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Trichloroethylene cancer epidemiology: a consideration of select issues.

A large body of epidemiologic evidence exists for exploring causal associations between cancer and trichloroethylene (TCE) exposure. The U.S. Environmental Protection Agency 2001 draft TCE health risk assessment concluded that epidemiologic studies, on the whole, support associations between TCE exposure and excess risk of kidney cancer, liver cancer, and lymphomas, and, to a lesser extent, cervical cancer and prostate cancer. As part of a mini-monograph on key issues in the health risk assessment of TCE, this article reviews recently published scientific literature examining cancer and TCE exposure and identifies four issues that are key to interpreting the larger body of epidemiologic evidence: a) relative sensitivity of cancer incidence and mortality data; b) different classifications of lymphomas, including non-Hodgkin lymphoma; c) differences in data and methods for assigning TCE exposure status; and d) different methods employed for causal inferences, including statistical or meta-analysis approaches. The recent epidemiologic studies substantially expand the epidemiologic database, with seven new studies available on kidney cancer and somewhat fewer studies available that examine possible associations at other sites. Overall, recently published

studies appear to provide further support for the kidney, liver, and lymphatic systems as targets of TCE toxicity, suggesting, as do previous studies, modestly elevated (typically 1.5-2.0) site-specific relative risks, given exposure conditions in these studies. However, a number of challenging issues need to be considered before drawing causal conclusions about TCE exposure and cancer from these data. Key words: cancer, drinking water exposures, epidemiology, occupational exposures, risk assessment, trichloroethylene. Environ Health Perspect 114:1471-1478 (2006). doi:10.1289/ehp.8949 available via http://dx.doi.org/ [Online 9 May 2006]

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Despite numerous reviews [Bruning and Bolt 2000; International Agency for Research on Cancer (IARC) 1995; Institute of Medicine 2002; Lynge et al. 1997; McLaughlin and Blot 1997; National Toxicology Program (NTP) 2002; Wartenberg et al. 2000; Weiss 1996; Wong 2004], including those of two multidisciplinary expert panels that concluded that trichloroethylene (TCE) is "probably" (IARC 1995) or "reasonably anticipated to be" (NTP 2002) carcinogenic in humans, the interpretation of the epidemiologic studies on cancer and TCE exposure remains an area of considerable debate. The strongest epidemiologic evidence for associations between TCE exposure and cancer is for liver cancer, kidney cancer, and lymphomas, but perspectives have differed about the causal inferences regarding the human carcinogenicity of TCE that can be drawn from the epidemiologic database as a whole (e.g., Mandel and Kelsh 2001; Wartenberg et al. 2000). Some of the key issues underlying different interpretations are the use of different qualitative and quantitative (e.g., meta-analysis) methods to synthesize the body of evidence and the weight given to studies on the basis of different measures of cancer risk (e.g., incidence versus mortality) and different methods of exposure assessment. In addition, interpretation of data on lymphomas poses unique challenges because of the use of different classification systems and an evolving understanding of their etiology. As discussed in the overview article on this mini-monograph (Chiu et al. 2006a), these are all issues on which the National Academy of Sciences (NAS) has been asked to provide advice.

In this review we first summarize the recent epidemiologic literature on TCE exposure and cancer occurrence and then discuss the issues identified above as key to interpreting the larger body of epidemiologic evidence. Although some scientific conclusions can be drawn from this updated body of data, speculation about the impact of these data on the final TCE risk assessment would be premature at this point, given the ongoing NAS consultation discussed in the overview article by Chiu et al. (2006a) and the planned revision of the U.S. Environmental Protection Agency (EPA) TCE risk assessment. Therefore, the purpose here and throughout this mini-monograph is to review recently published scientific literature in the context of how it informs the key scientific issues believed to be most critical in developing a revised risk assessment.

Epidemiologic Studies on Cancer and TCE Exposure

The epidemiologic analysis in the U.S. EPA draft TCE risk assessment (U.S. EPA 2001) was supported in large part by the review by Wartenberg et al. (2000). This review identified more than 80 studies that evaluated cancer and TCE exposure, concluding that the evidence more firmly supported associations of TCE exposure with kidney and liver cancer while providing some support for associations with non-Hodgkin lymphoma (NHL). Wartenberg et al. (2000) also noted possible associations between TCE exposure and multiple myeloma and prostate, laryngeal, and colon cancer as well as cervical cancer and TCE or perchloroethylene exposure.

A number of studies and literature reviews have been published since 2000. Tables 1-3 provide short descriptions of these studies, which include historical or retrospective cohort studies (Table 1), case-control studies (Table 2), and ecologic or community studies (Table 3). Most of the TCE cohort and case-control studies involve occupational exposure to TCE, primarily by inhalation, whereas community studies usually involve contaminated groundwater where potential TCE exposure may be through both ingestion of drinking water and inhalation from TCE vapor intrusion into subsurface residential areas or from showering. Many of these studies employed more sophisticated exposure assessment approaches, allowing better identification of likely TCE-exposed subjects (Bruning et al. 2003; Charbotel et al. 2006; DeRoos et al. 2001; Dumas et al. 2000; Hansen et al. 2001; Pesch et al. 2000a, 2000b; Raaschou-Nielsen et al. 2003; Zhao et al. 2005). Tables 4-7 show corresponding study results for cancers that either are newly reported to have associations (Table 4, total cancers and cancers of the bladder, breast, and esophagus) or have drawn the most attention in previous reviews [Table 5, kidney cancer or renal cell carcinoma (RCC); Table 6, cancer of the liver or liver and biliary passages; Table 7, lymphomas]. These recent studies substantially expand the epidemiologic database, providing additional insights on potential causal associations between TCE exposure and cancer occurrence. The following discussion focuses on the three groups of end points--kidney cancer and RCC, liver and biliary cancer, and lymphomas--previously identified as having the strongest evidence for potential causal association with TCE exposure (IARC 1995; NTP 2002; Wartenberg et al. 2000).

