5
Review of Epidemiologic Studies

This chapter reviews a large body of epidemiologic literature on specific drinking-water contaminants at Camp Lejeune, focusing primarily on trichloroethylene (TCE) and tetrachloroethylene (perchloroethylene, PCE). Most of the literature involves populations exposed occupationally to those solvents and other industrial chemicals. The goal is to determine whether exposure to TCE or PCE is associated with specific health outcomes. (Appendix D provides brief reviews of the epidemiologic literature on the six additional drinking-water contaminants identified in Chapter 2 as of possible concern—vinyl chloride, 1,1-dichloroethylene, 1,2-dichloroethylene, methylene chloride, benzene, and toluene.) Chapter 6 gives special consideration to studies of other communities whose populations and exposure to contaminants in drinking water are similar to those at Camp Lejeune. Chapter 7 provides an integrated discussion of the epidemiologic evidence in context with the toxicologic evidence on TCE and PCE presented in Chapter 4. Epidemiologic studies of former residents of Camp Lejeune are reviewed separately in Chapter 8.

EVALUATING THE EPIDEMIOLOGIC LITERATURE

To manage the review of the vast literature on the chemicals of concern at Camp Lejeune, the committee decided to use a categorization approached developed by the Institute of Medicine (IOM) for evaluating epidemiologic data on chemicals. The approach involves a comprehensive review of the epidemiologic literature on individual chemicals and assigning one of five categories to the evidence (see Box 5-1 for IOM’s categories of association). An assessment of whether the data indicate a statistical association between the chemicals and various cancer and noncancer health outcomes is the basis for the categorizations, except for the highest category of sufficient evidence of a causal relationship, which is also based on experimental data and evidence of causality. IOM’s approach has been used to evaluate exposure of veterans of the Vietnam War (IOM 1994, 1996, 1999) and the Gulf War (IOM 2003).

Statistical associations are generally estimated by calculating relative risks (RRs) or odds ratios (ORs). In our review, a “statistical association” does not imply that the measure of association is statistically significant or causal, only that an association of potential interest has been reported. The committee reviewed the conclusions of each study in light of its strengths and weaknesses, taking into account the strength of the association (the magnitude of the OR or RR estimate), the influence of exposure-measurement error, selection bias, statistical precision, and confounding bias. The coherence of the epidemiologic evidence was then assessed, and an assignment made to a category of association.

In the sections below, the committee used the conclusions drawn by IOM (2003) on cancer and noncancer health end points of TCE or PCE exposure as a starting point for its evaluation. Literature searches were performed on Medline to identify new (2003-2008) peer-reviewed epidemiologic studies of exposure to TCE, PCE, or mixtures of chlorinated solvents and various health outcomes. The committee weighed the strengths and weaknesses of the new evidence to draw conclusions about whether IOM’s



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5 Review of Epidemiologic Studies This chapter reviews a large body of epidemiologic literature on specific drinking-water contami- nants at Camp Lejeune, focusing primarily on trichloroethylene (TCE) and tetrachloroethylene (per- chloroethylene, PCE). Most of the literature involves populations exposed occupationally to those sol- vents and other industrial chemicals. The goal is to determine whether exposure to TCE or PCE is associated with specific health outcomes. (Appendix D provides brief reviews of the epidemiologic litera- ture on the six additional drinking-water contaminants identified in Chapter 2 as of possible concern— vinyl chloride, 1,1-dichloroethylene, 1,2-dichloroethylene, methylene chloride, benzene, and toluene.) Chapter 6 gives special consideration to studies of other communities whose populations and exposure to contaminants in drinking water are similar to those at Camp Lejeune. Chapter 7 provides an integrated discussion of the epidemiologic evidence in context with the toxicologic evidence on TCE and PCE pre- sented in Chapter 4. Epidemiologic studies of former residents of Camp Lejeune are reviewed separately in Chapter 8. EVALUATING THE EPIDEMIOLOGIC LITERATURE To manage the review of the vast literature on the chemicals of concern at Camp Lejeune, the committee decided to use a categorization approached developed by the Institute of Medicine (IOM) for evaluating epidemiologic data on chemicals. The approach involves a comprehensive review of the epi- demiologic literature on individual chemicals and assigning one of five categories to the evidence (see Box 5-1 for IOM’s categories of association). An assessment of whether the data indicate a statistical as- sociation between the chemicals and various cancer and noncancer health outcomes is the basis for the categorizations, except for the highest category of sufficient evidence of a causal relationship, which is also based on experimental data and evidence of causality. IOM’s approach has been used to evaluate ex- posure of veterans of the Vietnam War (IOM 1994, 1996, 1999) and the Gulf War (IOM 2003). Statistical associations are generally estimated by calculating relative risks (RRs) or odds ratios (ORs). In our review, a “statistical association” does not imply that the measure of association is statisti- cally significant or causal, only that an association of potential interest has been reported. The committee reviewed the conclusions of each study in light of its strengths and weaknesses, taking into account the strength of the association (the magnitude of the OR or RR estimate), the influence of exposure- measurement error, selection bias, statistical precision, and confounding bias. The coherence of the epi- demiologic evidence was then assessed, and an assignment made to a category of association. In the sections below, the committee used the conclusions drawn by IOM (2003) on cancer and noncancer health end points of TCE or PCE exposure as a starting point for its evaluation. Literature searches were performed on Medline to identify new (2003-2008) peer-reviewed epidemiologic studies of exposure to TCE, PCE, or mixtures of chlorinated solvents and various health outcomes. The committee weighed the strengths and weaknesses of the new evidence to draw conclusions about whether IOM’s 134

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Review of Epidemiologic Studies 135 BOX 5-1 Five Categories Used by IOM to Classify Associations (IOM 2003) Sufficient Evidence of a Causal Relationship Evidence from available studies is sufficient to conclude that a causal relationship exists between exposure to a specific agent and a specific health outcome in humans, and the evidence is supported by experimental data. The evidence fulfills the guidelines for sufficient evidence of an association (below) and satisfies several of the guidelines used to assess causality: strength of association, dose-response relationship, consistency of association, biologic plausibility, and a temporal relation- ship. Sufficient Evidence of an Association Evidence from available studies is sufficient to conclude that there is a positive association. A consis- tent positive association has been observed between exposure to a specific agent and a specific health outcome in human studies in which chance and bias, including confounding, could be ruled out with reasonable confidence. For example, several high-quality studies report consistent positive associations, and the studies are sufficiently free of bias, including adequate control for confounding. Limited/Suggestive Evidence of an Association Evidence from available studies suggests an association between exposure to a specific agent and a specific health outcome in human studies, but the body of evidence is limited by the inability to rule out chance and bias, including confounding, with confidence. For example, at least one high-quality study reports a positive association that is sufficiently free of bias, including adequate control for con- founding. Other corroborating studies provide support for the association, but they were not suffi- ciently free of bias, including confounding. Alternatively, several studies of less quality show consis- tent positive associations, and the results are probably not due to bias, including confounding. Inadequate/Insufficient Evidence to Determine Whether an Association Exists Evidence from available studies is of insufficient quantity, quality, or consistency to permit a conclu- sion regarding the existence of an association between exposure to a specific agent and a specific health outcome in humans. Limited/Suggestive Evidence of No Association Evidence from well-conducted studies is consistent in not showing a positive association between exposure to a specific agent and a specific health outcome after exposure of any magnitude. A con- clusion of no association is inevitably limited to the conditions, magnitudes of exposure, and length of observation in the available studies. The possibility of a very small increase in risk after exposure studied cannot be excluded. categorizations are still valid or should be changed. Each health-outcome section below brief summarizes the evidence as described in the 2003 IOM report, reviews the new evidence, and presents conclusions drawn from the totality of the epidemiologic evidence. Appendix E presents tables of details on each of the new studies. Whenever possible, the committee evaluated the associations between TCE or PCE and the end points and reported findings specifically on those solvents. If a study addressed solvent mixtures, the evidence was examined and a category of association was determined with the default presumption that there was not information specifically on TCE or PCE. The committee expands on IOM’s approach in Chapter 7 by explicitly considering how the toxicologic evidence presented in Chapter 4 adds to the weight of evidence in characterizing health risks related to the TCE and PCE.

