Errors in TCE Analysis: Response.

We thank Boice and McLaughlin for their letter commenting on our paper (1). They raise three types of issues with respect to our reporting on their study: a) differences between our reports of specific SMRs and their original report; b) our report of no data for a cancer site for which they report no cases; and c) differences between our reported confidence intervals (CIs) for their standardized mortality ratios (SMRs) and the CIs originally reported. We consider each below.

The principal goal in our review was to identify, critique, and summarize the cancer epidemiology of trichloroethylene (TCE)-exposed populations in a more complete and systematic manner than that carried out previously (2-4) while making our review and averaging process as transparent as possible. We wanted to enable readers to understand our methodology and to be able to replicate our results or modify our assumptions and make similar calculations using our published tables (1,5). Therefore, we reported in our tables the data input into our SMR-averaging algorithm rather than copying the exact values published in each original study. We recognized at that time that there were small differences, particularly in the confidence intervals, but felt that the transparency of our approach was of greatest importance.

Our values for multiple myeloma and stomach cancer were incorrect because we had miscopied the SMRs from Boice et al.'s paper (6). Using the point estimates presented by Boice et al. (7) and recalculating the average SMRs, the average SMRs for the Tier I mortality studies change from 1.9 (95% CI, 1.0-3.7) to 1.0 (95% CI, 0.6-1.9) for multiple myeloma and from 1.1 (95% CI, 0.8-1.6) to 1.3 (95% CI, 0.9-1.7) for stomach cancer. For these two sites, the contribution of the Tier I mortality studies to our overall conclusions is quite minimal. In our review, we suggested that there is weak support for an association between TCE and multiple myeloma, and no evidence for an association between TCE and stomach cancer (1). These conclusions remain the same and are still valid in light of the results from the Tier I incidence studies and from the Tier II and Tier III studies. In their letter, Boice and McLaughlin also point out that the SMR for leukemia was 1.05 in contrast to that listed in Table 5 of our paper (1) as 1.0. Risks that we present in all tables in our paper are rounded, and the difference between the data reported by Boice et al. (6) and,our data is due to an unfortunate rounding error. Our calculation of the average SMR for leukemia for the Tier I mortality studies, however, uses the value 1.05. Hence, the average SMR that is in our published paper remains unchanged.

The second issue raised by Boice and McLaughlin is for cervical cancer mortality for which we report no information, whereas Boice et al. (6) originally reported 0 observed cases with a 95% CI of 0.0-5.5. This again reflects our desire for transparency. We calculated the average risk by combining the logarithm of the SMRs; because log (0) is undefined, we could not use these data in our calculation. The entry in our table reflects how we handled the data in our calculations rather than how the data were reported originally. This also did not affect our calculations.

The third issue raised by Boice and McLaughlin is about the CIs for several of the SMRs. In particular, they questioned why we recalculated the CIs. Although we recognize that exact CIs are superior to the recalculated ones on statistical grounds, it is not possible to directly determine the underlying variance, a number we needed for our average risk calculations. In most cases, the CIs we calculated differ only slightly from those in the published papers. For example, in their Table 5, Boice et al. (6) state that the lower confidence interval for breast cancer is 0.6; in our paper (1), we list it as 0.5. The reason that we recalculated the CIs is that to conduct the average risk calculation using the Mantel-Haenszel method, as reported in our paper (1), we needed to calculate the variance of the reported relative risk (RR):

[MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII]

where 1/var[ln([RR.sub.i])]

To do so, we used the reported CI using the following equations:

[MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII]

If the logarithm of the published upper and lower CIs were not symmetric around the In(RR) (due to rounding errors or alternative calculation algorithms), we needed to choose one for the calculations. Because some of the lower CIs were 0, and the ln(0) is undefined, we used the upper CI. For consistency, we always used the upper CI to calculate the variance. We then used this variance to recalculate the lower CI. We presented our recalculated values rather than the original values because these were input into the statistical averaging program. We believe that this approach is more forthright than reporting the investigators' published lower CI in our tables while using our recalculated lower CI in our average risk calculation. The procedure we used is described in our paper (1). We cited Rothman and Boice (7) for the above equations.

We apologize for the two typographic errors and hope that our discussion adequately explains why the other numbers did not exactly match the values originally published.

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

Daniel Wartenberg
Daniel Reyner
Environmental and Occupational Health
Sciences Institute
UMDNJ--Robert Wood Johnson
Medical School
Piscataway, New Jersey
E-mail: [e-mail]

Cheryl Siegel Scott
U.S. Environmental Protection Agency
Washington, D.C.

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.) IARC. Dry Cleaning, Some Chlorinated Solvents and Other Industrial Chemicals. IARC Monogr Eval Carcinog Risks Chem Hum 63 (1995).

(3.) Weiss NS. Cancer in relation to occupational exposure to trichloroethylene. Occup Environ Mad 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.) Wartenberg D, Reyner D, Scott CS. TCE meta-analyses: Wartenberg et al.'s response [Letter]. Environ Health Perspect 108:A543-A544 (2000).

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

(7.) Rothman KJ, Boice JD Jr. Epidemiologic Analysis with a Programmable Calculator. 2nd ed. Newton, MA: Epidemiology Resources, 1982.