Opinion ID: 212992
Heading Depth: 2
Heading Rank: 2

Heading: Dr. Smith's Application of the Methodology

Text: In concluding that the weight of the evidence supported the conclusion that benzene can cause APL, Dr. Smith relied on his knowledge and experience in the field of toxicology and molecular epidemiology and considered five bodies of evidence drawn from the peer-reviewed scientific literature on benzene and leukemia. First, Dr. Smith considered the near-consensus among governmental agencies, experts, and active researchers in the field that benzene can cause AML as a class. The existence of this causal connection has been established since the late 1970s. See Bernard D. Goldstein & Gisela Witz, Benzene, in Environmental Toxicants: Human Exposures and Their Health Effects 459, 478 (Morton Lippmann ed., 3rd ed.2009). Dr. Smith noted that epidemiological studies have found a statistically significant increased incidence of AML in benzene-exposed workers and have identified a dose-response relationship. Second, Dr. Smith considered evidence concerning the etiology, or origins, of leukemia indicating that all types of AML derive from a genetically damaged pluripotent stem cell. Dr. Smith referred to a recent peer-reviewed article that provided a review of the current literature and reported numerous studies demonstrating that both AML and CML are stem cell diseases. He cited peer-reviewed studies finding that in the APL and Core Binding Factor (CBF) subtypes of AML, as well as in CML, the stem cell mutation is often in part caused by a chromosomal translocation. He also cited evidence that APL and CBF share common genetic susceptibility factors, common risk factors, and the same incidence pattern occurring at a constant incidence with age after age 20. Dr. Smith concluded that the best explanation for this evidence is that all AMLs, including APL, have a common etiology. [10] Third, Dr. Smith considered toxicology studies establishing that metabolites of benzene cause significant chromosomal damage at the stem cell level in the bone marrowthe type of damage that is known to cause APL and other types of AML. [11] He also cited peer-reviewed work published by his lab showing that leukemia cases associated with benzene exposure are more likely to contain clonal chromosome aberrations than leukemias arising in the general population. Fourth, Dr. Smith considered two sets of studies concerning the inhibition of a cellular enzyme known as topoisomerase II (or topo II) that is essential for the maintenance of proper chromosome structure and segregation. One set of studiesincluding both test tube and animal studieshas established that two benzene metabolites are catalytic inhibitors of topo II. A second set of studies has established that a variety of chemotherapeutic agents that are catalytic inhibitors of topo II cause APL. [12] Dr. Smith explained that taken together, these studies provided evidence of a known biological mechanism by which exposure to benzene could cause APL. Fifth, Dr. Smith considered the small set of epidemiological studies that provide data on the relationship between benzene exposure and subtypes of AML. [13] He concluded that the evidence showed an increased risk factor for APL, which although not statistically significant was consistent with causality, and provided no grounds for concluding otherwise. Dr. Smith explained that taking into account all of the evidence described abovethe fact that benzene causes AML as a class, that all subtypes of AML likely have a common etiology, that benzene is known to cause the general types of cellular damage that are known to cause APL, that benzene is known to inhibit an enzyme whose inhibition is known to cause APL, and that APL has been reported in benzene-exposed workers in a number of epidemiological studieshe reached the opinion that the weight of the evidence supports the conclusion that benzene exposure is capable of causing APL. Dr. Smith's opinion rests on a scientifically sound and methodologically reliable foundation, as is required by Daubert.