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Benzene
CASRN 71-43-2
(10/16/1998)
Contents
0276
Benzene; CASRN 71-43-2 (10/16/1998)
Health assessment information on a chemical substance is included in IRIS only
after a comprehensive review of chronic toxicity data by U.S. EPA health
scientists from several Program Offices and the Office of Research and
Development. The summaries presented in Sections I and II represent a
consensus reached in the review process. Background information and
explanations of the methods used to derive the values given in IRIS are
provided in the Background Documents.
STATUS OF DATA FOR Benzene
File First On-Line 03/01/1988
Category (section) Status Last Revised
----------------------------------------- -------- ------------
Oral RfD Assessment (I.A.) no data
Inhalation RfC Assessment (I.B.) no data
Carcinogenicity Assessment (II.) on-line 10/16/1998
_I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS
__I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD)
Substance Name -- Benzene
CASRN -- 71-43-2
Not available at this time.
__I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC)
Substance Name -- Benzene
CASRN -- 71-43-2
Not available at this time.
_II. CARCINOGENICITY ASSESSMENT FOR LIFETIME
EXPOSURE
Substance Name -- Benzene
CASRN -- 71-43-2
Last Revised -- 10/16/1998
Section II provides information on three aspects of the carcinogenic
assessment for the substance in question; the weight-of-evidence judgment of
the likelihood that the substance is a human carcinogen, and quantitative
estimates of risk from oral exposure and from inhalation exposure. The
quantitative risk estimates are presented in three ways. The slope factor is
the result of application of a low-dose extrapolation procedure and is
presented as the risk per (mg/kg)/day. The unit risk is the quantitative
estimate in terms of either risk per ug/L drinking water or risk per ug/cu.m
air breathed. The third form in which risk is presented is a drinking water
or air concentration providing cancer risks of 1 in 10,000, 1 in 100,000 or
1 in 1,000,000. The rationale and methods used to develop the
carcinogenicity information in IRIS are described in The Risk Assessment
Guidelines of 1986 (EPA/600/8-87/045) and in the IRIS Background Document.
IRIS summaries developed since the publication of EPA's more recent Proposed
Guidelines for Carcinogen Risk Assessment also utilize those Guidelines where
indicated (Federal Register 61(79):17960-18011, April 23, 1996). Users are
referred to Section I of this IRIS file for information on long-term toxic
effects other than carcinogenicity.
__II.A. EVIDENCE FOR HUMAN CARCINOGENICITY
___II.A.1. WEIGHT-OF-EVIDENCE CHARACTERIZATION
Benzene is classified as a "known" human carcinogen (Category A) under
the Risk Assessment Guidelines of 1986. Under the proposed revised Carcinogen
Risk Assessment Guidelines (U.S. EPA, 1996), benzene is characterized as a known
human carcinogen for all routes of exposure based upon convincing human evidence
as well as supporting evidence from animal studies. (U.S. EPA, 1979, 1985, 1998;
ATSDR, 1997).
Epidemiologic studies and case studies provide clear evidence of a causal
association between exposure to benzene and acute nonlymphocytic leukemia (ANLL)
and also suggest evidence for chronic nonlymphocytic leukemia (CNLL) and chronic
lymphocytic leukemia (CLL). Other neoplastic conditions that are associated with
an increased risk in humans are hematologic neoplasms, blood disorders such as
preleukemia and aplastic anemia, Hodgkin's lymphoma, and myelodysplastic syndrome
(MDS). These human data are supported by animal studies. The experimental animal
data add to the argument that exposure to benzene increases the risk of cancer in
multiple species at multiple organ sites (hematopoietic, oral and nasal, liver,
forestomach, preputial gland, lung, ovary, and mammary gland). It is likely that
these responses are due to interactions of the metabolites of benzene with DNA
(Ross, 1996; Latriano et al., 1986). Recent evidence supports the viewpoint that
there are likely multiple mechanistic pathways leading to cancer and, in
particular, to leukemogenesis from exposure to benzene (Smith, 1996).
___II.A.2. HUMAN CARCINOGENICITY DATA
Benzene is a known human carcinogen based upon evidence presented in
numerous occupational epidemiological studies. Significantly increased risks
of leukemia, chiefly acute myelogenous leukemia (AML), have been reported in
benzene-exposed workers in the chemical industry, shoemaking, and oil
refineries.
The following epidemiologic studies briefly described are the key studies
that support the weight-of-evidence classification that exposure to benzene is
causally related to an increase in the risk of cancer, specifically leukemia.
Aksoy et al. (1974) reported effects of benzene exposure among 28,500
Turkish workers employed in the shoe industry. The mean duration of employment
was 9.7 years (range 1 to 15 years) and the mean age was 34.2 years. Peak
exposure to benzene was reported to be 210 to 650 ppm. Twenty-six cases of
leukemia and a total of 34 leukemias or preleukemias were observed, corresponding
to an incidence of 13/100,000 (by comparison to 6/100,000 for the general
population). A follow-up analysis of the study (Aksoy, 1980) reported eight
additional cases of leukemia as well as evidence suggestive of increases in
other malignancies. This case study lacks detailed information on personal
exposure to benzene and potential exposure to other chemicals, a well-defined
comparison population, and control of confounding variables.
Infante et al. (1977b), in a retrospective cohort mortality study, examined
the leukemogenic effects of benzene exposure in 748 white male workers exposed
at least 1 day while employed in the manufacture of rubber products. Exposure
occurred from 1940 to 1949 and vital status was obtained through 1975. A
statistically significant increased risk of leukemia (7 observed, 1.48
expected; p < .002) was found by comparison of observed leukemia deaths in this
cohort with those expected based upon general U.S. population death rates.
