Occupational trichloroethylene exposure and antinuclear antibodies: a cross-sectional study in China.

OBJECTIVES: There has been concern over the possible risk of autoimmune diseases from exposure to trichloroethylene (TCE), an industrial solvent and common pollutant near hazardous waste sites. Studies of TCE-exposed lupus-prone mouse strains have reported increases in serum antinuclear antibodies (ANAs), a marker of autoimmunity, and autoimmune pathologic changes, while epidemiologic studies have provided limited support for an association between TCE exposure and scleroderma. To investigate exposure-related biologic evidence of autoimmunity in humans, we measured ANA levels in sera from a cross-sectional study of TCE-exposed (n=80) and TCE-unexposed (n=96) workers in Guangdong, China. METHODS: Full-shift personal air exposure measurements for TCE were taken prior to blood collection. Serum ANAs were detected by immunofluorescence on HEp-2 cells. We calculated ORs and 95% CI relating levels of TCE exposure (categorised using tertiles as cut-points) and ANA positivity (1+ intensity at 1:320 dilution) using multivariable logistic regression. RESULTS: Samples from 16 of 176 participants were ANA-positive. We found higher levels of TCE exposure (concentrations>17.27 ppm) to be associated with an elevated odds of ANA positivity (OR 4.7, 95% CI 1.3 to 16.8) compared with unexposed controls. This association remained after excluding two subjects with diagnosed autoimmune disease (OR 4.5, 95% CI 1.2 to 16.2). We did not observe an association with ANAs at lower exposure levels. CONCLUSIONS: Our findings, to our knowledge the first direct human evidence of an association between TCE exposure and systemic autoimmunity, provide biologic plausibility to epidemiologic evidence relating TCE and autoimmune disease.

Utility evaluation of HLA-B*13:01 screening in preventing trichloroethylene-induced hypersensitivity syndrome in a prospective cohort study.

OBJECTIVES: Trichloroethylene (TCE) -induced hypersensitivity syndrome (TIHS) is a potentially life-threatening disease. Several genetic susceptibility biomarkers have been found to be associated with TIHS, and this systematic prospective study has been conducted to evaluate the utility of these genetic susceptibility biomarkers in preventing the disease. METHODS: The newly hired TCE-exposed workers were recruited from March 2009 to October 2010. HLA-B*13:01 genotyping and 3-month follow-up procedure were conducted. All workers were monitored for adverse reaction by telephone interview every week. The workers with early symptoms of TIHS were asked to go to the hospital immediately for further examination, diagnosis and treatment. The medical expense record data of patients with TIHS were collected for cost-effectiveness analysis in 2018. RESULTS: Among 1651 workers, 158 (9.57%) were found to carry the HLA-B*13:01 allele and 16 (0.97%) were diagnosed with TIHS. HLA-B*13:01 allele was significantly associated with an increased TIHS risk (relative risk=28.4, 95% CI 9.2 to 86.8). As a risk predictor of TIHS, HLA-B*13:01 testing had a sensitivity of 75%, a specificity of 91.1% and an area under curve of 0.83 (95% CI 0.705 to 0.955), the positive and negative predictive values were 7.6% and 99.7%, respectively. The incidence of TIHS was significantly decreased in HLA-B*13:01 non-carriers (0.27%) compared with all workers (0.97%, p=0.014). Cost-effectiveness analysis showed that HLA-B*13:01 screening could produce an economic saving of $4604 per TIHS avoided. CONCLUSIONS: Prospective HLA-B*13:01 screening may significantly reduce the incidence of TIHS and could be a cost effective option for preventing the disease in TCE-exposed workers.

Role of miR-182-5p overexpression in trichloroethylene-induced abnormal cell cycle functions in human HepG2 cells.

Trichloroethylene (TCE), a widely used industrial solvent, occurs frequently in the global environment. TCE was found to induce hepatocarcinogenesis in mice and one of the underlying mechanisms was reported to involve miR-182-5p overexpression. Subsequently, miR-182-5p overexpression was shown to contribute to chemical-induced enhanced cell proliferation in mouse liver cells by targeting the gene Cited2. The aim of this study was to compare our findings in mice with those in a human hepatoma cell line HepG2. Data demonstrated that TCE at 0.1mM exerted no marked effect on human hepatoma cell line HepG2 cell migration, cell cycle, apoptosis, and DNA damage, but significantly stimulated cell proliferation rate and increased mRNA expression levels of proliferating cell nuclear antigen (PCNA), a cell proliferation biomarker. In addition, TCE enhanced miR-182-5p expression levels but lowered Cited2 mRNA expression. In summary, data showed that similar to mouse liver cells, TCE exposure also upregulated cells miR-182-5p expression and inhibited Cited2 expression in human hepatoma cell line HepG2. Our results suggest that the TCE-mediated alterations in the observed cellular functions involve interaction with miR-182-5p. It is of interest that utilization of liver cancer tissues from the Cancer Genome Atlas (TCGA) database also demonstrated that upregulated miR-182-5p expression and reduced Cited2 mRNA expression was detected suggesting that TCE-induced hepatocarcinogenesis involved processes similar to those in humans.

