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HOME > Ann Occup Environ Med > Volume 26; 2014 > Article
Review The Relationship between the Occupational Exposure of Trichloroethylene and Kidney Cancer
Inah Kim1,2, Jaehyeok Ha3, June-Hee Lee1,2, Kye-mook Yoo4, Jaehoon Rho1,2,5
Annals of Occupational and Environmental Medicine 2014;26:12.
DOI: https://doi.org/10.1186/2052-4374-26-12
Published online: June 3, 2014

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• Received: May 15, 2014   • Accepted: May 21, 2014

Copyright © 2014 Kim et al.; licensee BioMed Central Ltd.

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  • Trichloroethylene (TCE) has been widely used as a degreasing agent in many manufacturing industries. Recently, the International Agency for Research on Cancer presented “sufficient evidence” for the causal relationship between TCE and kidney cancer. The aim of this study was to review the epidemiologic evidences regarding the relationship between TCE exposure and kidney cancer in Korean work environments. The results from the cohort studies were inconsistent, but according to the meta-analysis and case–control studies, an increased risk for kidney cancer was present in the exposure group and the dose–response relationship could be identified using various measures of exposure. In Korea, TCE is a commonly used chemical for cleaning or degreasing processes by various manufacturers; average exposure levels of TCE vary widely. When occupational physicians evaluate work-relatedness kidney cancers, they must consider past exposure levels, which could be very high (>100 ppm in some cases) and associated with jobs, such as plating, cleaning, or degreasing. The exposure levels at a manual job could be higher than an automated job. The peak level of TCE could also be considered an important exposure-related variable due to the possibility of carcinogenesis associated with high TCE doses. This review could be a comprehensive reference for assessing work-related TCE exposure and kidney cancer in Korea.
  • Keywords: Trichloroethylene; Kidney cancer; Korea; Work-related; Occupation; Exposure
Trichloroethylene (TCE) has been widely used as a degreasing agent in many manufacturing industries (i.e., metal processing or electronic device production) due to its lipid solubility, volatility, no flammability, and economic efficiency [1]. TCE is a well-known carcinogen according to animal studies. The reactive metabolites of the glutathione pathway and the oxidation process of TCE could have carcinogenic effects in kidney and liver or lung, respectively [2].
Recently, the International Agency for Research on Cancer (IARC) categorized TCE as a Group 1 carcinogen and stated that there is “sufficient evidence” for the causal relationship between TCE and kidney cancer [3]. According to increasing epidemiologic evidences, the first work-related case of kidney cancer in Korea was reported in 2013 [4]. TCE is still widely used as degreasing or cleansing agents and high exposure levels of TCE could be prevalent in Korea. Moreover, the prevalence or incidence of target cancers associated with TCE (i.e., kidney cancer) has rapidly increased in the Korean population [5].
The aim of this study was to review the epidemiologic evidences regarding the relationship between TCE exposure and kidney cancer in the working population in Korea.
Incidence and risk factors of kidney cancer
According to the national cancer statistics, the age-standardized incidence rate of kidney cancer per 100,000 persons increased from 3.1 in 1999 to 3.5, 4.9, 5.4, 7.3, and 8.0 in 2002, 2005, 2006, 2010, and 2011, respectively. Kidney cancer had the third most rapid increase (6.2%), following thyroid (23.7%) and prostate (13.5%) cancers; but the incidence of esophageal, stomach, laryngeal, and cervical cancers decreased from 1999 to 2011. The annual percentage change over time, expressed as (exp(b) - 1) × 100, where b was the estimated slope of a linear regression from a logarithmic scaled age-standardized incidence rate and calendar year, was statistically significant in both genders. In 2011, the crude incidence rate of kidney cancer per 100,000 men was 10.9 (2,722 cases), which was the 9th most common cancer among Korean men, following cancers of the stomach, colon or rectum, lung, liver, prostate, thyroid, bladder, and pancreas (Table  1). The incidence of kidney cancer increased with age, but the incidence was found to be the highest for people ≥70 years, which was 44.5/100,000 for men and 16.5/100,000 for women (Table  2) [5]. The subtypes of renal cell cancer (RCC) were divided into the clear cell type, papillary type, chromophobe type, and collecting duct type. Currently, there is limited evidence to indicate that occupational risk factors increase RCCs of a specific subtype.
Table 1
Crude incidence rate (CR) and age-standardized incidence rate (ASR) of kidney cancer per 100,000 persons from 1999 to 2011 in Korea
 
 Total
 Men
 Women
  CR ASR CR ASR CR ASR
1999
 3.0
 3.1
 4.1
 4.7
 1.9
 1.7
2000
 3.0
 3.0
 4.1
 4.6
 1.9
 1.8
2001
 3.5
 3.4
 4.7
 5.1
 2.2
 2.0
2002
 3.6
 3.5
 5.0
 5.2
 2.3
 2.1
2003
 3.9
 3.6
 5.3
 5.4
 2.5
 2.2
2004
 4.3
 3.9
 5.8
 5.7
 2.8
 2.4
2005
 4.9
 4.2
 6.6
 6.3
 3.1
 2.5
2006
 5.4
 4.6
 7.4
 6.8
 3.5
 2.7
2007
 6.0
 5.0
 8.3
 7.4
 3.7
 2.9
2008
 6.6
 5.2
 9.0
 7.8
 4.1
 3.1
2009
 7.0
 5.5
 9.4
 7.9
 4.5
 3.3
2010
 7.3
 5.5
 10.1
 8.3
 4.3
 3.1
2011
 8.0
 6.2
 10.9
 8.6
 5.1
 3.6
APC*   6.2 (p<0.05)   5.9 (p<0.05)   6.3 (p<0.05)
*APC; Annual Percentage Change, expressed as (exp(b)-1)×100, where b is the estimated slope of a linear regression from a logarithmic scaled age-standardized rates and calendar years.
Table 2
Trends in kidney cancer incidence rates in Korea (per 100,000 persons)
 
