To Trichloroethylene Exposure Research Articles

Targeted proteomic scan identifies alteration of serum proteins among workers occupationally exposed to low levels of trichloroethylene.

Occupational exposure to trichloroethylene (TCE) has been associated with alterations in B-cell activation factors and an increased risk of non-Hodgkin's lymphoma (NHL). Here, we aimed to examine the biological processes influenced by TCE exposure to understand the underlying molecular mechanisms. This cross-sectional molecular epidemiology study included data of 1317 targeted proteins in the serum from 42 TCE exposed and 34 unexposed factory workers in Guangdong, China. We used multivariable linear regressions to identify proteins associated with TCE exposure and examined their exposure-response relationship across categories of TCE exposure (unexposed, low exposed: <10ppm, high exposed: ≥10ppm). We further examined pathway enrichment of TCE-related proteins to understand their biological response. Occupational exposure to TCE was associated with lower levels of tumor necrosis factor receptor superfamily member 17 (TNFRSF17; β=-.08; p-value=.0003) and kynureninase (KYNU; β=-.10, p-value=.002). These proteins also showed a significant exposure-response relation across the unexposed, low exposed, and high exposed workers (all p-trends < .001, false discovery rate [FDR] < 0.20). Pathway analysis of TCE-related proteins showed significant enrichment (FDR < 0.05) for several inflammatory and immune pathways. TCE exposure was associated with TNFRSF17, a key B-cell maturation antigen that mediates B-cell survival and KYNU, an enzyme that plays a role in T-cell mediated immune response. Given that altered immunity is an established risk factor for NHL, our findings support the biological plausibility of linking TCE exposure with NHL.

Increased serum anti-CYP2E1 IgG autoantibody levels may be involved in the pathogenesis of occupational trichloroethylene hypersensitivity syndrome: a case–control study

Occupational exposure to trichloroethylene (TCE) causes a systemic skin disorder with hepatitis known as TCE hypersensitivity syndrome (TCE-HS). Human Leukocyte Antigen (HLA)-B*13:01 is its susceptibility factor; however, the immunological pathogenesis of TCE-HS remains unknown. We herein examined the hypothesis that autoantibodies to CYP2E1 are primarily involved in TCE-HS. A case–control study of 80 TCE-HS patients, 186 TCE-tolerant controls (TCE-TC), and 71 TCE-nonexposed controls (TCE-nonEC) was conducted to measure their serum anti-CYP2E1 antibody (IgG) levels. The effects of TCE exposure indices, such as 8-h time-weighted-average (TWA) airborne concentrations, urinary metabolite concentrations, and TCE usage duration; sex; smoking and drinking habits; and alanine aminotransferase (ALT) levels on the antibody levels were also analyzed in the two control groups. There were significant differences in anti-CYP2E1 antibody levels among the three groups: TCE-TC > TCE-HS patients > TCE-nonEC. Antibody levels were not different between HLA-B*13:01 carriers and noncarriers in TCE-HS patients and TCE-TC. The serum CYP2E1 measurement suggested increased immunocomplex levels only in patients with TCE-HS. Multiple regression analysis for the two control groups showed that the antibody levels were significantly higher by the TCE exposure. Women had higher antibody levels than men; however, smoking, drinking, and ALT levels did not affect the anti-CYP2E1 antibody levels. Anti-CYP2E1 antibodies were elevated at concentrations lower than the TWA concentration of 2.5 ppm for TCE exposure. Since HLA-B*13:01 polymorphism was not involved in the autoantibody levels, the possible mechanism underlying the pathogenesis of TCE-HS is that TCE exposure induces anti-CYP2E1 autoantibody production, and HLA-B*13:01 is involved in the development of TCE-HS.

Application of multiple occupational health risk assessment models in occupation health risk prediction of trichloroethylene in the electroplating and electronics industries

Objectives. This study assessed the occupational health risks of work group exposure to trichloroethylene (TCE) in the electroplating and electronics industries in China. Methods. The UK Control of Substances Hazardous to Health (COSHH) Essential, the US Environmental Protection Agency (EPA) and the Singapore and the Chinese semiquantitative risk assessment models were used to assess the risks of TCE. Twenty degreasing groups and 14 cleaning groups were recruited in the companies selected. Results. The concentrations of TCE in 66.7% of the cleaning groups and 35.0% of the degreasing groups exceeded the permissible concentration time-weighted average (PC-TWA) in China, and the concentrations of TCE in 100.0% of the cleaning groups and 70.0% of the degreasing groups exceeded the permissible concentration short-term exposure limit (PC-STEL) in China. Over 60.0% of the work groups were evaluated at high risk and over half of the work groups were evaluated at high cancer risk by the risk assessment models. Conclusion. Most work groups exposed to TCE in the electroplating and electronics industries in China are at high risk. The cleaning groups may have a higher risk for TCE exposure. The Chinese exposure index method and the synthesis index method are more practical than the other methods.