The studies available since 2000 report consistent associations between kidney cancer or RCC and TCE exposure (Table 5). Two cohort studies with large numbers of exposed cases (Raaschou-Nielsen et al. 2003; Zhao et al. 2005) observed statistically significant associations with greater exposure level or duration of employment. These findings were supported by three recent case-control studies assessing TCE exposure in the metal industry in Germany (Bruning et al. 2003; Pesch et al. 2000a) and in France (Charbotel et al. 2006). The studies by Bruning et al. (2003) and Charbotel et al. (2006) were designed specifically to examine the a priori hypothesis of an association between RCC and TCE exposure. Charbotel et al. (2006) suggested that exposure intensity may contribute to the risk associated with cumulative exposure because risks were higher for subjects in the highest cumulative exposure category with peak TCE exposure [odds ratio (OR) = 2.7; 95% confidence interval (CI), 1.1-7.1] than for subjects with only high cumulative exposure (OR = 2.2; 95% CI, 1.0-4.6), compared with unexposed subjects.

Most of the recent cohort studies also provide information as to possible association between TCE and liver and/or biliary tract cancer, although many examined only the combined category (Table 6). Grouping the adjacent, but anatomically distinct, end points of primary liver cancer and biliary cancer, which includes cancer of the gallbladder, limits application of mode-of-action data and may introduce misclassification bias. The recent Nordic cohort studies (Hansen 2004; Raaschou-Nielsen et al. 2003) disaggregate these cancers, and the addition of these two studies doubles the total number of epidemiologic studies providing information for primary liver cancer. The study by Raaschou-Nielsen et al. (2003), having greater statistical power because of its larger cohort size, suggested that both sites are possible targets of TCE toxicity, reporting a standardized incidence ratio (SIR) for primary liver cancer similar to that for gallbladder and biliary tract cancer. Risks for the larger category of liver and biliary tract cancers are presented in both the Nordic studies and the two recent community studies (Lee et al. 2003; Morgan and Cassady 2002). These studies together suggest a modest association (risks between 1.1 and 2.8), with no clear pattern with duration of exposure. Furthermore, none of the studies have sufficient power to identify sex differences in susceptibility.

New information on lymphomas, including NHL and leukemia, and TCE exposure comes from cohort and community studies (Table 7). Both Nordic studies (Hansen et al. 2001; Raaschou-Nielsen et al. 2003) reported statistically significant associations with NHL, with increasing SIRs with increasing duration of employment. The risk of NHL mortality in Zhao et al. (2005) was more consistent than the NHL incidence with risks observed in Nordic cohorts. Except in the case of Raaschou-Nielsen et al. (2003), numbers of exposed NHL cases are small, limiting statistical power. The one available case-control study observed a strong but imprecise association between maternal exposure to TCE-contaminated drinking water during pregnancy and childhood leukemia (Costas et al. 2002). Aickin (2004) provides further evidence for an association between TCE in drinking water and childhood leukemia. Analyses using Bayesian statistical methods confirmed an elevated mortality in children from leukemia. Examining childhood leukemia incidence, Aickin (2004) reported that a rate ratio [less than or equal to] 1.0 was not credible, and risk > 2.0 could not be ruled out.

To illustrate the potential impact of these new studies, Figures 1-4 show relative risks, SIRs, and standardized mortality ratios (SMRs) from cohort studies and ORs from case-control studies for four cancer sites discussed above (liver, liver and biliary passages, kidney, and NHL, respectively). These figures include studies published before 2000 [reviewed in, e.g., Wartenberg et al. (2000)] and those discussed above. The integration of this new information will contribute substantially to the hazard characterization of a TCE health evaluation and become an integral part of the U.S. EPA revised TCE risk assessment. However, this integration requires consideration of a number of key issues related to interpretation and synthesis, as discussed below.

Issues Related to TCE Epidemiologic Evidence

Studies of cancer incidence or cancer mortality. Both cancer incidence and cancer mortality rates are potentially useful in risk assessment for identifying hazards and assessing dose-response relationships. Incidence rates, generally considered to provide an accurate indication of risk of a disease in a population, are rarely available. In the absence of incidence data, epidemiologic studies have commonly relied on mortality data to assess exposure-disease associations. An understanding of the accuracy of death certificate information as a surrogate for incidence data is important for evaluating observations in the mortality studies. Known inaccuracies exist between cancer incidence and death certificate recordings for some cancer sites important to evaluating TCE exposure, for example, cancer of liver (primary) and liver and biliary passages (Percy et al. 1990). In their study of death certificate accuracy, Percy et al. (1990) showed that only 53% of 2,388 incident cases of primary liver cancer were actually attributed on the death certificate to this disease. Zhao et al. (2005) were able to examine both incidence and mortality among TCE-exposed workers and observed underreporting on death certificates for several site-specific cancers, including NHL, leukemia, and kidney and bladder cancers.

Death certificate inaccuracies would obscure exposure-disease associations toward the null by reducing statistical power and may explain apparent inconsistencies between epidemiologic studies using incidence data versus those based on death certifications. For example, apparent inconsistencies in some observations from cohort studies of American workers, which were primarily based on mortality, and cohort studies of Nordic workers, which were largely based on incidence, may reflect misclassification of death certificates compared with incidence data.

Non-Hodgkin lymphoma. Lymphoma, including NHL, is a disease composed of numerous, etiologically distinct neoplasms (Fisher 2003; Herrinton 1998). Several issues may affect interpretation of NHL associations in the TCE epidemiologic studies and may be important to evaluating the consistency, or lack there of, across studies. First, epidemiologic studies evaluating NHL and TCE exposure have used a number of different International Classification of Diseases (ICD) revisions. All four Nordic studies (Anttila et al. 1995; Axelson et al. 1994; Hansen et al. 2001; Raaschou-Nielsen et al. 2003) classified NHL according to the seventh revision of the ICD [ICD-7; World Health Organization (WHO) 1957], and all reported consistent findings. Other revisions of the ICD were used in the more recent studies by Blair et al. (1998) [ICD Adapted (ICDA)-8, National Center for Health Statistics 1967], Boice et al. (1999) (ICD-9, WHO 1977), Garabrant et al. (1988) (ICD-9 in effect at date of death: ICD-7, ICDA-8, or ICD-9), Morgan et al. (1998, 2000) (ICD in effect at date of death: ICD-7, ICDA-8, or ICD-9), and Ritz (1999) (ICD-9). Few case-control studies on lymphoma are available. NHL cases in Hardell et al. (1994) were histologically verified and were classified using the Rappaport system. Persson et al. (1989) do not identify the system used to classify NHL cases in their study. Classification of lymphomas has changed with each revision.

