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Blood, Vol. 94 No. 4 (August 15), 1999:
pp. 1174-1182
REVIEW ARTICLE
Benzene and Multiple Myeloma: Appraisal of the Scientific Evidence
By
Daniel E. Bergsagel,
Otto Wong,
P. Leif Bergsagel,
Raymond Alexanian,
Kenneth Anderson,
Robert A. Kyle, and
Gerhard K. Raabe
From the Ontario Cancer Institute/Princess Margaret Hospital,
University of Toronto, Toronto, Ontario, Canada; Applied Health
Sciences, San Mateo, CA; the Department of Epidemiology, School of
Public Health, Tulane University Medical Center, New Orleans, LA; The
New York Presbyterian Hospital-Weill Medical College of Cornell
University, Center for Lymphoma and Myeloma, New York, NY; The
University of Texas M. D. Anderson Cancer Center, Houston, TX; the Dana
Farber Cancer Institute, Harvard University, Boston, MA; the Mayo
Clinic, Rochester, MN; and the Department of Medical Information and
Health Risk Assessment, Mobil Business Resources Corp, Global Medical
Services, New Hope, PA.
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INTRODUCTION |
CANCER PATIENTS OFTEN ask their physician
whether there are any factors in their family history, life style, or
work environment that might have increased the risk of developing their type of tumor. When clinicians consult the literature about oncology, toxicology, and epidemiology for answers to questions such as this,
they soon discover that the information can be extensive and
complicated and that guidance may be needed for the interpretation of
some of the data. This report will review the association of benzene
exposure with myeloma.
Since the first cases of acute myelogenous leukemia (AML) were reported
in workers exposed to high concentrations of benzene in shoe
manufacturing and rotogravure plants,1,2 there have been
extensive investigations of the role of benzene in the causation of the
hematologic malignancies. Data to be presented below convincingly link
high-level benzene exposure to the causation of AML. Case reports of
another hematologic malignancy, multiple myeloma, in persons exposed to
benzene3,4 prompted additional studies to determine whether
benzene might also be involved in the causation of this tumor.
The purposes of our appraisal are to update, review, and summarize
studies of the association of benzene with myeloma and to illustrate
the use of the criteria developed by Sir Austin Bradford
Hill5,6 in the evaluation of the role of benzene in the
causation of multiple myeloma. We will also review advances in the
detection of specific chromosome lesions in myeloma cells and those
associated with drug and chemical exposures.
Myeloma originates with the malignant transformation of a B lymphocyte
that has undergone V(D)J recombination and somatic hypermutation of its
Ig heavy and light chain genes and, almost always, isotype switch
recombination (IgM myeloma is rare). This clone is committed to the
production of a unique, monoclonal Ig (abbreviated as monoclonal- or
M-protein). The clone derived from the transformed B
lymphocyte must grow to approximately 1 billion cells before sufficient
M-protein is produced to allow detection in a serum electrophoresis
pattern. Subjects are asymptomatic during the initial phase (monoclonal
gammopathy of undetermined significance [MGUS]), when a small
M-protein is present in the serum, without bone lesions, renal failure,
or anemia, and the marrow contains less than 10% plasma cells. More
than 95% of the subjects discovered to have an M-protein in a
screening study of a population will be found to have
MGUS.7 Follow-up of 241 MGUS subjects at the Mayo Clinic
for 24 to 38 years showed that only 26% progressed to a symptomatic
B-lymphocyte malignancy, with bone destruction, bone pain, and other
manifestations of these malignancies.8 The studies to be
reviewed here deal only with the association of benzene with multiple
myeloma; the association of benzene with MGUS has not been evaluated.
Detailed molecular analyses of the reciprocal 11;14 breakpoints and the
productive switch recombination breakpoint in the myeloma cell line
U266 clearly indicate that, at least in this one example that has been
fully characterized, the aberrant 11;14 rearrangement resulted from an
error occurring at the time and is related to the process of productive
isotype switch recombination.9 These translocations are
characteristic in that t(4;14) and t(14;16) have only been described in
myeloma samples; similarly, a t(11;14) translocation occuring in the
switch region has only been described in myeloma samples. Many of these
translocations are not detected by conventional karyotypic analysis,
although recent analyses using reverse transcription-polymerase chain
reaction (RT-PCR),10 multicolor spectral
karyotypes,11 and dual-color interphase fluorescent in situ
hybridization12 indicate that these translocations occur at
a similar high frequency in primary patient material. Myeloma is also
characterized by frequent trisomies of chromosome 3, 5, 7, 9, 11, 15, 19, and 21 and monosomy 13.
