Blood, Vol. 95 No. 4 (February 15), 2000:
pp. 1512-1513
CORRESPONDENCE
 |
Letter |
To the editor:
The causal relation between benzene exposure and multiple myeloma
The evidence cited by Bergsagel et al in their recent review
does not at all support their conclusion that "there is no causal relationship between exposure to benzene or benzene-containing solvents
and multiple myeloma."1 The data they present in their Tables 3 and 4 is akin to a fishing expedition in waters
known to be sterile. It is unreasonable to ask the question of whether benzene causes multiple myeloma (MM) in a cohort in which the benzene
effect, if any, is too weak to observe an increase in the relative risk
of acute myelogenous leukemia (AML). AML is known to be caused by
benzene and has a higher background incidence and likely a shorter
latency period than MM, making the causal relation between benzene and
AML much easier to detect epidemiologically. Although not stated by
Bergsagel et al, the same epidemiological approach that did not find a
statistically significant increase in MM also did not find an increase
in AML in this cohort.2 It is as if the authors asked the
question of whether cigarette smoking causes MM but chose to address it
in a cohort in which the extent of cigarette smoking was sufficiently
minimal that there was no increase in lung cancer. The laboratory
equivalent would be to draw negative conclusions from a study in which
a positive control turned out to be negative.
Consideration of ionizing radiation should be sufficient to expose the
fallacy of the authors' assumption that just because different
hematological neoplasms have different manifestations and clinical
courses they must have different etiologies. For example, atom bomb
survivors and other radiation-exposed cohorts have shown multiple
hematological and nonhematological neoplasms, all with different
manifestations and clinical courses, arising from the same insult.
Similarly, Damashek's coining of the term "myeloproliferative
syndrome" reflects the recognition of the relatedness of a number of
clinically dissimilar cancers.3
Bergsagel et al fail to discuss the key points that make biologically
plausible the causal relation between benzene and MM, or to cite a
published article by one of us specifically discussing this
question.4 While not conclusive of causality, it is known that benzene metabolites are capable of causing cancer (AML) in the
organ system in which plasma cells are usually located; that the
lymphocyte is particularly sensitive to benzene toxicity; that
circulating lymphocytes, which are primarily B-lymphocytes, demonstrate
benzene-induced chromosomal abnormalities consistent with
cancer-causing effects; and that the B-lymphocyte is the precursor of
the plasma cell.
The authors are correct that there is a lack of conclusive
epidemiological evidence causally linking benzene to MM, although the
pliofilm worker study they discount is certainly
suggestive.5 If MM can be caused by benzene, an obvious
question is why has AML, but not MM, been observable in classic
epidemiological studies of exposed workers? Four major possible
explanations are 1) the relatively lower background incidence of MM,
which limits the power of epidemiologic studies to detect an effect, 2)
the relatively longer latency period for MM, 3) the imprecision of
metrics for estimation of exposure in observational epidemiologic
studies, and 4) the possibility of a relatively higher potency for
benzene in causing AML than for other tumors, similar to that observed for AML resulting from ionizing radiation and chemotherapy.
Despite there being no question that benzene causes AML, most cohort
studies of benzene-exposed work forces have not shown a
statistically significant increase in AML. Clearly this is at least in
part due to the relatively low levels of benzene exposure for most of
these large work forces, to the limited number of cases in most
studies, as well as to the fact that a number of studies did not
separate out cases by histologic type.6 The background
incidence of AML is sufficiently low that even a doubling of risk would
be difficult to observe in most workplace cohorts due to their lack of
size. A case in point is the study of close to 20,000 workers at 8 oil
refineries in Britain7 in which 31.96 acute leukemia deaths
were expected and only 30 were observed (SMR = 0.95) (6). Yet the
nested case-control analysis of those individuals dying of leukemia
found a greater likelihood of moderate to high levels of benzene
exposure during their working lifetime (OR = 2.0). One
epidemiological approach that avoids problems caused by the healthy
worker effect is to determine the proportionate mortality ratio (PMR).
Dement et al in a study of refinery workers in which the PMR for
leukemia was 175 showed an increased PMR of 124 for MM in refinery
workers, although this finding was not statically
significant.8
Another key issue explaining the lack of association and weakness of
association between benzene and AML or MM in most occupational studies
is the imprecision of the estimates of exposure. This imprecision
almost invariably results in a bias of the findings toward the null
it
is far easier and more likely that a negative study will be produced
than a positive study.
As noted by the authors, the MM incidence in China and in Japan is far
lower than the incidence in the United States and Western Europe.
Accordingly, the low incidence of MM in the recent Chinese studies
cited of benzene-exposed workers by Bergsagel et al is not surprising.