 Men
 Women
Age (years) 2002 2003 2004 2005 2009 2010 2011 2002 2003 2004 2005 2009 2010 2011
0–9
 0.6
 0.6
 0.7
 0.6
 0.8
 0.9
 0.8
 0.8
 0.5
 0.5
 0.6
 0.6
 0.7
 0.7
10–19
 0.0
 0.1
 0.3
 0.1
 0.1
 0.1
 0.1
 0.0
 0.1
 0.0
 0.1
 0.1
 0.1
 0.2
20–29
 0.4
 0.4
 0.4
 0.6
 0.8
 0.7
 0.7
 0.4
 0.3
 0.3
 0.3
 0.6
 0.3
 0.6
30–39
 1.9
 2.0
 2.1
 2.2
 3.8
 3.9
 4.3
 0.9
 1.2
 1.1
 1.0
 1.3
 1.7
 2.1
40–49
 5.4
 6.7
 6.5
 7.1
 9.4
 9.8
 10.3
 1.9
 3.0
 3.0
 2.5
 4.1
 3.7
 4.0
50–59
 13.7
 13.0
 12.4
 15.0
 18.4
 20.5
 21.1
 5.3
 4.3
 6.3
 5.6
 8.1
 7.7
 8.5
60–69
 22.7
 23.2
 24.7
 24.5
 31.8
 33.1
 33.6
 8.1
 8.9
 8.1
 10.1
 12.8
 12.3
 13.5
≥70 26.2 25.4 32.4 36.5 42.2 41.5 44.5 9.6 9.5 9.8 13.0 15.3 13.6 16.5
The risk factors for RCC include smoking, obesity, a past history of renal stones [6], and the presence of a genetic mutation known as Von Hippel-Lindau syndrome, which is present in 1/3~1/2 patients [7]. Various metals (i.e., arsenics, cadmium, lead, or uranium), poly-aromatic hydrocarbons, solvents (i.e., chlorinated hydrocarbons), and asbestos have been considered as occupational risk factors for RCC in several studies [8]. According to the IARC, TCE has sufficient evidence while arsenic and inorganic arsenic compounds, cadmium and its compounds, and printing processes have limited evidences for kidney cancer in humans [8].
Occupational exposure of trichloroethylene in Korea

Work environment survey in manufacturers in 2004

According to work environment survey for manufacturers, the annual amount of TCE usage was 7849 tons; 1982.4 tons by manufacturers of motor vehicles, trailers and semitrailers, 1085.9 tons by manufacturers of fabricated metal products, except machinery and furniture, 1056.4 tons by manufacturers of electric components, computer, radio, television, and communication equipment and apparatuses, and 483.8 tons by manufacturers of machinery and equipment. TCE was mostly used as a cleaning agent. About 5,949 workers in 1,540 companies could have been exposed to TCE during production processes in 2004 [9].

A survey on the status of using trichloroethylene

After 2 employees had died from Steven Johns syndrome related to TCE exposure in 2006, a survey on the distribution and usage of TCE was conducted using a database to work environment monitoring of the representative 103 companies. TCE was mostly used by manufacturers of motor vehicle and engine parts and accessories (23,920 L). The personal ambient exposure levels in this survey ranged from non-detectable (ND) to 49.87 ppm. The range of ambient exposure level of TCE was ND~49.87 ppm in manufacturers of motor vehicle and engine parts and accessories, 0.08~41.55 ppm in manufacturers of electric components, computer, radio, television, and communication equipment and apparatuses, and ND~30.80 ppm in manufacturers of fabricated metal products, except machinery and furniture (Table  3). Workers engaging in manual tasks or semi-automated processes were more frequently exposed to TCE than those who worked with automated processes (87% vs. 13%) [10].
Table 3
Exposure status according to trichloroethylene use in 2006 in Korea
Type of industry No. of factories No. of workers Amount used (L/month) Concentration range (ppm)
Total
 103
 390
 87,320
 -
Chemical
 3
 19
 4,116
 0.97~13.26
Plastics & rubber products
 1
 35
 6,830
 ND~42.63
Primary metal
 6
 18
 6,787
 2.91~37.35
Fabricated metal products
 24
 59
 11,990
 ND~30.80
Machinery
 18
 59
 3,950
 ND~48.48
Computer & electronic products
 9
 62
 19,596
 0.08~41.55
Electrical equipment, appliance
 10
 56
 4,771
 ND~21.29
Transportation equipment
 18
 30
 23,920
 ND~49.87
Others 14 52 5,360 ND~39.51
ND; Non-detectable, concentration level was lower than the detection limit.
(Source: Cho et al. 2007) [10].