The risk of leukemia was said by the authors to be potentially understated
since follow-up was only 75% complete. According to the authors, there was no
evidence of solvent exposure other than benzene. No effort was made to
evaluate individual exposures to benzene for the purpose of doing a
dose-response analysis. The main criticism of this study, as well as its later
updates, is the small size of the cohort.
In an extension and elaboration of the analysis done by Infante et al.
(1977b), Rinsky et al. (1981) reported seven deaths from leukemia in this same
cohort after achieving a 98% vital status ascertainment through June 1975.
Forty additional deaths from all causes were reported, but no new leukemia
deaths. Again, the risk of death from leukemia was statistically significant
(standardized mortality ratio [SMR] was 560 based upon 7 leukemia deaths,
p < .001). Some 437 members of the cohort were exposed for less than 1 year.
Those who received 5 or more years of exposure exhibited an SMR of 2100, based
upon 5 leukemia deaths versus 0.25 expected (p < .01). All seven leukemia
cases were of the myelogenous or monocytic cell type. Four additional deaths
from leukemia were also noted but could not be added to the total because they
did not fit the criteria for inclusion. The authors tried to reconstruct past
exposure to benzene at the two locations of this company and found that in
some areas of the plants airborne benzene concentrations occasionally rose to
several hundred parts per million, but most often employee 8-hour time-weighted
averages (TWA) fell within the LIMITS considered permissible at the time of
exposure. No dose-response analysis was attempted.
In an updated version of the Rinsky et al. (1981) study, the same authors
examined a somewhat expanded cohort of 1165 nonsalaried white men employed in the
rubber hydrochloride department for at least 1 day through December 1965 and
followed to December 31, 1981 (Rinsky et al., 1987). Followup was 98.6% complete.
Again, a statistically significant excess risk of leukemia was found for the total
cohort (9 observed, 2.7 expected; p < 0.05). For the first time, individual
measurements of cumulative exposure in terms of ppm-years were generated for all
members of the cohort utilizing the historical air-sampling data discussed above
or interpolating estimates based on the existing data. SMRs for leukemia ranged
from a nonsignificant 109 (2 observed, 1.83 expected) at cumulative exposures
under 40 ppm-years to a statistically significant SMR of 2339 (5 observed, 0.21
expected; p < .05) at 200 ppm-years or more of exposure. The authors found
significantly elevated risks of leukemia at cumulative exposures less than the
then equivalent current standard for occupational exposure, which was 10 ppm over
a 40-year working lifetime.
The Rinsky et al. (1981, 1987) study analyses, based upon the original
cohort of Pliofilm rubber workers studied by Infante et al. (1977b), were selected
by the Agency as the critical study for dose-response analysis and for the
quantitative estimation of cancer risk to humans. The Rinsky et al. (1981, 1987)
analyses show ample power, latency, reasonably good estimates of exposure to
benzene except prior to 1946, few confounders, and a wide range of exposure to
benzene from low levels to high levels. Limitations include the small cohort
size, reporting only nine leukemia deaths with no estimates of risk according to
cell type. There remain questions about the estimation of personal exposure to
benzene, especially prior to 1946 when no measurements of airborne benzene were
made. And finally, at levels less than 200 ppm-years it is not possible to
determine leukemia risk in this cohort because of lack of sensitivity of the
data at low levels.
Ott et al. (1978) observed a nonsignificantly increased risk of leukemia
(3 deaths) among 594 chemical workers exposed to benzene followed for at least
23 years in a retrospective cohort mortality study. Benzene exposures ranged
from under 2 ppm to over 25 ppm 8-hour TWA. Bond et al. (1986) updated this
report by following this cohort an additional 9 years to the end of 1982 and
adding an additional 362 exposed workers not studied previously. The authors
reported finding a nonsignificant excess risk (SMR = 194) of deaths from leukemia
based upon 4 cases. All were diagnosed as myelogenous leukemias. The authors
reported that this represented a significant excess (4 observed versus 0.9
expected, p < .011) for myelogenous leukemia based upon the International
Classification of Diseases and Causes of Death. It is not stated whether these
four deaths were acute or chronic. One additional death was classified as a
"pneumonia" death, but on the death certificate "acute myelogenous leukemia" was
noted as a significant contributing condition. Cumulative exposure estimates
ranged from 18 ppm-months to a high of 4211 ppm-months. The Bond et al. (1986)
study has little power to detect significant risk of leukemia at low doses. The
authors also state that their data should not be used for determining unit risk
estimates because of the small number of events, competing exposures to other
potentially hazardous materials, and the contribution of unquantified brief
exposures to benzene.
Wong (1983, 1987) reported on the mortality of male chemical workers who
had been exposed to benzene for at least 6 months during the years 1946 to 1975.
The study population of 4602 persons was drawn from seven chemical plants and
cumulative exposures to benzene were determined for all subjects. The control
subjects (3074 persons) held jobs at the same plants for at least 6 months but
were never subjected to benzene exposure. Dose-dependent increases were seen in
the risk of leukemia and the risk of lymphatic and hematopoietic cancer.
Chemical workers with a cumulative exposure to benzene of 720 ppm-months were
subject to a borderline significant relative risk of 3.93 (p = .05) for lymphatic
and hematopoietic cancer. None of the leukemia deaths were of the acute myeloid
cell type, the type that was known to be associated with exposure to benzene in
other studies. The author further observed that cumulative exposure, not peak
exposure, was the major variable in quantifying mortality risk from lymphopoietic
cancer. The Mantel-Haenszel chi-square for upward trend in risk of leukemia with
increasing cumulative exposure was significantly elevated at the 99% level of
confidence. Some of the limitations of this study include imprecise historical
industrial hygiene data, unusual distribution of leukemia cell types, i.e., there
were no acute cases of myelogenous leukemia out of seven leukemia cases, and
possible exposure of comparison subjects to potentially carcinogenic solvents
other than benzene.