Alterations in immune and renal biomarkers among workers occupationally exposed to low levels of trichloroethylene below current regulatory standards.

OBJECTIVES: The occupational exposure limit for trichloroethylene (TCE) in different countries varies from 1 to 100 ppm as an 8-hour time-weighted average (TWA). Many countries currently use 10 ppm as the regulatory standard for occupational exposures, but the biological effects in humans at this level of exposure remain unclear. The objective of our study was to evaluate alterations in immune and renal biomarkers among workers occupationally exposed to low levels of TCE below current regulatory standards. METHODS: We conducted a cross-sectional molecular epidemiology study of 80 healthy workers exposed to a wide range of TCE (ie, 0.4-229 ppm) and 96 comparable unexposed controls in China, and previously reported that TCE exposure was associated with multiple candidate biological markers related to immune function and kidney toxicity. Here, we conducted further analyses of all of the 31 biomarkers that we have measured to determine the magnitude and statistical significance of changes in the subgroup of workers (n=35) exposed to <10 ppm TCE compared with controls. RESULTS: Six immune biomarkers (ie, CD4+ effector memory T cells, sCD27, sCD30, interleukin-10, IgG and IgM) were significantly decreased (% difference ranged from -16.0% to -72.1%) and one kidney toxicity marker (kidney injury molecule-1, KIM-1) was significantly increased (% difference: +52.5%) among workers exposed to <10 ppm compared with the control group. These associations remained noteworthy after taking into account multiple comparisons using the false discovery rate (ie, <0.20). CONCLUSION: Our results suggest that occupational exposure to TCE below 10 ppm as an 8-hour TWA may alter levels of key markers of immune function and kidney toxicity.

Long-Term Combinatorial Exposure to Trichloroethylene and Inorganic Arsenic in Genetically Heterogeneous Mice Results in Renal Tubular Damage and Cancer-Associated Molecular Changes.

Trichloroethylene (TCE) and inorganic arsenic (iAs) are environmental contaminants that can target the kidney. Chronic exposure to TCE is associated with increased incidence of renal cell carcinoma, while co-exposure to TCE and iAs likely occurs in exposed human populations, such as those near Superfund sites. In order to better understand the kidney health consequences of TCE and/or iAs exposure, a genetically heterogeneous mouse population derived from FVB/NJ and CAST/EiJ mouse strains and deficient for multidrug resistance genes (Abcb1atm1Bor , Abcb1btm1Bor ) was chronically exposed for 52-weeks to varying concentrations of TCE and iAs. Although no exposure group resulted in primary renal cell tumors, kidneys from exposed mice did have significant increases in histologic and biochemical evidence of renal tubular disease with each toxicant alone and with combined exposure, with males having significantly higher levels of damage. Although no added increase in tubular disease was observed with combination exposure compared to single toxicants, molecular changes in kidneys from mice that had the combined exposure were similar to those previous observed in an embryonic stem cell assay for the P81S TCE-induced renal cell carcinoma mutation in the Von Hippel-Lindau syndrome (VHL) gene. While this model more accurately reflects human exposure conditions, development of primary renal tumors observed in humans following chronic TCE exposure was not reproduced even after inclusion of genetic heterogeneity and co-carcinogenic iAs.

New insights on occupational exposure and bladder cancer risk: a pooled analysis of two Italian case-control studies.

PURPOSE: The main risk factor for bladder cancer (BC) is cigarette smoking, but also occupational exposure to carcinogens is relevant, causing about 4-10% of BC. We aimed at investigating the association between BC risk, occupations held in the past and exposure to occupational carcinogens, also assessing whether these associations were influenced by tumour grade. METHODS: We pooled data from two Italian case-control studies on male BC, analyzing 893 cases and 978 controls. Occupations were classified using the International Standard Classification of Occupations and exposure to carcinogens was assigned using a validated Job Exposure Matrix. Logistic regression approach was used as well as a semi-Bayesian model, based on a priori information on exposure. RESULTS: A significantly increased BC risk was found for chemical engineering technicians, postmen, and lathe operators, but only, for the latter, the association remained significant after Bayesian control for type I error. Among carcinogens, cadmium and trichloroethylene were associated with BC. When analyzing data by grade, exposure to these carcinogens was associated with low-grade BC only. CONCLUSIONS: Our results suggest that monitoring workplaces to prevent exposure to carcinogenic agents is still an important task, which should be still given adequate importance in public health.

