Send letter to journal:
Re: Re: TCE exposure and NHL - supportive evidence

(author response)

We appreciate the interest in our recent meta-analysis of occupational trichloroethylene (TCE) exposure and non-Hodgkin’s Lymphoma (NHL)(1). Three criticisms were mentioned as, “serious limitations”: 1) that the alternative descriptions of the Group I occupational cohort studies (multiple industry vs. aerospace, incidence vs. mortality and Europe vs. U.S. studies) should have been characterized and discussed a priori 2) that mortality and incidence data should not be combined in a meta-analysis, and 3) our interpretation that the epidemiologic data are not supportive of a causal relationship is wrong and it is suggested that our analysis provides more evidence of a causal effect between TCE exposure and NHL. These criticisms, however, are not serious limitations and have little relevance in interpreting the meta-analysis findings. We also disagree that our meta-analysis provides further support for a causal association.

The author would have preferred that we consider interpretation of potential sources of heterogeneity a priori. The evaluation of heterogeneity across individual studies is a critical component of any meta-analysis and has not been addressed in previous studies (2,3). We did consider different approaches to stratification a priori, but preferred to discuss the interpretation of this after we had analyzed these (and other) potential sources of heterogeneity. Prior to conducting a quantitative analysis of heterogeneity, interpretation of potential findings would be mere speculation.

With respect to combining incidence and mortality data, we agree that incidence data are generally preferable if available. In our meta- analysis of subgroups of studies, we stratified studies on this characteristic and, in fact, the analysis of mortality studies was more homogeneous (Table 2). More importantly, if TCE exposure were causally associated with NHL, we would expect both incidence and mortality rates to reflect this.

Finally, with respect to causal interpretation of the available data, it is our opinion that causal inference needs to be made based on a comprehensive evaluation of the data. Such an evaluation is not limited to the calculation of relative risk estimates and confidence intervals (or p-values), but also includes evaluation of exposure-response, consistency, and other factors, in addition to potential sources of bias (4,5). Results were inconsistent across the different groups of studies (e.g. considering Group I, Group II and the case-control studies), available data in the Group I studies did not indicate exposure response trends, there were significant limitations with respect to exposure classification across all studies, and there was variation in findings across subgroups within the Group I cohort studies. These observations considered together led us to conclude that epidemiologic data of occupational TCE exposure and NHL were not consistent with a causal association.

Jeffrey H. Mandel, MD, MPH Michael Kelsh, Ph.D. Pamela J. Mink, Ph.D. Dominik D. Alexander, Ph.D.

Exponent Health Sciences

Conflict of interest: The authors have consulted for a number of private and governmental clients on health issues related to occupational and environmental TCE exposure.

References: 1. Wartenberg D. TCE exposure and NHL-supportive evidence. OEM.bmjjournals.com/cgi/eletters/oem.2005.022418v1#349 2. Wartenberg D, Reyner D, Scott CS. Trichloroethylene and cancer: The epidemiologic evidence. Environ Health Perspect 2000;108 (suppl 2):161-76. 3. Wartenberg D, Scott CS. Carcinogenicity of trichloroethylene (Letter). Environ Health Perspect 2002;110:A13-A14. 4. Susser M. 1973. Causal Thinking in the Health Sciences: Concepts and Strategies in Epidemiology. New York: Oxford University Press. 5. Bradford Hill A. 1965. The environment and disease: association or causation? Proc R Soc Med 58:295-300.

Send letter to journal:
Re: TCE exposure and NHL - supportive evidence

Dear Editor,

Mandel and colleagues' article on trichloroethylene (TCE) exposure and non-Hodgkin's lymphoma (NHL) provides an interesting review of relevant studies although it has serious limitations (1).

First, there are three alternative descriptions of their stratification of Group 1 studies: population source (multiple industries vs. only aerospace), outcome (incidence vs. mortality) and location (European vs. US). It would have been helpful to specify a priori the interpretive advantages and disadvantages of each rather than focusing on population source.

Second, in their cohort analyses, they combine incidence and mortality data. Implicit are several unjustified assumptions including: (1) TCE exposure confers quantitatively similar risks for incidence and mortality; (2) temporal changes in risk occur equally in incidence and mortality; (3) because mortality lags incidence, TCE exposure must have been relatively constant in each study longitudinally, (even though technological improvements likely decreased exposure); and, (4) although they state, “The increases for NHL in the general population over the past several decades have been for both morbidity and mortality, (p.20)� SEER data show incidence increased more than mortality (Figure 1), especially in white males (Figure 2), resulting in a nearly two-thirds increase in percent surviving at least 5 years from 1960 to 1995 (from 31% to 51% in white males)(2).

Third, although the authors conclude that, "there is insufficient evidence to suggest a causal link between TCE and NHL"� (abstract) all 8 Group I studies showed elevated risks, with 2 statistically significant, and all 4 summary risk estimates were elevated with 3 statistically significant. Group I comparisons of highest and lowest, cumulative, and duration of, exposures show similar patterns. Group II data are less compelling, although the case control data show some support.

In summary, contrary to Mandel et al.'s conclusions, the results, which extend our work (3,4) provide increasing support for a causal relationship between TCE and NHL.

Daniel Wartenberg, PhD, Professor
Department of Environmental and Occupational Medicine
Robert Wood Johnson Medical School
170 Hoes Lane
Piscataway, NJ 08854
Tel: 732-445-0197
Fax: 732-445-0784
dew@eohsi.rutgers.edu

Competing interests: Dr. Wartenberg has provided testimony on behalf of plaintiffs in TCE litigation.

References

1. Mandel JH, Kelsh M, Mink PJ, Alexander DD , Kalmes R, eingart M et al. Occupational trichloroethylene exposure and non Hodgkin's lymphoma: A review and meta-analysis. Occup Environ Med 2006;doi:10.1136:1-35.

2. Ries, L. A. G., Harkins, D., Krapcho, M., Mariotto, A., Miller, B. A., Feuer, E. J., Clegg, L., Eisner, M. P., Horner, M. J., Howlader, N., Hayat, M., Hankey, B. F., and Edwards, B. K. SEER Cancer Statistics Review, 1975-2003. 2006. Bethesda, MD, National Cancer Institute (http://seer.cancer.gov/csr/1975_2003).

3. Wartenberg D, Reyner D, Scott CS. Trichloroethylene and cancer: The epidemiologic evidence. Environ Health Perspect 2000;108 (suppl 2):161-76.

4. Wartenberg D, Scott CS. Carcinogenicity of trichloroethylene (Letter). Environ Health Perspect 2002;110:A13-A14.

Figure 1: SEER annual incidence and mortality data

Figure 2: SEER annual incidence and mortality Data for white males only