The National Cancer Institute of the U.S. National Institutes of Health and
the Chinese Academy of Preventative Medicine have been conducting a comprehensive
epidemiological study of 74,828 benzene-exposed workers employed from 1972 to 1987
in 672 factories in 12 cities of China (Dosemeci et al., 1994; Hayes et al., 1996,
1997; Yin et al., 1987, 1989, 1994, 1996). A comparison group of workers
consisting of 35,805 employees was assembled from non-benzene-exposed units of 69
of the same factories and 40 factories elsewhere. Workers in a variety of jobs in
painting, printing, footwear, rubber, chemical, and other industries were followed
for vital status for an average period of time of less than 12 years. Less than
0.3% were lost to follow-up. Employee work histories were linked to benzene
exposure data in order to derive individual time-specific estimates for each worker
(Dosemeci et al., 1994). This large cohort mortality study produced a significantly
elevated risk of hematologic neoplasms (RR = 2.2, 95% C.I. = 1.1-4.2) in workers
exposed to benzene at an average level of less than 10 ppm. A combination of ANLL
and MDS produced a risk of 3.2 (95% C.I .= 1.0-10.1). For exposure to a sustained
concentration of 25 ppm benzene, the risk of ANLL and MDS increased to 7.1
(95% C.I. = 2.1-23.7). The risk of other leukemias (other than ANLL), including
chronic myeloid and monocytic leukemia, was not significantly elevated (RR = 2.0).
Additionally, the risk of non-Hodgkin's lymphoma was significantly elevated
(RR = 4.2 with 95% C.I. = 1.1-15.9) for those with a sustained exposure to benzene
that occurred at least 10 years prior to diagnosis. The authors concluded that
benzene exposure "is associated with a spectrum of hematologic neoplasms and
related disorders in humans and that risks for these conditions are elevated at
average benzene-exposure levels of less than 10 ppm." Limitations of this study
include possible concurrent exposures to many different chemicals found in the
factories where the benzene exposure occurred. There is a lack of reliable
exposure information in the early days of the observation period, when only
3% of the exposure estimates were based on actual measurements.
All of the epidemiological studies referred to above have some
methodological problems, i.e., confounding exposures, lack of sufficient power,
and other limitations, but the consistent excess risk of leukemia across all of
these studies argues that such problems could not be entirely responsible for
the elevated risks of cancer. Most of these epidemiologic and case studies
have been reviewed in peer-reviewed publications (IARC, 1982; ATSDR, 1997;
U.S. EPA, 1998). They provide clear evidence of a causal association between
exposure to benzene and ANLL. The evidence is suggestive with respect to CNLL
and CLL.
The limitations of these studies, except for Rinsky et al. (1981, 1987),
preclude their use in quantitative risk estimation. This is further discussed
in the quantitative risk estimation sections (II.C.3 and II.C.4).
___II.A.3. ANIMAL CARCINOGENICITY DATA
Although human epidemiological studies provide the bulk of the evidence
reaffirming the classification of benzene as a category A, "known" human
carcinogen (U.S. EPA, 1979, 1985, 1998), many experimental animal studies,
both inhalation and oral, also support the evidence that exposure to benzene
increases the risk of cancer in multiple organ systems including the
hematopoietic system, oral and nasal cavities, liver, forestomach, preputial
gland, lung, ovary, and mammary gland. The key animal studies that support
the finding of an excess risk of leukemia in humans from exposure to benzene
by the inhalation route are Maltoni et al. (1982, 1983, 1985, 1989), Cronkite
et al. (1984, 1985, 1989), Snyder et al. (1988), and Farris et al. (1993); and
by the oral route, Huff et al. (1989), NTP (1986), and Maltoni et al. (1983,
1985, 1989). The details of these studies have been reviewed (ATSDR, 1997).
Studies on the carcinogenicity of benzene in rodents include inhalation
exposures to Sprague-Dawley rats, C57BL/6 mice, AKR mice, CD-1 mice, and CBA
mice; and gavage treatment of Sprague-Dawley rats, Wistar rats, F344 rats,
RF/J mice, Swiss mice, and B6C3F1 mice (Cronkite et al., 1989; Goldstein et
al., 1982; Huff et al., 1989; Maltoni et al., 1983, 1988; NTP, 1986; Snyder
et al., 1980, 1982, 1984; Farris et al., 1993). Inhalation concentrations
ranged from 0 to 1000 ppm and gavage doses ranged from 0 to 200 mg/kg.
It is noted that in humans the cancer induced by benzene exposure is
predominantly acute nonlymphocytic leukemia, while in rodents lymphocytic
leukemia was observed in two series of experiments in C57BL/6 mice (Snyder
et al., 1980) and CBA/Ca mice (Cronkite et al., 1989). The difference in
induction of hematopoietic cancers in mice and humans is not fully understood,
but it may be related to species-specific differences in hematopoiesis.
Lymphocytes make up a larger portion of the nucleated cells in mouse bone
marrow than in human bone marrow (Parmley, 1988) and could simply represent
a larger target cell population for benzene metabolites. The bone marrow,
Zymbal gland, and Harderian gland all contain peroxidases, which can activate
phenols to toxic quinones and free radicals. Sulfatases, which remove
conjugated sulfate and thus reform free phenols, are also present at high
levels in these target organs. The selective distribution of these two types
of enzymes in the body may explain the accumulation of free phenol,
hydroquinone, and catechol in the bone marrow and the resulting differences
in target organ toxicity of benzene metabolites in humans and animals. The
animal bioassay results may have some relevance to human leukemia, but it
should be emphasized that there is no well-demonstrated and reproducible
animal model for leukemia resulting from benzene exposure. The mechanism
of leukemia development following exposure to benzene is not well understood
(Low et al., 1989, 1995).