Work environment monitoring

The analysis of ambient exposure levels (time weighted average (TWA) from 8 hours) of TCE from the work environment monitoring (WEM) in the manufacturing industries conducted by private occupational health organizations during 2002–2010 is shown in Table  4. A total of 33,652 samples were analyzed and we re-classified the task categories to 22 from 537. The range of the geometric mean (GM) was 0.00015~0.25311 ppm. The exposure level of TCE was highest during plating (0.25311 ppm), followed by cleaning (0.16013 ppm) and degreasing (0.04185 ppm). The highest exposure level of TCE by personal sampler was 598 ppm for cleaning, followed by 237 ppm for assembly, 154 ppm for coating, 152 ppm for degreasing, and 148 ppm for painting. The median exposure levels of TCE were 3.18 ppm, 2.33 ppm, and 2.01 ppm for plating, cleaning, and degreasing, respectively. As a result, cleaning, degreasing, and plating could be high-risk jobs for TCE exposure.
Table 4
Exposure levels of trichloroethylene by Korean manufacturing industry jobs according to the regular work environment measurement (2002~2010)
Job No. of samples Arithmetic mean (ppm) Median (ppm) Geometric mean (ppm) Maximum (ppm)
Cleaning
 8,374
 8.953
 2.33495
 0.16013
 598
Degreasing
 421
 7.780
 2.01080
 0.04185
 152
Assembly
 1,146
 2.850
 0.08975
 0.00101
 237
Adhesion
 700
 1.044
 0.16850
 0.00172
 29
Coating
 671
 3.250
 0.48790
 0.01499
 154
Painting
 3,713
 1.326
 0.00000
 0.00015
 148
Processing
 1,046
 3.955
 0.41855
 0.01159
 108
Inspection
 890
 2.704
 0.59650
 0.01061
 94
Printing
 1,519
 1.948
 0.17800
 0.00518
 65
Soldering
 802
 2.053
 0.42860
 0.00881
 50
Plating
 399
 8.508
 3.17970
 0.25311
 63
Molding
 507
 4.545
 0.71700
 0.01194
 60
Laboratory
 317
 0.692
 0.00000
 0.00006
 48
Impregnation
 199
 7.697
 0.18200
 0.00839
 185
Mixing
 511
 1.807
 0.09700
 0.00111
 54
Heat treatment
 201
 4.982
 1.00000
 0.01987
 64
Plugging
 34
 0.565
 0.08136
 0.00063
 8
Infusion
 267
 5.846
 0.40630
 0.01467
 270
Reaction
 138
 0.461
 0.00000
 0.00005
 6
Packing
 273
 2.128
 0.27600
 0.00597
 45
Cast
 124
 2.601
 0.04165
 0.00060
 43
Others
 11,400
 9.318
 0.27935
 0.00540
 1,471
Total 33,652 6.497 0.40790 0.00840 –

Reliability of work environment monitoring

Considering the limitation of the reliability or validity of WEM, we analyzed reports from 16 enterprises, which were assessed for the reliability of WEM by the Korea Agency for Occupational Safety and Health for cleaning jobs, which were the most common jobs in 2006. The highest level of TCE exposure was 116.62 ppm in manufacturers of non-metallic mineral products (i.e., press and cleaning), followed by manual cleaning for optic device production (114.41 ppm), degreasing for rubber goods production (88.84 ppm), and cleaning for transport machineries and equipment production (49.86 ppm; Table  5).
Table 5
Exposure levels of cleaning or degreasing jobs using assessment of reliability of work environment monitoring in 2006 in Korea
Industry in manufacturer Job1 Job2 Method Range of concentration (ppm)
Electronic components (LCD panel frame)
 Press
 Processing & cleaning
 Solid sampler. NIOSH method 1022
 8.258~11.995
Power electric equipment (painting transformers)
 Storing component & cleaning
 Printing & cleaning
 Solid sampler. NIOSH method 1022
 Painting and cleaning: 0.343~9.742 masking: 1.099~16.432, touch up: 0.149~2.462
Measuring, optic and precision instrument
 Press & cleaning
 Grinding & cleaning
 Solid sampler. diffusive sample
 16.99~114.41 (including manual work)
Television and communication equipment
 Press molding & processing
 Assembly & cleaning
 Solid sampler. NIOSH method 1022
 85.44 in manual (closed 1 years ago), 2.16~3.75 in automatic
Optic equipment and lens
 Cutting
 Cleaning
 Solid sampler. NIOSH method 1022
 52.90 (in indoor)
Parts and accessories for motor vehicle
 Assembly & dipping
 Bonding & cleaning
 Sorbent tube
 11.57~18.52
Electronic components
 Press
 Cleaning
 Sorbent tube
 31.72~49.86
Textile
 Degummed and twist thread
 Decontamination
 Sorbent tube
 0.14~1.38
Plating
 1st cleaning
 2nd cleaning
 Sorbent tube
 1st cleaning: 28.59, 3.55
 
 2nd cleaning: 39.28, 1.81
Metal tooling
 Press
 Cleaning
 Solid sampler. NIOSH method 1022
 8.75~9.22
Parts and accessories for motor vehicle
 Mixing & surface treatment
 Degreasing
 KOSHA CODE-A-1-2004 (Method No. 016)
 2.56
Other electric equipment
 Wring & dipping
 Assembly & impregnation
 KOSHA CODE-A-1-2004 (Method No. 016)
 0.03~0.05
Rubber goods production
 Preparation
 Degreasing
 KOSHA CODE-A-1-2004 (Method No. 016)
 15.49~88.84
Other metal product
 Press and spot welding
 Cleaning
 KOSHA CODE-A-1-2004 (Method No. 016)
 7.21~11.7
Transport machineries and equipment
 Press and spot welding
 Cleaning
 KOSHA CODE-A-1-2004 (Method No. 016)
 14.90~49.83
Non-metallic mineral product Melting & extrusion Press & cleaning KOSHA CODE-A-1-2004 (Method No. 016) 41.32~116.62

Peer-reviewed and published papers in Korea

According to peer-reviewed and published papers in Korea, the exposure level of TCE in the period from 1970s’ to 1980s’ was higher than that in recent periods. Paik et al. reported that the exposure levels of TCE in 1970, were 110 ppm in the corners of the cleaning room, 124 ppm in regions where cleaning is initiated, and 221~301 ppm in regions where cleaning is terminated [11]. Kim et al. also reported that the exposure levels of TCE during the plating process in 1989: 19.8~50.3 ppm in the cleaning bath and 130.8~456.2 ppm in the drying bath [12]. The personal ambient exposure level of TCE for manual cleaning workers was 83.5 ppm and the regional ambient exposure level of TCE for manual polishing workers was 35.5 in 1989. At that time, the percentage of enterprises with ambient exposure levels higher than the occupational exposure limit set by the government (i.e., 75 ppm) was 54.2% in 1989 [13]. The GM of the 8 hours’ TWA for degreasing workers was 26 ppm and the range of the exposure level was 1.4~123 ppm. The GM of the 8 hours’ TWA for workers who assisted with cleaning was 11 ppm (range = 0.5~59 ppm) in 1994 [14]. In 1994, the GM of the 8 hours’ time weighted exposure level of workers using TCE was 9.9~35.3 ppm; 14.2% of workers had exposure levels above the occupational exposure limit set by the government [15]. The exposure level of workers who engaged in semi-automated cleaning was <1 ppm in 1995, but the peak exposure level of TCE (100 ppm) occurred during the replacement of the TCE solution, which was performed once per week. However, the ambient exposure level of TCE for manual cleaning workers was 107 ppm [16].
Scientific evidences for the causal relationship between trichloroethylene exposure and kidney cancer

