Transcript Epidemiological Issues in Determining Whether Benzene Causes Lymphatic Cancer or A Toxicologist’s Defense Against the Pump Handle Bernard D Goldstein University of Pittsburgh Graduate School of Public Health.

Epidemiological Issues in
Determining Whether Benzene
Causes Lymphatic Cancer
or
A Toxicologist’s Defense Against
the Pump Handle
Bernard D Goldstein
University of Pittsburgh
Graduate School of Public Health
The Three Laws of Toxicology
1. The dose makes the poison
2. Chemicals have specific effects
3. Humans are animals
Questions for Discussion
1) What does the epidemiology literature
tell us about whether benzene causes
non-Hodgkin’s lymphoma (NHL) or
multiple myeloma (MM)?
2) Can epidemiology tell us whether
benzene exposure doubles the risk of
NHL or MM - and why should anyone
care about the doubling of risk?
The National Safety Council Congress….. In 1921 held
a session on benzene poisoning. Dr. Lothar E. Weber
of the Boston India Rubber Laboratory stated that
benzene “has been criticized as very dangerous (and)
very injurious… and, personally, I feel an injustice has
been done to this particular substance.”…
In response, C.F. Horan of the Hood Rubber
Company replied that inhalation experiments with
benzene, toluene, and xylene on guinea pigs and
rabbits, showed acute toxicity of benzene compared to
the other two compounds. Not persuaded, Weber
rejoined that he was not going to change his opinion
altogether on the basis of a few guinea pig
experiments.
Hounshell & Smith, 1988
Benzene and Alkylbenzenes
CH3
CH3
CH3
Benzene
CH2
Toluene
CH3
Ethylbenzene
H3C
CH3
C
Xylene
H
Cumene
Occam’s Razor is Dull
Simplest Proposition:
One metabolite acting through one
mechanism attacking one target
Likely Truth:
Multiple metabolites acting through
multiple mechanisms attacking
multiple targets
Hematologic Effects of Benzene
Causality Proven
– Aplastic Anemia
– Myelodysplasia
– Acute Myelogenous leukemia
(Including Acute
Myelomonocytic Leukemia,
Acute Promyelocytic Leukemia,
Erythroleukemia)
Evidence Supporting Benzene
Leukemogenesis
1. Biomedical Plausibility
2. Case Studies
3. Epidemiology
A. Numerator Specific
B. Denominator Specific
Carcinogenic potency of benzene
calculated on the basis of animal data
Data Base
Lifetime risk Lifetime risk
per ppm
per ug/m3
Female rats (Maltoni,
et. al, 1982) a
3.4 x 10 –2
1.1 x 10 –5
Male rats (NTP, 1984) a
2.0 x 10 –2
6.0 x 10 –6
Female rats (NTP, 1982) a
3.3 x 10 –2
1.0 x 10 –5
Male rats (Snyder, et. al,
1980) b
1.4 x 10 –2
4.3 x 10 –6
2.4 x 10 –2
7.3 x 10 –6
GEOMETRIC MEAN
Observed and Expected Deaths due to
Leukemia in British Male Oil Refinery
Workers
Observed
Expected
O/E
All deaths
4,406
5,260
0.84
All neoplasms
1,147
1,286
0.89
30
32
0.94
Leukemia
Alderson & Rushton, 1982
Case Control Study of Benzene Exposure
and Leukemia in 36 British Male Oil
Refinery Workers
Benzene
Controls
Cases
Exposure
Low
18
72
Medium or High
18
36
RR (95% CI)
2.0 (0.93 – 4.30)
Rushton & Alderson, 1981
Case Control Study of Benzene Exposure
and Leukemia in 36 British Male Oil
Refinery Workers
Logistic Models Matched on Year of Birth
Benzene Exposure
Relative Risk
Confidence Interval
Benzene exposure
2.01
0.94 – 4.28
Benzene exposure
plus year of entry
2.26
1.01 – 1.43
Benzene exposure
plus length of service
2.99
1.24 – 7.20
Rushton & Alderson, 1981
Hematologic Effects of Benzene
Causality Probable but Unproven
–
–
–
–
–
Acute Lymphatic Leukemia
Non-Hodgkin’s Lymphoma
Multiple Myeloma
Paroxysmal Nocturnal Hemoglobinuria
Chronic Myelogenous Leukemia
Hematologic Effects of Benzene
Causality Possible
– Hodgkin’s Disease
– Chronic Lymphocytic Leukemia
(and other Myeloproliferative Disorders)
Multiple Myeloma
• Plasma cell tumor, usually of bone marrow
• Plasma cells are related to B Lymphocytes
and have the function of producing
antibody
• Diagnosis usually made based upon the
presence of a monoclonal protein spike on
serum protein electrophoresis, and on the
presence a large numbers of plasma cells
in the bone marrow.
Normal
Monoclonal
Gammopathy
Non-Hodgkin’s Lymphoma
• Lymphocytic tumors diagnosed by
exclusion - not Hodgkin’s disease nor
lymphocytic leukemias
• Broad and overlapping range of disease
entities and etiologies.
• Immune suppression common to a
number of causative factors, including
HIV infection.
Biological Plausibility of Causal Relationship
of Benzene to Multiple Myeloma
• Multiple myeloma is a tumor of plasma cells
which are a form of B lymphocytes
• Exposure to benzene destroys B lymphocytes
and causes chromosomal abnormalities in B
lymphocytes
• Benzene is a known cause of leukemia, a bone
marrow cancer, through a mechanism that
leads to the presence of a carcinogenic
metabolite within the bone marrow.
• Multiple myeloma is a bone marrow tumor.
Role of Biological Plausibility in
Determining Causal Relations of
Benzene to Multiple Myeloma
• Benzene causes the formation of a
carcinogen that is specific to the
organ at risk and that affects the
basic cell type, including producing
cytogenetic abnormalities.
Biological Plausibility of Causal Relationship
of Benzene to Non-Hodgkin’s Lymphoma
• Non-Hodgkin’s Lymphoma is a lymphocytic
tumor
• Exposure to benzene destroys lymphocytes and
causes chromosomal abnormalities in
lymphocytes
• Benzene is a known cause of leukemia, a bone
marrow cancer, through a mechanism that leads
to the presence of a carcinogenic metabolite
within the bone marrow.
• The bone marrow is a lymphoid organ.
• Rats exposed to benzene develop lymphomas
Pluripotential Bone Marrow Stem Cell(s)
Matures to precursors of:
•
•
•
•
Red blood cells
Platelets
Granulocytic white blood cells
Lymphocytic white blood cells
Case control study
• 309 matched pairs of hematopoietic and
lymphoid neoplasms in Kanawha County, WV.
• “association between chemical industry work
and death due to non-Hodgkin’s lymphoma,
multiple myeloma, and lymphoid leukemia…”
• For NHL, OR 3.11, p = .003 for those who died
at age <65
• For MM, OR 2.39, p = .039 for all age groups
• For all hematopoietic and lymphoid neoplasms;
OR 3.31, p = .001
Case control study
• 309 matched pairs of hematopoietic and lymphoid
neoplasms in Kanawha County, WV.
• “association between chemical industry work and
death due to non-Hodgkin’s lymphoma, multiple
myeloma, and lymphoid leukemia…”
• For NHL, OR 3.11, p = .003 for those who died
at age <65
• For MM, OR 2.39, p = .039 for all age groups
• For all hematopoietic and lymphoid neoplasms;
OR 3.31, p = .001
• Massoudi, Talbott, Day, Swerdlow, Marsh and
Kuller. Amer J Indust Med, 1997