Second, understanding of histopathologic and immunologic characteristics of lymphoma has grown since 1977, the publication date of ICD-9. Past classifications of lymphomas do not reflect the current biologic understanding of NHL and do not make distinctions between different cell types. From this perspective, lymphomas are defined broadly as B-cell and T-cell lymphomas, with further divisions into precursor neoplasms and mature neoplasms (Cogliatti and Schmid 2002). This implies that lymphomas classified in the past into distinct categories may share common biological properties and differentiation pathways. For example, a lymphoma of B-cell origin may be classified under older schemes as NHL, multiple myeloma, or leukemia. Emerging data on molecular markers of lymphoma suggest stage of cell differentiation at time of exposure as an important factor in NHL development (Staudt and Dave 2005).

Exposure assessment issues in TCE epidemiologic studies. The methods by which exposure is assessed in epidemiologic studies of TCE are diverse, ranging from use of broad job or industry categories to analysis of biomonitoring data. Generally, greater weight is assigned to studies with more precise and specific exposure estimates. Careful evaluation of a study's exposure assessment method is important in the evaluation of a body of epidemiologic data, particularly if divergent observations may be due to exposure misclassification bias reflecting incorrect assignment of study subjects to exposure groups. Many of the TCE studies lack actual exposure measurements for individual subjects, and surrogates such as available current or historical monitoring data are often used to reconstruct exposure parameters.

The three Nordic cohorts of Axelson et al. (1994), Anttila et al. (1995), and Hansen et al. (2001) identified study subjects using the TCE biological marker of urinary trichloroacetic acid (U-TCA), which provides some evidence of past TCE exposure, although usually not a full exposure history. These studies carry weight in the overall analysis because of their greater precision of exposure assessment compared with methods discussed below for other cohorts; however, a consideration of statistical power is also important because of fewer subjects compared with cohorts identified using other methods.

Other cohort and case-control studies have adopted a number of approaches for exposure assessment. TCE exposure has been assigned to subjects using surrogate information based on patterns of TCE use by job title obtained from historical job descriptions, from historical industrial hygiene surveys, or from personal interviews to develop job exposure matrices (JEMs). For several cohorts, industrial hygiene measurements either were absent before the 1970s (Boice et al. 1999; Marano et al. 2000; Morgan et al. 1998, 2000) or were quite limited (Blair et al. 1998; Stewart et al. 1991). Furthermore, some cohort (Ritz 1999) and case-control (Greenland et al. 1994) studies classified study subjects as TCE exposed using information obtained from personal interviews or generic JEMs or job-task exposure matrices (JTEMs) in the absence of historical monitoring. Two issues associated with the use of generic JEMs are sensitivity (i.e., the ability to identify study subjects as exposed) and specificity (i.e., the ability to identify study subjects as not exposed).

Still other cohort studies (Chang et al. 2003, 2005; Costa et al. 1989; Garabrant et al. 1988) have defined exposure using occupation and industry. TCE is identified as one of a number of potential exposures, but no information is provided on individual subjects with TCE exposure. The main shortcoming of this type of study is that the lack of an association with a particular job or industry may mask the effect of exposure to a specific chemical to which only some individuals in the job are exposed (Teschke et al. 2002). For this reason, a consideration of potential exposure misclassification bias is important in weighting these studies in an overall weight of evidence.

In addition, multiple solvents and chemical agents are common in the TCE studies, adding to the complexity of exposure assessment and inferences about causality. Some studies of TCE also identify exposures to other chlorinated solvents such as perchloroethylene and 1,1,1-trichloroethane (Blair et al. 1998; Boice et al. 1999; Marano et al. 2000; Morgan et al. 1998, 2000; Stewart et al. 1991; Zhao et al. 2005). The potential for exposure to multiple chlorinated solvents is an important consideration in the TCE epidemiologic studies for two reasons. First, these chemicals can share similar metabolic profiles or modes of action as TCE (U.S. EPA 2001), and second, some epidemiologic studies have also reported independent associations between exposure to these other solvents and cancer (Blair et al. 1998; Zhao et al. 2005). Physiologically based pharmacokinetic models such as those discussed by Chiu et al. (2006b) may be useful for better understanding cumulative exposure in these epidemiologic studies.

Approaches for Causal Inference

The practice of causal inference in environmental epidemiology relies on three approaches: narrative reviews, criteria-based inference methods, and, increasingly, meta-analysis (Weed 2002). All three have been employed in various analyses of the epidemiologic literature on cancer and TCE exposure. Narrative reviews of a body of epidemiologic evidence generally do not fully consider potential biases and confounding factors. By contrast, criteria-based approaches for assessing causality evaluate evidence according to a set of criteria or standards applied to the evidence (Weed 2002). For instance, the aspects proposed by Sir Bradford Hill (1965) are widely cited for framing the factors to consider in determining whether statistical associations are likely to be causal. Similar criteria are also presented in the U.S. EPA Guidelines for Carcinogen Risk Assessment (U.S. EPA 2005).

Criteria-based approaches have increasingly been supplemented with formal statistical methods such as meta-analysis for reviewing and summing a body of evidence (Weed 2002). Common meta-analytic methods can include fitting of fixed-effects or random-effects models, linear regression analysis to assess dose-response, or pooled analyses. Pooled analysis of the Nordic studies may be more feasible because of their similar design and similar follow-up period for documenting cancer incidence than for other TCE cohorts. As discussed in the overview article of this mini-monograph by Chiu et al. (2006a), the NAS has been asked to provide advice on appropriate meta-analysis methods, including the classification and weighting of individual studies.

Discussion and Summary

The U.S. EPA draft TCE assessment (U.S. EPA 2001) noted that epidemiologic studies, when considered as a whole, have associated TCE exposure with excess risk of kidney, liver, lymphohematopoietic, cervical, and prostate cancer. Recently published studies appear to provide further support for several of those conclusions, suggesting, as do previous studies, modestly elevated site-specific risk (typically between 1.5 and 2.0), given exposure conditions in the epidemiologic studies.

