Carcinogenicity of trichloroethylene. (Correspondence).

The possible carcinogenicity of trichloroethylene (TCE) remains a controversy. Over the past year the National Toxicology Program's Tenth Report on Carcinogens (1) reaffirmed the classification of TCE as "reasonably anticipated to be a human carcinogen." In a recent review (2), we summarized the results of published studies and concluded that the evidence suggested an association between TCE exposure and kidney and liver cancers, with somewhat weaker evidence of an association between TCE exposure and both Hodgkin's disease and non-Hodgkin's lymphoma. We pointed out that the data also suggested an association between TCE exposure and cervical cancer, although these data may have reflected exposure to tetrachloroethylene rather than to TCE because the observations of these cancers were mainly among dry cleaners. Others challenged our findings (3,4).

Two studies, an occupational cohort study by Hansen et al. (5) and a case-control study by Pesch and et al. (6), have appeared in the literature since the publication of our study (2); their findings provide further support for the carcinogenicity of TCE. The cohort study by Hansen et al. (5) is similar to two other studies identified in Tier I of our analysis (6,7); biomonitoring of urinary trichloroacetic acid was used to assess exposure to TCE. In Table 1 we present the standardized incidence ratios (SIRs) reported by Hansen et al. (5) for those cancers we identified as most likely associated with TCE exposure. Table 1 also includes recalculated average relative risks, which update the results of our previous review (2).

For kidney cancer, Hansen et al. (5) report a deficit of cases for males, an excess for females, and a slight decrement for both sexes combined. However, the relatively small number of cases does not affect the overall average relative risk in a substantial way. As noted by Hansen et al. (5), among others, the significance of the results hinge on the inclusion or exclusion of the study by Henschler et al. (11).

The report of five liver and biliary cancers and an elevated SIR in this newest study results in a larger and more precise estimate of the average risk. Our follow-up with Hansen revealed that the excess is largely due to the three cases of biliary cancer observed (10). Only two other studies reported on biliary cancer (7,12), and both reported an excess among TCE exposed workers: Anttila et al. (7), SIR = 1.6; 95% CI, 0.4-4.0; four cases; and Spirtas et al. (12): male; SMR = 2.4; 95% CI, 0.9-5.2; six cases. For liver cancer alone, the observation of Hansen et al. (5) is consistent with our previous study (2) and increases our concern that TCE may cause liver cancer.

A similar observation was seen for non-Hodgkin's lymphoma and cervical cancer. The inclusion of the findings of Hansen et al. (5) results in stronger and statistically significant average relative risks for each of these sites. Cervical cancer has a relatively high 5-year survival rate (> 67%) (13), particularly if diagnosed early, and suggests incidence as a more relevant end point. The studies reviewed, including that of Hansen et al. (5), show elevated incidence but not elevated mortality for this cancer, supporting the possible carcinogenicity of TCE. No cases of Hodgkin's disease were observed by Hansen et al. (5), and the average risk was largely unchanged.

The other notable finding in the study by Hansen et al. (5) is the elevated and statistically significant risk for esophageal cancer. Previous studies have not reported on the incidence of esophageal cancer, although the reported risks for esophageal cancer mortality are slightly elevated, particularly among dry cleaners.

A second European study also is consistent with a weak association between kidney cancer (specifically, renal cell carcinoma) and TCE exposure (6). In this multicenter case-control study with 935 incident cases, Pesch et al. (6) used a job exposure matrix and a job task exposure matrix to categorize exposure. Odds ratios were 1.1-1.3 for men and 0.8-1.8 for the smaller population of women.

In summary, we see the findings of Hansen et al. (5) and Pesch et al. (6) as providing additional support of our previous findings, which suggest that TCE exposure causes cancer in humans. Although alternative explanations, such as confounding and chance due to multiple comparisons, are possible explanations for this set of studies, as noted by Hansen et al. (5), we find it unlikely in light of the number of cases of cancer and sizes of the relative risks. Moreover, only a small number of subjects in the study by Hansen et al. (5) experienced TCE exposures at levels higher than the current permissible level (14), suggesting that excess cancer risks observed in this cohort study may be associated with low-level exposures to TCE.

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

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

Cheryl Siegel Scott
U.S. Environmental Protection Agency
Washington, DC
Table 1. Mean SIRs, 95% CIs, and number of observed
cases for selected cancer sites.