Although the first report of multiple myeloma appeared in
1844,13 the disease has presented problems in
classification in the past and, consequently, in analysis as
well.14 Historically, multiple myeloma was classified as a
bone tumor until the sixth revision of the International Classification
of Diseases (ICD), which was published in the late 1940s.13
Since then, multiple myeloma has been assigned a unique rubric (ICD
203) in the broad category of "neoplasms of the lymphatic and
hematopoietic tissues" (ICD 200-209), which includes non-Hodgkin
lymphoma, Hodgkin disease, and various types of leukemia.
According to the National Center for Health Statistics (NCHS), more
than 8,000 Americans die from multiple myeloma every year. In 1994, the
National Cancer Institute (NCI) estimated that 12,000 new cases were
diagnosed in the United States. Multiple myeloma is a disease of older
age. The NCI Surveillance, Epidemiology, and End Results (SEER) Program
reports that the incidence increases rapidly with age to reach
52/100,000 in caucasian men more than 85 years of age and to reach
33/100,000 in caucasian women 80 to 84 years of age.15
Multiple myeloma, unlike other lymphatic and hematopoietic
malignancies, is more common in blacks than in caucasians. The
age-adjusted incidence rate for caucasians is 4.1/100,000 and for
blacks is 9.1/100,000.15 The lowest incidence rates are for
Americans of Japanese (1.7/100,000) and Chinese (2.3/100,000)
descent.16 The most distinctive feature of myeloma is the
late age of onset, with a median age at diagnosis of 72 years of age,
which is somewhat older than the median age at diagnosis of all
cancers.17 Thus, age and race have an important influence on the incidence of myeloma. The strong influence of race on the incidence of myeloma and the occurrence of familial clusters of multiple myeloma cases18-23 suggest that genetic factors
may be involved in determining who will develop this disease. Other
risk factors for multiple myeloma (eg, autoimmune disorders, chronic immune stimulation, and ionizing radiation) have also been considered. The general epidemiology of multiple myeloma has been discussed recently in 2 reviews.24,25
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EXPOSURE, METABOLISM, AND TOXICITY OF BENZENE |
Benzene is a versatile industrial chemical. It is a natural component
of crude and refined petroleum products. It is also formed in the
combustion of organic materials. Benzene is used primarily as a raw
material in the manufacture of synthetic organic chemicals. In the
past, benzene was used extensively as an organic solvent. It was also
an important component of paint, thinners, adhesives, and degreasing
compounds. Although it is rarely used in commercial products today, it
is still present in many organic compounds as a contaminant.
Exposure to benzene is not limited to the occupational setting.
Nonoccupational exposure originating from the general environment or
derived from personal life style is not uncommon. The investigations of
the US Environmental Protection Agency26 have shown that the major route of personal exposure is through air. Living close to
major fixed sources of benzene (eg, oil refineries, storage tanks, and
chemical plants) had no effect on personal exposure. For smokers, the
overwhelming source of benzene exposure is mainstream cigarette smoke.
According to the International Agency for Research on Cancer
(IARC),27 benzene in cigarette smoke has been
measured at levels between 47 and 64 parts per million (ppm). Ambient
air benzene concentrations in urban areas have been recorded as high as
182 parts per billion (ppb) in Los Angeles, 98 ppb in Toronto, and 179 ppb in London. Surprisingly, benzene content in certain food items is
relatively high: 500 to 1,900 µg/kg in eggs and 120 µg/kg in
Jamaican rum.27
Benzene itself is not toxic. It must be broken down by enzymes in the
liver into metabolites that are potentially toxic.28 The
major toxicity observed in experimental animals (mice, rats, and
rabbits) has been on the blood-forming cells of the bone marrow, the
hemopoietic system. The most frequently observed toxic effect of heavy
benzene exposure in humans and animal models has been depression of
blood cell production, in some cases leading to aplastic
anemia.28 Detailed studies of humans, mice, and rats exposed to benzene have shown that, under certain circumstances, it can
lead to chromosome abnormalities, the formation of micronuclei, and
sister chromosome exchanges.29-33 Studies of workers
chronically exposed to high concentrations of benzene indicate that
benzene can cause AML (see below). Although these effects (ie,
aplastic anemia, chromosome damage, and leukemogenesis) are indicative of the ultimate effects of benzene on bone marrow, the underlying mechanisms by which they are initiated are not fully understood.