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Contaminated Water Supplies at Camp Lejeune—Assessing Potential Health Effects 136 STUDIES OF TRICHLOROETHYLENE AND PERCHLOROETHYLENE Cancer End Points Oral and Pharyngeal Cancer IOM 2003 Conclusions IOM (2003) found little evidence of a consistent association between chronic exposure to PCE and an increased risk of oral or pharyngeal cancer (“oral cancer”). The studies evaluated often involved only a small number of exposed persons. No studies specifically assessed TCE in relation to oral cancer, and no increase in risk was found in connection with solvent mixtures. IOM concluded that there was in- adequate/insufficient evidence to determine whether an association exists between chronic exposure to solvents and oral cancer. 2008 Evaluation The updated literature on TCE and oral cancer included five cohort studies with cancer incidence or mortality data (Hansen et al. 2001; Chang et al. 2003, 2005; Raaschou-Nielsen et al. 2003; Boice et al. 2006; Sung et al. 2007). Two studies of Danish workers (Hansen et al. 2001; Raaschou-Nielsen et al. 2003) evaluated the risk of oral cancer. Hansen et al. found an increased risk in exposed male workers based on only seven exposed cases. In the larger study by Raaschou-Nielsen et al. (2003), a standard inci- dence ratio (SIR) of 1.8 (95% confidence interval [CI], 0.84-3.24) was found for women employed at least 3 mo; the SIR for men (95 exposed cases) was only 1.1 (95% CI, 0.90-1.36). Other studies of work- ers in different industries did not report a consistently increased risk, although most involved only a small number of exposed persons. There was an indication of an increased risk in women potentially exposed to TCE in the Raaschou-Nielsen study, but the totality of the evidence does not indicate a consistent pattern of increased risk in TCE-exposed persons. The updated literature on PCE and oral cancer included two cohort studies with cancer mortality or incidence data (Blair et al. 2003; Chang et al. 2003, 2005). Neither study reported an increased risk posed by PCE exposure, but they involved only small numbers of exposed persons.  The updated literature on PCE and TCE continues to support a conclusion that there is inade- quate/insufficient evidence to determine whether an association exists between chronic exposure to these solvents and oral cancer. Nasal Cancer IOM 2003 Conclusions IOM (2003) found no studies that specifically evaluated TCE or PCE but reviewed a few studies that examined other solvents and nasal cancer. Increased but imprecise RR estimates were found in a Chinese study of benzene exposure and a study of shoemakers in England and France (Fu et al. 1996; Yin et al. 1996). IOM concluded that the evidence was inadequate/insufficient to determine whether an asso- ciation exists between chronic exposure to solvents and oral cancer. 2008 Evaluation No new studies of chronic exposure to solvents and nasal cancer were found.

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Review of Epidemiologic Studies 137  There continues to be inadequate/insufficient evidence to determine whether an association exists between chronic exposure to TCE or PCE and nasal cancer. Laryngeal Cancer IOM 2003 Conclusions Two studies (Blair et al. 1990; Vaughan et al. 1997) found an increased but imprecise risk posed by PCE and dry-cleaning solvents. IOM (2003) concluded that there was inadequate/insufficient evidence to determine whether an association exists between chronic exposure to PCE, TCE, or other solvents and laryngeal cancer. 2008 Evaluation The updated literature on TCE and laryngeal cancer included four cohort studies with cancer in- cidence or mortality data (Hansen et al. 2001; Chang et al. 2003; Raaschou-Nielsen et al. 2003; Boice et al. 2006; Sung et al. 2007). One study of Danish workers (Raaschou-Nielsen et al. 2003) found an SIR of 1.7 (95% CI, 0.33-4.82) for women employed at least 3 months (on the basis of three exposed cases); the SIR for men was 1.2 (95% CI, 0.87-1.52) on the basis of 53 exposed cases. Boice et al. (2006) reported a standardized mortality ratio (SMR) of 1.45 (95% CI, 0.18-5.25) on the basis of two exposed cases. The updated literature on PCE and laryngeal cancer included two cohort studies with cancer mor- tality data (Blair et al. 2003; Chang et al. 2003). Blair et al. (2003) performed an updated mortality as- sessment of a cohort of dry cleaners and found an increased risk in workers with medium to high expo- sure (SMR, 2.7; 95% CI, 1.0-5.8) on the basis of only six exposed cases. Chang et al. (2003) did not find any exposed cases in a Taiwanese cohort of electronics manufacturing workers.  The updated literature on TCE and PCE continues to support a conclusion that there is inade- quate/insufficient evidence to determine whether an association exists between chronic exposure to these solvents and laryngeal cancer. Esophageal Cancer IOM 2003 Conclusions IOM (2003) considered evidence from several cohort and case-control studies of esophageal can- cer in relation to chronic exposure to solvents, including TCE and PCE. Although several studies had positive results (Blair et al. 1990; Vaughan et al. 1997; Boice et al. 1999; Ruder et al. 2001), IOM was unable to reach a consensus on PCE but concluded that there was inadequate/insufficient evidence to de- termine whether an association exists between TCE and other solvents and solvent mixtures and esophag- eal cancer. 2008 Evaluation The new literature on TCE and esophageal cancer included an update on the Danish worker co- hort (Raaschou-Nielsen et al. 2003) and three cohorts studies with cancer incidence or mortality data (Chang et al. 2003; Zhao et al. 2005; Boice et al. 2006; Sung et al. 2007). One study of Danish workers (Raaschou-Nielsen et al. 2003) found an SIR of 1.9 for men employed at least 3 months. Other studies did not find a pattern of increased risk.

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Contaminated Water Supplies at Camp Lejeune—Assessing Potential Health Effects 138 The updated literature on PCE and esophageal cancer included two cohort studies with cancer mortality data and one case-control study (Blair et al. 2003; Chang et al. 2003; Lynge et al. 2006). Blair et al. (2003) performed an updated mortality assessment of a cohort of dry cleaners and found an increased risk in workers (SMR, 2.2; 95% CI, 1.5-3.3) on the basis of 26 exposed cases. No exposure-response pat- tern of increased risk was found when results were examined by exposure group. Chang et al. (2003) did not find any exposed cases in a Taiwanese cohort of electronics manufacturing workers, and Lynge et al. (2006) found a decreased risk.  The updated literature on TCE continues to support a conclusion that there is inade- quate/insufficient evidence to determine whether an association exists between chronic exposure to the solvent and esophageal cancer.  On the basis of the results of the Blair et al. (2003) study of dry cleaners and other studies, the committee concludes that there is limited/suggestive evidence of an association between chronic exposure to PCE and esophageal cancer. This constitutes a new conclusion, in that a consensus was not reached in the 2003 IOM report. Stomach Cancer IOM 2003 Conclusions IOM (2003) reviewed five occupational-cohort studies assessing the association between TCE and stomach cancer (Wilcosky et al. 1984; Anttila et al. 1995; Blair et al. 1998; Boice et al. 1999; Hansen et al. 2001). A study of Finnish workers biologically monitored for exposure (on the basis of urinary tri- chloroacetic acid) showed an increased risk of stomach cancer (SIR, 1.28; 95% CI, 0.75-2.04), and the risk was greater in workers who had their first measurement 20 years before (SIR, 2.98; 95% CI, 1.20- 6.13). However, there was no evidence of an exposure-response relationship with urinary trichloroacetic acid concentrations (Anttila et al. 1995). The overall conclusions drawn from the other studies were mixed. Similarly, the results of the three cohort studies of PCE-exposed populations were mixed (SMR, 0.61-1.42) (Blair et al. 1990; Ruder et al. 1994; Boice et al. 1999). Results of three mortality cohort stud- ies (Garabrant et al. 1988; Costantini et al. 1989; Acquavella et al. 1993) and a case-control study (Ek- strom et al. 1999) of workers exposed to unspecified mixtures of organic solvents and a cohort study of Swedish patients with acute solvent-related disorders (Berlin et al. 1995) were predominantly null except for increased risk of stomach cancer in a cohort of shoemakers in England and Florence (Fu et al. 1996). IOM concluded that there was inadequate/insufficient evidence to determine whether an association exists between chronic exposure to the solvents reviewed and stomach cancer. 2008 Evaluation The committee identified several new cohort studies of occupational groups exposed to TCE or PCE (Blair et al. 2003; Chang et al. 2003, 2005; Raaschou-Nielsen et al. 2003; Boice et al. 2006; Sung et al. 2007). The reported results on stomach cancer were mixed, as were those in the IOM (2003) report. However, in a case-control study of a community living downstream of an electronics factory and poten- tially exposed to PCE, the mortality odds ratio (MOR) for stomach cancer was increased (2.18; 95% CI, 0.97-4.89) (Lee et al. 2003).  The updated literature on TCE and PCE continues to support a conclusion that there is inade- quate/insufficient evidence to determine whether an association exists between chronic exposure to these solvents and stomach cancer.