The recent epidemiologic studies strengthen the evidence that the kidney is a target of TCE toxicity. It should be noted that kidney toxicity besides cancer has been found by Radican et al. (2006), who reported a statistically significant association with end-stage renal disease mortality and exposure to solvents, including TCE. Understanding the mechanism by which TCE may act in kidney toxicity, including cancer, can inform cause-effect evaluations. The glutathione S-transferase (GST) metabolic pathway has been hypothesized as important to mode-of-action considerations (Caldwell and Keshava 2006), and GST polymorphisms are reported to influence RCC risk associated with TCE exposure (Bruning et al. 1997). Brauch et al. (2004) examined somatic mutation to the von Hippel-Lindau tumor suppressor gene in renal cell tumors of non-TCE-exposed cases, comparing the prevalence of mutation to that found in renal tumors of TCE-exposed subjects reported in an earlier publication (Brauch et al. 1999). A higher prevalence of somatic mutations was found in renal cell tumors of TCE-exposed cases than in tumors of non-TCE-exposed cases. Moreover, the C > T transition at nucleotide 454, detected in some RCCs from TCE-exposed subjects, was not found among the non-TCE-exposed RCC cases.

The recent studies also support the liver and immune system as being targets for TCE toxicity, with most of these studies showing elevated (and in some cases statistically significant) cancer risks from TCE exposure. However, although the number of studies assessing primary liver cancer separately from biliary tract cancers has doubled, the total number is still only 4, compared to 11 examining the combined category. With lymphomas, there are also a number of classification issues, including the use of different ICD revisions, and the fact that these groupings may lump together etiologically distinct neoplasms. Moreover, studies evaluating these end points include both incidence and mortality studies, which may have different sensitivity and biases. Thus, the reduced specificity in most studies, in combination with the relatively small number of total cases due to low background incidence, complicates interpretation of these findings.

Of particular importance for assessment of epidemiologic evidence on TCE exposure is characterizing the totality of the evidence in light of factors that may contribute to false positive findings or to false negative observations. The evidence presented on issues regarding data sources, exposure assessment, and disease classification can influence the statistical power of the epidemiologic study to detect whether there is an underlying risk. The challenge is to consider these issues, along with well-articulated approaches when evaluating the body of evidence, including the application of meta-analysis methods and rationale for grouping individual studies, in identifying hazards and drawing causal conclusions.

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Cheryl Siegel Scott and Weihsueh A. Chiu

National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Washington, DC, USA

This article is part of the mini-monograph "Trichloroethylene Health Risks: Key Scientific Issues."

Address correspondence to C.S. Scott, U.S. EPA, 1200 Pennsylvania Ave. NW, Mail Code 8623D, Washington, DC 20460 USA. Telephone: (202) 564-3286. Fax: (202) 565-0078. E-mail: Scott.Cheryl@epa.gov

We thank the TCE team, including J. Blancato, J. Caldwell, C. Chen, M. Evans, J. Jinot, N. Keshava, J. Lipscomb, M. Okino, F. Power, and J. Schaum for their insightfulness and constructive input. Special thanks go to P. Preuss, J. Vandenberg, D. Bussard, and P. White for supporting this work.

The views expressed in this article are those of the authors and do not necessarily reflect the views or policies of the U.S. Environmental Protection Agency.

The authors declare they have no competing financial interests.

Received 22 December 2005; accepted 4 May 2006.
Table 1. Occupational cohort studies of cancer and TCE exposure.

 Size of study and
Reference Description comparison group

Aircraft and aerospace workers
 Zhao et al. 2005 Aerospace workers with at 6,044 (2,689 with
 least 2 years of employment high cumulative
 at Boeing/Rockwell/Rocketdyne exposure to TCE).
 (Santa Susana Field Mortality rates of
 Laboratory, Ventura, CA) subjects in lowest
 between 1950 and 1993. TCE exposure
 Cancer mortality as of 31 category.
 December 2001.
 Aerospace workers with at 5,049 (2,227 with
 least 2 years of employment high cumulative
 at Boeing/Rockwell/Rocketdyne exposure to TCE).
 (Santa Susana Field Incidence rates of
 Laboratory) between 1950 and subjects in lowest
 1993 who were alive as of TCE exposure
 1988. Cancer incidence was category.
 ascertained between 1988 and
 2000.
Cohorts identified from U-TCA
 Hansen et al. 2001 Workers biologically 803 (16,703 P-Y).
 monitored for occupational Cancer incidence
 exposure to TCE between 1947 rates of the Danish
 and 1989 using U-TCA and air population.
 TCE measurements between 1947
 and 1989 and alive as of 1
 April 1968. Follow-up for
 cancer incidence from 1 April
 1968 or date of first
 employment through 31
 December 1996.
Other cohorts
 Chang et al. 2005 Workers employed between 1978 86,868 (1,380,355,
 and 31 December 1998 at an P-Y). Incidence
 electronics factory in rates of Taiwanese
 Taiwan. Follow-up began on 1 population.
 January 1979 or date of entry
 to the cohort through 31
 December 1997. Cancer
 incidence ascertained as of
 31 December 1997.
Chang et al. 2003 Workers employed between 1978 86,868 (1,380,355
 and 31 December 1997 at an P-Y). Mortality
 electronics factory in rates of Taiwanese
 Taiwan. Follow-up began on 1 population.
 January 1985 or date or
 entry to the cohort through
 31 December 1997. Vital
 status ascertained from 1
 January 1985 through 31
 December 1997.
Raaschou-Nielsen Blue-collar workers employed 40,049 (14,360 with
 et al. 2003 between 1964 and 1997 for at presumably higher
 least 3 months and alive as level exposure to
 of 1 January 1968 at 347 TCE) (339,486 P-Y).
 Danish TCE-using companies. Cancer incidence
 Follow-up for cancer rates of the Danish
 incidence from 1 April 1968 population.
 or date of first employment
 through 31 December 1997.

