Registration Dossier

Toxicological information

Epidemiological data

Currently viewing:

Administrative data

epidemiological data
Type of information:
experimental study
Adequacy of study:
supporting study
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Limited epidemiology case control study with a questionable biological plausibility underpinning the study design.

Data source

Reference Type:
Occupational Trichloroethylene Exposure and Renal Carcinoma Risk: Evidence of Genetic Susceptibility by reductive metabolism gene variants
Moore et al.
Bibliographic source:
Cancer Research, 70(16): 6527-6536

Materials and methods

Study type:
case control study (retrospective)
Endpoint addressed:
Principles of method if other than guideline:
A retrospective Case Control study assessing occupational exposure to organic solvents, chlorinated solvents and trichloroethylene and kidney cancer. The study specifically looked at whether the risk of renal cell carcinoma was higher in populations with at least one intact GSTT1 allele versus those with no GSTT1 alleles. The study also looked at the impact of various genetic polymorphisms of the cycsteine conjugate beta lyase gene on renal cell carcinoma risk
GLP compliance:

Test material

Details on test material:
The study looked at exposure to organic solvents, chlorinated solvents and trichloroethylene in particular. Given the nature of the study there is no information on the purity of the trichloroethylene that the participants were exposed to or the individual solvents covered by the terms 'organic solvents' and 'chlorinated solvents'.


Type of population:
Ethical approval:
confirmed and informed consent free of coercion received
Details on study design:
The study was a hospital-based case-control study of renal cell carcinoma conducted between 1999 and 2003. Seven centers in four countries in Central and eastern Europe (Moscow, Russia; Bucharest, Romania; Lodz, Poland; Prague, Olomouc, Ceske-Budejovice and Brne, Czech Republic).
Cases were:
1) newly diagnosed and histologically confirmed cases of kidney cancer in each hospital identified between 1999 and 2003.
2) had t reside within the study area for at least 1 year prior to diagnosis
3) histological assessment and confirmation of kidney cancer performed by the US Natonal Cancer Institute.
Controls were:
1) patients admitted to the study hospitals (in or out patients) with non-tobacco related conditions
2) frequency matched with cases by sex, age (+/- 3 yrs) and by study center
3) patients with cancer or urogenitary disourders (excluding benign prostate hyperplasia) were excluded
4) prior history of cancer was not an exclusion criteria (but they ahd to be cancer free at the time of enrollment)
5) no single disease made up more than 20% of the diseases among the controls

The final study population contained 1097 Cases and 1476 controls.

Questionnaires were used in face to face interviews to assess life-styl habits including tobacco consumption anthropometric measures 1 year prior to diagnosis and personal and family medical history. A general questionnaire was used to collect the details of each job held for at least 1 year (description of tasks performed, machinary used, working environment, location of tasks performed and time spent on each task). Specialized oppucational questionnaires were used in cases where participants had worked in jobs known to entail exposure to known or suspected carcinogens.

No actual measurement of exposures took place. Estimates of exposure were made by 'experts' based on the output of the questionnaires, and their own industrial hygeine experience. the details on exposure are explained in more detail below.

In order to assess the genetic polymorphisms within the study population blood samples were colleceted and genotyping of the samples performed at the IARC and the National Cancer Institute Core Genotyping Facility. DNA was randomized to reduce potenital for Bias. 5% of the samples were analyzed in duplicate (at random) to assess quality control. Genotyping of the GSTT1 gene was performed for 925 cases (84.3%) and 1192 Controls (80.8%). Genotyping for the CCBL1 gene was performed using the Illumina GoldenDate platform and this had more stringent requirements for the quality and quantity of DNA necessary. As a consequnce the number of Cases and controls genotyped were 777 and 1035 respectively.

Exposure assessment:
Details on exposure:
Exposure assessment teams from each center with extensive knowledge of industries in each region received additional training by the NCI industrial hygienist (PS) for the evaluation of chlorinated solvents and TCE, in addition to that received for an earlier study of lung/head and neck cancers conducted in each center. For every job in each subject's work history, the team from each center evaluated the frequency and intensity of exposure to agents and groups of agents, based on the general occupational questionnaire, the specialized questionnaires, and their own experience in industrial hygiene and knowledge about historical working conditions at specific plants in their study area while blinded to case-control status. Job-specific questionnaires covered the following: (a) possible organic and chlorinated solvent exposures, (b) hours per week of exposure, (c) source of solvent exposure, and (d) a description of solvent use. Every job of each participant was coded for exposure to the agents previously evaluated in a case-control study of lung/head and neck cancer. Organic solvents included any organic chemical used as a dry cleaner, degreaser, thinner, resin solvent, or liquid extraction agent; and petroleum solvents (e.g., white spirits); aliphatic chlorinated solvents; oxygenated solvents (e.g., alcohol and glycol ethers); and others, such as gasoline, kerosene, and mineral spirits. The general category of aliphatic chlorinated organic solvents included perchloroethylene, methylene chloride, carbon tetrachloride, and trichloroethane, and specifically TCE. In attempt to reduce exposure misclassification, after completion of coding for all agents, all subjects originally coded as exposed to organic solvents in the original assessment were reevaluated at a later date by the same group of experts at each center. All coding in the reassessment was performed while blinded with respect to the previous assessment and to disease status.