___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY
The supporting evidence for the carcinogenic effects of exposure
to benzene comes from our current understanding of the metabolism and mode
of action (Stephens et al., 1994; Medinsky et al., 1996; Lee et al., 1996;
Valentine et al., 1996; Rothman, 1997). This is briefly summarized below
and reviewed in U.S. EPA (1998).
It is generally agreed that the toxicity of inhaled benzene results
from its biotransformation to reactive species. Benzene is metabolized in
the liver by cytochrome P4502E1 (CYP2E1) to its major metabolites: phenol,
hydroquinone, and catechol. The intermediate benzene oxide can also undergo
ring opening to trans-trans muconic acid. Although there is a scientific
consensus that metabolism of benzene is required for resultant toxicity and
carcinogenic response, the role of a metabolite or metabolites of benzene
in producing these adverse effects is controversial and more reSEARCH data
are needed to better define sequelae of pathogenesis following exposure to
benzene and its metabolites. Current evidence indicates that
benzene-induced myelotoxicity and genotoxicity result from a synergistic
combination of phenol with hydroquinone, muconaldehyde, or catechol.
Molecular targets for the action of these metabolites, whether acting
alone or in concert, include tubulin, histone proteins, topoisomerase II, and
other DNA-associated proteins. Damage to these proteins would potentially
cause DNA strand breakage, mitotic recombination, chromosomal translocations,
and malsegregation of chromosomes to produce aneuploidy. If these effects
took place in stem or early progenitor cells, a leukemic clone with selective
advantage to grow could arise as a result of protooncogene activation, gene
fusion, and suppressor-gene inactivation. Epigenetic effects of benzene
metabolites on the bone marrow stroma, and perhaps the stem cells themselves,
could then foster development and survival of a leukemic clone. Since these
plausible events have not been conclusively demonstrated, this remains a
hypothesis (Smith, 1996).
__II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE
THIS SECTION IS BEING CURRENTLY REVIEWED FOR THE APPROPRIATENESS OF THE
RECENT DATA/INFORMATION TO REVISE THE QUANTITATIVE ESTIMATE OF CARCINOGENIC
RISK FROM ORAL EXPOSURE TO BENZENE. THEREFORE, THIS SECTION II.B REMAINS
UNCHANGED AT THIS TIME.
___II.B.1. SUMMARY OF RISK ESTIMATES
Oral Slope Factor -- 2.9E-2 per (mg/kg)/day
Drinking Water Unit Risk -- 8.3E-7 per (ug/L)
Extrapolation Method -- One-hit (pooled data)
Drinking Water Concentrations at Specified Risk Levels:
Risk Level Concentration
-------------------- -------------
E-4 (1 in 10,000) 1E+2 ug/L
E-5 (1 in 100,000) 1E+1 ug/L
E-6 (1 in 1,000,000) 1E+0 ug/L
___II.B.2. DOSE-RESPONSE DATA (CARCINOGENICITY, ORAL EXPOSURE)
Tumor Type -- leukemia
Test Animals -- human
Route -- inhalation, occupational exposure
Reference -- Rinsky et al., 1981; Ott et al., 1978; Wong et al., 1983
The slope factor was derived from human data for inhalation exposure
(see dose-response data for inhalation quantitative estimate). The human
respiratory rate was assumed to be 20 cu.m/day and the human drinking water
intake was assumed to be 2 L/day. The fraction of the administered dose
absorbed systemically via inhalation and via drinking water were assumed
to be equal.
___II.B.3. ADDITIONAL COMMENTS (CARCINOGENICITY, ORAL EXPOSURE)
The unit risk estimate is the geometric mean of four ML point
estimates using pooled data from the Rinsky et al. (1981) and Ott et al.
(1978) studies, which was then adjusted for the results of the Wong et al.
(1983) study as described in the additional comments section for
inhalation data.
The unit risk should not be used if the water concentration exceeds
1E+4 ug/L, since above this concentration the unit risk may not be
appropriate.
___II.B.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, ORAL EXPOSURE)
The pooled cohorts were sufficiently large and were followed for an
adequate time period. The increases in leukemias were statistically
significant and dose-related in one of the studies. Wong et al. (1983)
disagrees that exposures reported in Rinsky et al. (1981) were within the
recommended standards. For the five leukemia deaths in persons with 5 or
more years exposure, the author notes that mean exposure levels (range
15-70 ppm) exceeded the recommended standard (25 ppm) in 75% of the work
locations sampled. A total of 21 unit risk estimates were prepared using
6 models and various combinations of the epidemiologic data. These range
over slightly more than one order of magnitude. A geometric mean of these
estimates is 2.7E-2. Regression models give an estimate similar to the
geometric mean.
The risk estimate above based on reconsideration of the Rinsky et al.
(1981) and Ott et al. (1978) studies is very similar to that of 2.4E-2/ppm
(cited in U.S. EPA, 1980) based on Infante et al. (1977a,b), Ott et al. (1978)
and Aksoy et al. (1974). It was felt by the authors of U.S. EPA (1985) that
the exposure assessment provided by Aksoy was too imprecise to warrant
inclusion in the current risk estimate.
Risk estimates based on animal gavage studies are about 5 times higher
than those derived from human data. Pharmacokinetic data which could impact
the risk assessment are currently being evaluated.