Exposure reconstruction of trichloroethylene among patients with occupational trichloroethylene hypersensitivity syndrome.

Occupational trichloroethylene (TCE) exposure can induce life-threatening generalized dermatitis accompanied by hepatitis: TCE hypersensitivity syndrome (HS). Since the patients' exposure levels have not been fully clarified, this study estimated end-of-shift urinary concentrations of trichloroacetic acid (TCA) and their lower limit below which the disease occurrence was rare. TCA concentration was measured in 78 TCE HS patients whose urine was collected at admission between 2nd and 14th d after their last shift. Then a linear regression model was used to calculate the mean TCA concentration with 95% confidence interval (95% CI) and 95% prediction interval (95% PI) in the end-of-shift urine. The estimated mean concentration was 83 (95% CI, 49-140) mg/l with 95% PI 9.6-720 mg/l. TCA concentrations were also measured in the end-of-shift urine of 38 healthy workers involved in the same job as were the patients. The geometric mean and its 95% CI were 127 mg/l and 16-984 mg/l, respectively. The exposure levels in HS patients might have thus overlapped with those in workers without HS. Accordingly, it was suggested that HS occurred in the environment where the workers were exposed to the TCE concentration corresponding to the urinary TCA concentration as low as 10 mg/l.

Respiratory effects of trichloroethylene.

Trichloroethylene (TCE) is a chlorinated solvent that has been used widely around the world in the twentieth century for metal degreasing and dry cleaning. Although TCE displays general toxicity and is classified as a human carcinogen, the association between TCE exposure and respiratory disorders are conflicting. In this review we aimed to systematically evaluate the current evidence for the respiratory effects of TCE exposure and the implications for the practicing clinician. There is limited evidence of an increased risk of lung cancer associated with TCE exposure based on animal and human data. However, the effect of other chlorinated solvents and mixed solvent exposure should be further investigated. Limited data are available to support an association between TCE exposure and respiratory tract disorders such as asthma, chronic bronchitis, or rhinitis. The most consistent data is the association of TCE with autoimmune and vascular diseases such as systemic sclerosis and pulmonary veno-occlusive disease. Although recent data are reassuring regarding the absence of an increased lung cancer risk with TCE exposure, clinicians should be aware of other potential respiratory effects of TCE. In particular, occupational exposure to TCE has been linked to less common conditions such as systemic sclerosis and pulmonary veno-occlusive disease.

Toxicological effects of trichloroethylene exposure on immune disorders.

Trichloroethylene (TCE) is one of the most common ground water contaminants in USA. Even though recent regulation mandates restricted utilization of TCE, its use is not completely prohibited, especially in industrial and manufacturing processes. The risk of TCE on human health is an ongoing field of study and its implications on certain diseases such as cancer has been recognized and well-documented. However, the link between TCE and immune disorders is still an under-studied area. Studies on the risk of TCE on the immune system is usually focused on certain immune class disorders, but consensus on the impact of TCE on the immune system has not been established. This review presents representative work that investigates the effect of TCE on immune disorders and highlights future opportunities. We attempt to provide a broader perspective of the risks of TCE on the immune system and human health.

Occupational exposure to chlorinated solvents and kidney cancer: a case-control study.

OBJECTIVES: Trichloroethylene, a chlorinated solvent widely used for metal degreasing, is classified by the International Agency for Research on Cancer as a kidney carcinogen. Other chlorinated solvents are suspected carcinogens, most notably the cleaning solvent perchloroethylene, although it is unclear whether they are associated with kidney cancer. We investigated kidney cancer associations with occupational exposure to 6 chlorinated solvents (trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, carbon tetrachloride, chloroform, and methylene chloride) within a case-control study using detailed exposure assessment methods. METHODS: Cases (n=1217) and controls (n=1235) provided information on their occupational histories and, for selected occupations, on tasks involving potential exposure to chlorinated solvents through job-specific interview modules. Using this information, an industrial hygienist assessed potential exposure to each solvent. We computed ORs and 95% CIs for different exposure metrics, with unexposed participants as the referent group. RESULTS: 1,1,1-trichloroethane, carbon tetrachloride, chloroform, and methylene chloride were not associated with kidney cancer. Among jobs with high exposure intensity, high cumulative hours exposed to perchloroethylene was associated with increased risk, both overall (third tertile vs unexposed: OR 3.1, 95% CI 1.3 to 7.4) and after excluding participants with ≥50% exposure probability for trichloroethylene (OR 3.0, 95% CI 0.99 to 9.0). A non-significant association with high cumulative hours exposed to trichloroethylene was observed (OR 1.7, 95% CI 0.8 to 3.8). CONCLUSIONS: In this study, high exposure to perchloroethylene was associated with kidney cancer, independent of trichloroethylene. Additional studies are needed to further investigate this finding.