Reference Exposure assessment

Aircraft and aerospace workers
 Zhao et al. 2005 Industrial hygienist assessment from walk-through
 visits, interviews, and review of historical
 facility reports. Each job title ranked for
 presumptive TCE exposure as high (3), medium (2),
 low (1), or no (0) exposure. Cumulative TCE
 assigned to individual subjects using JEM.
 Exposure-response patterns assessed using
 cumulative exposure.
Cohorts identified from U-TCA
 Hansen et al. 2001 Of the 803 subjects, 712 had U-TCA, 89 had air TCE
 measurement records and 2 had records of both
 types. Median TCE concentration was 19 mg/
 [m.sup.3]. Mean and median concentrations of U-TCA
 were 250 [micro]mol/L and 92 [micro]mol/L,
 respectively. There were on average 2.2 U-TCA
 measurements per individual.
Other cohorts
 Chang et al. 2005 National Labor Department inspection reports and
 the company's import/export statistics indicated
 use of many chlorinated solvents, including TCE,
 in the manufacturing process. No information on
 TCE use, potential TCE exposure concentrations, or
 the percentage of study subjects whose job titles
 indicated potential TCE exposure.
Chang et al. 2003
Raaschou-Nielsen Employers had documented TCE use. Blue-collar
 et al. 2003 versus white-collar workers and companies with
 [less than or equal to] 200 workers were variables
 identified as increasing the likelihood for TCE
 exposure. Subjects were identified from the
 following industries: iron and metal, electronics,
 painting, printing, chemical, and dry cleaning.

Abbreviations: JEM, job exposure matrix; P-Y; person-years; U-TCA,
urinary trichloroacetic acid.

Table 2. Case-control epidemiologic studies examining cancer and TCE
exposure.

 Cases
Reference Population (no.) Controls (no.)

Brain (neuroblastoma)
 DeRoos et al. Cases in children 504 504
 2001 [less than or equal to] 19
 Olshan et al. years of age selected from
 1999 Children's Cancer Group and
 Pediatric Oncology Group
 with diagnosis in 1992-1994;
 population controls (random
 digit dialing) matched to
 control for birth date.
Rectal
 Dumas et al. Male cases, 35-70 years of 257 1,295
 2000 age, diagnosed in 1979-1985 (group 1)
 and histologically 533
 confirmed; controls with (group 2)
 cancers at other sites
 chosen from same cancer
 registry as cases (group 1)
 or population controls
 (group 2).
Renal cell Histologically confirmed 134 401
 Bruning et al. cases from German hospitals
 2003 (Arnsberg) in 1992-2000;
 controls frequency-matched
 (one case, three controls)
 by sex and age to cases,
 from hospitals with urology
 department (and local
 geriatric department for
 older controls) serving
 Arnsberg.
 Charbotel et al. Histologically confirmed 86 316
 2005, 2006 cases from three hospitals
 Fevotte et al. and urologists in the High
 2006 Savoy area and surrounding
 region in France and from
 Geneva, Switzerland, in
 1993-2003; controls
 selected from urologists'
 files matched 1:4 to case
 for birth year and sex.
 Pesch et al. Histologically confirmed 935 4,298
 2000a cases from German hospitals
 (five regions) in 1991-1995;
 controls randomly selected
 from residency registries
 matched for region, sex, and
 age.
Urothelial Histologically confirmed 1,035 4,298
 Pesch et al. cases from German hospitals
 2000b (five regions) in 1991-1995;
 controls randomly selected
 from residency registries
 matched for region, sex, and
 age.

 Response Statistical
Reference rate (%) Exposure assessment analysis

Brain (neuroblastoma)
 DeRoos et al. Cases, 73 Telephone interview Logistic
 2001 Controls, 74 with parent using regression with
 Olshan et al. questionnaire to covariate for
 1999 assess parental child's age and
 occupation and self- material race,
 reported exposure age, and
 history and judgment education.
 -based attribution
 of exposure to TCE
 and other solvents.
Rectal Cases, 85 In-person or Logistic
 Dumas et al. Controls, 100 telephone interview regression
 2000 (group 1) to assess self- analyses
 Controls, 72 reported adjusted for
 (group 2) occupational age, education,
 history: TCE cigarette
 exposure assigned smoking, beer
 to subject using consumption,
 work history body mass
 obtained by index, and
 interview and JEM. respondent
 status.
Renal cell Cases, 83 In-person interview Logistic
 Bruning et al. Controls, no with case or regression with
 2003 information next-of-kin; covariates for
 questionnaire age, sex, and
 assessing smoking.
 occupational
 history using
 job title and
 JEM of Pannett
 et al. (1985).
 Charbotel et al. Cases, 74 Blinded telephone Matched pairs
 2005, 2006 Controls, 78 interview with case conditional
 Fevotte et al. or next-of-kin; logistic
 2006 questionnaire regression with
 assessing covariates for
 occupational body mass index
 history using JTEM and tobacco
 or self-reported smoking.
 exposure to assign
 TCE and other
 exposures.
 Pesch et al. Cases, 88 In-person interview Logistic
 2000a Controls, 71 with case or regression with
 next-of-kin; covariates for
 questionnaire age, family
 assessing income,
 occupational history ethnicity,
 using job title or smoking, and
 self-reported respondent
 exposure to assign status.
 TCE and other
 exposures.
Urothelial
 Pesch et al. Cases, 84 In-person interview Logistic
 2000b Controls, 71 with case or regression with
 next-of-kin; covariates for
 questionnaire age, family
 assessing income,
 occupational history ethnicity,
 using job title or smoking, and
 self-reported respondent
 exposure to assign status.
 TCE and other
 exposures.

JTEM, job-task exposure matrix.

Table 3. Community studies on cancer and TCE exposure.