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Review of Epidemiologic Studies 139 Colon Cancer IOM 2003 Conclusions IOM (2003) reviewed five cohort studies with incidence or mortality data (Anttila et al. 1995; Blair et al. 1998; Boice et al. 1999; Hansen et al. 2001) and one case-control study (Fredriksson et al. 1989) on the association between TCE exposure and colon cancer. The Blair et al. study showed a posi- tive association between TCE exposure and both mortality and incidence, but there was evidence of an exposure-response relationship only between years of work and incidence (Blair et al. 1998). The results of the other studies were mixed, and IOM was not able to reach a consensus opinion about chronic expo- sure to TCE and colon cancer. For PCE, IOM included one cohort study of intestinal-cancer mortality in dry cleaners (Ruder et al. 2001) and two case-control studies—one defining exposure on the basis of work as a dry cleaner (Fredriksson et al. 1989) and the other on the basis of exposure to contaminated drinking water on Cape Cod (Paulu et al. 1999). The results showed evidence of increased risk, but there was no evidence of an exposure-response relationship, the numbers were small, and diseases were not well de- fined. Therefore, IOM concluded that the literature was inadequate/insufficient to determine whether an association exists between PCE exposure and colon cancer. IOM also reviewed three studies of unspeci- fied mixtures of organic solvents (Fredriksson et al. 1989; Anttila et al. 1995; Berlin et al. 1995). In- creased risks were observed only in the Fredriksson study, and in all three the numbers of exposed cases were small. IOM concluded that there was inadequate/insufficient evidence to determine whether an asso- ciation exists between chronic exposure to unspecified solvents and colon cancer. 2008 Evaluation The updated literature on TCE and colon cancer includes six occupational-cohort studies with in- cidence or mortality data on colon cancer or colon and rectal cancer. In most studies, the SIRs or SMRs were around 1.1 (Raaschou-Nielson et al. 2003; Boice et al. 2006; Sung et al. 2007). Zhao et al. (2005) assessed incidence and mortality in a cohort of aerospace workers. The SMRs were also around 1.1, but the SIRs were not increased, and there was no evidence of an exposure-response relationship (exposure was defined by an industrial-hygiene review). In a study of test-stand mechanics determined by an indus- trial-hygiene review to be exposed to TCE, the SMR was 1.66 (95% CI, 0.54-3.87) (Boice et al. 2006). A study of electronics and mechanical workers in Taiwan exposed to TCE and PCE found an SMR of 1.36 (95% CI, 0.82-2.13) on the basis of 19 cases (Chang et al. 2003). In an incidence study of the same popu- lation, there was no clear evidence of an association (Chang et al. 2005). Two studies of community ex- posures to TCE and PCE in drinking water did not find increased risks of colon cancer (Morgan and Cas- sady 2002; Lee et al. 2003). IOM also reviewed one cohort of dry cleaners exposed to PCE (Blair et al. 2003). The SMR was 1.2 (95% CI, 0.9-1.5) and there was some evidence of an exposure-response rela- tionship. No new studies on exposure to unspecified mixtures of organic solvents and colon cancer were found.  The committee concludes that there is inadequate/insufficient evidence to determine whether an association exists between chronic exposure to TCE or PCE and colon cancer. The conclusion regarding TCE constitutes a new conclusion, in that a consensus was not reached in the 2003 IOM report. Rectal Cancer IOM 2003 Conclusions IOM (2003) reviewed five cohort studies with incidence or mortality data (Anttila et al. 1995;

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Contaminated Water Supplies at Camp Lejeune—Assessing Potential Health Effects 140 Blair et al. 1998; Morgan et al. 1998; Boice et al. 1999; Hansen et al. 2001) and one case-control study (Dumas et al. 2000) on the association between exposure to TCE and rectal cancer. Although increased risks were observed in all but the Blair et al. study, the numbers of cancers in exposed persons were small, no more than 12 in each study. IOM included two studies in its review of PCE and dry-cleaning solvents: a cohort study of intestinal cancer in dry-cleaning workers (Ruder et al. 2001) and a study of colon and rectal cancer in Cape Cod residents exposed to contaminated water (Paulu et al. 1999). Both studies were discussed above under “Colon Cancer.” Three cohort studies assessed the incidence of or mortality from rectal cancer and exposure to unspecified mixtures of organic solvents (Garabrant et al. 1988; Anttila et al. 1995; Berlin et al. 1995). Excess risks were observed only in the Anttila et al. study. IOM concluded that there was inadequate/insufficient evidence to determine whether an association exists between chronic exposure to TCE, PCE, or solvent mixtures and rectal cancer. 2008 Evaluation The updated literature on TCE and rectal cancer included two cohort studies. Raaschau-Nielsen et al. (2003) observed SIRs of 1.1 in men and women working in jobs involving TCE exposure. Chang et al. (2003) assessed mortality in a cohort of electronics manufacturers exposed to TCE and PCE. On the basis of only 15 exposed cases (13 in women and two in men), the SMR for women was increased (1.67; 95% CI, 0.89-2.85), but the SMR for men was not (0.73; 95% CI, 0.08-2.65). An additional cohort study re- ported an increased risk of rectal-cancer mortality in dry cleaners (SMR, 1.3; 95% CI, 0.7-2.2) (Blair et al. 2003).  The updated literature on TCE and PCE continues to support a conclusion that there is inade- quate/insufficient evidence to determine whether an association exists between chronic exposure to these solvents and rectal cancer. Pancreatic Cancer IOM 2003 Conclusions IOM (2003) reviewed five occupational-cohort studies with incidence or mortality data on the as- sociation between TCE exposure and pancreatic cancer (Anttila et al. 1995; Blair et al. 1998; Morgan et al. 1998; Boice et al. 1999; Hansen et al. 2001). The results were mixed, and there was no evidence of an exposure-response relationship. The Anttila et al. study also assessed exposure to PCE, dry-cleaning sol- vents, and unspecified mixtures of organic solvents and observed increased SIRs. Ruder et al. (2001) ob- served increased SMRs in 18 exposed dry-cleaning labor-union workers. IOM reviewed an additional case-control study (Kauppinen et al. 1995) and six mortality cohort studies of exposure to unspecified mixtures of organic solvents (McMichael et al. 1976; Pippard and Acheson 1985; Garabrant et al. 1988; Costantini et al. 1989; Acquavella et al. 1993; Fu et al. 1996). The numbers of exposed cases were small, and the results were mixed. IOM concluded that there was inadequate/insufficient evidence to determine whether an association exists between chronic exposure to TCE, PCE, or other solvents and pancreatic cancer. 2008 Evaluation The updated literature on TCE and pancreatic cancer included five cohort studies with cancer in- cidence or mortality data (Chang et al. 2003; Raaschou-Nielsen et al. 2003; Zhao et al. 2005; Boice et al. 2006; Sung et al. 2007). Two studies of electronics workers (Chang et al. 2003; Sung et al. 2007) reported

