," Ph.D.
Thesis, University of California
Philip, P., and M.K. Jensen. (1970) "Benzene-induced
chromosome abnormalities in rat bone marrow cells," Acta.
Pathol. Microbiol. Scand. Sect. A., 78:489-490.
Picciano, D. (1978) Unpublished report.
Pollini, G., and R. Colombi (1964) "Lymphocyte chromosome
damage in benzene blood dyscrasia," Me_d. Lav. 55:641-654.
Pollini, G., et al. (1964) "Relationship between chromosomal
alterations and severity of benzol blood dyscrasia," Med.
Lav. 55:735-751.2
Sellyei, M., and E. Kelemen (1971) Chromosome study in a
case if granulocytic leukemia with "Pelgerisation" 7 years
after benzene pancytopenia. Eur. Jour. Cancer, 7:83-85.
Shahin, M.M. (1977) Unpublished results.. The University of
Alberta, Canada. Cited in Mutation Research 47:75-97
(1978).
Simmon, V.F., et al. (1977) "Mutagenic activity of chemicals
identified in drinking water." Second International Conf.
on Environmental Mutagens, Edinburgh, Scotland, July 1977.
Tough, I.M., and W.M. Court Brown (1965). "Chromosome
aberrations and exposure to ambient benzene, "Lancet, 1:684.
Tough, I.M., et al. (1970) "Chromosome studies in workers
exposed to atmospheric benzene. The possible influence of
age," Eur. Jour. Cancer, 6:49-55.
Yigliani, E.G., and A. Forni. 1969. Benzene, chromosome
changes and leukemia," Jour. Occup. Med., 11:148-149.
Yigliani, E.G., and A. Forni (1976) "Benzene and leukemia "
Environ. Res., 11:122-127.
Vigliani, E.G., and G. Sanita (1964) "Benzene and leukemia."
N.E. Jour. Med., 271:872-876.
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Warren, E.W., VanVoorhee, R.F., and Sampson, A.F., "Post.
Hearing Brief of API, NPRA, and Individual Member Companies
Regarding the Proposed Revised Permanent Standards for
Occuopation Exposure to Benzene," OSHA Docket Mo. H-059
September 22, 1977.
Young-, R.J. National Institute of Occupational Safety and
Health, Personal Communication, October, 1977.
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TECHNICAL REPORT DATA
(Please read Instructions on the reverse before completing}
HfrPORTNO.
EPA-450/5-80-004
'TITLE AND SUBTITLE
"Carcinogen Assessment Group's Final Report on
Population Risk to Ambient Benzene Exposures"
5. REPORT DATE
AUTHOB(S)
8. PERFORMING ORGANIZATION REPORT NO.
Roy E. Albert
'PERFORMING ORGANIZATION NAME AND ADDRESS
U.S. Environmental Protection Agency
Office of Research and Development
401 M Street, S.W.
Washington, D.C. 20460
January 1979
6. PFiRFOHMING ORGANIZATION CODE
10. PROGRAM ELEMENT NO.
11. CONTRACT/GRANT NO.
2. SPONSORING AGENCY NAME AND ADDRESS
Environmental Protection Agency
Office of Air Quality Planning and Standards
and Office of Research and Development
Research Triangle Pa r k, N.C. 27713
13. TYPE OF
Final
14. SPONSORING AGENCY CODE
EPA 200/04
s.SUPPLEMENTARY NOTES jhis report supercedes all findings and conclusions in the
September 1978 report entitled "Carcinogen Assessment Group's Final Report on
Population Risk to Ambient Benzene Exposures."
6. ABSTRACT
This report is one of three reports which were prepared by E.P.A. to determine
what regulatory action should be taken by E.P.A. to control sources of atmospheric
emissions of benzene. This report estimates from three epidemiological studies the
leukemia risk associated with current general population exposures to benzene in
the United States. These studies were conducted by Infante, et al., (1977),
Ott et al., (1977), and Askoy et al., (1977, 1976, 1974). The original report has
received extensive review by the interested public and E.P.A.'s Science Advisory^
Board. All comments received on this first report were reviewed and considered in
preparation of this report.
KEY WORDS AND DOCUMENT ANALYSIS
DESCRIPTORS
Benzene
Air pollution
Populations
Health effects
Risk
).IDENTIFIERS/OPEN ENDED TERMS
COSATI Held/Group
13B
13. DISTRIBUTION STATEMENT
Unlimited
19. SECURITY CLASS ,
Unclassified
Report}
20»SECURITY CLASS (Thispage)
Unclassified
22. PRICE
EPA Form 2220-1 (9-73)
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