The toxicity of benzene was first tested on experimental animals and
tissue cultures of human cells in the laboratory. Unfortunately, there
is no good animal model for the AML caused by prolonged high benzene
exposure in humans, and because benzene must be converted into toxic
metabolites before it can damage hemopoietic cells, it has been
difficult to study the underlying mechanism directly in tissue
cultures. Despite a great deal of effort, little has been learned about
the role of benzene as a potential cause of the hematologic
malignancies in the laboratory. In contrast, detailed studies of
exposures to benzene in the workplace have yielded much useful information.
The detection of cases of cytopenia, aplastic anemia, and leukemia
among shoe and leather workers using adhesives containing up to 88%
benzene in Turkey in the 1960s and 1970s provided strong suggestions
about the leukemogenic potential of this agent.1,34 Average
air concentrations experienced by the Turkish shoe and leather workers
ranged from 16 to 30 ppm during nonwork hours, with an increase during
work hours to 212 ppm, and sometimes as high as 640 ppm, when glues
containing benzene were used.35 Reports of similar cases
from Italy among workers in rotogravure plants, where benzene
concentrations in the air were estimated to range between 200 and 400 ppm, with peaks up to 1,500 ppm, and in shoe factories increased the
concern about benzene.2 These case reports set the stage
for detailed epidemiological studies of the role of benzene as a cause
of hematological malignancies.
Based on a crude investigation in the 1970s, Aksoy et al36
found an excess of leukemia (~2-fold) among Turkish shoemakers using
adhesives containing benzene. Exposure data were inadequate for a
dose-response analysis. Thus, the only conclusion one can draw from the
data is that exposure to benzene at such high levels can increase the
risk of leukemia. However, Aksoy et al36 did make the
important observation that the prominent cell-type of the leukemia was AML.
In the past, leukemia was considered as a single statistical category
in most occupational epidemiologic studies. This occurred partly
because of the historical nomenclature, potential misdiagnoses in some
cases, lack of an understanding of the biological mechanisms, the
unavailability of cell-type specific rates for comparison, and, most
importantly, the paucity of cases by cell-type in individual studies.28,29,37,38 Recently, epidemiologic studies have demonstrated the importance of cell-type specific analysis in studying
leukemia. It has now been recognized that the diseases collectively
known as leukemia are several distinct malignancies with different
etiologic factors.
The importance of specific cell-types of leukemia has also been
recognized by hematologists, who have found that the characteristics of
the disease fit a more homogeneous pattern if the leukemias are
subdivided on the basis of morphology (eg, lymphocytic or myelogenous)
and the course of the disease (eg, acute or chronic). More recently,
specific subtypes, for instance AML, have been associated with distinct
chromosome translocations [eg, t(8;21), inv(16), t(15,17), and
t(11q23)]. Tumors that share the same chromosome translocations also
share similar morphology, prognosis, and response to treatment, and
cytogenetics is now recognized as one of the most important prognostic
factors in AML.39 In the subset of AML secondary to
inhibitors of DNA topoisomerase II (eg, etoposide), characteristic
reciprocal translocations involving the loci 11q23 (MLL) and 21q22
(AML1) have been recognized. These have been postulated to result from
site-specific DNA cleavage induced by the topoisomerase inhibitors.40,41 The distribution of translocation
breakpoints on 11q23 in therapy-related AML has been shown to be
distinct from that of AML arising de novo, with a concentration in a
region rich in topoisomerase II cleavage sites.42 Thus,
recent advances in other disciplines confirm the epidemiologic
observation that leukemia is a group of distinct malignancies that
should be analyzed separately.
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CASE REPORTS OF MULTIPLE MYELOMA AND BENZENE EXPOSURE |
Interest in the relationship between multiple myeloma and benzene
exposure arises from observations that multiple myeloma involves the
bone marrow and that benzene is a recognized bone marrow toxin. In
1970, Torres et al3 described 2 cases of multiple myeloma
in leather workers in Spain who used benzene-containing glues. In 1984, Aksoy et al4 reported 4 cases of multiple myeloma over a
period of 10 years in Turkey in workers who were exposed to benzene.
The occupations of these 4 workers included a shoemaker, a plastic
factory manager, an airplane technician, and a furniture worker. These
2 reports have been cited frequently as evidence suggestive of as well
as supportive of an association between multiple myeloma and benzene
exposure. However, case reports alone are insufficient for the
determination of causation.