__II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION
EXPOSURE
___II.C.1. SUMMARY OF RISK ESTIMATES
____II.C.1.1. Air Unit Risk:
A range of 2.2 × 10-6 to 7.8 × 10-6 is the increase in the lifetime
risk of an individual who is exposed for a lifetime to 1 µg/m3 benzene in air.
____II.C.1.2. Extrapolation Method:
Low-dose linearity utilizing maximum likelihood estimates (Crump, 1992, 1994).
Air Concentrations at Specified Risk Levels:
Risk Level Concentration
E-4 (1 in 10,000) 13.0 to 45.0 µg/m3
E-5 (1 in 100,000) 1.3 to 4.5 µg/m3
E-6 (1 in 1,000,000) 0.13 to 0.45 µg/m3
___II.C.2. DOSE-RESPONSE DATA FOR CARCINOGENICITY, INHALATION EXPOSURE
Tumor Type -- Leukemia
Test Species -- Humans
Route -- Inhalation
References -- Rinsky et al., 1981, 1987; Paustenbach et al., 1993; Crump
and Allen, 1984; Crump, 1992, 1994; U.S. EPA, 1998.
___II.C.3. ADDITIONAL COMMENTS (CARCINOGENICITY, INHALATION EXPOSURE)
The Pliofilm workers of Rinsky et al. (1981, 1987) provide the best
published set of data to date for evaluating human cancer risks from exposure
to benzene. Compared to the published studies of Ott et al. (1978), Bond
et al. (1986), and Wong (1987), this cohort has fewer reported co-exposures
to other potentially carcinogenic substances in the workplace that might
confound risk analysis for benzene. This cohort also provides a greater range
of exposures than those of Ott et al. (1978), Bond et al. (1986), and Wong
(1987). The Rinsky et al. data were used for developing the unit cancer risk
by Crump (1992, 1994). Differences in the unit risk estimates, in addition to
the choice of model used, stem largely from differences in the exposure
estimates and the dose-response model used.
Although the ongoing Chinese cohort studies (Dosemeci et al., 1994; Hayes
et al., 1996, 1997; Yin et al., 1987, 1989, 1994, 1996) provide a large data
set and perhaps may provide information in the future to better characterize
risk of cancer at low dose exposure, their use in the derivation of risk
estimates remains problematic at present for the reasons cited in Section II.A.2.
The two most important determinants of the magnitude of the unit risk
number are the choice of extrapolation model to be used to estimate risk at
environmental levels of exposure and the choice of the exposure estimates to
which the Pliofilm workers (Rinsky et al., 1981, 1987) were subjected. Crump
(1992, 1994) presented 96 unit risk calculation analyses by considering
different combinations of the following factors: (1) different disease
endpoints, (2) additive or multiplicative models, (3) linear/nonlinear
exposure-response relationships, (4) two different sets of exposure measurements
(Crump and Allen [1984] vs. exposure estimates by Paustenbach et al. [1993]) and
(5) cumulative or weighted exposure measurements. The unit risk estimates range
from 8.6 × 10-5 to 2.5 × 10-2 at 1 ppm (3200 µg/m3) of benzene air concentration
(Crump, 1992, 1994).
The risk estimates would fall into the lower range if a sublinear exposure
response model were found to be more plausible. However, the shape of the
exposure dose-response curve cannot be considered without a better understanding
of the biological mechanism(s) of benzene-induced leukemia. Understanding of
the mechanisms by which exposure to benzene and its metabolites exert their
toxic and carcinogenic effects remains uncertain (U.S. EPA, 1998). It is likely
that more than one mechanistic pathway may be responsible for the toxicity of
benzene contributing to the leukemogenic process. Not enough is known to
determine the shape of the dose-response curve at environmental levels of
exposure and to provide a sound scientific basis to choose any particular
extrapolation model to estimate human cancer risk at low doses. In fact, recent
data (Hayes et al., 1997) suggest that because genetic abnormalities appear at
low exposures in humans, and the formation of toxic metabolites plateaus above
25 ppm, the dose-response curve could be supralinear below 25 ppm. Given this,
EPA believes that use of a linear extrapolation model as a default approach is
appropriate.
When a linear model was employed, the choice of cancer unit risk estimates
narrows to a range between 7.1 × 10-3 and 2.5 × 10-2 at 1 ppm (2.2 × 10-6
to 7.8 × 10-6 at 1 µg/m3 of benzene in air), depending on which
exposure measurements were used, i.e., Crump and Allen (1984) or Paustenbach et
al. (1993). The choice of these LIMITS was dictated by the following
considerations: (1) use of the (1981, 1987) Rinsky cohort, (2) use of Crump's
(1992, 1994) analysis of the Crump and Allen (1984) and the Paustenbach (1992,
1993) exposure measurements. The range of risks nearly includes the 1985 EPA
risk estimate of 2.6 × 10-2 at 1 ppm (8.1 × 10-6 at 1 µg/m3). The set of risk
estimates falling within this interval reflects both the inherent uncertainties
in the risk assessment of benzene and the limitations of the epidemiologic studies
in determining dose-response and exposure data.
___II.C.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, INHALATION
EXPOSURE)
The major conclusion of this update (U.S. EPA, 1998) is a reaffirmation
within an order of magnitude of the benzene interim unit risk estimates derived
in EPA's 1985 interim risk assessment (U.S. EPA, 1985), which established the
probability of humans developing cancer from exposure to 1 ppm of benzene.
Review of the 1985 interim risk assessment required addressing two main concerns.
