Trichloroethylene and Occupational Kidney Cancer

Background

1. "Aside from genetic predisposition, risk factors associated with RCC [renal cell carcinoma] include cigarette smoking, obesity, hypertension, and the use of diuretics." [Chapter on "Tumors of the Kidney, Bladder, Ureters, and Renal Pelvis" in Goldman's Cecil Medicine, 24th Ed.]

2. "It's not clear what causes renal cell carcinoma. Doctors know that kidney cancer begins when some kidney cells acquire mutations in their DNA. The mutations tell the cells to grow and divide rapidly. The accumulating abnormal cells form a tumor that can extend beyond the kidney. Some cells can break off and spread (metastasize) to distant parts of the body." Mayo Clinic website on "Kidney cancer"

3. "Renal cell cancer is not generally considered an occupationally associated tumor. . . . Considerable interest has recently been focused on the solvent trichloroethylene (TCE), largely as a result of bioassay findings in animals and of three studies conducted in the same area of Germany, which were initiated in response to clusters of renal cell cancer cases and which reported strikingly elevated relative risks for renal cell cancer associated with TCE exposure. These findings contrast starkly with results from other investigations, and several serious methodological shortcomings of these studies have been noted. . . . Thus, the weight of the evidence to date provides little credible support for the hypothesis that TCE cause renal cell cancer in humans." [Chapter on "Renal Cancer" in Cancer Epidemiology and Prevention, 3rd Ed.]

4. "What are the risk factors for kidney cancer?" Many studies have suggested that workplace exposure to certain substances increases the risk for renal cell carcinoma. Some of these substances are asbestos, cadmium (a type of metal), some herbicides, benzene, and organic solvents, particularly trichloroethylene." American Cancer Society

5. ATSDR published a monograph on "Trichloroethylene Toxicity" in 1992 as one of a series of "Case Studies in Environmental Medicine." The authors write, "Until 1977, when certain uses were banned, TCE was employed as an inexpensive, nonflammable, and self-administered obstetrical anesthetic (Tri-lene). It was discovered that alkali in rebreathing systems could lead to the production of dichloroacetylene, which produced cranial nerve injuries." The monograph lists renal effects as, "TCE-induced renal failure in humans has been reported." Renal cancer is not mentioned, but the report notes that regarding carcinogenic effects, "Some inconsistencies between results of animal and human studies may be due to metabolic saturation and formation of reactive intermediates that occur in animals exposed to high TCE levels but not in humans after lo-level exposure." The monograph was updated in 2007, and is available as a course on the ATSDR website at http://www.atsdr.cdc.gov/csem/tce/docs/tce.pdf. Nephrotoxicity and kidney cancer are both mentioned in the updated monograph. Regarding kidney injury, the authors cite the 1993 paper by Selden, Hultberg et al, "Another study of a small group of male metal degreasers in Sweden observed no increase in N-acetyl-β-glucosamineidase (NAG) excretion into urine, and concluded that TCE was not nephrotoxic at low exposures levels (Selden, Hultberg et al. 1993)."

6. The ACGIH TLV of 10 ppm was last revised in 2007. The TLV ranged from 150 to 200 ppm from 1948 until 1993 and was reduced to 50 ppm in 1993. The ACGIH committee in Documentation of TLVs and BEIs concludes that, "Extensive epidemiologic cohort studies of TCE-exposed workers do not indicate significant increases in cancer incidence, but case-control studies suggest that prolonged exposure to high concentrations of TCE (hundreds to thousands of ppm) can increase the incidence of renal cancer." [Highlighting emphasis is mine.]

What extent/how many years of exposure to TCE are necessary to develop kidney cancer? 

1. In the 2012 paper in Lancet that announced the classification change of TCE by IARC, the authors use the phrase, "high cumulative exposure." 

2. In the 2003 Green et al. paper is the statement:
   "As in the rat studies, kidney toxicity is believed to be a prerequisite for the development of renal cancer in humans following exposure to trichloroethylene."

3. The "Conclusion" in the Green et al. paper is:
   "Although there was no evidence of kidney toxicity within the population studied, the results suggest that kidney damage could occur at exposure concentrations higher (>250 ppm) than those encountered in this study."