Also misleading is the authors' description of the Decouflé et
al study9 as having "reported only one death from MM in
259 petrochemical workers who were exposed to benzene." A better
description is that of the 58 deaths in this cohort, two were related
to MM, one of whom died from treatment-related acute leukemia. This
study should not be cited as evidence of a lack of a causal relation
between benzene and MM.
A recent case-control study, not referenced by Bergsagel et al,
observed a statistically significant (OR = 2.4, p = .039) association of MM with employment in the chemical
industry.10 Also deserving consideration is a Canadian
cohort study11 of 156,242 male farmers in which there was a
statistically significant association in the highest exposure group
between MM and a surrogate of fuel oil use (OR = 1.7, 95% CI
1.1-2.7), but not herbicides.
The first law of toxicology is that the dose makes the poison.
Fortunately, we now rarely find large cohorts of workers who are
heavily exposed to benzene in countries that have an appreciable background incidence of MM. What we still see in the United States are
individual cases of MM in people who have had heavy exposure to benzene
at exposure levels that are far higher than occur in the large
well-controlled workplace cohorts that are a requisite for classical
epidemiology studies.
The current controversy about MM is reminiscent of the situation from
the 1940's through the 1970's in which both biological plausibility
and individual case reports led hematology textbooks to list benzene as
a likely cause of AML. Until the 1976 study of pliofilm
workers,5 however, epidemiologists fought this designation,
due to the absence of a sufficiently large well-studied cohort with
enough benzene exposure to lead to a statistically significant increase
in leukemia deaths. This unwillingness to address biological data was
instrumental in the delay of decades in adopting rigorous controls to
protect workers against benzene. While we agree that the causal
relation between benzene and MM remains unproven, there are sufficient
data to make this association highly probable.
Bernard D. Goldstein Stuart L. Shalat
Environmental and Occupational Health Sciences Institute
(EOHSI), EOHSI is a jointly sponsored program of UMDNJ-Robert
Wood Johnson Medical School and Rutgers, The State University of New
Jersey
| |
References |
1.
Bergsagel DE, Wong O, Bergsagel PL, et al.
Benzene and multiple myeloma: appraisal of the scientific evidence.
Blood.
1999;94:1174-1182[Free Full Text].
2.
Wong O, Trent L, Harris F.
Nested case-control study of leukaemia, multiple myeloma, and kidney cancer in a cohort of petroleum workers exposed to gasoline.
Occup Environ Med.
1999;56:217-221[Abstract/Free Full Text].
3.
Damashek W.
Some speculations on the myeloproliferative syndromes.
Blood.
1951;6:372-375[Free Full Text].
4.
Goldstein BD.
Is exposure to benzene a cause of human multiple myeloma?
Ann NY Acad Sci
1990;609:225-230[Medline]
[Order article via Infotrieve].
5.
Rinsky RA, Smith AB, Hornung R, et al.
Benzene and leukemia: an epidemiologic risk assessment.
N Engl J Med.
1987;316:1044-1050[Abstract].
6.
Savitz DA, Andrews KW.
Review of epidemiologic evidence on benzene and lymphatic and hematopoietic cancers.
Am J Ind Med.
1997;31:287-295[Medline]
[Order article via Infotrieve].
7.
Rushton L, Alderson MR.
A case-control study to investigate the association between exposure to benzene and deaths from leukemia in oil refinery workers.
British J of Cancer.
1981;43:77-84[Medline]
[Order article via Infotrieve].
8.
Dement JM, Hensely L, Kieding S, Lipscomb H.
Proportionate mortality among union members employed at three Texas refineries.
Am J Ind Med.
1998;33:327-340[Medline]
[Order article via Infotrieve].
9.
Decouflé P, Blattner WA, Blair A.
Mortality among chemical workers exposed to benzene and other agents.
Environmental Research.
1983;30:16-25[Medline]
[Order article via Infotrieve].
10.
Massoudi BL, Talbott EO, Day RD, Swerdlow SH, Marsh GM, Kuller LH.
A case-control study of hematopoietic and lymphoid neoplasms: the role of work in the chemical industry.
Am J Ind Med.
1997;31:21-27[Medline]
[Order article via Infotrieve].
11.
Semenciw RM, Morrison HI, Riedel D, Wilkins K, Ritter L, Mao Y.
Multiple myeloma mortality and agricultural practices in the prairie provinces of Canada.
JOM.
1993;35:557-561.
Response:
Benzene and multiple myeloma: scientific evidence
Goldstein and Shalat overstate the conclusion of our review.
Our conclusion was that "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." In fact, Goldstein and Shalat agree with us and reiterate the same conclusion in
the fourth paragraph of their letter.