The first concern was the use of the updated epidemiologic data from Rinsky
et al.'s (1987) cohort of Pliofilm workers and selection of appropriate estimates
of their exposure to benzene for the derivation of the unit risk estimate.
Although numerous epidemiological studies demonstrate an association of exposure
to benzene and increased risk of human cancer, these studies are not without
methodological limitations. The Rinsky et al. (1981, 1987) study continues to
provide the best available data for derivation of unit cancer risk estimates.
This study had the least number of confounders and a wide range of exposure to
benzene.
The second major concern was continued application of the low-dose linearity
concept to the model used to generate estimates of unit risk. It was concluded
that at present there is insufficient evidence to reject this concept, and a
linear extrapolation was used (U.S. EPA, 1998). If one assumes that the linear
extrapolation model is the appropriate model to be used, given the uncertainties
outlined, then the range of suitable estimates is defined by the choice of
exposure estimates selected. The lowest unit risk among linear choices is
determined by the exposure estimates of Paustenbach et al. (1993) according to the
calculations of Crump (1992, 1994), simply because Paustenbach's exposure
estimates for the Rinsky cohort are highest. That estimate is 7.1 × 10 at
1 ppm (2.2 × 10-6 at 1 µg/m3). The highest risk number is determined by Crump
(1992, 1994) using the lower exposure estimates from Crump and Allen (1984),
and that is 2.5 × 10-2 at 1 ppm (7.8 × 10-6 at 1 µg/m3).
At present, the true cancer risk from exposure to benzene cannot be
ascertained, even though dose-response data are used in the quantitative cancer
risk analysis, because of uncertainties in the low-dose exposure scenarios and
lack of clear understanding of the mode of action. A range of estimates of risk
is recommended, each having equal scientific plausibility. The range estimates
are maximum likelihood values (i.e., best statistical estimates) and were derived
from observable dose responses using a linear extrapolation model to estimate low
environmental exposure risks. The extrapolation range is on the order of 20-60
depending on what environmental level is of interest. This range is fairly low
and thus does not suggest any unusual lack of plausibility about the estimates.
The use of a linear model is a default public health protective approach and an
argument both for and against recognizing supra- and sublinear relationships at
low doses and nonthreshold or threshold modes of action on exposure to benzene.
Therefore, the true risk could be either higher or lower. The numerical
difference between the 1985 risk estimate (2.6 × 10-2 at 1 ppm or 8.1 × 10-6 at
1 µg/m3) compared to the new high-end risk (2.5 × 10-2 at 1 ppm or 7.8 × 10-6 at
1 µg/m3) is insignificant and no scientific inferences about the merit of one
value versus the other should be made.
__II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY
ASSESSMENT)
___II.D.1. EPA DOCUMENTATION
Source Documents -- U.S. EPA, 1998; U.S. EPA, 1985; U.S. EPA, 1979.
The EPA (1998) assessment on which this summary was based was externally
peer reviewed by a panel of experts meeting held on July 16, 1997. Their
comments have been evaluated carefully and incorporated in finalization of
this IRIS summary. A summary record of the comments and EPA responses is
included as an appendix to the benzene support document file.
The EPA 1979 and 1985 documents provide the basis for the classification
of benzene as a Group A carcinogen.
___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT)
Agency Consensus Date -- 09/30/1998
___II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT)
Please contact the Risk Information Hotline for all questions concerning
this assessment or IRIS, in general, at (513) 569-7254 (phone), (513) 569-7159
(fax), or RIH.IRIS@EPAMAIL.EPA.GOV (Internet address).
_VI. BIBLIOGRAPHY
Benzene
CASRN -- 71-43-2
Last Revised -- 10/16/1998
__VI.A. ORAL RfD REFERENCES
N.A.
__VI.B. INHALATION RfC REFERENCES
N.A.
__VI.C. CARCINOGENICITY ASSESSMENT REFERENCES
Aksoy, M. (1980) Different types of malignancies due to occupational
exposure to benzene: a review of recent observations in Turkey. Environ
Res 23:181.
Aksoy, M; Erden, S; Dincol, G. (1974) Leukemia in shoe workers exposed
chronically to benzene. Blood 44:837-841.
ATSDR (Agency for Toxic Substances and Disease Registry). (1997)
Toxicological profile for benzene. Update. Public Health Service,
U.S. Department of Health and Human Services, Atlanta, GA.
Bond, GG; McLaren, EA; Baldwin, CL; et al. (1986) An update of mortality
among chemical workers exposed to benzene. Br J Ind Med 43:685-691.
Cronkite, EP; Bullis, JE; Inoue, T; et al. (1984) Benzene inhalation
produces leukemia in mice. Toxicol Appl Pharmacol 75:358-361.
Cronkite, EP; Drew, RT; Inoue, T; et al. (1985) Benzene hematotoxity
and leukemogenesis. Am J Ind Med 7:447-456.
Cronkite, EP; Drew, RT; Inoue, T; et al. (1989) Hematotoxicity and
carcinogenicity of inhaled benzene. Environ Health Perspect 82:97-108.
Crump, KS. (1992) Exposure-response analyses of Pliofilm cohort. Work
supported by Western States Petroleum Association. Draft.
Crump, KS. (1994) Risk of benzene-induced leukemia: a sensitivity
analysis of the Pliofilm cohort with additional follow-up and new
exposure estimates. J Toxicol Environ Health 42:219-242.
Crump, KS; Allen, BC. (1984) Quantitative estimates of risk of leukemia
from occupational exposure to benzene. Prepared for the Occupational
Safety and Health Administration by Science Research Systems, Inc.,
Ruston, LA.