The 'Experts' assessed the frequency, intensity, and confidence of exposure to organic solvents, chlorinated solvents and TCE in particular for each job held by each participant.
Frequency of exposure was coded into three categories, representing the average percentage of a working day during which occupational exposure was likely as follows:
1% to 4.9% of a day (i.e., 5–20 min/d),
5% to 30% of a day (0.5– 2.4 h/d),
and >30% of a day (>2.5 h/d).
For estimation of subjects' cumulative exposure (ppm-year), the midpoint of the frequency categories used was as follows: 0.025, 0.175, and 0.50, respectively. A midpoint of 0.50 was used for the highest category because we assumed a log-normal exposure distribution.

The intensity of exposure to organic and chlorinated solvent groups was coded on a three-point scale (low, medium, and high). For cumulative organic and chlorinated solvent exposure, respective weights equal to 2.5, 25, and 100 were assigned to the three intensity categories, each corresponding to the midpoint of the estimated range of the solvent exposure levels (ppm).
TCE intensity was coded to one of three categories:
0 to <5 ppm (<27 μg/m3),
5 to 50 ppm (27–270 μg/m3),
and >50 ppm (>270 μg/m3),
Midpoint weights for cumulative exposure were set as 2.5, 25, and 75, respectively. For each solvent considered to be present, the industrial hygienists also noted the degree of confidence that a job would entail exposure to an agent. Confidence of exposure that represented the expected percentage of workers that would be exposed in that job was categorized as possible (i.e., <40% workers at a job were expected to be exposed), probable (40–89% of workers were expected to be exposed), or definite (at least 90% of workers were expected to be exposed). After reassessment of TCE exposure, agreement was 100% in Romania (13 subjects) and Poland (3 subjects), and 83% in the Czech Republic (90 subjects). Reassessment of TCE exposure was not conducted in Moscow because Moscow subjects who were exposed to organic solvents were very unlikely to be exposed to TCE.
Statistical methods:
See information in the 'Any other information on materials and methods' below

Results and discussion

This study appears to demonstrate an association between trichloroethylene exposure and kidney cancer. Odds Ratios of between 1.63 and 2.34 were reported for the various exposure indices in the paper (TCE exposure, years of exposure, hours of exposure, cumulative (ppm-years) and average intesity. The association appeared to be strengthened when only the 'high confidence exposure estimates' were analysed. I.e. within the study design there was an assessment of the degree of confidence inthe exposure assessment.

Considering the effect of the GSTT1 genotype, the investigators report that tehre appeared to be no association between genotype and renal cancer in general. However when analysis was restricted to those participants with exposure to TCE, there was an apparent association. After stratification by GSTT1 genotype, significant associations were only observed among subjects ever exposed to TCE with an active genotype (OR = 1.88; 95% CI, 1.06–3.33) but not among GSTT1 nulls (OR = 0.93; 95% CI, 0.35–2.44). Similarly, associations with other exposure metrics were observed only among subjects with at least one active GSTT1 genotype (ORs from 2.13–2.77 in the top 50th percentile) but not among GSTT1 null subjects (ORs from 0.53–1.22 in the top 50th percentile), compared with unexposed subjects. The interaction between TCE exposure and GSTT1 genotype did not reach statistical significance.

With respect to the CCBL1 genotyping, there were several associations with differnet polymorphisms of the gene but the interpretation is unclear.
Confounding factors:
Body mass index, place of residence (urban/rural), tobacco use and self reported hypertension were assessed but not adressed in the statistical models in the data presented. the authors indicate that this is due to these factors not altering the odds ratios by >10%. However, given the association between hypertension, tobacco use and renal cancer it would seem that correcting for these would should have been done irrespective of the degree to which odds ratios were affected, particularly given some of the weak associations.
Strengths and weaknesses:
The study is a case control study and as such has many potential issues when it comes to study conduct and interpretation.
Considering the study population, the authors of the study state that one of the strenghts of the study was the large number of cases and controls (each over 1000). However, when one considers the population that were exposed to TCE, there were only 48 cases and 40 controls. This would make the assessment of whether TCE exposures could be associated with renal cancer rather challenging and is illustrated by the typically weak assocaitions reported.
With respect to the exposure characterisation, a significant challenge with all Case/Control studies is the exposure assessment. This study, like many others, used expert judgement and questionnaires to estimate exposure to the various chemicals addressed. Although there appears to have been a lot of effort to maximise the accuracy/validity of the exposure estimation there does not appear to have been any attempt to validate exposures in any way.
With respect to the interpetation of the data, the analysis was performed using categorical exposure indices even though a continuous measure (cumulative exposure) had been made. It is difficult to understand why the continuous data were not analysed.

When considering the GSTT1 association, again the numbers of cases are very small and it seems likely that some assocaition could be due to chance and small sample size.

Applicant's summary and conclusion

This study reports both a positive association between TCE exposure and kidney cancer, and indicates that there is an association between cancer risk following TCE exposrue depending on the GSTT1 genotype. However, the study is limited by small size, non-validated exposure assessment and a fundamental lack of biological plausibility. The weak associations reported are therefore potentially a a result of inherrent bias within the study design and small sample size.