Meta-Analyses of TCE Carcinogenicity.

We read with interest the recent report by Wartenberg et al. (1) in which they described an "ad hoc system" and "meta-analysis--type approach" for evaluating the carcinogenicity of trichloroethylene (TCE). In particular, we are concerned that their methods may obscure rather than clarify the relationship between TCE and human cancer.

Briefly, Wartenberg et al. (1) categorized studies on the basis of their design: cohort, case--control, community-based, and case series. Cohort studies were then divided "into three tiers based on the specificity of the exposure information" contained in each. Next, the authors estimated the average relative risk for each tier, which was calculated using

   a weighted average of the individual measures of effect, where the weights
   are the inverse of the variance of the individual measures.

That approach, although defensible (2), does not necessarily lead to results that are either biologically or epidemiologically meaningful. To the contrary, it may encourage analysis of groups of studies that would more logically be analyzed separately. Such meta-analyses can either amplify or conceal underlying causal associations.

This can be illustrated by reference to the analysis of kidney cancer incidence rates in the cohort studies (1). There were seven Tier I cohort studies, of which six are large occupational cohort studies: Anttila et al. (3), Axelson et al. (4), Blair et al. (5), Boice et al. (6), Morgan et al. (7), and Ritz (8). Four of the Tier I studies included incidence data used to calculate a summary relative risk for renal cancer incidence. Of these four, three were large cohort studies [Anttila et al. (3), Axelson et al. (4), and Blair et al. (5)] that considered renal cancer in 18,182 individuals (12,848 exposed to TCE). The fourth of these studies, Henschler et al. (9), was a small study of only 359 subjects (169 exposed to TCE), which has been the subject of ongoing methodologic controversy and debate because it originated as an investigation of a cancer cluster. For that reason, the International Agency for Research on Cancer (IARC) did not include it when calculating summary relative risks in its assessment of TCE and human cancer (10).

To determine the impact of including the Henschler study (9), we recalculated Wartenberg's computations, using their inverse variance-weighted technique, with and without the Henschler data. The summary relative risk for renal cancer in the three large cohorts excluding the Henschler study was 0.98 [95% confidence interval (CI), 0.58-1.66]. Including the Henschler data (9), the summary relative risk is 1.7 (95% CI, 1.1-2.7), which agrees with the calculations of Wartenberg et al. (1). Although inclusion of the Henschler study increased the combined study population by only 169 exposed and 359 total subjects (1.32% and 1.97%, respectively), it increased the relative risk by nearly 74% and reversed the conclusions of the analysis.

The impact of the Henschler data (9) stems from its very high incidence rate of renal cancer, about 8-fold higher than that of the other cohorts. It is therefore important whether this population was studied because of a renal cancer cluster in that small TCE-exposed worksite, a finding that assured an elevated incidence rate.

Wartenberg et al. (1) justify inclusion of the Henschler study as follows: "An argument can be made that studies initiated by a cluster report should be excluded ... we disagree." This statement, with which we disagree, has been and will continue to be debated in the scientific literature (11,12). More immediately, the assignment of the Henschler study (9) to Tier I status solely on the basis of the exposure data specificity, without regard to its origin as a cluster investigation, represents a methodologic weakness of the approach of Wartenberg et al. This small cluster investigation overwhelmed the combined findings of several large cohort studies.

Looking at the data, it is obvious that the positive result was produced by the Henschler study (9). A more formal test, such as calculation of a Q statistic to assess homogeneity across studies (2,13,14), demonstrates the substantial heterogeneity between the Henschler cluster evaluation and the three large cohort studies (3-5). The calculated Q-statistic for the three large cohort studies, but excluding the Henschler study, is associated with a p-value of 0.47, whereas inclusion of the Henschler study yields a p-value [is less than] 0.001, which leads to formal rejection of the statistical hypothesis that the four studies are homogeneous. Although debate surrounds the value of such testing as prerequisite to combing relative risks in meta-analyses, this case demonstrates its utility.

In contrast, because Wartenberg et al. (1) ignored the informative value of the exposure data and instead emphasized methodologic specificity, their approach might have obscured an association between TCE and renal cancer. An example of such concern is the growing evidence that renal effects of high- and low-dose TCE exposures are not strictly dose related. It is probable that, under some conditions, TCE is metabolized via glutathione-dependent pathways to yield a nephrotoxic metabolite, dichlorovinylcysteine (DCVC) (15,16). There is also evidence from animal studies that TCE does not cause renal cancer in the absence of toxic tubular injury (17). Moreover, studies of humans with renal cancer indicate that those with a history of high-dose TCE exposures also have a significantly greater frequency and level of proximal tubular damage than do those without such an exposure history (18,19).

