TCE Meta-Analyses: Wartenberg et al.'s Response

We appreciate the interest of Borak, Russi, and Puglisi in our summary of the epidemiologic evidence on the possible carcinogenicity of trichloroethylene (TCE) (1). We share their concern for a clear presentation of study results and identifications of methods used in meta-summaries of epidemiologic studies, and labored to do so in our review. The ease with which Borak et al. were able to identify cohort studies that examined renal cancer incidence, reproduce reported results, and recompute estimates on a reduced set of study results using the same summary methods belies their criticism of concealment or obfuscation.

The principal goal in our review was to identify, critique and summarize the cancer epidemiology of TCE-exposed populations in a more complete and systematic manner than that carried out previously (2-4). As such, our approach was to provide a broad overview that summarized the major trends and patterns in the data while reserving most study-specific insights and patterns in the data for other venues. Our challenge was to examine and summarize the patterns of results from over 80 epidemiologic publications that we identified. Although we recognize the utility in certain contexts of selecting subjectively only the "best" studies and reporting their results, as is done by IARC (2), we explicitly chose not to do so. Rather, we identified, critiqued, and summarized all studies in a comprehensive assessment. Faced with a large number of studies, we categorized them by design and then subdivided the cohort studies by the likelihood of TCE exposure and the quality of the exposure assessment. Some may quibble about our particular categorization of the studies, but we believe that our approach is well justified overall and that the analyses were presented clearly and comprehensively. Further, we do not see this venue as the appropriate one to debate the merits and limitations of meta-analysis, in general, nor specifically the opinions of Borak et al. regarding the interpretation of such analyses. This debate has occurred elsewhere [e.g., see references in Petitti (5)]. Our goal in calculating the average risks was to assess the possible role of chance variation in the observed results and to determine whether this body of studies had sufficiently unusual results to warrant further consideration and investigation.

Borak et al. question the inclusion of the controversial Henschler et al. study (6) in our Tier I summary risk calculation. They suggest that the study should have been excluded because it originated as a duster investigation. They also note that the kidney cancer results from the Tier I studies including the Henschler et al. study (6) are statistically heterogeneous and thus misleading.

The comment raised by Borak et al. regarding the inclusion of the study by Henschler et al. (6) has been raised by others, notably Weiss (3) and McLaughlin and Blot (4), and we explicitly addressed this issue in the discussion of our paper. The notion that data should be excluded from a general review because they were first noted in a duster seems to misinterpret the very references (9,10) cited by Borak et al. The context of those studies was a discussion of the interpretation of a single cluster study without exposure data and without an a priori idea of what was being investigated other than an overall excess of disease. First, the study by Henschler et al. (6) is not a cluster investigation but a cohort study that was initiated by the observation of excess disease, albeit a cluster. Further, we included it in a comprehensive review of the literature because excess kidney cancer in this workplace with extremely high TCE exposures was a plausible a priori hypothesis based on both animal bioassay and human epidemiologic data that previously had shown increased renal cancer rates from TCE exposure. Further, the results of Henschler et al. (6) were so extreme (5 cases where 0.628 were expected) that the probability of observing such a situation is less than 5 x [10.sup.-5], under Poisson assumptions. In other words, if there were no association, one would have to search for 500,000 similar workplaces with comparable TCE exposures to find such occurrence due to chance alone. Therefore, these data warranted further consideration, particularly with respect to other studies of TCE exposure and renal cancer. We agree that the study of Henschler et al. (6) is not sufficient on its own to confirm a causative relationship between TCE and renal cancer, as Rothman (7) and Fleming et al. (8) caution with respect to cluster studies. In combination with all the other studies in our review, however, the case for an elevated kidney cancer risk is much stronger.

Second, we are well aware of the issues surrounding heterogeneity in meta-analyses (9-13). We share Borak et al.'s concerns about heterogeneity but disagree with their interpretation. We did provide summary results for each study for the interested reader who can recalculate as they see fit, as Borak et al. did. If we had provided only the average risks, we would have obscured this issue and thus been remiss. The general issue that we were confronted with was how to help guide the reader through 14 tables of data summarizing over 80 articles reporting cancer rates for 23 different anatomical sites. Any summarization of this volume of information will necessarily omit some relevant information. Our point of summarizing these data was to omit what we thought was of lesser importance so that the more casual reader would still understand the main point of the paper without laboring over all of the tables. In fact, we left out even more data because most of the papers report on either effects at several exposure levels or exposures to several chemicals or responses to different subsets of the study population. When available, we did present observations for the most highly exposed subgroup to be consistent with Henschler et al. (6). It was our judgment that the information we included was the most important information for the reader, given the stated goal of our review. Those more interested readers could recalculate various summaries or even go back to the original papers for more detailed information and investigation. We accept criticism on this issue but note that we fulfilled our goal and provided a stimulus for scientific debate on the carcinogenicity of TCE.

Despite their comments, Borak et al. seem to place Some weight on the elevated kidney cancer risks reported by Henschler et al. (6), because they explain that these tumors may have resulted from high exposure leading to tubular damage and subsequent cancer. We find this hypothesis intriguing but not entirely satisfying since some TCE metabolites, notably those of the glutathione-S-transferase pathway, are highly mutagenic (14,15). Therefore, tubular damage may not be a necessary precursor to TCE-induced renal cancer. Borak et al.'s hypothesis, nonetheless, is worthy of replication in another highly exposed population. A comparable study, however, may be difficult to undertake because the average exposure levels for populations in the remaining studies included in our analysis were substantially lower than was typical in the Henschler et al. study (6). For example, in the studies of Axelson et al. (16) and Anttila et al. (17), the median exposures were around 50 ppm, lower than typically assumed in Henschler's cohort (7). Furthermore, incidence rather than mortality should be evaluated due to the differences in the rates between the two measures. In the end, Borak et al. apparently agree with our interpretation that exposure to TCE is a risk factor for renal cancer. Unfortunately, we remain at odds with them about our alternative approaches for summarizing rather overwhelming amounts of information.