Goldstein and Shalat miss the point by using the radiation analogy.
Epidemiologic data show that exposure to radiation induces cancer in
more than one site. This is not true in studies of even highly exposed
benzene workers. Further, the probable mode of action of benzene is
quite different from that of radiation. Benzene does not induce point
mutations which, in the case of radiation, partially explains why it is
associated with cancers at more than one site. We did not reference Dr.
Goldstein's review1 because it was outdated and written
before the most recent reanalyses of the pliofilm
cohort.2,3 These analyses found no association between MM
and exposure to benzene.
Goldstein and Shalat state: "AML is known to be caused by benzene
and has a higher background incidence and likely a shorter latency
period than MM making the causal relation between benzene and AML much
easier to detect epidemiologically." This statement is incorrect.
The incidence rate of AML is lower than the rate for MM in the USA.
According to the NCI SEER data4 the age-adjusted incidence
rate, 1987-91, for AML in males was 2.9/100,000 (1.4/100,000 for age
<65 and 17.1/100,000 for age 65+). The corresponding rates for MM
were 5.5/100,000 (2.1/100,000 for age <65 and 36.3/100,000 for age
65+). It is not clear where Goldstein and Shalat obtained relevant data
for the latency period for MM, since no agent has been causally
associated with this disease. The latency period cannot be determined
if no causative factor has been identified.
Goldstein and Shalat argue that benzene exposure levels in the
petroleum industry are too low to detect an increased risk of MM. In
our review we cite Wong and Raabe,5 who identified three
refineries with a significant increase in leukemia mortality (SMR = 1.91, 95% CI: 1.39-2.56, 43 observed deaths), but no increase in MM mortality (SMR = 1.02. 95% CI: 0.68-1.46, 29 observed deaths). Thus, Goldstein and Shalat's argument that the reason for not finding
an increase in MM mortality in petroleum workers is due to low benzene
exposure (as indicated by a lack of leukemia increase) is incorrect.
Goldstein and Shalat cite a nested case-control study of leukemia (not
MM) in the United Kingdom,6 implying that we should have
examined nested case-control studies for the issue of MM. Among studies
of petroleum workers there were only two nested case-control studies
with quantitative exposure levels.7,8 We reviewed both
studies in our paper, and found no exposure-response relationship
between exposure and MM.
Goldstein and Shalat also cite a proportional mortality
study.9 This study design is inferior to the cohort study
design, primarily because information on the population at risk is
missing, and, as such, proportional mortality ratios (PMRs) do not
measure risk per se.10-12 Furthermore, the
particular proportional mortality study cited by Goldstein and Shalat
was based on an incomplete sample of death certificates among employees
at 3 Texas refineries. All 3 refineries have been studied with the more
appropriate cohort study design,13-15 and were included in
the review by Wong and Raabe.5
The small mortality study of 259 petrochemical workers,16
cited by Goldstein and Shalat consisted of only one death from MM (as
the underlying cause of death). Goldstein and Shalat argue that there
was another death with MM as the secondary cause of death. In cohort
mortality studies, only the underlying causes of death are analyzed,
since the expected deaths are based on comparison rates of underlying
causes of death only. If one includes secondary causes of death as well
in a study, then similar rates based on multiple causes from the
general population must be used for comparison. Neither the original
authors (Decouflé et al) nor Goldstein and Shalat offer
such multiple causes of death rates for comparison.
Goldstein and Shalat also cite a population-based case-control study in
West Virginia.17 First, the occupation information was
based entirely on death certificates, which might not be accurate. Second, "employment in the chemical industry" is an extremely broad and heterogeneous classification, and is not identical to or
specific for "exposure to benzene." Goldstein and Shalat argue that we should not expect to find an increase in MM in a study unless
there was a corresponding increase in AML, (as an indicator for
"sufficient" benzene exposure). In the West Virginia case-control study, the odds ratios for "employment in the chemical industry" were 2.39 (95% CI: 1.04-5.48) for MM and 1.09 (95% CI: 0.40-2.96) for
AML. Since there was no increase of AML in the West Virginia study
(i.e., insufficient benzene exposure), the increase in MM could not
have been related to benzene. Further, in our paper we reviewed 7 case-control studies that examined the specific relationship between
exposure to benzene, or benzene-containing solvents, and MM. In these
studies, exposure information was obtained from interviews or
employment/pension records, and not from death certificates. The risk
ratios from these studies ranged from 0.5 to 1.1, supporting the
conclusion that there is no relationship between benzene exposure and MM.