Meta-analysis

The first meta-analysis was reported in 2011 and included 24 cohort and case–control studies; in the TCE exposed group, the relative risk (RR) was 1.27 and the 95% confidence interval (CI) was 1.13~1.43. The RR of higher exposure group was 1.58 (95% CI = 1.28~1.96) and the strength of association increased in the higher exposure group compared to the lower exposure group [17]. The second meta-analysis, which included 15 cohort and 13 case–control studies, was conducted during 1950~2011 and was published in 2012. In the second analysis, the RR for kidney cancer from the cohort studies, case-controlled studies, and the pooled RR of all studies was 1.26 (95% CI = 1.02~1.56), 1.35 (95% CI = 1.17~1.57), and 1.32 (95% CI = 1.17~1.50), respectively. The authors of this study concluded that significant and strong associations were consistent among the studies to measure exposure levels and also emphasized the possibility of underestimating risk due to the misclassification of exposure (i.e., exposure to TCE was usually broadly measured with exposure to chlorinated hydrocarbon or other organic solvents) [18]. This was a reasonable conclusion considering that differences in carcinogenicity among halogenated hydrocarbons; unsaturated short-chain halogenated hydrocarbons were identified to have carcinogenic effects in animal studies. TCE, an unsaturated short-chain hydrocarbon, has carcinogenic effects, but trichloroethane, which is similar to TCE in chemical structure, is saturated and is not carcinogenic [19].

Cohort studies

Most studies regarding the association between TCE exposure and kidney cancer were conducted in aerospace workers in the United States and Demark by measuring their exposure level using a job-exposure matrix (JEM) based on the job name or code. Zhao et al. reported a significant RR (4.90, 95% CI = 1.23~19.60) of incidence in only the high exposure group, which consisted of 5,049 male aerospace workers who work for >2 years during 1950~1993 and were followed during 1988~2000 [20]. In manual workers who worked >5 years and used TCE in Denmark, the RR was 1.5 (95% CI = 1.1~2.2) [21]. Although the RRs in the early cohort study [22] and other subgroups in the same cohorts were statistically insignificant, the dose–response relationship between the risk for kidney cancer and TCE exposure was also identified (Table  6) [20-23].
Table 6
Summary of risk measurement of the major cohort and case–control studies
Authors, (years) country Study subjects/design Exposure measurement Overall OR or RR ORs or RRs according to exposure level
Moore et al. (2010) [24] Czech Republic, Poland, Romania, Russia
 Hospitals in 4 European countries (n = 1,097), 1999–2003; hospital controls with diagnoses unrelated to smoking or genitourinary disorders (n = 1,476)/case–control
 Specialized job-specific questionnaire for specific jobs or industries of interest focused on TCE with exposure assignment by frequency and confidence of TCE exposure
 1.63 (1.04–2.54) for all subjects 2.05 (1.13–3.73) for high-confidence assessments only
 Duration
<13.5 yrs: 1.89 (0.84–4.28)
≥13.5 yrs: 2.25 (0.95–5.29)
<1080 hrs: 1.22 (0.48–3.12)
≥1080 hrs: 2.86 (1.31–6.23)
Cumulative
<1.58 ppm·yr: 1.77 (0.64–4.80)
≥1.58 ppm·yr: 2.23 (1.07–4.64)
Average intensity
<0.076 ppm: 1.73 (0.75–4.02)
≥0.076 ppm: 2.41 (1.05–5.56)
*reference group: non-exposed
Chabotel et al. (2006) [25] France
 RCC (n = 87), from urologists’ files and area teaching hospitals, 1993–2003; urologist or general practitioner patient controls (n = 316)/case–control
 Semi-quantitative cumulative TCE exposure and presence/absence of peak TCE exposure assigned to subjects using a JEM designed using information obtained from questionnaires and routine atmospheric monitoring of workshops or biological monitoring (U-TCA) of workers carried out since the 1960s.
 1.64 (0.95–2.84) for full study; 1.68 (0.97–2.91) with 10-yr lag
 High cumulative level: 3.34 (1.27–8.74)
ppm·yrs
1–154: 0.85 (0.10–7.41)
155–335: 1.03 (0.29–3.70)
>335: 3.34 (1.27–8.74)
peak + cumulative level
(-)/low-medium: 0.90 (0.27–3.01)
(+)/low-medium: 1.34 (0.13–14.0)
(-)/high: 2.74 (0.66–11.4)
(+)/high: 3.80 (1.27–11.4)
with 10-yr lag
high: 2.16 (1.01–4.65)
+peaks: 3.15 (1.19–8.38)
Zhao et al. (2005) [20] USA
 Aerospace workers with >2 yrs of employment at Rockwell/Rocketdyne’s Santa Susana Field Laboratory, 1950–1993, follow up 1950–2001 (mortality, n = 6,044), 1988–2000 (incidence, n = 5,049) /cohort
 Using job titles, job codes, dates of employment related with JEM and calculated cumulative intensity scores
  