4. The current ACGIH TLV is 10 ppm (54 mg/m3), and the OSHA PEL is 100 ppm.

5. In the 2013 Hansen et al. paper on the Nordic Cohort Studies, the authors mention the IARC decision in 2012 to link TCE to occupational kidney cancer. In explaining why their study found no association between TCE and kidney cancer, the authors write:
   "Duration of exposure, as well as exposure levels of TCE, have in general been relatively low in Finland, Sweden, and Denmark, and if TCE is a risk factor for kidney cancer only at extremely high levels of TCE-exposure, this may explain in part our overall null finding for this cancer."
   "No increased risk of kidney cancer was observed in any country either among men or women; the pooled standardized incidence ratio was 1.01 (95% CI=1.32 to 3.75) based on 32 cases."
   "For kidney cancer, we observed a hazard rate ratio of 2.04 (95% CI =0.81 to 5.17) in the highest category and hazard rate ratios roughly about 1 for levels below."
   For the above, note that the highest category was >50 mg/L of the urinary metabolite trichloroacetic acid (U-TCA). ACGIH uses the same urinary metabolite as a BEI (biological exposure index) for occupational exposure to TCE. The BEI (measured at end of shift at end of workweek) is 15 mg/L. This corresponds to the air level (TLV) of 10 ppm, and the worker is considered to be safe on a chronic basis if his BEI or TLV remain below these threshold levels.

6. In a 1993 paper, Selden et al. studied metal degreasers in central Sweden. Eighty-six percent of 8-hour TCE levels in air were well below 50 mg/m3. The authors conclude:
   "TRI [TCE] does not seem to be nephrotoxic at low exposure levels."

7. In the discussion section of their 2012 paper "Occupational trichloroethylene exposure and kidney cancer risk: a meta-analysis," Karami et al. write:
   "Kidney toxicity following exposure to TCE is postulated to be a prerequisite for the development of renal cancer in humans. Although TCE exposure has been shown to be related to nephrotoxicity in animal studies, human nephrotoxicity has only been observed at high exposure levels (>35 ppm)."

8. In the conclusion of their 2006 paper "Case-Control Study on Renal Cell Cancer and Occupational Exposure to Trichloroethylene. Part II: Epidemiological Aspects," Fevotte et al. write:
   "This study suggests an association between exposures to high levels of TCE and increased risk of RCC. Further epidemiological studies are necessary to analyze the effect of lower levels of exposure."

Is there a latency period between exposure and disease development?

1. There is this general statement from Cancer Epidemiology and Prevention:
   "There may be considerable variation among patients with respect to the time required for progression to invasive cancer. For instance, reports suggest that progression of precursor lesions of the pancreas may require many years--29 years in one case. Progression of colonic adenomas to carcinoma has been estimated to require 10-15 years. . . . The rate of progression varies with the extent to which the cellular and architectural changes in the precursor lesion resemble those of the corresponding invasive cancer; such host factors as age, sex, ethnicity, and hormonal status; and the extent of genetic changes." (Chapter on "Cancer Precursors" in Cancer Epidemiology and Prevention, 3rd Ed.)

2. There is this statement from Hansen et al. 2013 paper on the Nordic Cohort Studies:
   "To include latency periods, exposure follow-up was delayed by 10 and 20 years from date of first known measurements of U-TCA."

What type of jobs or labor categories would be most involved?

1. In the 2012 paper in Lancet that announced the classification change of TCE by IARC , the uses and exposures of TCE are listed as, "chemical intermediate; metal degreasing."

2. In the 2013 paper by Vlaanderen et al., the authors write:
   "TCE was used extensively form the early 1920s through to the 1970s, mainly as a degreasing agent in metal fabricating operations. . . . After the 1970s, the use of TCE decreased because of environmental concerns. Occupational exposures probably also decreased due to better release controls and improvements in worker protection."

3. The updated "ATSDR Case Studies in Environmental Medicine" on "Trichloroethylene Toxicity" lists the following occupations as having increased likelihood of exposure: dry cleaners, mechanics, oil processors, printers, resin workers, rubber cementers, shoemakers, textile and fabric cleaners, varnish workers, and workers reducing nicotine in tobacco.

4. In a 2007 paper about the use of trichloroethylene in U.S. industry, Bakke, Stewart, and Waters write:
   "Historical occupational exposures occurred mainly through degreasing operations but also through dry cleaning, textile scouring, and in handling adhesives, drugs, paints, leather, and other products. Exposure concentrations across industries and decades were generally below the current threshold limit value (TLV) of 50 ppm, with an AM of the measurements across all industries and decades of about 38 ppm." 