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USING EPIDEMIOLOGY TO IDENTIFY CAUSAL FACTORS IN CHRONIC DISEASES |
To determine the relationship between multiple myeloma and benzene
exposure, epidemiologic studies based on well-defined populations of
exposed workers were needed. Epidemiologic studies involve the
comparison of disease patterns and rates between groups of persons with
and without the exposure of interest or groups with varying degrees
and/or durations of exposure. The comparison is generally based on risk
ratios between the 2 groups (the risk of the exposed workers compared
with nonexposed persons). Risk ratios can be standardized mortality
ratios (SMR) in cohort studies or odds ratios (relative risks) in
case-control studies. A risk ratio greater than 1 may indicate an
increased risk. Associated with each risk ratio is a 95% confidence
interval. The risk ratio is statistically significant if the 95%
confidence interval does not include 1, which means that the observed
result is real and probably not due to chance. Case reports, by
definition, are incapable of providing any estimate of risk ratio,
because the underlying population at risk is not defined. Only properly
conducted epidemiologic studies, particularly those with quantitative
exposure information, can provide the basic data needed for a causation analysis.
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HILL'S CRITERIA FOR ASSESSING CAUSATION IN CHRONIC DISEASES |
The criteria for assessing causation in chronic diseases, such as
cancer, was formulated by Hill5 more than 3 decades ago and
is used by the Surgeon General's Committee in assessing the relationship between smoking and cancer43 as well as by
IARC in the evaluation of carcinogenicity of substances.44
Hill's criteria include the following:
(1) The strength of the association. How large is the difference
between the incidence of the disease in subjects exposed to the
chemical versus the unexposed? Large differences are more likely to be
associated with causal factors. Furthermore, the risk ratio must be
statistically significant before one can conclude that there is an
increased risk, ie, the excess is not likely due to chance.
(2) The consistency of the association. Has the association been
repeatedly observed in more than one group, in different places, and
under different circumstances?
(3) The specificity of the association. The association should be
specific in terms of both exposure and disease. Nevertheless, it must
be remembered that some diseases, such as cancer, can have more than
one cause.
(4) The temporality of association. The exposure to the chemical must
precede the development of the disease. For chronic diseases, because
of the usual long latency, recent exposures do not play a significant
role in the disease process.
(5) Exposure-response relationship in the association. There should be
evidence that greater exposures lead to a higher incidence of the disease.
(6) Biological plausibility. If the chemical agent is known to cause
some biological effect that could lead to the development of the
disease in question, it is helpful in establishing causation. However,
this feature cannot be demanded in every case, because for many
chemicals the biologic mechanisms are unknown.
(7) Experimental evidence. With respect to human carcinogens, direct
experimental evidence is seldom available. Occasionally, it is possible
to draw on semiexperimental evidence (mostly resulting from
intervention or preventive action). For example, the incidence of acute
leukemia in shoe workers began to decrease in Istanbul after the use of
benzene in their work was phased out,45 and no new cases of
AML have been detected in the Ohio Pliofilm cohort (see next section)
in workers hired after 1950, when the levels of benzene exposure were
reduced. These observations support the view that benzene, at high
concentrations, was involved in causing AML.
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EPIDEMIOLOGIC STUDIES OF WORKERS EXPOSED TO BENZENE |
In evaluating the causal relationship, if any, between benzene exposure
and multiple myeloma, Hill's criteria must be considered. In
particular, the available data must be examined in terms of the
strength, consistency, and specificity of the association, as well as
the exposure-response relationship, which can be addressed by
epidemiologic data directly. In addition, studies of the association of
exposure to a chemical with the subsequent development of a relatively
rare malignancy such as multiple myeloma require long-term studies of
the largest possible sample of exposed people, because the risk of a
false-negative result is great.
In studying chronic diseases such as myeloma, which appear to evolve
slowly, it is important to follow the study cohort for many years
because of the potential problem of latency, ie, the interval between
the toxic exposure that injures a B lymphocyte and the eventual
development of myeloma. Because this interval may be of many years
duration, the follow-up period must be long enough for the effects of
the exposure to become manifest.
One of the frequently cited studies of benzene-exposed workers is a
cohort of workers involved in the manufacture of rubber hydrochloride
(Pliofilm) in Ohio. This cohort was analyzed on several occasions by
the National Institute for Occupational Safety and Health (NIOSH), as
well as by others.
The first report was by Infante et al46 in 1977. The
mortality through 1975 of 748 caucasian male workers occupationally exposed to benzene for varying periods between 1940 and 1949 in two
Pliofilm manufacturing facilities was evaluated. The vital status of
only 75% of the cohort was determined. Causes of death were determined
from death certificates. Two populations were chosen as control groups:
the first was US caucasian males, and the second was employees at a
fibrous glass construction products facility over the same period. For
lymphatic and hemopoietic malignancies, there were 9 observed deaths
versus 3.34 expected when compared with US caucasian males. This
difference was statistically significant and was attributed to an
increased leukemia mortality. No analysis was reported for multiple myeloma.