 mortality medium: 0.85 (0.15–4.93) & 1.69 (0.29–9.70) with 20-yrs lag
high: 0.96 (0.09–9.91) & 1.82 (0.09–38.6) with 20-yrs lag
incidence medium: 1.26 (0.26–6.14) & 1.19 (0.22–6.40) with 20-yrs lag
high: 7.71 (0.65–91.4) & 7.40 (0.47–116)
Brüning et al. (2003) [26] Germany
 Histologically confirmed RCC (n = 134), from hospitals, 1992–2000; hospital controls (n = 401)/case–control
 Self-reported exposure duration using JEM
 2.47 (1.36–4.49)
 <10 yr: 3.78 (1.54–9.28)
10-<20 yr: 3.78 (1.54–9.28)
≥20 yr: 2.69 (0.84–8.66)
Raaschou-Nielsen et al. (2003) Denmark
 Blue-collar workers employed >1,968 at 347 TCE-using companies (n = 40,049; 14,360 with presumably higher-level exposure to TCE). Follow up to 1997/cohort
 duration of employment, yrs of 1st employment at a TCE-using company, number of employees in the company
 1.20 (0.94–1.50)
 ≥5 years all subject: 1.6 (1.1–2.2) in
subcohort with expected higher exposure levels: 1.7 (1.1–2.4)
Pesch et al. (2000) [27] Germany
 Histologically confirmed RCC from hospitals (5 regions) (n = 935), 1991–1995; controls randomly selected from residency registries (n = 4,298)/case–control
 TCE and other exposures assigned by questionnaire, assessed occupational history using job title (JEM approach)
 1.24 (1.03–1.49)
 substantial exposure
men: 1.3 (0.8–2.1)
women: 1.8 (0.6–5.0)
high exposure men: 1.1 (0.8–1.5)
women: 1.8 (0.6–1.9)
medium exposure
men: 1.3 (1.0–1.8)
women: 1.3 (0.7–2.6)
Morgan et al. (1998) [22] USA Aerospace workers with >6 mths during 1950–1985 at Hughes (Tucson, AZ) (n = 20,503; 4,733 with TCE exposure), follow up 1950–19/cohort TCE exposure intensity assigned using JEM. 1.14 (0.51–2.58) High cumulative exposure score: 1.59 (0.68–3.71)
Inconsistencies in the results from the cohort studies could be due to risk underestimation (i.e., non-deferential misclassification of exposure). Most of the authors of the cohort studies measured exposure-related variables using the JEM, which is a type of ecological exposure indicator, and assumed that the exposure level would be consistent for the same job. These inconsistencies could lead to the misclassification of exposure and decreased statistical power in their results.

Case–control studies

The main results of the case–control studies are presented in Table  6. According to the case–control studies, consistent associations and dose–response relationships were observed after adjusting for various confounding variables. A review of the classification of exposure levels in individual research papers was important to fully evaluate work-related TCE exposures. According to a recent study by Moor et al., the risk of kidney cancer in the exposure group was twice as high as the non-exposure group. A dose–response relationship was identified in this study; the odds ratio (OR) of the exposed group <13.5 years was 1.89 (95% CI = 0.84~4.28) and ≥13.5 years was 2.25 (95% CI = 0.95~5.29). If the total exposure time was <1080 hours, the OR of the exposed group was 1.22 (95% CI = 0.48~3.12); if the exposure time was ≥1080 hours, the OR was 2.86 (95% CI = 1.31~6.23). An exposure time of 1080 hours is about 27 weeks or 6 months for a 40-hour work-week. A dose–response relationship could be identified for the cumulative exposure level; the ORs were 1.77 (95% CI = 0.64~4.80) and 2.23 (95% CI = 1.07~4.64) for <1.58 ppm・year and ≥1.58 ppm・year, respectively. The ORs of the average exposure level was 1.73 (95% CI = 0.75~4.02) and 2.41 (95% CI = 1.05~5.56) for <0.0076 ppm and ≥0.0076 ppm, respectively, compared with the non-exposure group [24]. Therefore, kidney cancer can possible develop in people with a low cumulative exposure level or a short exposure duration.
In 2006, Charbotel et al. reported the results from case–control studies based on 87 RCC cases and 316 control groups in France. The cumulative exposure levels of TCE were divided into the following 3 groups: low exposure group (1~155 ppm·year), medium exposure group (155~355 ppm·year), and high exposure group (>335 ppm·year). The ORs were determined to be 3.34 (95% CI = 1.27~8.74), 1.03 (95% CI = 0.29~3.70), and 0.85 (95% CI = 0.10~7.41) in the high, medium, and low exposure groups, respectively. Peak exposure was defined as being exposed to 200 ppm of TCE for >15 minutes. The OR for peak exposure was 3.80 (95% CI = 1.27~11.40) [25].
In an earlier case–control study, Brüning et al. evaluated occupational exposure levels of TCE in 134 kidney cancer cases and 401 controls from 1992~2000; the OR of the exposed group was 1.80 (95% CI = 1.01~3.20), and the OR of workers involved with cutting and cleaning was 5.57 (95% CI = 2.33~13.32). The OR of the exposure group <10 years, 10~20 years, and >20 years of exposure was 3.78 (95% CI = 1.54~9.28), 1.80 (95% CI = 0.67~4.79), and 2.69 (95% CI = 0.84~8.66), respectively [26]. Pescht et al. also presented statistically significant increase of OR [27].
In some studies, the possibility of a high-dose phenomenon or genetic sensitivity related to TCE exposure and the risk of kidney cancer has been reported. Therefore, renal tubule toxicity would be more important than genetic toxicity for carcinogenesis. A history of peak exposures was the most important variable related to exposure in another study [28]. The presence of a genetically susceptible population for which the glutathione S-transferase theta 1 enzyme was active has also been reported in a case-controlled study [24].
The association between TCE exposure and kidney cancer should be definite according to epidemiologic studies. Although the findings from the cohort studies were inconsistent, the results from the case–control studies were consistent. Considering the limitations of cohort studies and the low prevalence of kidney cancer in those studies, the results of the well-designed case–control studies could be more useful for evaluating the causal association between TCE exposure and kidney cancer risk. The study subjects of the cohort studies were restricted to a few jobs or industries (i.e., aerospace workers or workers using TCE in the United Sates and Denmark) and exposure levels were measured based on the JEM, which can possible lead to the misclassification of exposure. According to the results from the meta-analyses and case–control studies, an increased risk for the exposure group and a dose–response relationship was identified using various exposure measures, such as cumulative exposure level, exposure duration, peak exposure, or JEM. Therefore, the epidemiologic evidence for the causal relationship between TCE exposure and kidney cancer could be sufficient.
In Korea, TCE remains a widely used chemical by various manufacturers. Occupational physicians should remember that past exposure levels of TCE could have been very high in patients when evaluating work-related causes of kidney cancer. TCE exposure levels have been as high as >100 ppm in some studies; plating, cleaning, or degreasing were common high-risk jobs for TCE exposure. Furthermore, the exposure level for manual jobs could be higher than automated jobs. The peak exposure level of TCE could also be considered an important variable due to the possibility of carcinogenesis, which is related to high dose phenomenon.
In summary, TCE is a widely used chemical and the incidence of kidney cancer has increased with the development of novel diagnostic techniques. Therefore, the construction of a JEM, case–control studies to evaluate risk factors associated with TCE exposure, and proper preventive policies are necessary. This review could be a comprehensive reference for evaluating the relationship between work-related TCE exposure and kidney cancer in Korea.
The authors declared that they have no competing interests.
IK: The first author of this article. She designed this research, collected and interpreted the data, prepared the draft of this manuscript, and approved the final version of the manuscript. JH: He reviewed and interpreted the epidemiologic articles and revised the draft of this manuscript, and approved the final version of the manuscript. JHL: He collected and reviewed the exposure status related report or papers and prepared the draft of the manuscript. KY: He collected and analyzed the exposure measurement data, revised the draft of this manuscript, and approved the final version of the manuscript. JR: The corresponding author of this article. He suggested the design of this research, interpreted data, revised the draft of this manuscript, and approved the final version of the manuscript.
This review was the part of study of Korean Society of Occupational and Environmental Medicine supported by Ministry of Employment and Labor.
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Figure & Data

