Part 7B: Effects Other Than Cancer
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PART 7B: EFFECTS OTHER THAN CANCER 7.10. INTRODUCTION Human exposure to 2,3,7,8-TCDD has been associated with noncancer effects in most systems. The majority of effects have been reported among occupationally exposed groups, such as chemical production workers, pesticide users, and individuals who handled or were exposed to materials treated with 2,3,7,8-TCDD-contaminated pesticides, and among residents of communities contaminated with tainted waste oil (Missouri, USA) and industrial effluent (Seveso, Italy). These effects represent a complex network of responses ranging from changes in hepatic enzyme levels which, based on current evidence, do not appear to be related to clinical disease, to observable alterations in the character and physiology of the sebaceous gland, as in chloracne (Calvert et al., 1992; Taylor, 1979). This section of Chapter 7 describes, by system , the noncancer effects associated with exposure to 2,3,7,8-TCDD. The characterization of the effects by system provides a context within which to compare the results of the various studies. However, it is important to recognize that the observed effects are not independent events but rather may be one outcome in a series of interrelated outcomes, some of which we may be incapable of measuring with the present technology or which we currently do not recognize as an outcome of exposure to 2,3,7,8-TCDD. The information describing human effects attributed to exposure to 2,3,7,8-TCDD- contaminated materials is derived from a wide variety of sources, including clinical assessments (case reports) of exposed individuals and analytic epidemiologic studies using case-control, cross-sectional, and cohort designs. The case reports describe the acute outcomes of exposure to 2,3,7,8-TCDD and provide the basis for hypothesis generation for controlled epidemiologic studies; however, they are not suitable for testing causal relationships between exposure and related effects (Ashe and Suskind, 1950; Suskind et al., 1953; Bauer et al., 1961; Goldman, 1972). As described in the previous section, cohort and case-control studies have been used to investigate hypothesized increases in malignancies among the various 2,3,7,8-TCDD-exposed populations (Fingerhut et al., 1991a, b; Steenland et al., 1999; Manz et al., 1991; Eriksson et al., 1990). Cross-sectional studies have been conducted to evaluate the prevalence or extent of disease in living 2,3,7,8-TCDD-exposed groups (Suskind and Hertzberg, 1984; Moses et al., 1984; Lathrop et al., 1984, 1987; Roegner et al., 1991; Grubbs et al. 1995; Sweeney et al., 1989; Centers for Disease Control Vietnam Experience Study, 1988a; Webb et al., 1989; Ott and Zober, 1994). Many of the earliest studies were unable to define exposure-outcome relationships owing to a variety of shortcomings, including small sample size, poor participation, short latency periods, selection of inappropriate controls, and the inability to quantify exposure to December 2003 7B-1 DRAFT—DO NOT CITE OR QUOTE 2,3,7,8-TCDD or to identify confounding exposures. In more recent cross-sectional studies of U.S. chemical workers (Sweeney et al., 1989), U.S. Air Force Ranch Hand personnel (Roegner et al., 1991; Grubbs et al., 1995), and Missouri residents (Webb et al., 1989), serum or adipose tissue levels of 2,3,7,8-TCDD were measured to evaluate 2,3,7,8-TCDD-associated effects in exposed populations. The ability to measure tissue or serum levels of 2,3,7,8-TCDD for all or a large sample of the subjects confirmed exposure to 2,3,7,8-TCDD and permitted the investigators to test hypothesized dose-response relationships. 7.11. CROSS-SECTIONAL STUDIES: USES AND LIMITATIONS Most of the studies that describe nonmalignant effects were designed as cross-sectional medical studies. These types of studies are useful for assessing the current status of the surviving study population; however, they are inherently limited by a number of factors, including survivor and participation biases, exposure and disease misclassification, recall bias, and interobserver variability. Survivor and participation biases may have occurred because the studies included only those who were living at the time of the study, and did not or could not obtain similar information on those who died or were too ill to participate. Studies of groups exposed to agents that contribute to early deaths or cause severe illnesses may exclude the populations who were at highest risk. Exclusion of the sick and deceased whose condition was associated with 2,3,7,8- TCDD may erroneously cause the risk estimate to be closer to the null than the true risk. Disease misclassification may be introduced in a variety of ways. Medical tests in many reviewed studies