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Epidemiological Issues in Determining Whether Benzene Causes Lymphatic Cancer or A Toxicologist’s Defense Against the Pu

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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. The dose makes the poison

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Epidemiological Issues in Determining Whether Benzene Causes Lymphatic CancerorA Toxicologist’s Defense Against the Pump Handle

Bernard D Goldstein

University of Pittsburgh

Graduate School of Public Health

the three laws of toxicology
The Three Laws of Toxicology
  • The dose makes the poison
  • Chemicals have specific effects
  • Humans are animals
questions for discussion
Questions for Discussion
  • What does the epidemiology literature tell us about whether benzene causes non-Hodgkin’s lymphoma (NHL) or multiple myeloma (MM)?
  • Can epidemiology tell us whether benzene exposure doubles the risk of NHL or MM - and why should anyone care about the doubling of risk?
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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
Benzene and Alkylbenzenes

CH

3

CH

3

CH

3

Benzene

Toluene

Xylene

CH

3

CH

CH

H

C C H

2

3

3

Ethylbenzene

Cumene

occam s razor is dull
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
Hematologic Effects of Benzene

Causality Proven

  • Aplastic Anemia
  • Myelodysplasia
  • Acute Myelogenous leukemia

(Including Acute Myelomonocytic Leukemia, Acute Promyelocytic Leukemia, Erythroleukemia)

evidence supporting benzene leukemogenesis
Evidence Supporting Benzene Leukemogenesis
  • Biomedical Plausibility
  • Case Studies
  • Epidemiology

A. Numerator Specific

B. Denominator Specific

carcinogenic potency of benzene calculated on the basis of animal data
Carcinogenic potency of benzene calculated on the basis of animal data

Lifetime risk

per ppm

Lifetime risk

per ug/m3

Data Base

Female rats (Maltoni, et. al, 1982)a

1.1 x 10 –5

3.4 x 10 –2

2.0 x 10 –2

6.0 x 10 –6

Male rats (NTP, 1984)a

3.3 x 10 –2

1.0 x 10 –5

Female rats (NTP, 1982)a

1.4 x 10 –2

4.3 x 10 –6

Male rats (Snyder, et. al, 1980)b

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 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

Leukemia

30

32

0.94

Alderson & Rushton, 1982

case control study of benzene exposure and leukemia in 36 british male oil refinery workers
Case Control Study of Benzene Exposure and Leukemia in 36 British Male Oil Refinery Workers

Benzene Exposure

Controls

Cases

Low

18

72

Medium or High

18

36

RR (95% CI)

2.0 (0.93 – 4.30)

Rushton & Alderson, 1981

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Case Control Study of Benzene Exposure and Leukemia in 36 British Male Oil Refinery WorkersLogistic 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

1.01 – 1.43

2.26

Benzene exposure plus length of service

2.99

1.24 – 7.20

Rushton & Alderson, 1981

hematologic effects of benzene16
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 benzene17
Hematologic Effects of Benzene

Causality Possible

  • Hodgkin’s Disease
  • Chronic Lymphocytic Leukemia

(and other Myeloproliferative Disorders)

multiple myeloma
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.
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Normal

Monoclonal Gammopathy

non hodgkin s lymphoma
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
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
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
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
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
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 study26
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
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