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      The Relationship between the Occupational Exposure of Trichloroethylene and Kidney Cancer
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    		Total
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    		4.1
    		4.6
    		1.9
    		1.8
    2001
    		3.5
    		3.4
    		4.7
    		5.1
    		2.2
    		2.0
    2002
    		3.6
    		3.5
    		5.0
    		5.2
    		2.3
    		2.1
    2003
    		3.9
    		3.6
    		5.3
    		5.4
    		2.5
    		2.2
    2004
    		4.3
    		3.9
    		5.8
    		5.7
    		2.8
    		2.4
    2005
    		4.9
    		4.2
    		6.6
    		6.3
    		3.1
    		2.5
    2006
    		5.4
    		4.6
    		7.4
    		6.8
    		3.5
    		2.7
    2007
    		6.0
    		5.0
    		8.3
    		7.4
    		3.7
    		2.9
    2008
    		6.6
    		5.2
    		9.0
    		7.8
    		4.1
    		3.1
    2009
    		7.0
    		5.5
    		9.4
    		7.9
    		4.5
    		3.3
    2010
    		7.3
    		5.5
    		10.1
    		8.3
    		4.3
    		3.1
    2011
    		8.0
    		6.2
    		10.9
    		8.6
    		5.1
    		3.6
    APC* 6.2 (p<0.05) 5.9 (p<0.05) 6.3 (p<0.05)
     
