tencies in results, two factors that should carry great weight in selecting key studies for calculating an RfC. For example, test outcomes (neurologic signs, emotional lability, choice reaction time, cancellation d2, and digit symbol) in a study by Seeber (1989) were worse in the low-exposure group compared with the high-exposure group. EPA’s discussion of the study (Section did not mention that discrepancy. In another example, the committee judged the study by Echeverria et al. (1995) to be stronger than is characterized in the draft assessment (see detailed discussion in Chapter 3 of the present report). EPA discounted the study because (p. 4-77 to 4-78) “the lack of an unexposed control group limits the ability of the study to fully characterize the magnitude of the effects on visuospatial ability and to detect exposure-related symptoms or effects on tests of non-visuospatial cognitive ability. It also limits the extrapolation of the results to other populations exposed to tetrachloroethylene.” The committee judged that although there was no unexposed comparison group, the use of an internal comparison group (the group with the lowest exposure) has the advantage that any selection and confounding factors related to working in drycleaning facilities are present in both groups and reduces potential confounding by unmeasured factors.

The committee applied several criteria in selecting the epidemiologic studies that it considered most useful in establishing reference values for tetrachloroethylene. Three general criteria were addressed: the validity of individual studies, the internal consistency of results with the hypothesis of a causal role for tetrachloroethylene (for example, is there an association in a low-exposure group but not in the high-exposure group?), and the consistency of the findings with what is known from other sources (how the study fits into the overall picture of what is known). Those criteria are discussed in detail in Chapter 3.

EPA selected the study by Altmann et al. (1995), conducted in Mülheim, Germany, for calculating the RfC because it involved environmental exposures that are more relevant than occupational exposures for determining values designed to protect public health and it used a standardized computer-assisted testing battery. Those study factors are reasonable considerations, but they are not the most relevant for selecting a critical study. The committee concluded that the validity of the 1995 Altmann et al. study was seriously compromised by methodologic deficiencies, which are discussed in detail in Chapter 3 and summarized briefly below.

  • The most important concern is that the referent group was inappropriate in that it did not represent the counterfactual example. It was selected from among employees of the Public Health Office or the Medical Institution of Environmental Hygiene in Mülheim and matched to exposed subjects by age and sex. This selection bias resulted in a reference group clearly was more educated than the exposed group, and because the authors used only three categories of education, it is unlikely that differences in education were adequately controlled for. Because several of the primary outcomes are influenced by education, it is likely that substantial confounding remained. For example, there was no association between

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