High-resolution metabolomics of occupational exposure to trichloroethylene.

BACKGROUND: Occupational exposure to trichloroethylene (TCE) has been linked to adverse health outcomes including non-Hodgkin's lymphoma and kidney and liver cancer; however, TCE's mode of action for development of these diseases in humans is not well understood. METHODS: Non-targeted metabolomics analysis of plasma obtained from 80 TCE-exposed workers [full shift exposure range of 0.4 to 230 parts-per-million of air (ppma)] and 95 matched controls were completed by ultra-high resolution mass spectrometry. Biological response to TCE exposure was determined using a metabolome-wide association study (MWAS) framework, with metabolic changes and plasma TCE metabolites evaluated by dose-response and pathway enrichment. Biological perturbations were then linked to immunological, renal and exposure molecular markers measured in the same population. RESULTS: Metabolic features associated with TCE exposure included known TCE metabolites, unidentifiable chlorinated compounds and endogenous metabolites. Exposure resulted in a systemic response in endogenous metabolism, including disruption in purine catabolism and decreases in sulphur amino acid and bile acid biosynthesis pathways. Metabolite associations with TCE exposure included uric acid (ß = 0.13, P-value = 3.6 × 10-5), glutamine (ß = 0.08, P-value = 0.0013), cystine (ß = 0.75, P-value = 0.0022), methylthioadenosine (ß = -1.6, P-value = 0.0043), taurine (ß = -2.4, P-value = 0.0011) and chenodeoxycholic acid (ß = -1.3, P-value = 0.0039), which are consistent with known toxic effects of TCE, including immunosuppression, hepatotoxicity and nephrotoxicity. Correlation with additional exposure markers and physiological endpoints supported known disease associations. CONCLUSIONS: High-resolution metabolomics correlates measured occupational exposure to internal dose and metabolic response, providing insight into molecular mechanisms of exposure-related disease aetiology.

Association Between Kidney Cancer and Occupational Exposure to Trichloroethylene.

OBJECTIVE: This study investigates the association between occupational exposure to trichloroethylene (TCE) and kidney cancer, as this correlation has been questioned. METHODS: The incidence of cancers was studied in a dynamic cohort of 997 male workers who for many years had been occupationally exposed to TCE. RESULTS: During a 50-year observation period, 13 cases of kidney cancer were observed (7.5 expected) with a standardized incidence ratio of 1.7 and a 95% confidence interval of 1.0 to 3.0. Four other cases, not included in the SIR analysis, were also observed. Long-term TCE exposure was positively confirmed for 14 of the 17 incident cases. There is reason to assume that the remaining cases also had been exposed to TCE. CONCLUSIONS: The present study supports the view that TCE is a kidney carcinogen.

Managing risks of noncancer health effects at hazardous waste sites: A case study using the Reference Concentration (RfC) of trichloroethylene (TCE).

A method for determining a safety range for non-cancer risks is proposed, similar in concept to the range used for cancer in the management of waste sites. This safety range brings transparency to the chemical specific Reference Dose or Concentration by replacing their "order of magnitude" definitions with a scientifically-based range. EPA's multiple RfCs for trichloroethylene (TCE) were evaluated as a case study. For TCE, a multi-endpoint safety range was judged to be 3 µg/m(3) to 30 µg/m,(3) based on a review of kidney effects found in NTP (1988), thymus effects found in Keil et al. (2009) and cardiac effects found in the Johnson et al. (2003) study. This multi-endpoint safety range is derived from studies for which the appropriate averaging time corresponds to different exposure durations, and, therefore, can be applied to both long- and short-term exposures with appropriate consideration of exposure averaging times. For shorter-term exposures, averaging time should be based on the time of cardiac development in humans during fetal growth, an average of approximately 20-25 days.

Trichloroethylene Is Associated with Kidney Cancer Mortality: A Population-based Analysis.