    		Men
    		Women
    Age (years)20022003200420052009201020112002200320042005200920102011
    0–9
    		0.6
    		0.6
    		0.7
    		0.6
    		0.8
    		0.9
    		0.8
    		0.8
    		0.5
    		0.5
    		0.6
    		0.6
    		0.7
    		0.7
    10–19
    		0.0
    		0.1
    		0.3
    		0.1
    		0.1
    		0.1
    		0.1
    		0.0
    		0.1
    		0.0
    		0.1
    		0.1
    		0.1
    		0.2
    20–29
    		0.4
    		0.4
    		0.4
    		0.6
    		0.8
    		0.7
    		0.7
    		0.4
    		0.3
    		0.3
    		0.3
    		0.6
    		0.3
    		0.6
    30–39
    		1.9
    		2.0
    		2.1
    		2.2
    		3.8
    		3.9
    		4.3
    		0.9
    		1.2
    		1.1
    		1.0
    		1.3
    		1.7
    		2.1
    40–49
    		5.4
    		6.7
    		6.5
    		7.1
    		9.4
    		9.8
    		10.3
    		1.9
    		3.0
    		3.0
    		2.5
    		4.1
    		3.7
    		4.0
    50–59
    		13.7
    		13.0
    		12.4
    		15.0
    		18.4
    		20.5
    		21.1
    		5.3
    		4.3
    		6.3
    		5.6
    		8.1
    		7.7
    		8.5
    60–69
    		22.7
    		23.2
    		24.7
    		24.5
    		31.8
    		33.1
    		33.6
    		8.1
    		8.9
    		8.1
    		10.1
    		12.8
    		12.3
    		13.5
    ≥7026.225.432.436.542.241.544.59.69.59.813.015.313.616.5
    Type of industryNo. of factoriesNo. of workersAmount used (L/month)Concentration range (ppm)
    Total
    		103
    		390
    		87,320
    		-
    Chemical
    		3
    		19
    		4,116
    		0.97~13.26
    Plastics & rubber products
    		1
    		35
    		6,830
    		ND~42.63
    Primary metal
    		6
    		18
    		6,787
    		2.91~37.35
    Fabricated metal products
    		24
    		59
    		11,990
    		ND~30.80
    Machinery
    		18
    		59
    		3,950
    		ND~48.48
    Computer & electronic products
    		9
    		62
    		19,596
    		0.08~41.55
    Electrical equipment, appliance
    		10
    		56
    		4,771
    		ND~21.29
    Transportation equipment
    		18
    		30
    		23,920
    		ND~49.87
    Others14525,360ND~39.51
    JobNo. of samplesArithmetic mean (ppm)Median (ppm)Geometric mean (ppm)Maximum (ppm)
    Cleaning
    		8,374
    		8.953
    		2.33495
    		0.16013
    		598
    Degreasing
    		421
    		7.780
    		2.01080
    		0.04185
    		152
    Assembly
    		1,146
    		2.850
    		0.08975
    		0.00101
    		237
    Adhesion
    		700
    		1.044
    		0.16850
    		0.00172
    		29
    Coating
    		671
    		3.250
    		0.48790
    		0.01499
    		154
    Painting
    		3,713
    		1.326
    		0.00000
    		0.00015
    		148
    Processing
    		1,046
    		3.955
    		0.41855
    		0.01159
    		108
    Inspection
    		890
    		2.704
    		0.59650
    		0.01061
    		94
    Printing
    		1,519
    		1.948
    		0.17800
    		0.00518
    		65
    Soldering
    		802
    		2.053
    		0.42860
    		0.00881
    		50
    Plating
    		399
    		8.508
    		3.17970
    		0.25311
    		63
    Molding
    		507
    		4.545
    		0.71700
    		0.01194
    		60
    Laboratory
    		317
    		0.692
    		0.00000
    		0.00006
    		48
    Impregnation
    		199
    		7.697
    		0.18200
    		0.00839
    		185
    Mixing
    		511
    		1.807
    		0.09700
    		0.00111
    		54
    Heat treatment
    		201
    		4.982
    		1.00000
    		0.01987
    		64
    Plugging
    		34
    		0.565
    		0.08136
    		0.00063
    		8
    Infusion
    		267
    		5.846
    		0.40630
    		0.01467
    		270
    Reaction
    		138
    		0.461
    		0.00000
    		0.00005
    		6
    Packing
    		273
    		2.128
    		0.27600
    		0.00597
    		45
    Cast
    		124
    		2.601
    		0.04165
    		0.00060
    		43
    Others
    		11,400
    		9.318
    		0.27935
    		0.00540
    		1,471
    Total33,6526.4970.407900.00840–
    Industry in manufacturerJob1Job2MethodRange of concentration (ppm)
    Electronic components (LCD panel frame)
    		Press
    		Processing & cleaning
    		Solid sampler. NIOSH method 1022
    		8.258~11.995
    Power electric equipment (painting transformers)
    		Storing component & cleaning
    		Printing & cleaning
    		Solid sampler. NIOSH method 1022
    		Painting and cleaning: 0.343~9.742 masking: 1.099~16.432, touch up: 0.149~2.462
    Measuring, optic and precision instrument
    		Press & cleaning
    		Grinding & cleaning
    		Solid sampler. diffusive sample
    		16.99~114.41 (including manual work)
    Television and communication equipment
    		Press molding & processing
    		Assembly & cleaning
    		Solid sampler. NIOSH method 1022
    		85.44 in manual (closed 1 years ago), 2.16~3.75 in automatic
    Optic equipment and lens
    		Cutting
    		Cleaning
    		Solid sampler. NIOSH method 1022
    		52.90 (in indoor)
    Parts and accessories for motor vehicle
    		Assembly & dipping
    		Bonding & cleaning
    		Sorbent tube
    		11.57~18.52
    Electronic components
    		Press
    		Cleaning
    		Sorbent tube
    		31.72~49.86
    Textile
    		Degummed and twist thread
    		Decontamination
    		Sorbent tube
    		0.14~1.38
    Plating
    		1st cleaning
    		2nd cleaning
    		Sorbent tube
    		1st cleaning: 28.59, 3.55
     