Dosemeci, M; Li, GL; Hayes, RB; et al. (1994) Cohort study among workers
exposed to benzene in China: II. Exposure assessment. Am J Ind
Med 26:401-411.
Farris, GM; Everitt, JI; Irons, RD; et al. (1993) Carcinogenicity of
inhaled benzene in CBA mice. Fundam Appl Toxicol 20(4):503-507.
Goldstein, BD; Snyder, CA; Laskin, S; et al. (1982) Myelogenous leukemia
in rodents inhaling benzene. Toxicol Lett 13:169-173.
Hayes, RB; Yin, SN; Dosemeci, M; et al. (1996) Mortality among
benzene-exposed workers in China. Environ Health Perspect 104(suppl 6)
:1349-1352.
Hayes, RB; Yin, SN; Dosemeci, MS; et al. (1997) Benzene and the
dose-related incidence of hematologic neoplasms in China. J Nat Cancer
Inst 89:1065-1071.
Huff, JE; Haseman, JK; DeMarini, DM; et al. (1989) Multiple-site
carcinogenicity of benzene in Fischer 344 rats and B6C3F1 mice.
Environ Health Perspect 82:125-163.
IARC (International Agency for Research on Cancer). (1982) Benzene.
In: Some industrial chemicals and dyestuffs. IARC Monographs on the
evaluation of carcinogenic risk of chemicals to humans. Lyon, France:
IARC, WHO, 29:93-148.
Infante, P.F., R.A. Rinsky, J.K. Wagoner and R.J. Young. (1977a)
Benzene and Leukemia. The Lancet. 2(8043): 867-869.
Infante, PF; R.A. Rinsky, J.K. Wagoner and R.J. Young (1977b)
Leukemia in benzene workers. Lancet 2:76-78.
Latriano, L: Goldstein, BD; Witz, G. (1986) Formation of muconaldehyde,
an open ring metabolite of benzene, in mouse liver microsomes: an
additional pathway of toxic metabolites. Proc Natl Acad Sci USA 83:8356-8360.
Lee, SST; Buters, JTM; Pineau,T; et al. (1996) Role of CYP2E1 in the
hepatotoxicity of acetaminophen. J Biol Chem 15:3012-3022.
Low, LK; Meeks, J; Norris, KJ; et al. (1989) Pharmacokinetics and metabolism
of benzene in Zymbal gland and other key target tissues after oral
administration in rats. Environ Health Perspect 82:215-222.
Low, LK; Lambert, C; Meeks, J; et al. (1995) Tissue-specific metabolism of
benzene in Zymbal gland and other solid tumor target tissues in rats.
J Am Coll Toxicol 14:40-60.
Maltoni, C; Cotti, G; Valgimigli, L; et al. (1982) Zymbal gland carcinomas
in rats following exposure to benzene by inhalation. Am J Ind Med 3:11-16.
Maltoni, C; Conti, B; Cotti, G. (1983) Benzene: a multipotential carcinogen.
Results of the long-term bioassays performed at the Bologna Institute of
Oncology. Am J Ind Med 4:589-630.
Maltoni, C; Conti, B; Cotti, G; et al. (1985) Experimental studies on
benzene carcinogenicity at the Bologna Institute of Oncology: Current
results and ongoing reSEARCH. Am J Ind Med 4:446-450.
Maltoni, C; Conti, B; Perino, G; et al. (1988) Further evidence of benzene
carcinogenicity. Results on Wistar rats and Swiss mice treated by ingestion.
Ann NY Acad Sci 534:412-426.
Maltoni, C; Ciliberti, A; Cotti et al. (1989) Benzene, an experimental
multipotential carcinogen: results of the long-term bioassays performed at
the Bologna Institute of Oncology. Environ Health Perspect 82:109-124.
Medinsky, MA; Kenyon, EM; Seaton, MJ; et al. (1996) Mechanistic considerations
in benzene physiological model development. Environ Health Perspect 104(suppl 6)
:1399-1404.
National Toxicology Program (NTP), Public Health Service, U.S. Department of
Health and Human Services. (1986) NTP technical report on the toxicology and
carcinogenesis studies of benzene (CAS No. 71-43-2) in F344/N rats and B6C3F1
mice (gavage studies). NTP TR 289. Research Triangle Park, NC: National
Institutes of Health.
Ott, MG; Townsend, JC; Fishbeck, WA; et al. (1978) Mortality among individuals
occupationally exposed to benzene. Arch Environ Health 33:3-10.
Parmley, R. (1988) Mammals. In: Vertebrate blood cells. Rowley, AF; Ratcliffe,
NA, eds. Cambridge: Cambridge University Press, pp. 337-424.
Paustenbach, DJ; Price, PS; Ollison, W; et al. (1992) Reevaluation of benzene
exposure for the Pliofilm (rubberworker) cohort (1936-1976). J Toxicol Environ
Health 36:177-231.
Paustenbach, D; Bass, R; Price, P. (1993) Benzene toxicity and risk assessment,
1972-1992: implications for future regulation. Environ Health Perspect
101(Suppl 6):177-200.
Rinsky, R; Young, RJ; Smith, AB. (1981) Leukemia in benzene workers. Am J Ind
Med 2:217-245.
Rinsky, RA; Smith, AB; Hornung, R; et al. (1987) Benzene and leukemia: an
epidemiologic risk assessment. N Engl J Med 316:1044-1050.
Ross, D. (1996) Metabolic basis of benzene toxicity. Eur J Haematol 57(suppl)
:111-118.
Rothman, N; Smith, MT; Hayes, R; et al. (1997) Benzene poisoning, a risk factor
for hematological malignancy, is associated with the NQ01 C-609- > T mutation
and rapid fractional excretion of chlorzoxazone. Cancer Res 57:2839-2842.