were most often performed once, without follow-up. For some disorders, multiple testing is preferred to obviate normal variations in some test parameters, e.g., immunologic tests or hormone levels. In other situations, self-reported medical histories were collected and, by design, were not or could not be confirmed by medical records. When the exposed group incorrectly reports more disease than the unexposed group, recall and reporting biases may falsely raise the risk estimate. Exposure misclassification, particularly in the early studies, was a major limitation. In the earlier studies of production workers or community residents, exposure to 2,3,7,8-TCDD was determined only by an individual's presence (residing or working) in an area that was contaminated with 2,3,7,8-TCDD (Suskind and Hertzberg, 1984; Moses et al., 1984; Hoffman et al., 1986; Poland et al., 1971; May, 1973, 1982; Martin, 1984; Bond et al., 1983, 1989; Filippini et al., 1981; Ideo et al., 1985; Mocarelli et al., 1986). The lack of a measurement to quantify exposure hindered the ability to confirm exposure and to assess the magnitude of an exposure- response relationship. If the misclassification is nondifferential, it tends to bias the measure of effect toward the null. December 2003 7B-2 DRAFT—DO NOT CITE OR QUOTE As described above, in studies conducted a decade later (Roegner et al., 1991; Grubbs et al., 1995; Sweeney et al., 1989; Centers for Disease Control Veterans Health Studies, 1988; Webb et al., 1989) researchers were able to confirm and quantify exposure to 2,3,7,8-TCDD in serum or adipose tissue. This breakthrough helped establish that certain previously exposed populations had 2,3,7,8-TCDD levels well above the background level of less than 20 picograms per gram of lipid (pg/g) (Patterson et al., 1989) and that the nonexposed comparison group was truly not exposed to greater than background levels. Yet, because the occupational populations were exposed to 2,3,7,8-TCDD-contaminated substances for as many as 40 years before being tested, levels attained at the time of exposure can only be estimated. It appears that for some populations with higher exposures, such as workers, the estimate reflects continuous exposure over an extended period. For example, despite the intervening period between last exposure to 2,3,7,8- TCDD and the determination of serum 2,3,7,8-TCDD levels in workers employed in the production of 2,4,5-TCP and 2,4,5-T (15 to 37 years after last occupational exposure), the duration of occupational exposure was highly correlated to serum levels of 2,3,7,8-TCDD obtained at the time of the study (1987-1988) (Pearson product moment correlation coefficient [r] = 0.7) (Sweeney et al., 1989). These data suggest a strong relationship between length of occupational exposure and serum 2,3,7,8-TCDD regardless of the length of the intervening period. The deposition, metabolism, and excretion of high doses of 2,3,7,8-TCDD in the human system have not been fully described. A study by Pirkle et al. (1989) suggests that 2,3,7,8-TCDD decays by one-half in approximately 7.1 years, based on a one-compartment model and using a standard half-life equation. If this is true, exposures to trichlorophenol production workers may have been as high as 30,000 pg/g (Fingerhut et al., 1991a) and in excess of 50,000 pg/g in some residents of Seveso (Mocarelli et al., 1991). The data may be limited by the lack of complete information on the manner in which human metabolism handles 2,3,7,8-TCDD exposure. In a separate analysis, Michalek et al. (1996) estimated the half-life among veteran Ranch Hands to be 8.7 years (95% CI = 8.0-9.5 years). This calcuation was based on a mean decay rate of 0.0797 per year. In this analysis half-life increased with increasing body fat, but not age. This section of Chapter 7 is a selective review of studies that, to date, provide the most information on the relationship between nonmalignant outcomes and exposure to 2,3,7,8-TCDD- contaminated materials. Animal studies have been reviewed in other chapters of this document and will not be discussed in detail. Case reports will not be reviewed, but will be used to provide support for the analytic studies. In the assessment of mortality from nonmalignant causes of death, only cohort studies in which standardized mortality ratios (SMR) or equivalent population- based risk ratios were calculated will be discussed. December 2003 7B-3 DRAFT—DO NOT CITE OR QUOTE 7.12. DESCRIPTION OF PRINCIPAL STUDIES In the following section, we have provided a summary of the population description and methods of the studies that reported results for two or more systems or effects. Studies that are referenced only once will be described when cited. Results of these studies will be described in subsequent sections.