The next analysis of the Pliofilm cohort was conducted by Rinsky et
al47 in 1981. Vital status was obtained for 98% of the original group of 748 men (group 1). A second group of 258 caucasian, male workers first employed in departments with benzene exposure between January 1, 1950 and December 31, 1959 (group 2) was added. In
group 1, 10 deaths of lymphatic and hematologic malignancy were
observed versus 3.03 expected, with 7 leukemia deaths versus 1.25 expected (SMR = 5.60). In group 2, there was 1 death from myelogenous
leukemia. This individual started his employment at the plant in May
1950 and died in 1954. The major findings of this analysis confirmed
that of the previous report. Again, no analysis was reported for
multiple myeloma.
The third report, also by Rinsky et al48 in 1987, was an
update of the earlier report. Benzene levels were estimated for jobs
held by the cohort members, and cumulative exposure (ppm-years) was
estimated for each worker. A total of 1,165 caucasian males with at
least 1 ppm-day of benzene exposure were observed through December 31, 1981. There was a significant increase in deaths from all lymphatic and
hematologic neoplasms (15 observed v 6.6 expected; SMR = 2.27).
The increase was due to leukemia (9 observed v 2.7 expected;
SMR = 3.37) and myeloma (4 observed v 1 expected; SMR = 4.09).
The principal findings of this analysis were a positive exposure-response relationship between benzene and all leukemias. On
the other hand, no exposure-response relationship was found for myeloma.
A further updated analysis of this cohort was conducted by Paxton et
al49,50 with vital status follow-up through 1987. For the
entire cohort a significantly increased SMR for all leukemia of 3.60 was found (14 observed v 3.89 expected). No new cases of
myeloma were discovered. Although Paxton et al49,50 did not
calculate an SMR for multiple myeloma, they stated that, with the
increased follow-up time (hence, more expected deaths), the statistical
association with myeloma reported by Rinsky et al48 was
"weakened to nonsignificance." Similar to the previous analysis, a positive exposure-response relationship with leukemia was found. Paxton et al49,50 concluded that the leukemia data were
consistent with a threshold model (ie, an exposure greater than the
threshold is required before the risk of leukemia is increased). It is
important to note that both Rinsky et al48 and Paxton et
al49,50 grouped all cell-types of leukemia together as a
single disease in their analyses (thus violating one of Hill's
criteria: specificity).
Citing recent advances in our understanding of the biological
mechanisms of benzene leukemogenesis and observations from recent epidemiologic studies, Wong51 criticized the lumping of
"lymphatic and hematological malignancies" or "leukemias of
all cell-types combined" for analysis in the study of the Pliofilm
cohort. Each hematological malignancy originates from the malignant
transformation of different precursor cells. The malignancies that
result are very different, as shown by differences in the course and
treatment of acute myelogenous leukemia, chronic myelogenous leukemia,
chronic lymphocytic leukemia, myeloma, and lymphomas that are included in these broad categories. In the absence of specific data, it cannot
be assumed that the same chemical is capable of causing all of these
different neoplasms. Whether the same chemical can cause more than one
disease can only be demonstrated through analyses specific to each
individual disease in question. In other words, Hill's criterion of
specificity must be met before a causation conclusion can be drawn.
This issue has been addressed by a number of
investigators.52-58
Wong52 reanalyzed the data from the Pliofilm cohort, using
data updated through 1987, as reported by Paxton et
al.49,50 Among male workers, there were 10 deaths from
leukemia: 6 from AML, 2 from chronic myelogenous leukemia (CML), 1 from
monocytic leukemia, and 1 from Di Guglielmo's acute myelocytic
leukemia. Wong51 determined the number of observed deaths
from AML for each exposure level, as estimated by Rinsky et
al,48 and compared the observed with the expected deaths
from AML based on age-specific rates derived from AML data provided by
the National Center for Health Statistics and by the National Cancer
Institute (Table 1).
Table 1 shows that, for the total cohort, 6 deaths from AML were
observed versus 1.19 expected. The SMR of 5.03 was significantly elevated, with a 95% confidence interval (95% CI) of 1.84 to 10.97. Furthermore, there was a strong exposure-response relationship, with an
SMR of 98.37 for those with 400 or more ppm-years. On the other hand,
the exposure-response analysis also shows a threshold. The risk of
developing AML was not increased in workers exposed to less than 200 ppm-years. As stated by Wong,51 had more realistic exposure
estimates been used in the Pliofilm study,59,60 the AML
threshold would have been higher (between 370 and 530 ppm-years).