5. In a 2001 paper examining 2397 TCA measurements made in Danish workers exposed to TCE from 1947-1985, Raaschou-Nielsen et al. note:
   "The regression analyses showed that (1) a four-fold decrease in TCA concentrations occurred from 1947 to 1985; (2) the highest concentrations were observed in the iron and metal and dry cleaning industries; (3) TCA levels were two times higher among men compared with women in the iron and metal and dry cleaning industries;"

What level of exposure to TCE occurred in the industrial processes of degreasing?

1. In Recognition of Health Hazards in Industry, William Burgess describes the main two types as cold degreasing and vapor-phase degreasing. 
   "Data on the exposures of vapor degreaser operators is meager. The earliest full shift data is shown in Table 5.6 (Hickey, 1977). Shipman and Whim (1980) have presented extensive data on 57 open-top vapor degreasers operating with trichloroethylene in the United Kingdom. Extended personal air samples revealed that in 95% of the samples the TWA was less than 50 ppm and in 86% it was less than 30 ppm. A study of full-shift exposures of 29 Swedish vapor degreaser operators to trichloroethylene over one week showed a median personal air sample concentration of 16 mg/m3 with a range of measurements of 3-144 mg/m3 (Ulander et al., 1992)."

2. In their 2007 paper, Bakke, Stewart, and Waters provide Table II "Trichloroethylene Exposure Measurements by Industry" and note on page 385:
   "Reported personal and area air levels of TCE from degreasing operations were substantial compared with the TLV (e.g., the range of reported AMs in  vapor degreasing operations was 1-566 ppm [median = 43], Table II)."

3. In their 2006 paper on "Case-Control Study on Renal Cell Cancer and Occupational Exposure to Trichloroethylene. Part I: Exposure Assessment," Fevotte et al. describe basic levels of exposure for several types of degreasing:

References

1. 2013. Hansen J. Risk of cancer among workers exposed to trichloroethylene: analysis of three Nordic cohort studies.

2. 2013. Vlaanderen J. Occupational exposure to trichloroethylene and perchloroethylene and the risk of lymphoma, liver, and kidney cancer in four Nordic countries.

3. 2012. IARC. Carcinogenicity of trichloroethylene, tetrachloroethylene, some other chlorinated solvents, and their metabolites.

4. 2012. Karami S. Occupational trichloroethylene exposure and kidney cancer risk: a meta-analysis.

5. 2012. Vermeulen R. Elevated urinary levels of kidney injury molecule-1 among Chinese factory workers exposed to trichloroethylene.

6. 2011. Fontanilla J. Kidney injury molecule-1 as an early detection tool for acute kidney injury and other kidney diseases.

7. 2011. Scott CS. Trichloroethylene and cancer: systematic and quantitative review of epidemiologic evidence for identifying hazards.

8. 2010. Moore LE. Occupational trichloroethylene exposure and renal carcinoma risk: evidence of genetic susceptibility by reductive metabolism gene variants.

9. 2007. Bakke B. Uses of and exposure to trichloroethylene in U.S. industry: a systematic literature review.

10. 2006. Fevotte J. Case-control study on renal cell cancer and occupational exposure to trichloroethylene. Part I: Exposure assessment.

11. 2006. Fevotte J. Case-control study on renal cell cancer and occupational exposure to trichloroethylene. Part II: Epidemiological aspects.

12. 2006. Boice JD Jr. Mortality among Rocketdyne workers who tested rocket engines, 1948-1999.

13. 2005. Zhao Y. Estimated effects of solvents and mineral oils on cancer incidence and mortality in a cohort of aerospace workers.

14. 2003. Green T. Biological monitoring of kidney function among workers occupationally exposed to trichloroethylene.

15. 2001. Raaschou-Nielsen O.Urinary concentrations of trichloroacetic acid in Danish workers exposed to trichloroethylene, 1947-1985.

16. 1993. Selden A. Trichloroethylene exposure in vapour degreasing and the urinary excretion of N-acetyl-beta-D-glucosaminidase.

17. 1989. Nagaya T. Urinary total protein and beta-2-microglobulin in workers exposed to trichloroethylene.

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