 Statistical
Reference Description methods

Ahrens et al. 2001 Incident leukemia cases Illustration of
Waller and Turnbull 1993 from 1978-1982 from eight three statistical
Waller et al. 1992 counties in upstate New methodologies to
Turnbull et al. 1990 York. assess clustering
 of leukemia cases
 and 12 hazardous
 waste sites.
Aickin 2004 Deaths due to cancer, Standardized rate
Aickin et al. 1992 including leukemia, ratios for
Flood et al. 1990, 1997 congenital anomalies, mortality from
Flood and Chapin 1988 injuries, and cardio- Poisson
 vascular diseases in 1996- regression
 1986 and childhood leukemia modeling.
 incident cases (1965-1986) Childhood
 among residents of Maricopa leukemia
 County, Arizona. incidence data
 evaluated using
 Bayes methods and
 Poisson
 regression
 modeling.
Costas et al. 2002, Childhood leukemia Logistic
Massachusetts ([less than or equal to] 19 regression with
 Department of Public years age) diagnosed in composite
 Health 1997 1969-1989 in residents of covariate, a
 Woburn, MA; controls weighted variable
 randomly selected from of individual
 Woburn public school covariates.
 records, matched for age.
Lee et al. 2003 Cancer deaths in 1966-1997 Mortality OR
 in two villages in Taiwan; using Mantel-
 controls were Haenszel method
 cardiovascular and and stratified by
 cerebrovascular disease gender and age
 deaths from same underlying and logistic
 area as cases. regression with
 covariates for
 age and period.
Morgan and Cassady 2002 Cancer cases diagnosed Standardized
 between 1 April 1988 and 31 incidence rates
 December 1998 among for all cancer
 residents of 13 census sites and 16
 tracts in Redlands area, site-specific
 San Bernardino County, CA. cancers; expected
 numbers of
 cancers using
 incidence rates
 of site-specific
 cancer of a four-
 county region in
 1988-1992.

Reference Exposure assessment

Ahrens et al. 2001 Residence in census tract or census block
Waller and Turnbull 1993 group with a previously identified inactive
Waller et al. 1992 hazardous waste site.
Turnbull et al. 1990
Aickin 2004 Resident of Maricopa County, AZ, at the time
Aickin et al. 1992 of diagnosis or death as surrogate for
Flood et al. 1990, 1997 exposure.
Flood and Chapin 1988
Costas et al. 2002, Questionnaire administered to parents
Massachusetts separately assessing demographic and lifestyle
 Department of Public characteristics, medical history information,
 Health 1997 environmental and occupational exposure, and
 use of public drinking water in the home.
 Hydraulic mixing model used to infer drinking
 water containing TCE and other solvents
 delivered to residence.
Lee et al. 2003 Location of residence as recorded on death
 certificate. Monitoring in 1999-2000 of TCE in
 groundwater or well water was used to infer
 exposure to TCE to village residents.
Morgan and Cassady 2002 TCE and perchlorate detected in some county
 wells; no information on distribution of
 contaminated water to residents. TCE
 concentrations in water after 1991 were below
 maximum contaminant level of 5 ppb.

OR, odds ratio.

Table 4. Select epidemiologic studies: site-specific cancer and exposure
to TCE.

 Exposed
Reference Study population cases (no.)

Total cancer
 Cohort studies
 Hansen et al. 2001 Male 109
 Female 19
 Chang et al. 2003 Male 66
 Female 250
 Raaschou-Nielsen et al. Male 2,434
 2003 Female 624
 Community studies
 Lee et al. 2003 Upstream village 266 (a)
 Downstream village
 Morgan and Cassady 13 census tracts in San
 2002 Bernardino County, CA 3,098
Bladder
 Cohort studies
 Hansen et al. 2001 Male 10
 Female 0
 Chang et al. 2003 Male 1
 Female 1
 Raaschou-Nielsen et al. Male 203
 2003 Female 17
 Zhao et al. 2005 (c) Low TCE score 7
 Medium TCE score 7
 High TCE score 3
 Case-control studies
 Pesch et al. 2000b JTEM, male
 Medium TCE exposure 47
 High TCE exposure 74
 Substantial TCE exposure 36
 Community studies
 Morgan and Cassady 13 census tracts in San
 2002 Bernardino County, CA 82
Breast
 Cohort studies
 Hansen et al. 2001 Female 4
 Chang et al. 2005 Female 215
 Raaschou-Nielsen et al. Male 2
 2003 Female 145
 Community studies
 Morgan and Cassady Females in 13 census 536
 2002 tracts in San
 Bernardino County, CA
Esophagus
 Cohort studies
 Hansen et al. 2001 Male 6
 Female 0
 Chang et al. 2005 Male 0
 Female 0
 Raaschou-Nielsen et al. Male 23 (d)
 2003 Female 0
 Zhao et al. 2005 (c,e) Low TCE score 7
 Medium TCE score 7
 High TCE score 3

 Estimated
 relative
Reference Study population risk (95% CI)

Total cancer
 Cohort studies
 Hansen et al. 2001 Male 1.0 (0.9-1.3)
 Female 1.0 (0.6-1.6)
 Chang et al. 2003 Male 0.7 (0.5-0.8)
 Female 1.0 (0.9-1.1)
 Raaschou-Nielsen et al. Male 1.1 (1.0-1.1)
 2003 Female 1.2 (1.1-1.3)
 Community studies
 Lee et al. 2003 Upstream village 1.0
 Downstream village 2.1 (1.3-3.3) (b)
 Morgan and Cassady 13 census tracts in San
 2002 Bernardino County, CA 1.0 (0.9-1.0)
Bladder
 Cohort studies
 Hansen et al. 2001 Male 1.1 (0.5-2.0)
 Female
 Chang et al. 2003 Male 1.0 (0.01-5.4)
 Female 1.0 (0.01-5.4)
 Raaschou-Nielsen et al. Male 1.0 (0.9-1.2)
 2003 Female 1.6 (0.9-2.6)
 Zhao et al. 2005 (c) Low TCE score 1.0
 Medium TCE score 1.5 (0.8-2.9)
 High TCE score 2.0 (0.9-4.2)
 Case-control studies
 Pesch et al. 2000b JTEM, male
 Medium TCE exposure 0.8 (0.6-1.2)
 High TCE exposure 1.3 (0.9-1.7)
 Substantial TCE exposure 1.8 (1.2-2.7)
 Community studies
 Morgan and Cassady 13 census tracts in San
 2002 Bernardino County, CA 1.0 (0.8-1.2)
Breast
 Cohort studies
 Hansen et al. 2001 Female 0.9 (0.2-2.3)
 Chang et al. 2005 Female 1.2 (1.0-1.4)
 Raaschou-Nielsen et al. Male 0.5 (0.1-1.9)
 2003 Female 1.1 (0.9-1.2)
 Community studies
 Morgan and Cassady Females in 13 census 1.1 (1.0-1.2)
 2002 tracts in San
 Bernardino County, CA
Esophagus
 Cohort studies
 Hansen et al. 2001 Male 4.2 (1.5-9.2)
 Female
 Chang et al. 2005 Male
 Female
 Raaschou-Nielsen et al. Male 1.8 (1.2-2.7)
 2003 Female
 Zhao et al. 2005 (c,e) Low TCE score 1.0
 Medium TCE score 1.7 (0.6-4.4)
 High TCE score 1.3 (0.2-4.0)

CI, confidence interval.
(a) Total cancer deaths in the two villages. (b) 99% CI. (c) Zhao et al.
(2005) present both cancer incidence and cancer mortality. Relative
risks in this table are for cancer incidence. (d) Adenocarcinoma of the
esophagus. (e) Esophageal and stomach cancer incidence.