For cell types other than AML, the Pliofilm study does not provide
sufficient cases for any meaningful analysis. The cell-type with the
second largest number of cases was CML, consisting of only 2 deaths.
One of the 2 CML cases was employed at the plant for 1 month in 1948 and died 2 years later in 1950. Given the slow progression of the
disease (ie, long latency), this case could not have been related to
exposure at the plant (Hill's criterion of temporality). Thus, only
AML was associated with benzene exposure in the Pliofilm study.
Recent laboratory studies of the effect of benzene metabolites on the
growth regulation of myeloid cell progenitors by Irons et
al61 and others62 offer a biological mechanism
to explain the selective increase in AML (Hill's criterion of
biological plausibility). These investigations have shown that
hydroquinone (a benzene metabolite) increases the recruitment or
stimulation of myeloid progenitor cells that respond to a specific
myeloid growth factor (granulocyte-macrophage colony-stimulating factor [GM-CSF]), thereby increasing the number of these cells at risk of
developing leukemia. This effect, on the other hand, has not been shown
for growth factors associated with other progenitor cells.
Wong51 concluded that analysis specific for AML shows the
importance of taking specificity of disease into consideration in
causation analysis. His investigation shows that previous studies based
on a combination of all types of leukemia have set the estimated threshold too low on one hand and underestimated the risk for exposure
above the threshold on the other.
In addition to AML, Wong52 also reanalyzed the updated
Pliofilm cohort with respect to myeloma. The results are reproduced in
Table 2. For the total cohort, 4 deaths
from myeloma were observed, versus 1.37 expected; the corresponding SMR
of 2.91 was not statistically significant. More importantly, there was no exposure-response relationship. In fact, 3 of the 4 deaths occurred
in workers in the lowest exposure category. One of these workers was
employed at the plant for only 4 days, and the other 2 workers were
employed for 9 months and 1.5 years, respectively.
Thus, in this Pliofilm cohort, a significant increase in the risk of
developing AML was observed in benzene-exposed workers, and there was a
strong exposure-response relationship between cumulative benzene
exposure and the risk of AML. Furthermore, all AML deaths occurred
among workers who were exposed before 1950, after which benzene
exposure at these plants was markedly reduced. According to Rinsky et
al,47 "(the) employees' 8-hour time-weighted average
exposures were within the recommended standards in effect at the
time." The benzene threshold limit value (TLV) was reduced from 100 to 50 ppm in 1947 and was further reduced in 1948 to 35 ppm. It can be
assumed that exposure after 1950 would have been much lower than that
in the early or mid-1940s. No deaths from AML have been observed among
the Pliofilm workers employed after 1950. Furthermore, in the Pliofilm
study there was no evidence for a causal relationship between benzene
exposure and the risk of developing leukemias other than AML or the
risk of developing multiple myeloma.
In the United States, there is another often-cited cohort study of
workers exposed to benzene. Wong37,38 reported the
mortality experience of a cohort study of more than 7,000 chemical
workers in the United States. Most of these workers were exposed to
benzene in the 1940s and 1950s, with some whose first exposure occurred in the 1920s and 1930s. Furthermore, some of these workers were exposed
to relatively high benzene levels in the past (in the range of 50 to
100 ppm). There were 3 deaths from multiple myeloma among the workers
exposed to benzene. The expected deaths were estimated to be 2.58, with
adjustment for age and race. The corresponding SMR was 1.16, with a
95% CI of 0.24 to 3.39. Thus, a significantly increased mortality from
multiple myeloma was not observed in this cohort of chemical workers
exposed to benzene.
There are 2 additional small cohort studies of benzene workers in the
United States. Bond et al63 reported only 1 death due to
multiple myeloma among 594 chemical workers in Michigan who were
exposed to benzene. The investigators stated that the multiple myeloma
death "did not represent an excess over expectation." In another
small study, Decouflé et al64 also reported only 1 death from multiple myeloma in 259 petrochemical workers who were
exposed to benzene at a petrochemical plant in Baltimore. Although
these 2 studies were small and no firm conclusion could be drawn from
them alone, neither provided any support for a causal relationship
between benzene exposure and multiple myeloma.
Similar results have been reported in studies from other countries as
well. Paci et al65 reported significantly elevated risks
from both aplastic anemia and leukemia in a cohort of more than 2,000 Italian shoe workers who were exposed to glues containing more than
70% benzene by weight, but no death due to multiple myeloma. It is
interesting to point out that an Italian law was introduced in 1963 limiting the use of benzene. The benzene content in the glues used by
Italian shoe workers was reduced to less than 2%. No increase of
leukemia or aplastic anemia was reported among those who began their
employment after 1964 (Hill's criterion of "experimental"
evidence resulting from intervention).