Smith, MT. (1996) The mechanism of benzene-induced leukemia: a hypothesis and
speculations on the causes of leukemia. Environ Health Perspect 104:1219-1225.
Snyder, CA; Goldstein, BD; Sellakumar, AR; et al. (1980) The inhalation
toxicology of benzene: incidence of hematopoietic neoplasms and hematotoxicity
in AKR/J and C57BL/6J mice. Toxicol Appl Pharmacol 54:323-331.
Snyder, CA; Goldstein, BD; Sellakumar, A; et al. (1982) Toxicity of chronic
benzene inhalation: CD-1 mice exposed to 300 ppm. Bull Environ Contam Toxicol
29:385-391.
Snyder, CA; Goldstein, BD; Sellakumar, AR; et al. (1984) Evidence for
hematotoxicity and tumorigenesis in rats exposed to 100 ppm benzene. Am J Ind
Med 5:429-434.
Snyder, CA; Sellakumar, AR; James, DJ et al. (1988) The carcinogenicity of
discontinuous inhaled benzene exposures in CD-1 and C57BL/6 mice. Arch
Toxicol 62:331-335.
Stephens, EA; Taylor, JA; Kaplan, N; et al. (1994) Involvement of 11p15 and
3q21q26 in therapy-related myeloid leukemia (t-ML) in children. Case reports
and review of the literature. Cancer Genet Cytogenet 75:11-22.
U.S. Environmental Protection Agency (U.S. EPA). (1979) Carcinogen Assessment
Group's final report on population risk to ambient benzene exposures. National
Technical Information Service, PB82-227372.
U.S. EPA. (1980) Ambient Water Quality Criteria Document for Benzene.
Prepared by the Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office (Cincinnati, OH) and Carcinogen Assessment
Group (Washington, DC), and the Environmental Research Labs (Corvalis, OR;
Duluth, MN; Gulf Breeze, FL) for the Office of Water Regulations and
Standards, Washington, DC. EPA 440/5-80-018.
U.S. EPA. (1985, Feb. 15) Interim quantitative cancer unit risk estimates due
to inhalation of benzene. Prepared by the Carcinogen Assessment Group, Office
of Research and Development, Washington, DC. EPA/600/X-85-022.
U.S. EPA. (1986, Sept. 24) Guidelines for carcinogenic risk assessment.
Federal Register 51(185):33992-34003.
U.S. EPA. (1996, April 23) Proposed guidelines for carcinogen risk assessment.
Federal Register 61(79):17960-18011.
U.S. EPA. (1998, April 10) Carcinogenic effects of benzene: An update. Prepared
by the National Center for Environmental Health, Office of Research and
Development. Washington, DC. EPA/600/P-97/001F.
Valentine, JL; Lee, SST; Seaton, MJ; et al. (1996) Reduction of benzene
metabolism and toxicity in mice that lack CYP2E1 expression. Toxicol Appl
Pharmacol 141:205-213.
Wong, O. (1987) An industry-wide study of chemical workers occupationally
exposed to benzene. Br J Ind Med 44:382-395.
Wong, O; Morgan, RW; Whorton, MD. (1983, Dec. 8) An industry-wide mortality
study of chemical workers occupationally exposed to benzene. Technical report
submitted to Chemical Manufacturers Association by Environmental Health
Associates, Berkeley, CA.
Yin, SN; Li, GL; Tain, FD; et al. (1987) Leukaemia in benzene workers: A
retrospective cohort study. Br J Ind Med 44:124-128.
Yin, SN; Li, GL; Tain, FD; et al. (1989) A retrospective cohort study of
leukemia and other cancers in benzene workers. Environ Health Perspect
82:207-213.
Yin, SN; Linet, MS; Haynes, RB; et al. (1994) Cohort study among workers
exposed to benzene in China: I. General methods and resources. Am J Ind
Med 26:383-400.
Yin, SN; Hayes, RB; Linet, MS; et al. (1996) A cohort study of cancer
among benzene-exposed workers in China: Overall results. Am J Ind Med
29:227-235.
_VII. REVISION HISTORY
Benzene
CASRN -- 71-43-2
Date Section Description
12/01/1988 II.A.4. Anderson and Richardson citation year corrected
12/01/1988 II.A.4. Kissling and Speck citation year corrected
07/01/1989 I.B. Inhalation RfD now under review
02/01/1990 II. Clarified citations
02/01/1990 II.A.3. Corrected Maltoni, 1979 to Maltoni and
Scarnato, 1979
02/01/1990 II.A.3. Corrected Maltoni, 1983 to Maltoni et al., 1983
02/01/1990 II.A.3. Corrected Synder et al., 1980 to 1981
02/01/1990 VI. Bibliography on-line
03/01/1990 VI.C. Clarify Maltoni et al., 1983 and NTP, 1986
references
08/01/1990 III.A.10 Primary contact changed
08/01/1990 IV.F.1. EPA contact changed
01/01/1991 II. Text edited
01/01/1991 II.C.1. Inhalation slope factor removed (global change)
01/01/1992 IV. Regulatory actions updated
04/01/1992 II.B.2. Text revised
02/01/1994 II.D.3. Secondary contact's phone number changed
10/16/1998 II., VI. Revised inhalation carcinogenicity section
and references
VIII. SYNONYMS
Benzene
CASRN -- 71-43-2
Last Revised -- 03/01/1988
71-43-2
Benzene
benzol
coal naphtha
cyclohexatriene
phene
phenyl hydride
polystream
pyrobenzol
Last updated: 14 October 1998
URL: http://www.epa.gov/iris/SUBST/0276.HTM
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