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Review of Epidemiologic Studies 141 increased risk of pancreatic cancer in women, but the number of cases was small (16 in the two studies combined), and in one study TCE exposure was not distinguished from PCE exposure (Chang et al. 2003). Two studies of dry cleaners with data on PCE exposure and pancreatic cancer were identified; the SMR in a cohort study was 1.1 (95% CI, 0.7-1.5) (Blair et al. 2003), and the OR in a case-control study was 1.27 (95% CI, 0.90-1.80) (Lynge et al. 2006).  The updated literature on TCE and PCE continues to support a conclusion that there is inade- quate/insufficient evidence to determine whether an association exists between chronic exposure to these solvents and pancreatic cancer. Hepatobiliary Cancer IOM 2003 Conclusions IOM (2003) did not find a consistent association between chronic exposure to TCE, PCE, or un- specified mixtures of organic solvents and an increased risk of hepatobiliary cancer (liver cancer and can- cers of the gallbladder and biliary tract). IOM concluded that there was inadequate/insufficient evidence to determine whether an association exists between chronic exposure to solvents and hepatobiliary cancer. 2008 Evaluation The updated literature on TCE and hepatobiliary cancer included five cohort studies with inci- dence or mortality data (Morgan and Cassady 2002; Chang et al. 2003; Raaschou-Nielsen et al. 2003; Boice et al. 2006; Sung et al. 2007) and one case-control study (Lee et al. 2003). The updated Danish study of workers with TCE exposure showed some increased SIRs for women (for example, 2.8 and a 95% CI of 1.13-5.80 for women employed at least 3 months; seven cases in exposed people), but most estimates were based on small numbers of cases in exposed people (Raaschou-Nielsen et al. 2003). The updated literature on PCE and hepatobiliary cancer included three cohort studies with cancer incidence or mortality data (Morgan and Cassady 2002; Blair et al. 2003; Chang et al. 2003) and two case-control studies (Lee et al. 2003; Lynge et al. 2006). Lynge et al. (2006) reported an RR of 0.76 (95% CI, 0.38- 1.52) in a cohort of Nordic dry-cleaning workers. The case-control study by Lee et al. (2003) of a Tai- wanese community exposed to solvents from an electronics factory reported an increased MOR for men (2.57; 95% CI, 1.21-5.46), but the exposure assessment was weak.  The updated literature on TCE and PCE continues to support a conclusion that there is inade- quate/insufficient evidence to determine whether an association exists between chronic exposure to these solvents and hepatobiliary cancer. Lung Cancer IOM 2003 Conclusions IOM (2003) determined that the cohort and case-control studies of TCE and lung cancer were limited by exposure assessment and inadequate control for confounding factors, especially smoking. The studies generally did not show any increased risk, so the evidence regarding chronic exposure to TCE and lung cancer was considered inadequate/insufficient for determining whether an association exists. Al- though several studies of PCE exposure had positive results (Blair et al. 1990; Brownson et al. 1993; Ant- tila et al. 1995; Paulu et al. 1999; Pohlabeln et al. 2000; Ruder et al. 2001), IOM was unable to reach a

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Contaminated Water Supplies at Camp Lejeune—Assessing Potential Health Effects 142 consensus, because of some committee members’ concerns regarding confounding by cigarette-smoking and the small numbers of exposed persons. 2008 Evaluation The updated literature on TCE and lung cancer included seven cohort studies with lung-cancer incidence or mortality data (Hansen et al. 2001; Morgan and Cassady 2002; Chang et al. 2003, 2005; Raaschou-Nielsen et al. 2003; Zhao et al. 2005; Boice et al. 2006; Sung et al. 2007) and one case-control study (Lee et al. 2003). The new papers on PCE and lung cancer include three cohort studies (Morgan and Cassady 2002; Blair et al. 2003; Chang et al. 2003, 2005) and a case-control study (Lee et al. 2003). The updated Danish study of workers with TCE exposure (Raaschou-Nielsen et al. 2003) found increased SIRs for men and women (for example, 1.9 with a 95% CI of 1.48-2.35 for women employed at least 3 months), although there was no appearance of a trend with years of employment. Other studies did not report an increased risk with TCE exposure. The small number of studies of PCE exposure generally showed no increase in risk. However, the Blair et al. (2003) updated mortality analysis of dry cleaners showed increased SMRs, including an SMR of 1.5 (95% CI, 1.2-1.9) for workers with presumed medium or high PCE exposure. On the basis of the strengths of that study, including its size and exposure assess- ment, and the previous studies that had positive results, the committee determined that the evidence of an association was limited/suggestive.  The updated literature on TCE continues to support a conclusion that there is inade- quate/insufficient evidence to determine whether an association exists between chronic exposure to that solvent and lung cancer.  On the basis of new data, the committee concludes that there is limited/suggestive evidence of an association between chronic exposure to PCE and lung cancer. This constitutes a new conclusion, in that a consensus was not reached in the 2003 IOM report. Bone Cancer IOM 2003 Conclusions IOM (2003) identified one cohort study that reported on the association between occupational ex- posure to TCE and bone cancer (Blair et al 1998). On the basis of five exposed cases, the SMR was 2.1 (95% CI, 0.2-18.8). Two cohort studies reported on incidence of (Nielsen et al. 1996) or mortality from (Fu et al. 1996) bone cancer after occupational exposure to unspecified mixtures of organic solvents. In- creased risks were reported, but a total of only seven exposed cases were identified. There were no studies of the association of PCE with bone cancer. Because of the small number of studies and the unstable es- timates, IOM concluded that there was inadequate/insufficient evidence to determine whether an associa- tion exists between chronic exposure to TCE, PCE, or other solvents and bone cancer. 2008 Evaluation The committee found two cohort studies that yielded no evidence of an association between oc- cupational exposure to TCE and bone-cancer incidence (three cases in exposed people) (Sung et al. 2007) or bone-cancer mortality (no cases in exposed people) (Boice et al. 2006). In a mortality study of elec- tronics workers with indeterminate exposure to TCE and PCE, the SMR was 1.63 (95% CI, 0.44-4.18) on the basis of four cases in exposed people (Chang et al. 2003). In an incidence study of the same popula- tion, the SIR in female workers (six cases in exposed people) was 1.28 (05% CI, 0.47-2.78) (Chang et al. 2005). Only one male worker was exposed.

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Review of Epidemiologic Studies 143  The updated literature on TCE and PCE continues to support a conclusion that there is inade- quate/insufficient evidence to determine whether an association exists between chronic exposure to these solvents and bone cancer. Soft-Tissue Sarcoma IOM 2003 Conclusions IOM (2003) could not draw any conclusion regarding an association between chronic exposure to solvents and soft-tissue sarcoma because of the lack of available studies (only one study was identified). 2008 Evaluation The updated literature on soft-tissue sarcoma included a cancer-mortality study (Chang et al. 2003) and an incidence analysis (Chang et al. 2005) of a cohort of workers in a Taiwanese electronics factory exposed to TCE and PCE. The mortality analysis did not find any deaths from connective-tissue and other soft-tissue cancer. The incidence study found an increased but imprecise SIR for connective- tissue and other soft-tissue cancer in men (1.43; 95% CI, 0.29-4.17); no increase in risk was found in women.  The committee concludes that there is inadequate/insufficient evidence to determine whether an association exists between chronic exposure to TCE or PCE and soft-tissue sarcoma. This constitutes a new conclusion, in that no conclusion was drawn in the 2003 IOM report. Melanoma IOM 2003 Conclusions IOM (2003) concluded that there was inadequate/insufficient evidence to determine whether an association exists between chronic exposure to TCE, PCE, or unspecified mixtures of solvents and mela- noma. 2008 Evaluation The updated literature on TCE and melanoma included seven cohort studies with cancer inci- dence or mortality data (Hansen et al. 2001; Morgan and Cassady 2002; Chang et al. 2003, 2005; Raaschou-Nielsen et al. 2003; Boice et al. 2006; Sung et al. 2007). The updated publications on PCE and melanoma included three cohort studies (Morgan and Cassady 2002; Blair et al. 2003; Chang et al. 2003). The study by Morgan and Cassady found a significantly increased SIR for residents in a community ex- posed to drinking water contaminated with TCE and PCE (SIR, 1.42; 99% CI, 1.13-1.77), but the authors attributed the observation to the high socioeconomic status (SES) of the residents of the community. The incidence patterns of other cancers in the community—especially those of lung, colorectal, and uterine cancer—appeared to be consistent with and supportive of the authors’ explanation. None of the other studies reported an increased risk of melanoma in those exposed to TCE or PCE.  The updated literature on TCE and PCE continues to support a conclusion that there is inade- quate/insufficient evidence to determine whether an association exists between chronic exposure to these solvents and melanoma.