AIM: To examine the association between the distribution of trichloroethylene (TCE) exposure and mortality from kidney cancer (Kca) across United States counties. MATERIALS AND METHODS: Multiple linear regression was used to assess the association of TCE discharges from industrial sites and age-adjusted incidence and mortality rates for Kca during 2005 through 2010, controlling for confounders. A total of 163 counties were included in analysis. RESULTS: We observed an excess risk of Kca mortality associated with higher amounts of environmental TCE releases. A significant dose-response relationship was observed between TCE releases and Kca mortality in females. Smoking, education, income, hypertension, and obesity were significant predictors of incidence and mortality, consistent with previous research on the epidemiology of Kca. CONCLUSION: TCE exposure may increase the risk of mortality from Kca, an association not highlighted before. There is a need for policy measures to limit TCE discharge to the environment if these results are validated.

Exposure to chlorinated solvents and lung cancer: results of the ICARE study.

OBJECTIVE: To investigate the role of occupational exposure to chlorinated solvents in lung cancer aetiology. METHODS: ICARE (Investigation of occupational and environmental CAuses of REspiratory cancers) is a French, multicentre, population-based, case-control study. Information on the lifelong work history of 2926 cases and 3555 controls was collected using standardised questionnaires. Occupational exposures were assessed using job-exposure matrices for five chlorinated solvents. Solvents were studied separately and in combinations. ORs were computed using unconditional logistic regression models adjusted for classic risk factors, including a history of cigarette smoking and exposure to asbestos. Adjustment for socioeconomic status (SES) was also made. RESULTS: After adjustment for exposure to asbestos, we observed a positive, statistically significant association with lung cancer for men and women exposed to a combination of perchloroethylene (PCE), trichloroethylene and dichloromethane (DCM). Further adjustment for SES slightly decreased this association. In contrast, no statistically significant associations were found for other solvent combinations. CONCLUSIONS: These results suggest that exposure to PCE may constitute a risk factor for lung cancer, especially among women, who seem to have a higher prevalence of exposure than men.

[The establishment of diagnosis model on occupational medicamentosa-like dermatitis induced by trichloroethylene].

OBJECTIVE: Based on magnetic beads based weak cation exchange chromatography (MB-WCX), matrix assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF-MS) and ClinProTools software, the polypeptides of serum about occupational medicamentosa-like dermatitis induced by trichloroethylene (OMLDT) patients were studied, and a diagnostic model of OMLDT was built. METHODS: According to diagnostic criteria of OMLDT, serum of 28 OMLDT patients and 28 controls which were diagnosed by Shenzhen prevention and treatment center for occupational disease were collected. With the combination of MB-WCX and MALDI-TOF-MS, the polypeptides fingerprint of serum of 14 OMLDT patients and 14 controls were detected, what's more, the ClinProTools software and SNN algorithm was used for screening characteristic polypeptides and establishing diagnostic model of OMLDT. Then other objects were applied to validate the model to evaluate accuracy. RESULTS: A total of 159 peaks were attained by ClinProTools software, of which 33 peaks were statistical content (P < 0.05). What is more, comparing with the control group, 20 peaks in case group were decreased, and 13 peaks were increased. Two peaks of them were identified, that is 2106.29 and 3263.78, to classify and determine that two groups by receiver operating characteristic curve (ROC) analysis.2D peaks distribution map certified this finding and the area under the ROC curve was closed to 1. A model was established by SNN algorithm, whose cross validation and recognition capability were 87.5% and 98.5%, respectively. Its sensitivity and specificity were 84.8% and 82.1%, separately, which displayed good separating capacity. CONCLUSION: In the combination of MB-WCX, MALDI-TOF-MS and ClinProTools software, specifical different polypeptides were screened and OMLDT diagnostic model was built primarily. Also, the model and the results were positively validated, which would play a significant role in early diagnosis.

Peptide-binding motifs and characteristics for HLA -B*13:01 molecule.

Trichloroethylene (TCE)-induced hypersensitivity dermatitis is one of the critical occupational diseases among workers in China. Our previous studies have identified a strong linkage between the disease and the HLA-B*13:01 allele. In this study, we searched for peptides bound to the HLA-B*13:01 molecule; 57 HLA-B*13:01-bound peptides in total were identified and 54 peptides were used to calculate frequency of amino acid residues to obtain binding motifs of HLA-B*13:01 molecule. The results showed P2, P3, and P9 were the primary binding anchor positions with the dominant anchor motifs of L, Q at P2, L at P9, D at P3. HLA-B*13:01-bound peptides were identified for the first time in our research, the results of which could contribute to the human leukocyte antigen (HLA)-binding peptides database.