1. 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

2. The Three Laws of Toxicology 1.The dose makes the poison 2.Chemicals have specific effects 3.Humans are animals

3. 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?

5. 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

6. Benzene and Alkylbenzenes CH 3 3 H 3 C C H CH 3 Benzene CH 3 Toluene Xylene Cumene Ethylbenzene CH 2 3

8. 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

9. Hematologic Effects of Benzene Causality Proven –Aplastic Anemia –Myelodysplasia –Acute Myelogenous leukemia (Including Acute Myelomonocytic Leukemia, Acute Promyelocytic Leukemia, Erythroleukemia)

10. Evidence Supporting Benzene Leukemogenesis 1.Biomedical Plausibility 2.Case Studies 3.Epidemiology A.Numerator Specific B.Denominator Specific

12. Carcinogenic potency of benzene calculated on the basis of animal data 7.3 x 10 –6 2.4 x 10 –2 GEOMETRIC MEAN 4.3 x 10 –6 1.4 x 10 –2 Male rats (Snyder, et. al, 1980) b 1.0 x 10 –5 3.3 x 10 –2 Female rats (NTP, 1982) a 6.0 x 10 –6 2.0 x 10 –2 Male rats (NTP, 1984) a 1.1 x 10 –5 3.4 x 10 –2 Female rats (Maltoni, et. al, 1982) a Lifetime risk per ug/m 3 Lifetime risk per ppm Data Base

13. Observed and Expected Deaths due to Leukemia in British Male Oil Refinery Workers 0.943230 Leukemia 0.891,2861,147 All neoplasms 0.845,2604,406 All deaths O/EExpectedObserved Alderson & Rushton, 1982

14. Case Control Study of Benzene Exposure and Leukemia in 36 British Male Oil Refinery Workers 2.0 (0.93 – 4.30)RR (95% CI) 3618Medium or High 7218Low Controls Cases Benzene Exposure Rushton & Alderson, 1981

15. Case Control Study of Benzene Exposure and Leukemia in 36 British Male Oil Refinery Workers Logistic Models Matched on Year of Birth 1.24 – 7.202.99 Benzene exposure plus length of service 1.01 – 1.43 2.26 Benzene exposure plus year of entry 0.94 – 4.282.01Benzene exposure Confidence IntervalRelative Risk Benzene Exposure Rushton & Alderson, 1981

16. Hematologic Effects of Benzene Causality Probable but Unproven –Acute Lymphatic Leukemia –Non-Hodgkin’s Lymphoma –Multiple Myeloma –Paroxysmal Nocturnal Hemoglobinuria –Chronic Myelogenous Leukemia

17. Hematologic Effects of Benzene Causality Possible –Hodgkin’s Disease –Chronic Lymphocytic Leukemia (and other Myeloproliferative Disorders)

18. 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.

19. Monoclonal Gammopathy Normal

20. 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.

21. 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.

22. 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.

23. 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

24. Pluripotential Bone Marrow Stem Cell(s) Matures to precursors of: Red blood cells Platelets Granulocytic white blood cells Lymphocytic white blood cells

25. 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

26. 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