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Contaminated Water Supplies at Camp Lejeune—Assessing Potential Health Effects 144 Nonmelanoma Skin Cancer IOM 2003 Conclusions IOM (2003) concluded that there was inadequate/insufficient evidence to determine whether an association exists between chronic exposure to TCE, PCE, or unspecified mixtures of solvents and non- melanoma skin cancer. 2008 Evaluation No studies of TCE or PCE and nonmelanoma skin cancer were identified.  There continues to be inadequate/insufficient evidence to determine whether an association exists between chronic exposure to TCE or PCE and nonmelanoma skin cancer. Breast Cancer IOM 2003 Conclusions IOM (2003) concluded that there was inadequate/insufficient evidence to determine whether an association exists between chronic exposure to TCE, PCE, or unspecified mixtures of organic solvents and breast cancer. Results of occupational-cohort studies of breast-cancer risk were mixed (Garabrant et al. 1988; Shannon et al. 1988; Blair et al. 1990, 1998; Anttila et al. 1995; Morgan et al. 1998; Boice et al. 1999; Hansen et al. 2001; Ruder et al. 2001). Those studies were limited by exposure misclassification, poor control for confounding, and low statistical power due to small numbers. Information on reproduc- tive risk factors was available in the three case-control studies (including one community study), and their results showed positive associations between exposure to PCE and unspecified mixtures and breast cancer (Aschengrau et al. 1998; Hansen 1999; Band et al. 2000). The one case-control study of male breast can- cer observed no association with exposure to solvents. 2008 Evaluation The committee identified five new or updated occupational-cohort studies that assesse breast- cancer incidence or mortality associated with TCE or PCE (Blair et al. 2003; Chang et al. 2003, 2005; Raaschou-Nielsen et al. 2003; Sung et al 2007). The reported SIRs and SMRs ranged from 1.1 to 1.2 in most studies. Sung et al. (2007) found an SIR of 1.38 (95% CI, 1.11-1.70) in electronics workers em- ployed before June 1974 and exposed to TCE and mixed solvents. Chang et al. (2003) reported an in- creased incidence of breast cancer in employees exposed to TCE and PCE at an electronics factory in Taiwan. The highest SIR was associated with 5-10 years of exposure (SIR, 1.69; 95% CI, 1.02-2.64), but the association was stronger for more recent employment than for employment 5 or 10 years before diag- nosis. In an update of their 1998 case-control study in a community exposed to PCE-contaminated drink- ing water, Aschengrau et al. (2003) continued to see increased, but attenuated, associations with breast cancer (ORs ranged from 0.9 to 1.9 depending on exposure). There was no clear evidence of the appropri- ate latency period (Vieira et al. 2005). In a community-based cohort study of PCE and TCE contamina- tion of the public drinking-water supply, the SIR was consistent with that in the occupational studies (1.09; 99% CI, 0.97-1.21) (Morgan and Cassady 2002). The Aschengrau et al. study was the only new study that controlled for confounding by reproductive risk factors. No new studies included cases of male breast cancer.

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Contaminated Water Supplies at Camp Lejeune—Assessing Potential Health Effects 154 did not find a pattern of association except for a study of gastroschisis that reported several increased but imprecise ORs (Torfs et al. 1996). IOM (2003) concluded that there was inadequate/insufficient evidence to determine whether an association exists between chronic exposure to solvents and congenital malfor- mations. 2008 Evaluation A community study that assessed residential proximity to a TCE-emitting facility did not find an overall association with congenital heart defects but reported an association with presumed TCE exposure among older mothers (among exposed mothers 38 years or older) and such defects (OR, 4.1; 95% CI, 1.5- 11.2) (Yauck et al. 2004). A case-control study of maternal occupational exposure to organic solvent mix- tures found an increased but very imprecise OR (9.2; 95% CI, 2.5-35.3) for oral clefts among offspring (Chevrier et al. 2006).  There continues to be inadequate/insufficient evidence to determine whether an association exists between chronic exposure to TCE or PCE and congenital malformations. Male Fertility IOM 2003 Conclusions Many studies have investigated potential paternal occupational exposure to solvents and male in- fertility. They used occupation or industry as a surrogate for solvent exposure. IOM (2003) reviewed only studies that had a better characterization of solvent exposure. Nonetheless, only one study performed a specific assessment of TCE or PCE exposure. The five studies reviewed by IOM that examined male sol- vent exposure and effects that persisted after cessation of exposure had inconsistent results, including some associations with poorer semen quality. Most studies tended to be small and recruited men from infertility clinics or couples seeking an infertility consultation. Others reported inconsistent associations between solvents and indirect measures of fertility, including hormone concentrations and time to preg- nancy. IOM concluded that there was inadequate/insufficient evidence to determine whether an associa- tion exists between chronic exposure to solvents and male infertility. 2008 Evaluation A study of men occupationally exposed to solvents (painters and millwrights) reported an asso- ciation between increasing follicle-stimulating hormone and indexes of exposure to all solvents and to chlorinated solvents (Luderer et al. 2004). No association with luteinizing hormone concentration or time to pregnancy was found.  The committee concludes that there continues to be inadequate/insufficient evidence to determine whether an association exists between chronic exposure to TCE or PCE and male infertility. Female Fertility IOM 2003 Conclusions A few studies have evaluated miscellaneous solvent exposure, not TCE or PCE specifically, in re- lation to fecundability (ability to become pregnant), typically measured as time to pregnancy. In those studies, a lower hazard ratio means that conception was less likely in exposed than in unexposed women.

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Review of Epidemiologic Studies 155 Reduced fecundability was found in female printing-industry workers (fecundability ratio, 0.52; 95% CI, 0.28-0.99) (Plenge-Bonig and Karmaus 1999), women in jobs determined by biologic monitoring to have high solvent exposure (fecundability ratio, 0.41; 95% CI, 0.27-0.62) (Sallmen et al. 1995), and semicon- ductor-industry workers exposed to ethylene glycol ethers (fecundability ratio, 0.37; 95% CI, 0.11-1.19) (Eskenazi et al. 1995). One additional study used subfertility, the inability to conceive within 1 year, as the outcome measure and found an increased risk in female semiconductor workers (OR, 4.6; 95% CI, 1.6-13.3) (Correa et al. 1996). The only reported estimates of effects of TCE and PCE exposure come from the study by Sallmen et al. (1995), who found fecundability ratios of 0.61 (95% CI, 0.28-1.33) and 0.69 (95% CI, 0.31-1.52), respectively, consistent with the pattern for solvents in general. IOM concluded that there was inadequate/insufficient evidence to determine whether an association exists between expo- sure to TCE, PCE, or other solvents reviewed and female infertility after cessation of exposure. It drew no conclusions about the evidence on concurrent exposure to solvents and effects on fertility, because its re- view focused on fertility risks to veterans after deployment (after cessation of exposure). 2008 Evaluation No additional studies addressing female infertility were identified after the 2003 IOM report. The committee evaluated the studies included in that review (see above) to draw conclusions about the evi- dence on concurrent exposure to solvents and female fertility.  There continues to be inadequate/insufficient evidence to determine whether an association exists between exposure to TCE or PCE and female infertility after exposure cessation; this agrees with IOM (2003).  The committee concludes that there is limited/suggestive evidence of an association between con- current exposure to solvents and female infertility, which was not addressed in the 2003 IOM report. Pregnancy Outcomes (Maternal Exposure) IOM 2003 Conclusions The IOM (2003) report focused on delayed or chronic effects of exposure that are manifested in adverse pregnancy outcomes after cessation of exposure. IOM summarized the available evidence, which was primarily on exposure during pregnancy. Preconception exposure of women and later adverse preg- nancy outcomes were not addressed in any of the studies. A number of studies have suggested that mater- nal exposure to solvents in general and dry-cleaning work in particular are associated with miscarriage. Four studies that reported some evidence of an association between maternal dry-cleaning employment and miscarriage were cited (Kyyronen et al. 1989; Ahlborg 1990; Olsen et al. 1990; Doyle et al. 1997), and a greater number of other reports suggested an association with other sources of occupational solvent exposure, including work in semiconductor plants, shoe factories, and laboratories. Although consistent among studies, the quality of exposure assessment in all the studies is limited, and there are difficulties to identifying and documenting the occurrence of miscarriage accurately. Few studies have considered other pregnancy outcomes (such as preterm birth and fetal growth restriction), and they yielded little support of an association. IOM concluded that there was inadequate/insufficient evidence to determine whether an association exists between maternal preconception exposure to TCE, PCE, or other solvents reviewed and miscarriage or other adverse pregnancy outcomes. It drew no conclusions about the evidence on exposure during pregnancy, because its review was focused on risks to veterans of war and it was assumed that no female soldiers were pregnant while deployed.