                            Hansen et al. (5)

Cancer
type                     Mean SIR (95%CI)   No.

Kidney cancer              0.9 (0.2-2.6)      3 M
                           2.4 (0.03-14)      1 F
Liver cancer               1.8              2 M (b)
                           0.1 Expected      F (b)
Liver/biliary cancer       2.6 (0.8-6.0)      5 M
                           0.4 Expected        F
Hodgkin's disease          0.5 Expected        M
                           0.1 Expected        F
Non-Hodgkin's lymphoma     3.5 (1.5-6.9)      8 M
                           0.3 Expected        F
Cervical cancer            3.8 (1.0-9.8)      4 F

                          Wartenberg et al (2)

Cancer
type                     Mean SIR (95%CI)   No.

Kidney cancer             1.7 (1.1-2.7)      21
Liver cancer              1.9 (1.0-3.4)      12
Liver/biliary cancer      1.1 (0.3-4.8)       4
Hodgkin's disease         1.5 (0.6-3.7)       4
                                --
Non-Hodgkin's lymphoma    1.5 (0.9-2.3)      22
                                --
Cervical cancer           2.4 (1.2-4.8)     8 F

                           New calculations (a)

Cancer
type                     Mean SIR (95%CI)   No.

Kidney cancer             1.6 (1.1-2.4)      25
Liver cancer              1.9 (1.1-3.2)      14
Liver/biliary cancer      2.0 (1.0-4.3)      9
Hodgkin's disease         1.5 (0.6-3.7)      4
Non-Hodgkin's lymphoma    1.9 (1.3-2.8)      30
Cervical cancer           2.7 (1.6-4.8)     12 F

Cancer
type                     Conclusions

Kidney cancer            Small change; still strongly suggestive
Liver cancer             New data provide additional support
Liver/biliary cancer     New data provide additional support
Hodgkin's disease        Small change; still suggestive overall
Non-Hodgkin's lymphoma   New data provide additional support
Cervical cancer          New data provide additional support

Abbreviations: CI, confidence interval; F, female; M, male.

(a) All average risks except those for kidney cancer are homogeneous
based on the Q-test for homogeneity (p > 0.2) (9).

(b) Data from Hansen (10).

REFERENCES AND NOTES

(1.) National Toxicology Program Report on Carcinogens: What is under consideration for the 10th RoC? Available: http://ntp-server.niehs.nih.gov/NewHomeRoc/ 10thConsideration.html [cited 12 December 2001].

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

(3.) Borak J, Russi M, Puglisi JP. Meta-analyses of TCE carcinogenicity [Letter]. Environ Health Perspect 108:A542-A543 (2000).

(4.) Boice JD Jr, McLaughlin JK. Errors in TCE analysis [Letter]. Environ Health Perspect 109:A108 (2001).

(5.) Hansen J, Raaschou-Nielsen O, Christensen JM, Johansen I, McLaughlin JK, Lipworth L, Blot WJ, Olsen JH. Cancer incidence among Danish workers exposed to trichloroethylene. J Occup Environ Med 43:133-139 (2001).

(6.) Pesch B, Haerting J, Ranft U, Klimpel A, Oelschlagel B, Schill W, MURC Study Group. Occupational risk factors for renal cell carcinoma: agent-specific results from a case-control study in Germany. Int J Epidemiol 29:1014-1024 (2000).

(7.) 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).

(8.) 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).

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

(10.) Hansen J. Personal communication.

(11.) 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).

(12.) Spirtas R, Stewart PA, Lee JS, Marano DE, Forbes CD, Grauman DJ, Pettigrew HM, Blair A, Hoover RN, Cohen JL Retrospective cohort mortality study of workers at an aircraft maintenance facility. I. Epidemiological results. Br J Ind Med 48:515-530 (1991).

(13.) Ries LAG, Kosary CL, Hankey BF, Miller BA, Harras A, Edwards BK, eds. SEER Cancer Statistics Review, 1973-1994. NIH Publication no. 97-2789. Bethesda, MD:National Cancer Institute, 1997. Available: http://seer.cancer.gov/Publications/CSR7394/ [cited 3 December 2001].

(14.) Raaschou-Nielsen O, Hansen J, Christensen JM, Blot WJ, McLaughlin JK, Olsen JH. Urinary concentrations of trichloroacetic acid in Danish workers exposed to trichloroethylene, 1947-1985. Am J Ind Med 39:320-327 (2001).