    		2nd cleaning: 39.28, 1.81
    Metal tooling
    		Press
    		Cleaning
    		Solid sampler. NIOSH method 1022
    		8.75~9.22
    Parts and accessories for motor vehicle
    		Mixing & surface treatment
    		Degreasing
    		KOSHA CODE-A-1-2004 (Method No. 016)
    		2.56
    Other electric equipment
    		Wring & dipping
    		Assembly & impregnation
    		KOSHA CODE-A-1-2004 (Method No. 016)
    		0.03~0.05
    Rubber goods production
    		Preparation
    		Degreasing
    		KOSHA CODE-A-1-2004 (Method No. 016)
    		15.49~88.84
    Other metal product
    		Press and spot welding
    		Cleaning
    		KOSHA CODE-A-1-2004 (Method No. 016)
    		7.21~11.7
    Transport machineries and equipment
    		Press and spot welding
    		Cleaning
    		KOSHA CODE-A-1-2004 (Method No. 016)
    		14.90~49.83
    Non-metallic mineral productMelting & extrusionPress & cleaningKOSHA CODE-A-1-2004 (Method No. 016)41.32~116.62
    Authors, (years) countryStudy subjects/designExposure measurementOverall OR or RRORs or RRs according to exposure level
    Moore et al. (2010) [24] Czech Republic, Poland, Romania, Russia
    		Hospitals in 4 European countries (n = 1,097), 1999–2003; hospital controls with diagnoses unrelated to smoking or genitourinary disorders (n = 1,476)/case–control
    		Specialized job-specific questionnaire for specific jobs or industries of interest focused on TCE with exposure assignment by frequency and confidence of TCE exposure
    		1.63 (1.04–2.54) for all subjects 2.05 (1.13–3.73) for high-confidence assessments only
    		Duration
    <13.5 yrs: 1.89 (0.84–4.28)
    ≥13.5 yrs: 2.25 (0.95–5.29)
    <1080 hrs: 1.22 (0.48–3.12)
    ≥1080 hrs: 2.86 (1.31–6.23)
    Cumulative
    <1.58 ppm·yr: 1.77 (0.64–4.80)
    ≥1.58 ppm·yr: 2.23 (1.07–4.64)
    Average intensity
    <0.076 ppm: 1.73 (0.75–4.02)
    ≥0.076 ppm: 2.41 (1.05–5.56)
    *reference group: non-exposed
    Chabotel et al. (2006) [25] France
    		RCC (n = 87), from urologists’ files and area teaching hospitals, 1993–2003; urologist or general practitioner patient controls (n = 316)/case–control
    		Semi-quantitative cumulative TCE exposure and presence/absence of peak TCE exposure assigned to subjects using a JEM designed using information obtained from questionnaires and routine atmospheric monitoring of workshops or biological monitoring (U-TCA) of workers carried out since the 1960s.
    		1.64 (0.95–2.84) for full study; 1.68 (0.97–2.91) with 10-yr lag
    		High cumulative level: 3.34 (1.27–8.74)
    ppm·yrs
    1–154: 0.85 (0.10–7.41)
    155–335: 1.03 (0.29–3.70)
    >335: 3.34 (1.27–8.74)
    peak + cumulative level
    (-)/low-medium: 0.90 (0.27–3.01)
    (+)/low-medium: 1.34 (0.13–14.0)
    (-)/high: 2.74 (0.66–11.4)
    (+)/high: 3.80 (1.27–11.4)
    with 10-yr lag
    high: 2.16 (1.01–4.65)
    +peaks: 3.15 (1.19–8.38)
    Zhao et al. (2005) [20] USA
    		Aerospace workers with >2 yrs of employment at Rockwell/Rocketdyne’s Santa Susana Field Laboratory, 1950–1993, follow up 1950–2001 (mortality, n = 6,044), 1988–2000 (incidence, n = 5,049) /cohort
    		Using job titles, job codes, dates of employment related with JEM and calculated cumulative intensity scores
    		 
    		mortality medium: 0.85 (0.15–4.93) & 1.69 (0.29–9.70) with 20-yrs lag
    high: 0.96 (0.09–9.91) & 1.82 (0.09–38.6) with 20-yrs lag
    incidence medium: 1.26 (0.26–6.14) & 1.19 (0.22–6.40) with 20-yrs lag
    high: 7.71 (0.65–91.4) & 7.40 (0.47–116)
    Brüning et al. (2003) [26] Germany
    		Histologically confirmed RCC (n = 134), from hospitals, 1992–2000; hospital controls (n = 401)/case–control
    		Self-reported exposure duration using JEM
    		2.47 (1.36–4.49)
    		<10 yr: 3.78 (1.54–9.28)
    10-<20 yr: 3.78 (1.54–9.28)
    ≥20 yr: 2.69 (0.84–8.66)
    Raaschou-Nielsen et al. (2003) Denmark
    		Blue-collar workers employed >1,968 at 347 TCE-using companies (n = 40,049; 14,360 with presumably higher-level exposure to TCE). Follow up to 1997/cohort
    		duration of employment, yrs of 1st employment at a TCE-using company, number of employees in the company
    		1.20 (0.94–1.50)
    		≥5 years all subject: 1.6 (1.1–2.2) in
    subcohort with expected higher exposure levels: 1.7 (1.1–2.4)
    Pesch et al. (2000) [27] Germany
    		Histologically confirmed RCC from hospitals (5 regions) (n = 935), 1991–1995; controls randomly selected from residency registries (n = 4,298)/case–control
    		TCE and other exposures assigned by questionnaire, assessed occupational history using job title (JEM approach)
    		1.24 (1.03–1.49)
    		substantial exposure
    men: 1.3 (0.8–2.1)
    women: 1.8 (0.6–5.0)
    high exposure men: 1.1 (0.8–1.5)
    women: 1.8 (0.6–1.9)
    medium exposure
    men: 1.3 (1.0–1.8)
    women: 1.3 (0.7–2.6)
    Morgan et al. (1998) [22] USAAerospace workers with >6 mths during 1950–1985 at Hughes (Tucson, AZ) (n = 20,503; 4,733 with TCE exposure), follow up 1950–19/cohortTCE exposure intensity assigned using JEM.1.14 (0.51–2.58)High cumulative exposure score: 1.59 (0.68–3.71)
    Table 1 Crude incidence rate (CR) and age-standardized incidence rate (ASR) of kidney cancer per 100,000 persons from 1999 to 2011 in Korea

    *APC; Annual Percentage Change, expressed as (exp(b)-1)×100, where b is the estimated slope of a linear regression from a logarithmic scaled age-standardized rates and calendar years.

    Table 2 Trends in kidney cancer incidence rates in Korea (per 100,000 persons)

    Table 3 Exposure status according to trichloroethylene use in 2006 in Korea

    ND; Non-detectable, concentration level was lower than the detection limit.

    (Source: Cho et al. 2007) [10].

    Table 4 Exposure levels of trichloroethylene by Korean manufacturing industry jobs according to the regular work environment measurement (2002~2010)

    Table 5 Exposure levels of cleaning or degreasing jobs using assessment of reliability of work environment monitoring in 2006 in Korea

    Table 6 Summary of risk measurement of the major cohort and case–control studies

    Table 1

    Table 2

    Table 3

    Table 4

    Table 5

    Table 6

    Ann Occup Environ Med : Annals of Occupational and Environmental Medicine
    © Korean Society of Occupational & Environmental Medicine.
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