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Contaminated Water Supplies at Camp Lejeune—Assessing Potential Health Effects 156 2008 Evaluation No additional studies of maternal solvent exposure and miscarriage were identified.  There continues to be inadequate/insufficient evidence to determine whether an association exists between maternal preconception exposure to TCE or PCE and miscarriage or other adverse pregnancy outcomes (such as preterm birth and fetal growth restriction).  The committee concludes there is inadequate/insufficient evidence to determine whether an asso- ciation exists between maternal solvent exposure during pregnancy and preterm birth or fetal growth re- striction.  The committee concludes that there is limited/suggestive evidence of an association between ma- ternal exposure to PCE (and to solvents in general) during pregnancy and miscarriage. Pregnancy Outcomes (Paternal Exposure) IOM 2003 Conclusions Four studies that addressed paternal exposure to solvents and pregnancy outcomes were identi- fied. Scattered positive associations were reported but no consistent evidence of an association with mis- carriage, the most frequently studied pregnancy outcome. The studies tended to be small, relied on self- reported exposure, and had indirect assessment of solvent exposure (and not specifically exposure to TCE or PCE). The one study of dry-cleaning workers (Eskenazi et al. 1991) did not find a positive association. IOM concluded that there was inadequate/insufficient evidence to determine whether an association exists between paternal exposure to TCE, PCE, or other solvents reviewed and miscarriage or other adverse pregnancy outcomes. 2008 Evaluation No additional studies of paternal solvent exposure and pregnancy outcomes were identified.  There continues to be inadequate/insufficient evidence to determine whether an association exists between paternal exposure to TCE, PCE, and other solvents and adverse pregnancy outcomes. Cardiovascular Effects IOM 2003 Conclusions IOM found a number of studies of short-term effects of acute, relatively high-dose exposure to solvents. Effects tended to be exacerbation of symptoms of underlying cardiovascular disease that were reversible. Many cohort mortality studies of solvent-exposed workers have been conducted, but they were limited by the healthy-worker effect to various degrees, and none provided much support of increased mortality from cardiovascular disease associated with solvent exposure. The magnitude of solvent expo- sure encountered in occupational settings would be substantially greater than that in the community, and the solvents would be inhaled or absorbed dermally, unlike the ingestion found in community studies. IOM concluded that there was inadequate/insufficient evidence to determine whether an association exists between exposure to specific solvents and cardiovascular disease.

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Review of Epidemiologic Studies 157 2008 Evaluation Several studies have extended the followup of dry-cleaning workers (Ruder et al. 2001; Blair et al. 2003) and continue to generate evidence of no increase in mortality from cardiovascular disease.  The committee concludes that there continues to be inadequate/insufficient evidence to determine whether an association exists between solvent exposure and cardiovascular disease. Hepatic Effects IOM 2003 Conclusions Liver function. Acute, high-level TCE exposure has effects on liver function, as does exposure to other solvents, but there is little evidence of lingering effects of chronic low-level exposure. Studies of workers with chronic exposure to solvents (such as painters and dry-cleaning workers) have not shown abnormal enzyme concentrations indicative of deleterious effects on liver function. Mild increases in he- patic enzymes have been noted in a few studies, but the studies did not differentiate past and current, con- tinuous solvent exposure, so it was not possible to distinguish long- and short-term effects. Hepatic steatosis. Acute, high-level exposure to such solvents as chloroform and carbon tetra- chloride causes injury to the liver. Case series and some small epidemiologic studies of petrochemical and dry-cleaning workers indicate that a variety of solvents can cause fatty changes in the liver (steatosis) and that the problem persists after exposure ceases (Dossing et al. 1983; Redlich et al. 1990; Cotrim et al. 1999). The association seems clear for acute effects of high-level solvent exposure, but the dose-response gradient and the temporal course of exposure, response, and potential reversal are not well established. Cirrhosis. Except for some case reports of cirrhosis associated with high-level solvent exposure, there are few informative data on solvent exposure and cirrhosis. Some studies of solvent-exposed work- ers have suggested an increased risk of cirrhosis, but the substantial influence of alcohol use and viral ex- posure on risk leaves open the potential for serious confounding.  IOM concluded that there was inadequate/insufficient evidence to determine whether an associa- tion exists between exposure to TCE, PCE, or other solvents reviewed and chronic changes in hepatic function or cirrhosis.  IOM concluded there was limited/suggestive evidence of an association between chronic expo- sure to solvents in general and hepatic steatosis that “could persist” after cessation of exposure. 2008 Evaluation Extended followup of dry-cleaning workers continues to show no increased risk of hepatic effects (Ruder et al. 2001; Blair et al. 2003).  The committee concludes that there continues to be inadequate/insufficient evidence determine whether an association exists between solvent exposure and changes in hepatic function or cirrhosis and limited/suggestive evidence of an association between chronic exposure to solvents and hepatic steatosis, which may persist after cessation of exposure. Gastrointestinal Effects IOM 2003 Conclusions The only gastrointestinal effect that has been investigated as a possible consequence of solvent

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Contaminated Water Supplies at Camp Lejeune—Assessing Potential Health Effects 158 exposure is chronic pancreatitis. It is a persistent inflammatory condition strongly affected by alcohol consumption. One study examined a variety of occupational exposures in relation to chronic pancreatitis (McNamee et al. 1994), including solvent-exposed occupations, but found only an imprecise suggestion of a possible association with high cumulative exposure to chlorinated solvents. IOM concluded that there was inadequate/insufficient evidence to determine whether an association exists between exposure to TCE, PCE, or other solvents reviewed and chronic pancreatitis. 2008 Evaluation No additional studies of solvent exposure and gastrointestinal effects were identified.  There continues to be inadequate/insufficient evidence to determine whether an association exists between solvent exposure and gastrointestinal effects. Renal Effects IOM 2003 Conclusions Several renal diseases have been examined in epidemiologic studies, including such specific con- ditions as acute tubular necrosis and chronic glomerulonephritis and such nonspecific conditions as indi- cators of renal function and end-stage renal disease. Studies of the effects of short-term and long-term solvent exposure on renal function below the threshold of clinical disease have yielded some support of an association between exposure to high concentrations of solvents and acute tubular necrosis. A series of case-control studies have evaluated chronic glomerulonephritis, an immune-mediated disease, in relation to solvent exposure and have yielded mixed evidence of an association, including several reasonably strong positive studies showing dose-response gradients. None of the studies addressed TCE or PCE di- rectly; the closest any came was one that reported an association with “degreasing agents” (Porro et al. 1992). IOM concluded that there was limited/suggestive evidence of an association between exposure to solvent mixtures and chronic glomerulonephritis. Several studies have addressed the effect of solvent ex- posure on indicators of renal function; they used various magnitudes of exposure and had varied quality of exposure assessment. One study (Steenland et al. 1990) reported a fairly strong association between degreasing solvents and end-stage renal disease. 2008 Evaluation No new studies of solvent exposure and glomerulonephritis were identified. An occupational- cohort study of aircraft-maintenance employees implicates solvents and points toward TCE more than PCE in relation to end-stage renal disease (Radican et al. 2006). Retrospective exposure assessment was detailed and identified greater than two-fold increases in risk with higher exposure. Study of renal func- tion in workers exposed to TCE showed decrements in renal function in the clinically normal range (Green et al. 2004). The additional evidence strengthens the quantity and quality of information on TCE.  The committee concludes that there continues to be limited/suggestive evidence of an association between mixed solvent exposure and chronic glomerulonephritis but inadequate/insufficient evidence to determine whether an association exists specifically between TCE or PCE and chronic glomerulonephri- tis.

