Occupational Trichloroethylene Exposure and Renal Carcinoma Risk: Evidence of Genetic Susceptibility by Reductive Metabolism Gene Variants

Abstract

Trichloroethylene (TCE) is a suspected renal carcinogen. TCE-associated renal genotoxicity occurs predominantly through glutathione S-transferase (GST) conjugation and bioactivation by renal cysteine β-lyase (CCBL1). We conducted a case-control study in Central Europe (1,097 cases and 1,476 controls) specifically designed to assess risk associated with occupational exposure to TCE through analysis of detailed job histories. All jobs were coded for organic/chlorinated solvent and TCE exposure (ever/never) as well as the frequency and intensity of exposure based on detailed occupational questionnaires, specialized questionnaires, and expert assessments. Increased risk was observed among subjects ever TCE exposed [odds ratio (OR) = 1.63; 95% confidence interval (95% CI), 1.04-2.54]. Exposure-response trends were observed among subjects above and below the median exposure [average intensity (OR = 1.38; 95% CI, 0.81-2.35; OR = 2.34; 95% CI, 1.05-5.21; P trend = 0.02)]. A significant association was found among TCE-exposed subjects with at least one intact GSTT1 allele (active genotype; OR = 1.88; 95% CI, 1.06-3.33) but not among subjects with two deleted alleles (null genotype; OR = 0.93; 95% CI, 0.35-2.44; P interaction = 0.18). Similar associations for all exposure metrics including average intensity were observed among GSTT1-active subjects (OR = 1.56; 95% CI, 0.79-3.10; OR = 2.77; 95% CI, 1.01-7.58; P trend = 0.02) but not among GSTT1 nulls (OR = 0.81; 95% CI, 0.24-2.72; OR = 1.16; 95% CI, 0.27-5.04; P trend = 1.00; P interaction = 0.34). Further evidence of heterogeneity was seen among TCE-exposed subjects with ≥1 minor allele of several CCBL1-tagging single nucleotide polymorphisms: rs2293968, rs2280841, rs2259043, and rs941960. These findings provide the strongest evidence to date that TCE exposure is associated with increased renal cancer risk, particularly among individuals carrying polymorphisms in genes that are important in the reductive metabolism of this chemical, and provides biological plausibility of the association in humans.

Target Organ Metabolism, Toxicity, and Mechanisms of Trichloroethylene and Perchloroethylene: Key Similarities, Differences, and Data Gaps

“…Additionally, positive exposureresponse relationships were reported in several case-control (Charbotel et al, 2006;Moore et al, 2010) and cohort studies (Zhao et al, 2005;Raaschou-Nielsen et al, 2003) using different exposure metrics. In Moore et al (2010), statistically significant associations between occupational exposure to TCE and renal cell carcinoma were only observed in individuals with an active GSTT1 genotype and certain CCBL1 genotypes. Two metaanalyses (Scott and Jinot, 2011;Karami et al, 2012) support the observations from individual studies, reporting an approximately 30% increased risk of kidney cancer associated with TCE exposure as well as a positive exposure-response relationship.…”

“…An increased risk of kidney cancer was reported in all of the studies in which there was a moderate to very high level of estimated TCE exposure (Henschler et al, 1995;Morgan et al, 1998;Vamvakas et al, 1998;Brüning et al, 2003;Raaschou-Nielsen et al, 2003;Zhao et al, 2005;Boice et al, 2006;Charbotel et al, 2006;Radican et al, 2008;Moore et al, 2010;Hansen et al, 2013), with most risk estimates being statistically significant. Additionally, positive exposureresponse relationships were reported in several case-control (Charbotel et al, 2006;Moore et al, 2010) and cohort studies (Zhao et al, 2005;Raaschou-Nielsen et al, 2003) using different exposure metrics. In Moore et al (2010), statistically significant associations between occupational exposure to TCE and renal cell carcinoma were only observed in individuals with an active GSTT1 genotype and certain CCBL1 genotypes.…”

“…Toxic effects in experimental systems are not fully characterized, and the human relevance of these effects is poorly understood. In the kidney, GSH-mediated conjugative pathways can yield genotoxic metabolites, as is supported by epidemiologic evidence on TCE (Moore et al, 2010). In other tissues, the role of target organ metabolism in ultimate adverse response is unclear.…”

Common Polymorphisms in<i> GSTA1</i>, <i>GSTM1</i> and <i>GSTT1 </i>Are Associated with Susceptibility to Urinary Bladder Cancer in Individuals from Balkan Endemic Nephropathy Areas of Serbia

“…GSTT1 in bioactivation of various cancerogenic compounds, such as trichloroethylene (Moore et al 2010). Indeed, our group has showed that GSTT1-active genotype is associated with TCC risk in men exposed to pesticides .…”

Trichloroethylene-induced formic aciduria: Effect of dose, sex and strain of rat

“…As a consequence, TCE has been detected in the blood of a large number of nonoccupationally exposed adults (Churchill et al, 2001;Blount et al, 2006). Concern was raised about possible long term health effects of TCE and a number of epidemiology studies has suggested links between TCE exposure and an increased incidence of tumours at a number of sites (Moore et al, 2010;Scott and Chiu, 2006;Scott and Jinot, 2011;Wartenberg et al, 2000).…”