Finally, Goldstein and Shalat cite a cohort study of farmers in Canada
by Semenciw et al, in which MM was analyzed in relation to agricultural
practices.18 Goldstein and Shalat state: "there was a
statistically significant association in the highest exposure group
between MM and a surrogate of fuel oil use (OR = 1.7, 95% CI:
1.1-2.7), but not herbicides." First, this was a cohort study, and
the risk estimates were relative risks and not odds ratios. Second, the reported relative risk of 1.69 (95% CI: 1.08-2.65) was for
the group of farmers who spent more than $900 in 1970 for
fuel and oil for farming. Goldstein and Shalat assume that these
farmers were exposed to high levels of benzene, and that the observed
increased risk could be attributed to benzene and not to any other
factor in the farm environment, such as fertilizers or herbicides. This
assumption is not valid. Without knowing the specific fuels or oils
used, it cannot be stated with any level of certainty that
the farmers were exposed to appreciable amounts of benzene.
Goldstein and Shalat point out that the increased MM was not due to
herbicides, but they leave out fertilizers. Semenciw et
al18 made a distinction between herbicides and fertilizers in the study. In a detailed analysis the authors concluded: "The relationships between fertilizer use, fuel and oil expenditures, and
multiple myeloma risk were explored further and are displayed in Table
4. The risk was highest for farmers reporting low fuel expenditures but high fertilizer use (relative risk = 5.18,
95% CI = 1.24 to 21.5)." Thus, the authors conclusion does not
support Goldstein and Shalat.
In summary, Goldstein and Shalat do not offer any scientific data to
refute our conclusion. We stand by the conclusion in our paper that
"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."
Daniel E. Bergsagel
Ontario Cancer Institute/Princess Margaret Hospital
University
of Toronto
Toronto, ON, Canada
Otto Wong
Applied Health Sciences, San Mateo, CA; and
Department of
Epidemiology, School of Public Health,
Tulane University, New
Orleans, LA
P. Leif Bergsagel
Weill Medical College of Cornell University
Center for Lymphoma
and Myeloma
New York, NY
Raymond Alexanian
University of Texas M.D. Anderson Cancer Center
Houston, TX
Kenneth C. Anderson
Dana Farber Cancer Institute, Harvard University
Boston, MA
Robert A. Kyle
Mayo Clinic
Rochester, MN
Gerhard K. Raabe
Department of Medical Information and Health Risk
Assessment
Mobil Business Resources Corp, Global Medical
Services
New Hope, PA
| |
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Goldstein BD.
Is exposure to benzene a cause of human multiple myeloma?
Ann N Y Acad Sci.
1990;609:225-230.
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Leukemia risk associated with benzene exposure in the pliofilm cohort: I. Mortality update and exposure distribution.
Risk Anal.
1994;14:147-154[Medline]
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Wong O.
Risk of acute myeloid leukemia and multiple myeloma in workers exposed to benzene.
Occup Environ Med.
1995;52:380-384[Abstract/Free Full Text].
4.
National Cancer Institute.
SEER Cancer Statistics Review, 1973-1991. Washington, DC: NIH; 1994.
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Wong O, Raabe GK.
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Rushton L, Alderson MR.
A case-control study to investigate the association between exposure to benzene and deaths from leukemia in oil-refinery workers.
Br J Cancer.
1981;43:77-84.
7.
Wong O, Trent L, Harris F.
Nested case-control study of leukaemia, multiple myeloma, and kidney cancer in a cohort of petroleum workers exposed to gasoline.
Occup Environ Med.
1999;56:217-221.
8.
Schnatter AR, Armstrong TW, Nicolich MJ, et al.
Lymphohaematopoietic malignancies and quantitative estimates of exposure to benzene in Canadian petroleum distribution workers.
Occup Environ Med.
1996;53:773-781[Abstract/Free Full Text].
9.
Dement JM, Hensley L, Kieding S, Lipscomb H.
Proportionate mortality among union members employed in three Texas refineries.
Am J Ind Med.
1998;33:327-340.
10.
Monson RR.
Occupational Epidemiology. 2nd ed. Boca Raton, FL: CRC Press; 1990.
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Decouflé P, Blattner WA, Blair A.
Mortality among chemical workers exposed to benzene and other agents.
Environ Res.
1983;30:16-25.
17.
Massoudi BL, Talbott EO, Day RD, Swerdlow SH, Marsh GM, Kuller LH.
A Case-Control Study Of Hematopoietic and Lymphoid Neoplasmsthe Role Of Work In the Chemical-Industry.
Am J Ind Med.
1997;31:21-27.
18.
Semenciw RM, Morrison HI, Deidel D, Wilkins K, Ritter L, Mao Y.
Multiple myeloma mortality and agricultural practices in the prairie provinces of Canada.
J Occup Med.
1993;35:557-561[Medline]
[Order article via Infotrieve].
