Trichloroethylene cancer epidemiology: a consideration of select issues.
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]
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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|Author:||Chiu, Weihsueh A.|
|Publication:||Environmental Health Perspectives|
|Article Type:||Disease/Disorder overview|
|Date:||Sep 1, 2006|
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