In short, our analysis more strongly suggests an association between TCE and renal cancer. Renal cancer is a relatively rare disease and our analysis is based on few incident cases. The addition or subtraction of any one study in the analysis can alter the magnitude of the association. The findings of relative risks above 1.0 for incidence in two of the three other cohort studies (16-18) in Tier 1, in addition to elevated risks between TCE exposure and renal cancer in two recent case--control studies (19,20), are supportive of the overall association between elevated renal cancer risk and TCE exposure. Moreover, mode of action' hypotheses regarding the genotoxic effects of TCE metabolites and their presence in the kidney add further support for the human observations.

We recognize many limitations of our approach to summarizing the large amount of epidemiologic data on the possible carcinogenicity of TCE. Although other approaches are possible and some have been used in previous reviews of the epidemiologic literature on TCE, they too have their short comings. We look forward to further discussion and debate in the scientific community leading to greater consensus about the possible hazards of TCE exposure.

REFERENCES AND NOTES

(1.) Wartenberg D, Reyner D, Scott CS. Trichloroethylene and cancer: the epidemiologic evidence. Environ Health Perspect 108(suppl 2):161-176 (2000).

(2.) International Agency for Research on Cancer. Dry Cleaning, Some Chlorinated Solvents and Other Industrial Chemicals IARC Monogr Eval Carcinog Risks Hum 63 (1995).

(3.) Weiss NS. Cancer in relation to occupational exposure to trichloroethylene. Occup Environ Med 53:1-5 (1996).

(4.) McLaughlin JK, Blot WJ. A critical review of epidemiology studies of trichloroethylene and perchloroethylene and risk of renal-cell cancer. Int Arch Occup Environ Health 70:222-231 (1997).

(5.) Petitti D. Meta-Analysis, Decision Analysis, and Cost-Effectiveness Analysis. 2nd ed. New York:Oxford University Press, 2000.

(6.) Henschler D, Vamvakas S, Lammert M, Dekant W, Kraus B, Thomas B, Ulm K. Increased incidence of renal cell tumors in a cohort of cardboard workers exposed to trichloroethene. Arch Toxicol 69:291-299 (1995).

(7.) Rothman KJ. A sobering start for the Cluster Buster's Conference. Am J Epidemiol 132(suppl):6-13 (1990).

(8.) Fleming L, Ducatman A, Shalat S. Disease clusters in occupational medicine: a protocol for their investigation in the workplace. Am J Ind Med 22:33-47 (1992).

(9.) Colditz GA, Burdick E, Mosteller F. Heterogeneity in meta-analysis of data from epidemiologic studies: a commentary. Am J Epidemiol 142:371-382 (1995).

(10.) Lau J, Ioannidis JPA, Schmid CH. Quantitative synthesis in systematic reviews. Ann Int Med 127:829-826 (1997).

(11.) Hardy RJ, Thompson SG. Detecting and describing heterogeneity in meta-analysis. Stat Med 17:841-856 (1998).

(12.) Poole C, Greenland S. Random-effects meta-analyses are not always conservative. Am J Epidemiol 150:469-475 (1999).

(13.) Thompson SG, Sharp SJ. Explaining heterogeneity in meta-analysis: a comparison of methods. Stat Med 18:2693-2708 (1999).

(14.) Lash LH, Parker JC, Scott CS. Modes of action of trichloroethylene for kidney tumorigenesis. Environ Health Perspect 108(suppl 2):225-240 (2000).

(15,) Moore MM, Harrington-Brock K. Mutagenicity of trichloroethylene and its metabolites: implications for risk assessment of trichloroethylene. Environ Health Perspect 108(suppl 2):215-223 (2000).

(16.) Axelson O, Selden A, Andersson K, Hogstedt C. Updated and expanded Swedish cohort study of trichloroethylene and cancer risk. J Occup Med 36:556-562 (1994).

(17.) Anttila A, Pukkala E, Sallmen M, Hernberg S, Hemminki K. Cancer incidence among Finnish workers exposed to halogenated hydrocarbons. J Environ Occup Med 37:797-806 (1995).

(18.) Blair A, Hartge P, Stewart PA, McAdams M, Lubin J. Mortality and cancer incidence of aircraft maintenance workers exposed to trichloroethylene and other organic solvents and chemicals: extended follow up. Occup Environ Med 55:161-171 (1998).

(20.) Vamvakas S, Bruning T, Thomasson B, Lammert M, Baumuller A, Bolt F, Dekant W, Birner G, Henschler D, Ulm K. Renal cell cancer correlated with occupational exposure to trichloroethene. J Cancer Res Clin Oncol 124:374-382 (1998).

(21.) Dosemeci M, Cocco P, Chow WH. Gender differences in risk of renal cell carcinoma and occupational exposures to chlorinated aliphatic hydrocarbons. Am J Ind Med 36:54-59 (1999).

Daniel Wartenberg Daniel Reyner Environmental and Occupational Health Sciences Institute UMDNJ-Robert Wood Johnson Medical School Piscataway, New Jersey E-mail: [email protected] Cheryl Siegel Scott U.S. Environmental Protection Agency Washington, D.C.

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