Recently, a large-scale cohort study of more than 74,000 Chinese
workers in a variety of occupations and industries (predominately painters) who were exposed to benzene as well as to other chemicals was
completed by scientists from China and the US National Cancer Institute.66 The observation period was from 1972 to 1987. A total of 1,369 deaths were reported. There was a significant increase in mortality from AML. Mortality from aplastic anemia was also significantly elevated. On the other hand, no death was due to multiple
myeloma (SMR = 0; 95% CI, 0 to 3.2). Therefore, the cohort studies of Italian and Chinese workers exposed to relatively high benzene levels (as indicated by the increased risk of leukemia or
aplastic anemia) do not provide any evidence for a causal association between benzene exposure and multiple myeloma.
Another source of data for assessing the health effects of benzene
exposure is the petroleum industry. Exposure to hydrocarbons in the
petroleum industry includes inhalation of vapors and dermal contact
with crude oil, feed stocks, intermediate products during refining, and
end products such as gasoline in marketing or
distribution.44 Many of these products contain varying
amounts of benzene. Therefore, workers in the petroleum industry
constitute a valuable database to assess the relationship between
multiple myeloma and benzene exposure.
Although there are numerous studies of petroleum workers, there are
only 2 studies with adequate quantitative exposure data. In a
relatively large cohort study of distribution workers, exposure to
gasoline vapor was measured in terms of total hydrocarbons (THC).67,68 The benzene component in gasoline vapor is
highly correlated with total hydrocarbons. Based on more than 400 industrial hygiene samples reported by the International Agency for
Research on Cancer, which were collected under a variety of
environmental conditions, benzene concentration in gasoline vapor is
approximately 1.6% of that of total hydrocarbons.44
Mortality from multiple myeloma in this cohort of distribution workers
was examined by various exposure indices (job category, length of
exposure, cumulative exposure [ppm-years], and cumulative frequency
of peak exposure [an episode of exposure in excess of 500 ppm THC
lasting 15 to 90 minutes]) in a subsequent nested
case-control study by Wong et al.69 Analyses were based on
both the Mantel-Haenszel procedure and conditional logistic regression
(ie, internal comparisons). The major results are summarized in
Tables 3 and 4. In
general, drivers can be considered to have higher exposure than the
others. As indicated in Table 3, the relative risk of multiple myeloma for drivers was 0.91 (95% CI, 0.21 to 3.96). Similarly, none of the
exposure indices were found to be associated with multiple myeloma risk
(Table 4). In particular, the risk ratios were 0.96, 1.00, and 1.00 for
length of exposure, cumulative exposure, and cumulative frequency of
peak exposure, respectively.
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Table 3.
Relative Risk and 95% CI of Multiple Myeloma by Job
Category in a Nested Case-Control Study of Gasoline Distribution
Workers
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Table 4.
Conditional Logistic Regression Analysis of Risk of
Multiple Myeloma and Exposure to Total Hydrocarbons in a Nested
Case-Control Study of Gasoline Distribution Workers
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A similar nested case-control study of lymphohemopoietic cancers in
Canadian distribution workers was conducted by Schnatter et
al.70 Exposures were measured in terms of cumulative
exposure and intensity of exposure. No relationship between multiple
myeloma and exposure to total hydrocarbons or benzene was found. For
example, with respect to benzene exposure, the risk ratios were 1.00, 0.44, 1.44, and 0 for cumulative exposure categories 0.0 to 0.90, greater than 0.90 to 9.9, greater than 9.9 to 9.99, and greater than
9.99 ppm-years, respectively.
Recently, the results of a record-linkage study of approximately 19,000 service station workers in 4 Scandinavian (Denmark, Norway, Sweden, and
Finland) countries were reported.71 No increased multiple
myeloma risk was found: among men, the standardized incidence ratio
(SIR) was 0.6 (9 observed v 15.99 expected), with a 95% CI of
0.3 to 1.2, and among women, no multiple myeloma case was observed
(1.65 expected).