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Review of Epidemiologic Studies 159 Systemic Rheumatic Disease IOM 2003 Conclusions Scleroderma, an autoimmune disease resulting in abnormal growth of connective tissue, has been addressed in several epidemiologic studies in relation to occupational solvent exposure, most of which relied on job-exposure matrices to infer solvent exposure. A report by Nietert et al. (1998) found an OR of 3.3 (95% CI, 1.0-10.3) for TCE and scleroderma in men but not in women, who have a higher overall risk of this disease. Other small, relatively crude studies with limited exposure assessment have generated mixed findings regarding the existence of an association. IOM concluded that there was inade- quate/insufficient evidence to determine whether an association exists between solvent exposure and scleroderma. 2008 Evaluation Since the IOM review, there have been four studies of solvent exposure and scleroderma that used more sophisticated methods of assessing exposure. A case-control study of women in Michigan con- sidered self-reported and expert-confirmed exposure and found a two-fold increased risk associated with TCE exposure but no association with PCE exposure (Garabrant et al. 2003). A case-control study in France found markedly increased risk of scleroderma associated with solvents, which challenges the plau- sibility of the findings, but the list of implicated solvents included TCE (Diot et al. 2002). A small study of women in Hungary found an increased risk associated with solvent exposure (Czirják and Kumanovics 2002). Finally, a case-control study in Italy found that solvent exposure increased the risk of scleroderma by a factor of 2.5 (Bovenzi et al. 2004).  On the basis of the findings of new studies, the committee concludes that the evidence of an asso- ciation between mixed solvent exposure and scleroderma is limited/suggestive and that some evidence points toward TCE exposure in particular. This constitutes a change in IOM’s 2003 conclusion. Amyotrophic Lateral Sclerosis IOM 2003 Conclusions IOM (2003) considered four case-control studies in evaluating the association between solvent exposure and amyotrophic lateral sclerosis (ALS) (Chio et al. 1991; Gunnarsson et al. 1992; Strickland et al. 1996; McGuire et al. 1997). Chio et al. defined exposure by using occupational information drawn from hospital charts and municipal records. Gunnarsson et al. and Strickland et al. used only self-reported exposure. Only McGuire et al. (1997) used a more sophisticated assessment of exposure by a panel of industrial hygienists. In that study, the age- and education-adjusted OR for self-reported exposure to sol- vents in both men and women was 1.6 (95% CI, 1.1-2.5). However, when the industrial-hygiene assess- ment was used, the association was attenuated (OR, 1.2; 95% CI, 0.8-1.9). Of 28 specific agents assessed, only “cleaning solvents or degreasers” had a positive association with both self-reported exposure (OR, 1.8; 95% CI, 1.2-2.8) and industrial-hygiene assessment (OR, 1.9; 95%: CI 1.1-3.3). The association was limited to females in stratified models, and there was no evidence of a dose-response relationship. On the basis of the results of that study and the insufficiency of exposure assessment in the other studies, IOM concluded that there was inadequate/insufficient evidence to determine whether an association exists be- tween exposure to solvents and ALS.

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Contaminated Water Supplies at Camp Lejeune—Assessing Potential Health Effects 160 2008 Evaluation No new studies of exposure to solvents and ALS 2003 were identified.  There continues to be inadequate/insufficient evidence to determine whether an association exists between exposure to solvents and ALS. Parkinson Disease IOM 2003 Conclusions IOM (2003) evaluated studies with only Parkinson disease as the outcome measure rather than the more generic diagnosis of parkinsonism. Only two studies were found to be sufficiently rigorous in de- sign to be useful in providing evidence on the relationship between solvent exposure and Parkinson dis- ease (Hertzman et al. 1994; Seidler et al. 1996). Both were case-control studies that used prevalent cases, and one of the studies (Hertzman et al. 1994) focused on pesticides and presented little pertaining to sol- vent exposure. Although both studies found an association between past exposure to solvents and Parkin- son disease, they were likely to have been subject to recall bias. Overall, little attention has been focused on solvent exposure as a risk factor for Parkinson disease. IOM concluded that there was inade- quate/insufficient evidence to determine whether an association exists between exposure to the solvents reviewed and Parkinson disease. 2008 Evaluation The relationship between exposure to solvents and Parkinson disease was assessed in a case- control study in the United Kingdom that was restricted to men (McDonnell et al. 2003). Potential cases (176) were obtained by searching the pension-fund archive of a major engineering company for death cer- tificates that mentioned Parkinson disease, and potential controls (599) were identified from the same da- tabase. Exposure to solvents was determined on the basis of occupational records, which were not avail- able for many subjects. In the end, 57 people with the diagnosis (32% of the 176) and 206 controls (34% of the 599) were included in the analysis. Thirty-one people with the disease and 93 controls had worked in jobs involving exposure to solvents; the OR was 1.53 (95% CI, 0.81-2.87). There was a significant trend in the odds of disease with increasing duration of exposure. The study included a small number of cases and lacked information on other possible risk factors or confounders. Another case-control study of Parkinson disease assessed the role of solvent exposure (Dick et al. 2007). It was conducted in five European countries and included 767 prevalent cases and 1,989 controls. Cases were ascertained through clinical visits or by reviewing medical records, and the control group in- cluded a mixture of hospital controls and community controls. Subjects were interviewed about lifetime occupational and hobby-related exposure to solvents. The OR was 1.01 (95% CI, 0.84-1.23) for any expo- sure to solvents. When average annual intensity of exposure was evaluated, the ORs for those with low and high exposure were 1.17 (95% CI, 0.92-1.50) and 0.88 (95% CI, 0.69-1.12), respectively. This study is characterized by a large number of subjects and provided no evidence of an association between solvent exposure and Parkinson disease. A study by Gash et al. (2008) included a group of 30 workers at a single factory who had long- term (8-33 years) chronic exposure to TCE. The study was initiated because one of the workers had re- ceived a diagnosis of Parkinson disease and suspected that his occupational exposure to TCE was a factor in his disease. The investigators mailed questionnaires to 134 former workers, of whom 65 responded and 27 agreed to a clinical examination. Three workers with workstations adjacent to the TCE source and sub- jected to chronic inhalation and dermal exposure from the handling of TCE-soaked metal parts had Park- inson disease, whereas workers more distant from the TCE source and receiving chronic respiratory expo-

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Review of Epidemiologic Studies 161 sure displayed features of parkinsonism. Because of the “cluster investigation” type of design, the signifi- cance of the study is difficult to judge.  The committee concludes that there continues to be inadequate/insufficient evidence to determine whether an association exists between solvent exposure and Parkinson disease. Multiple Sclerosis IOM 2003 Conclusions At the time of the IOM (2003) report, four case-control studies of solvent exposure (in general) and multiple sclerosis (MS) had been conducted in Scandinavia. Two had negative results, and the other two, conducted in Sweden and based on overlapping populations, reported some positive associations be- tween self-reported occupational and leisure-time solvent exposure and MS in men. The positive findings are tempered by the limited quality of exposure assessment, the lack of adjustment for potential con- founders, and small sample and were thus short of “limited/suggestive” evidence of an association. No studies focused specifically on TCE or PCE were found. IOM concluded that there was inade- quate/insufficient evidence to determine whether an association exists between exposure to TCE, PCE, or other solvents reviewed and MS. 2008 Evaluation No additional studies of solvent exposure and MS were identified.  There continues to be inadequate/insufficient evidence to determine whether an association exists between solvent exposure and MS. Alzheimer Disease IOM 2003 Conclusions After evaluating five studies of solvent exposure and Alzheimer disease, all of which were case- control studies, IOM (2003) concluded that there was inadequate/insufficient evidence to determine whether an association exists between exposure to the solvents under review and the disease. The very nature of the disease—late onset and dementia leading to the need for proxy respondents—makes it ex- tremely difficult to study the association. Several authors commented that occupational solvent exposure is most likely to occur in men, but population-based studies suggest that women are at greater risk for Alzheimer disease. 2008 Evaluation The committee identified a study that was not included in the 2003 IOM review (Tyas et al. 2001). It evaluated the relationship between solvent exposure and Alzheimer disease in a prospective co- hort. Cognitively intact subjects completed a questionnaire that assessed many potential risk factors, in- cluding exposure to solvents. Five years later, 36 subjects developed the disease, and 694 remained cogni- tively intact. The analysis for exposure to solvents (degreasers), which included 28 cases and 531 noncases, resulted in an OR of 0.88 (95% CI, 0.31-2.50). Although the study had a unique design, it does not have a major effect on the overall evidence to determine whether an association exists between sol- vent exposure and Alzheimer disease.