Such findings suggest that if TCE induces renal cancer in humans, it does so at doses that also cause proximal tubular nephritis. They also suggest that toxic nephritis is necessary for TCE to cause renal cancer (15,17). It can be reasonably anticipated that TCE-related nephritis occurs only from exposures that exceed some threshold dose and that lower-dose exposures would not be expected to cause nephritis. Accordingly, combining subjects with high and not-so-high TCE exposures might conceal whatever statistical association linked TCE and cancer.

The subjects in the Henschler study (9) were likely exposed to very high levels of TCE for prolonged periods: "concentrations of 500 ppm were regularly achieved and exceeded in this situation" (17). If so, subjects were exposed to levels 10-20 times higher than those reported for subjects in the other cohort studies. Combining the subjects of those various studies would serve to minimize any underlying relationship between TCE and renal cancer, particularly if most of the other cohort subjects were exposed to levels below the threshold dose expected to cause nephritis.

Thus, for different but related reasons, the Wartenberg approach could either enhance a spurious association or obscure a meaningful one. In this case, the former seems to have occurred: inclusion of the Henschler study (9) has probably led to a spurious association. However, the more important and general issue concerns appropriate methods for performing meta-analysis. Meta-analyses that ignore important distinguishing features of individual studies, that emphasize statistical procedures over biologic and epidemiologic issues, and that disregard homogeneity of exposure are unlikely to resolve issues such as the human carcinogenicity of TCE.

REFERENCE AND NOTES

(1.) Wartenberg D, Reyner D, Siegel-Scott C. Trichloroethylena and cancer: Epidemiologic evidence. Environ Health Perspect 108(suppl 2):161-176 (2000).

(2.) Petitti DB. Meta-analysis, Decision Analysis, and Cost-effectiveness Analysis. New York:Oxford University Press, 1994;106-108.

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

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

(5.) 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).

(6.) Boice JD Jr., Marano DE, Fryzek JP, Sadler CJ, McLaughlin JK. Mortality among aircraft manufacturers workers. Occup Environ Med 56:581-597 (1999).

(7.) Morgan RW, Kelsh MA, Zhao K, Heringer S. Mortality of aerospace workers exposed to trichloroethylene. Epidemiology 9:424-431 (1998).

(8.) Ritz B. Cancer mortality among workers exposed to chemicals during uranium processing. J Occup Environ Med 41:556-566 (1999).

(9.) 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).

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

(11.) Rothman KJ. Keynote Presentation: A sobering start for the cluster busters' conference. Am J Epidemiol 132:6-13 (1990).

(12.) Fleming LE, Ducatman AM, Shalat SL. Disease clusters: a central and ongoing role in occupational health. J Occup Med 33:818-825 (1991).

(13.) Fleiss JL, Gross AJ. Meta-analysis in epidemiology, with special reference to studies of the association between exposure to environmental tobacco smoke and lung cancer: a critique. J Clin Epidemiol 44:127-139 (1991).

(14.) DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 7:177-188 (1986).

(15.) Goeptar AR, Commandeur JNM, van Ommen B, van Bladeren PJ, Vermeulen NPE. Metabolism and kinetics of trichloroethylene in relation to toxicity and carcinogenicity. Relevance of the mercapturic acid pathway. Chem Res Toxicol 8:3-21 (1995).

(16.) Birner G, Vamvakas S, Dekant W, Henschler D. Nephrotoxic and gentoxic N-acetyl-S-dichlorovinyl-L-cysteine is a urinary metabolite after occupational 1,1,2-trichloroethene exposure in humans: implications for the risk of trichloroethene exposure. Environ Health Perspect 99:281-284 (1993).

(17.) Bruning T, Bolt HM. Renal toxicity and carcinogenicity of trichloroethylene: key results, mechanisms, and controversies. Crit Rev Toxicol 30:253-285 (2000).

(18.) Bruning T, Mann H, Melzer H, Sundberg ACM, Bolt HM. Pathological excretion patterns of urinary proteins in renal cell cancer patients exposed to trichloroethylene. Occup Med 49:1-7 (1999).

(19.) Bruning T, Sundberg ACM, Birner G, Lammert M, Bolt HM, Appelkvist EE, Nilsson R, Dallner G. Glutathione transferase alpha as a marker for tubular damage after trichloroethylene exposure. Arch Toxicol 73:246--254 (1999).

Jonathan Borak Mark Russi John Paul Puglisi Yale University New Haven, Connecticut E-mail [e-mail]