Table 5. Select epidemiologic studies: kidney or renal cell cancer and
exposure to TCE.

 Exposed
Reference Study population cases (no.)

Cohort studies
 Hansen et al. 2001 Male 3
 Female 1
 Chang et al. 2005 Male 0
 Female 3
 Raaschou-Nielsen et Male 93
 al. 2003 Female 10
 Duration of employment, male
 [less than or equal to] 1 year 14
 1-4.9 years 25
 [greater than or equal to] 5 29
 years
 Duration of employment, female
 [less than or equal to] 1 year 2
 1-4.9 years 3
 [greater than or equal to] 5 3
 years
 Zhao et al. 2005 (a) Low TCE score 6
 Medium TCE score 6
 High TCE score 4
Case-control
 Pesch et al. 2000 (a) JTEM, male
 Medium exposure 68
 High exposure 59
 Substantial exposure 22
 JTEM, female
 Medium exposure 11
 High exposure 7
 Substantial exposure 5
 Bruning et al. 2003 Employment in industry 117
 with TCE exposure
 Self-assessed, TCE 25
 Duration of exposure
 No exposure 109
 [less than or equal to] 10 14
 years
 10- [less than or equal to] 20 13
 years
 20+ years 6
 Charbotel et al. Cumulative TCE dose
 2005, 2006 Nonexposed 49
 Low 12
 Medium 9
 High 16
 Cumulative TCE dose + peaks
 Nonexposed 49
 High + peaks 8
Community studies
 Morgan and Cassady 13 census tracts in 54
 2002 San Bernardino County, CA

 Estimated
 relative
Reference Study population risk (95% CI)

Cohort studies
 Hansen et al. 2001 Male 0.9 (0.2-2.6)
 Female 2.4 (0.03-14)
 Chang et al. 2005 Male
 Female 1.2 (0.2-3.4)
 Raaschou-Nielsen et Male 1.2 (1.0-1.5)
 al. 2003 Female 1.2 (0.6-2.1)
 Duration of employment, male
 [less than or equal to] 1 0.8 (0.5-1.4)
 year
 1-4.9 years 1.2 (0.8-1.7)
 [greater than or equal to] 5 1.6 (1.1-2.3)
 years
 Duration of employment, female
 [less than or equal to] 1 year 1.1 (0.1-3.8)

 1-4.9 years 1.2 (0.2-3.5)
 [greater than or equal to] 5 1.5 (0.3-4.3)
 years
 Zhao et al. 2005 (a) Low TCE score 1.0
 Medium TCE score 1.9 (0.6-6.2)
 High TCE score 4.9 (1.2-20)
Case-control
 Pesch et al. 2000 (a) JTEM, male
 Medium exposure 1.3 (1.0-1.8)
 High exposure 1.1 (0.8-1.5)
 Substantial exposure 1.3 (0.8-2.1)
 JTEM, female
 Medium exposure 1.3 (0.7-2.3)
 High exposure 0.8 (0.4-1.9)
 Substantial exposure 1.8 (0.6-5.0)
 Bruning et al. 2003 Employment in industry 1.8 (1.2-2.7)
 with TCE exposure
 Self-assessed, TCE 2.5 (1.4-4.5)
 Duration of exposure
 No exposure 1.0
 [less than or equal to] 10 3.8 (1.5-9.3)
 years
 10- [less than or equal to] 20 1.8 (0.7-4.8)
 years
 20+ years 2.7 (0.8-8.7)
 Charbotel et al. Cumulative TCE dose
 2005, 2006 Nonexposed 1.0
 Low 1.6 (0.8-3.5)
 Medium 1.2 (0.5-2.8)
 High 2.2 (1.0-4.6)
 Cumulative TCE dose + peaks
 Nonexposed 1.0
 High + peaks 2.7 (1.1-7.1)
Community studies
 Morgan and Cassady 13 census tracts in 0.8 (0.6-1.1)
 2002 San Bernardino County, CA

(a) Zhao et al. (2005) present both cancer incidence and cancer
mortality. Relative risks in this table are for cancer incidence.

Table 6. Select epidemiologic studies: liver cancer and exposure to TCE.

 Exposed cases
Reference Study population (no.)

Liver, primary
 Cohort studies (a)
 Hansen et al. 2001
 Hansen 2004 Male, female 2
 Chang et al. 2003 Male 0
 Female 0
 Raaschou-Nielsen et Male 27
 al. 2003 Female 7
 Duration of employment, male
 [less than or equal to] 1 9
 year
 1-4.9 years 9
 [greater than or equal to] 5 9
 years
 Duration of employment, female
 [less than or equal to] 1 2
 year
 1-4.9 years 4
 [greater than or equal to] 5 1
 years
Liver and bile ducts
 Cohort studies (a)
 Hansen et al. 2001
 Hansen 2004 Male and female 5
 Chang et al. 2003 Not reported
 Raaschou-Nielsen et Males 41
 al. 2003 Females 16
 Duration of employment, male
 [less than or equal to] 1 13
 year
 1-4.9 years 13
 [greater than or equal to] 5 15
 years
 Duration of employment, female
 [less than or equal to] 1 4
 year
 1-4.9 years 10
 [greater than or equal to] 5 2
 years
 Community studies
 Lee et al. 2003 Upstream village 53 (b)
 Downstream village
 Morgan and Cassady 13 census tracts in San 28
 2002 Bernardino County, CA

 Estimated
 relative risk
Reference Study population (95% CI)