Finally, to determine the risk of multiple myeloma, data from cohort
studies of petroleum workers (the majority being refinery workers) were
reviewed and pooled by Wong and Raabe.72 The methodology of
pooled, or meta-analysis, of cohort studies has been described elsewhere.73,74 A total of 22 cohort mortality studies of
petroleum workers in the United States, the United Kingdom, Canada, and Australia, which satisfied certain criteria, were included in the
pooled analysis. Authors of these studies were contacted, and data on
the number of observed deaths and age-specific person-years of
observation were requested. Data from individual studies were combined
in a pooled analysis (meta-analysis). In addition to the pooled
analyses, results for individual cohorts, most of which have never been
reported before, were also presented. The combined multinational cohort
consisted of more than 250,000 petroleum workers, and the observation
period covered an interval of 55 years from 1937 to 1991. A total of
205 deaths from multiple myeloma were observed, compared with 220.93 expected, which were derived from respective national mortality rates.
The corresponding SMR was 0.93 and the 95% CI was 0.81 to 1.07 (Table 5). Additional analyses were performed by type of
facility and industrial process. Stratum-specific SMRs (95% CIs) were
0.92 (0.77 to 1.09) for refinery workers and 0.93 (0.69 to 1.23) for
distribution workers. The pooled analysis indicates that petroleum
workers are not at an increased risk of multiple myeloma as a result of
their exposure to benzene, benzene-containing liquids, or other
petroleum products in their work environment.
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Table 5.
Multiple Myeloma in a Multinational Cohort of More Than
250,000 Petroleum Workers by Country and Industrial Division
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Further supporting evidence that there is no causal relationship
between exposure to benzene or benzene-containing solvents and multiple
myeloma can be derived from population-based case-control studies. In a
US NCI case-control study consisting of 100 multiple myeloma patients
in the Baltimore area, Linet et al75 reported a risk ratio
of 1.1 (95% CI, 0.4 to 3.7) for benzene exposure. In a second
case-control study sponsored by NCI, Morris et al76 compared the occupational exposure histories of 698 patients with newly
diagnosed multiple myeloma in Washington, Utah, Michigan, and Georgia
to their controls. For those exposed to aromatic hydrocarbons (including benzene), a risk ratio of 0.6 (95% CI, 0.3 to 1.0) was reported.
Case-control studies from other countries also support the finding of
no causal relationship between multiple myeloma and benzene exposure
from American studies. Based on a study of 131 multiple myeloma
patients in Sweden, Flodin et al77 reported a risk ratio of
1.0 (95% CI, 0.6 to 1.8) for exposure to solvents. The second Swedish
study, based on 275 multiple myeloma patients in the northern part of
the country, was reported by Eriksson and Karlsson.78 No
increased risk was reported for occupational exposure to organic
solvents (risk ratio of 0.5; 90% CI, 0.38 to 1.21). Two case-control
studies of multiple myeloma in Denmark were reported by Heineman et
al79 and Pottern et al.80 The first study
consisted of 1,098 male multiple myeloma patients. For those with
probable exposure to organic solvents, the risk ratio was 0.9 (95% CI,
0.7 to 1.2), and for those with probable exposure to benzene in
particular, the risk ratio was 0.8 (95% CI, 0.6 to 1.1). The second
study consisted of 1,010 female multiple myeloma patients. The risk
ratio for probable exposure to organic solvents was 0.6 (95% CI, 0.2 to 1.4). The last case-control study was reported by Cuzick and De
Stavola81 from the United Kingdom. The exposure histories
of 399 multiple myeloma patients in England and Wales were compared
with those of matched controls. An analysis by length of exposure to
"solvents/benzene" did not show any upward trend. Although no
numerical risk ratio was presented in the report, the investigators
stated that "excess risks were not found amongst individuals exposed
to solvents." Thus, these case-control studies support the results
from cohort studies of benzene or petroleum workers that there is no
increased risk of multiple myeloma associated with exposure to benzene
or solvents containing benzene (Hill's criterion of consistency).
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CONCLUSIONS |
Based on a thorough analysis of the existing scientific data according
to well-established criteria, the following conclusions can be made:
(1) There is strong evidence linking high levels of exposure to benzene
with an increased risk of developing acute myelogenous leukemia. The
evidence for this association satisfies all of Sir Austin Bradford
Hill's criteria, and the relationship can be judged as causal in
nature. Furthermore, cell-type specific analysis indicates that the
threshold is most likely around 370 to 530 ppm-years.
(2) In contrast, there is no scientific evidence to support a causal
relationship between exposure to benzene or other petroleum products
and the risk of developing multiple myeloma.
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FOOTNOTES |
Submitted September 2, 1998; accepted May 26, 1999.
Address reprint requests to Daniel E. Bergsagel, MD, DPhil, Ontario
Cancer Institute/Princess Margaret Hospital, University of Toronto, 610 University Avenue, Toronto, ON, M4W 2S7, Canada.
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INTRODUCTION
EXPOSURE, METABOLISM, AND...