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Contaminated Water Supplies at Camp Lejeune—Assessing Potential Health Effects 162  The committee concludes that there continues to be inadequate/insufficient evidence to determine whether an association exists between solvent exposure and Alzheimer disease. Neurobehavioral Effects IOM 2003 Conclusions Review of over 300 studies of solvent exposure and neurobehavioral symptoms (such as fatigue, lack of coordination, and sensory disturbances) or neurobehavioral test results (such as results of tests of attention, reaction time, and visuomotor coordination) by IOM (2003) yielded only seven studies that had isolated former exposure from current exposure. The only way to identify chronic effects that continue past the period of active exposure is through studies that consider formerly (but not currently) solvent- exposed people. Of those studies, several (Mikkelsen et al. 1988; Parkinson et al. 1990; Hanninen et al. 1991; Daniell et al. 1993; Lundberg et al. 1995; Stollery 1996) found evidence of continued deficits in formerly solvent-exposed workers compared with reasonably constituted unexposed groups. Many studies compared painters or other solvent-exposed workers with people in similar occupations (such as carpen- try) that did not have the same exposure history. The most specific and sophisticated evaluation of those previously exposed to solvents was conducted by Daniell et al. (1999), who found dose-dependent effects on neurobehavioral function some time after cessation of exposure. Although each of the studies found that one or more symptoms or test realms showed a deficit in function, there is not much consistency among the studies in which specific symptom or test was found to be affected, the comparison groups are not necessarily precisely comparable, and confounding factors were controlled to various degrees, so even relatively consistent evidence of some effects falls short of conclusive data. IOM concluded that there is limited/suggestive evidence of an association between past exposure to solvents and neurobehavioral out- comes, with the most support for decrements in visuomotor and motor function, for fatigue, for headache, and for difficulty in concentrating. 2008 Evaluation Recent studies have addressed the relationship between solvent exposure and neurobehavioral outcomes, including one focused on TCE (Reif et al. 2003) and one on PCE (Janulewicz et al. 2008). The study by Reif et al. (2003) evaluated neurobehavioral function in 184 adults who had been exposed through contaminated drinking water many years before testing. Higher exposure was associated with poorer performance on several tests (such as digit symbol and contrast sensitivity) and with increased symptoms (such as confusion, depression, and tension). The study of PCE (Janulewicz et al. 2008) ad- dressed prenatal exposure in the Cape Cod water-contamination episode and evaluated school records for indications of learning or behavioral disorders. It found essentially no support of such an association. The studies of community water-supply contamination continue to provide mixed findings, as was found in the 2003 IOM report.  The committee concludes that there continues to be limited/suggestive evidence of an association between past solvent exposure and neurobehavioral outcomes. Long-Term Reduction in Color Discrimination IOM 2003 Conclusions IOM (2003) reviewed a series of studies of occupational solvent exposure that addressed an ill- defined combination of past and present solvent exposure in relation to measures of color discrimination.

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Review of Epidemiologic Studies 163 Because the exposure was continuing, it is not possible from these studies, a number of which provide evidence of a relationship between solvent exposure and reduction in color discrimination, to address the question of whether there is a long-term effect that continues beyond the period of exposure. One report addressed dry-cleaning workers exposed to PCE (Gobba et al. 1998) and found that there was a dose- related decrement in visual discrimination that did not decline after a period of diminishing exposure but, as in other studies, there was no exposure-free interval before visual testing, so the study results do not address whether PCE’s effects were short-term or long-term. IOM concluded that there was inade- quate/insufficient evidence to determine whether an association exists between exposure to TCE, PCE, or other solvents reviewed and long-term reduction in color discrimination. 2008 Evaluation A report by Schreiber et al. (2002) that was not included in the IOM review evaluated residents who lived in an apartment building or attended day care above a dry-cleaning facility. Changes in visual contrast sensitivity and visual acuity were addressed but not color discrimination itself. The authors re- ported that visual contrast sensitivity but not visual acuity was reduced. No additional reports on reduc- tion in color discrimination were identified.  The committee concludes that there continues to be inadequate/insufficient evidence to determine whether an association exists between exposure to TCE or PCE and long-term reduction in color dis- crimination. Long-Term Hearing Loss IOM 2003 Conclusions IOM (2003) reviewed a series of studies addressing the potential for occupational solvent expo- sure to exacerbate the well-established adverse effect of noise exposure on hearing. Several of the studies that were reviewed yielded evidence that supported the hypothesis that workers exposed to solvents and noise would experience greater hearing loss than those exposed to noise alone (Bergström and Nyström 1986; Morata et al. 1993, 1997), but none considered whether there is a long-term effect of solvents that continues beyond the period of exposure, and there is some evidence that the effect is a short-term one. IOM concluded that there was inadequate/insufficient evidence to determine whether an association exists between exposure to TCE, PCE, or other solvents and long-term hearing loss. 2008 Evaluation No additional studies of solvent exposure and long-term hearing loss were identified.  There continues to be inadequate/insufficient evidence to determine whether an association exists between exposure to TCE, PCE, or other solvents and long-term hearing loss. Long-Term Reduction in Olfactory Function IOM 2003 Conclusions Several cross-sectional studies addressed occupational solvent exposure and reduction in olfac- tory function. Studies of paint manufacturing were mixed—one positive (Schwartz et al. 1990) and the other negative (Sandmark et al. 1989)—and the one study of toluene exposure reported a positive associa-

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Contaminated Water Supplies at Camp Lejeune—Assessing Potential Health Effects 164 tion (Hotz et al. 1992). In all cases, exposure was current, and no study could evaluate whether any ad- verse effects persisted beyond the period of exposure. IOM concluded that there was inade- quate/insufficient evidence to determine whether an association exists between exposure to TCE, PCE, or other solvents and long-term reduction in olfactory function. 2008 Evaluation No additional studies of solvent exposure and long-term reduction in olfactory function were identified.  There continues to be inadequate/insufficient evidence to determine whether an association exists between exposure to TCE, PCE, or other solvents and long-term reduction in olfactory function. CONCLUSIONS The committee undertook a general review of the epidemiologic evidence on TCE, PCE, and sol- vent mixtures. On the basis of the reviews referred to in this chapter, the committee concludes that the strongest evidence of an association between TCE or PCE and health outcomes is in the category of lim- ited/suggestive evidence of an association related to the following end points:  Esophageal cancer (PCE)  Lung cancer (PCE)  Breast cancer (PCE)  Bladder cancer (PCE)  Kidney cancer (TCE, PCE)  Miscarriage (PCE) The strongest evidence of an association between solvent mixtures and health outcomes is in the category of limited/suggestive evidence of an association related to the following end points:  Adult leukemia  Multiple myeloma  Kidney toxicity  Liver toxicity (hepatic steatosis)  Female infertility  Scleroderma  Neurobehavioral effects For all other outcomes considered, the committee categorized the evidence as inade- quate/insufficient for determining whether associations exit. Chapter 6 presents a more detailed review of the epidemiologic studies that involved community exposure to drinking water contaminated with TCE or PCE, and Chapter 8 reviews studies of former Camp Lejeune residents. Chapter 7 provides an integrated discussion of the epidemiologic evidence in context with the toxicologic evidence on TCE and PCE.