Liver, primary
 Cohort studies (a)
 Hansen et al. 2001
 Hansen 2004 Male, female 1.7 (0.2-6.0)
 Chang et al. 2003 Male
 Female
 Raaschou-Nielsen et Male 1.1 (0.7-1.6)
 al. 2003 Female 2.8 (1.1-5.8)
 Duration of employment, male
 [less than or equal to] 1 1.3 (0.6-2.5)
 year
 1-4.9 years 1.0 (0.5-1.9)
 [greater than or equal to] 5 1.1 (0.5-2.1)
 years
 Duration of employment, female
 [less than or equal to] 1 2.8 (0.3-10)
 year
 1-4.9 years 4.1 (1.1-11)
 [greater than or equal to] 5 1.3 (0.0-7.1)
 years
Liver and bile ducts
 Cohort studies (a)
 Hansen et al. 2001
 Hansen 2004 Male and female 2.1 (0.7-4.9)
 Chang et al. 2003 Not reported
 Raaschou-Nielsen et Males 1.1 (0.8-1.5)
 al. 2003 Females 2.8 (1.6-4.5)
 Duration of employment, male
 [less than or equal to] 1 1.2 (0.6-2.1)
 year
 1-4.9 years 0.9 (0.5-1.6)
 [greater than or equal to] 5 1.1 (0.6-1.7)
 years
 Duration of employment, female
 [less than or equal to] 1 2.5 (0.7-6.4)
 year
 1-4.9 years 4.5 (2.1-8.3)
 [greater than or equal to] 5 1.1 (0.1-3.8)
 years
 Community studies
 Lee et al. 2003 Upstream village 1.0
 Downstream village 2.6 (1.2-5.5)
 Morgan and Cassady 13 census tracts in San 1.3 (0.9-1.9)
 2002 Bernardino County, CA

(a) Zhao et al. (2005) did not present relative risks for liver or liver
and bile duct cancer in their article. (b) Total liver cancer deaths in
the two villages.

Table 7. Select epidemiologic studies: lymphoma and exposure to TCE.

 Exposed cases
Reference Study population (no.)

NHL
 Cohort studies
 Hansen et al. Male 8
 2001 Female 0
 Duration of employment, male
 Unknown 2
 [less than or equal to] 6.25 2
 years
 [greater than or equal to] 6.25 4
 years
 Chang et al. Male 5
 2005 Female 10
 Raaschou- Male 83
 Nielsen Female 13
 et al. 2003 Duration of employment, male
 [less than or equal to] 1 year 23
 1-4.9 years 33
 [greater than or equal to] 5 27
 years
 Duration of employment, female
 [less than or equal to] 1 year 2
 1-4.9 years 6
 [greater than or equal to] 5 5
 years
 Zhao et al. Low TCE score 28
 2005 (a) Medium TCE score 16
 High TCE score 1
 Community
 studies
 Morgan and 13 census tracts in San 111
 Cassady 2002 Bernardino County, CA
Leukemia
 Cohort studies
 Hansen et al. Male 5
 2001 Female 1
 Chang et al. Male 2
 2005 Female 8
 Raaschou- Male 69
 Nielsen Female 13
 et al. 2003
 Community
 studies
 Costas et al. Exposed to water from
 2002 TCE-contaminated wells G and H
 2 years before pregnancy to
 leukemia diagnosis
 Never 3
 Least 9
 Most 7
 Exposed to water from
 TCE-contaminated wells G and H
 during pregnancy
 Never 9
 Least 3
 Most 7
 Morgan and 13 census tracts in San 77
 Cassady 2002 Bernardino County, CA

 Estimated
 relative risk
Reference Study population (95% CI)

NHL
 Cohort studies
 Hansen et al. Male 3.5 (1.5-6.9)
 2001 Female
 Duration of employment, male
 Unknown 3.7 (0.4-13)
 [less than or equal to] 6.25 2.5 (0.3-9.2)
 years
 [greater than or equal to] 6.25 4.2 (1.1-11)
 years
 Chang et al. Male 1.3 (0.4-3.0)
 2005 Female 1.1 (0.6-2.1)
 Raaschou- Male 1.2 (1.0-1.5)
 Nielsen et Female 1.4 (0.7-2.3)
 al. 2003
 Duration of employment, male
 [less than or equal to] 1 year 1.1 (0.7-1.6)
 1-4.9 years 1.3 (0.9-1.8)
 [greater than or equal to] 5 1.4 (0.9-2.0)
 years
 Duration of employment, female
 [less than or equal to] 1 year 0.7 (0.1-2.4)
 1-4.9 years 1.6 (0.6-3.5)
 [greater than or equal to] 5 1.8 (0.6-4.3)
 years
 Zhao et al. Low TCE score 1.0
 2005 (a) Medium TCE score 0.9 (0.5-1.7)
 High TCE score 0.2 (0.03-1.5)
 Community
 studies
 Morgan and 13 census tracts in San 1.1 (0.9-1.3)
 Cassady 2002 Bernardino County, CA
Leukemia
 Cohort studies
 Hansen et al. Male 1.9 (0.6-4.4)
 2001 Female 3.1 (0.04-18)
 Chang et al. Male 0.4 (0.05-1.6)
 2005 Female 0.5 (0.2-1.1)
 Raaschou- Male 1.1 (0.8-1.4)
 Nielsen et Female 1.7 (0.9-2.9)
 al. 2003
 Community
 studies
 Costas et al. Exposed to water from
 2002 TCE-contaminated wells G and H 2
 years before pregnancy to
 leukemia diagnosis
 Never 1.0
 Least 5.0 (0.7-34)
 Most 3.6 (0.5-25)
 Exposed to water from
 TCE-contaminated wells G and H
 during pregnancy
 Never 1.0
 Least 3.5 (0.2-58)
 Most 14 (0.9-224) (b)
 Morgan and 13 census tracts in San 1.0 (0.8-1.3)
 Cassady 2002 Bernardino County, CA

(a) Zhao et al. (2005) present both cancer incidence and cancer
mortality. Relative risks in this table are for NHL and leukemia
incidence combined. (b) Test for trend is statistically significant, p
[less than or equal to] 0.05.
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Article Details
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Title Annotation:Mini-Monograph
Author:Chiu, Weihsueh A.
Publication:Environmental Health Perspectives
Article Type:Disease/Disorder overview
Date:Sep 1, 2006
Words:9842
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