Human exposure to trichloroethylene is associated with increased variability of blood DNA methylation that is enriched in genes and pathways related to autoimmune disease and cancer

ABSTRACTHuman exposure to trichloroethylene (TCE) is linked to kidney cancer, autoimmune diseases, and probably non-Hodgkin lymphoma. Additionally, TCE exposed mice and cell cultures show altered DNA methylation. To evaluate associations between TCE exposure and DNA methylation in humans, we conducted an epigenome-wide association study (EWAS) in TCE exposed workers using the HumanMethylation450 BeadChip. Across individual CpG probes, genomic regions, and globally (i.e., the 450K methylome), we investigated differences in mean DNA methylation and differences in variability of DNA methylation between 73 control (< 0.005 ppm TCE), 30 lower exposed (< 10 ppm TCE), and 37 higher exposed ( 10 ppm TCE) subjects’ white blood cells. We found that TCE exposure increased methylation variation globally (Kruskal-Wallis p-value = 3.75e-3) and in 25 CpG sites at a genome-wide significance level (Bonferroni p-value < 0.05). We identified a 609 basepair region in the TRIM68 gene promoter that exhibited hypomethylation with increased exposure to TCE (FWER = 1.20e-2). Also, genes that matched to differentially variable CpGs were enriched in the ‘focal adhesion’ biological pathway (p-value = 2.80e-2). All in all, human exposure to TCE was associated with epigenetic alterations in genes involved in cell-matrix adhesions and interferon subtype expression, which are important in the development of autoimmune diseases; and in genes related to cancer development. These results suggest that DNA methylation may play a role in the pathogenesis of TCE exposure-related diseases and that TCE exposure may contribute to epigenetic drift.

Association between occupational exposure to trichloroethylene and serum levels of microRNAs: a cross-sectional molecular epidemiology study in China.

The objective of our study was to evaluate the association between occupational exposure to trichloroethylene (TCE), a suspected lymphomagen, and serum levels of miRNAs in a cross-sectional molecular epidemiology study of TCE-exposed workers and comparable unexposed controls in China. Serum levels of 40 miRNAs were compared in 74 workers exposed to TCE (median: 12ppm) and 90 unexposed control workers. Linear regression models were used to test for differences in serum miRNA levels between exposed and unexposed workers and to evaluate exposure-response relationships across TCE exposure categories using a three-level ordinal variable [i.e., unexposed, < 12ppm, the median value among workers exposed to TCE) and ≥ 12ppm)]. Models were adjusted for sex, age, current smoking, current alcohol use, and recent infection. Seven miRNAs showed significant differences between exposed and unexposed workers at FDR (false discovery rate) < 0.20. miR-150-5p and let-7b-5p also showed significant inverse exposure-response associations with TCE exposure (Ptrend= 0.002 and 0.03, respectively). The % differences in serum levels of miR-150-5p relative to unexposed controls were -13% and -20% among workers exposed to < 12ppm and ≥ 12ppm TCE, respectively. miR-150-5p is involved in B cell receptor pathways and let-7b-5p plays a role in the innate immune response processes that are potentially important in the etiology of non-Hodgkin lymphoma (NHL). Further studies are needed to replicate these findings and to directly test the association between serum levels of these miRNAs and risk of NHL in prospective studies.

Cytokine expression and cytokine-based T-cell profiling in occupational medicamentosa-like dermatitis due to trichloroethylene

Early diagnosis and treatment of occupational medicamentosa-like dermatitis due to trichloroethylene (OMLDT) are absence of specific and reliable diagnostic/therapeutic biomarkers. This study was conducted on 30 cases of OMLDT, 58 workers exposed to trichloroethylene (TCE) and 40 unexposed controls in order to identify any cytokine signatures that give an index to CD4+T cell differential and serve as biomarkers of OMLDT. Expression profiles of Th1, Th2, Th17 and Treg cell type-specifying transcription factors and cytokines were analyzed using real time quantitative PCR (RT-qPCR) assay. To explore whether such expression profiles reflected their steady state plasma levels, a Luminex liquid fluorescence analysis was conducted. We found that the expression of transcription factors FoxP3 transcription factors (P = 0.006 and P < 0.0001) and IL-10 cytokine (P = 0.0008 and P < 0.0001) of the Treg subset were significantly higher in patients than TCE exposure workers and unexposed controls, suggesting that Treg cells were active after the occurrence of OMLDT. The transcript levels of IL-6 were significantly lower in the TCE exposure groups including patients and exposure workers as compared to the unexposed controls (P < 0.0001 and P = 0.0008). Circulating levels of assessed cytokines of IL-6 (P = 0.001 and P = 0.011) and TFN-α (P = 0.005 and P < 0.0001) were lower in the exposure groups than in the unexposed controls. Compared to the controls, the levels of IL-10 in patients were higher (P = 0.001 and P = 0.0008). There was a significantly positive correlation between the plasma levels IL-6 and IL-10 in TCE exposed workers. These alterations in the expression of transcription factors and cytokines highlight the underlying dysregulation of T cell subsets in OMLDT that reflect an immune tolerance or immune inhibition. Therefore, the elevation of IL-10 level may be a kind of pathogenesis indicator, and the decline in IL-6 level may be a kind of TCE exposure biomarker. These biomarkers need additional longitudinal follow-up studies to warrant to clinically useful biomarkers of OMLDT.

Trichloroethylene perturbs HNF4a expression and activity in the developing chick heart

Exposure to trichloroethylene (TCE) is linked to formation of congenital heart defects in humans and animals. Prior interactome analysis identified the transcription factor, Hepatocyte Nuclear Factor 4 alpha (HNF4a), as a potential target of TCE exposure. As a role for HNF4a is unknown in the heart, we examined developing avian hearts for HNF4a expression and for sensitivity to TCE and the HNF4a agonist, Benfluorex. In vitro analysis using a HNF4a reporter construct showed both TCE and HFN4a to be antagonists of HNF4a-mediated transcription at the concentrations tested. HNF4a mRNA is expressed transiently in the embryonic heart during valve formation and cardiac development. Embryos were examined for altered gene expression in the presence of TCE or Benfluorex. TCE altered expression of selected mRNAs including HNF4a, TRAF6 and CYP2C45. There was a transition between inhibition and induction of marker gene expression in embryos as TCE concentration increased. Benfluorex was largely inhibitory to selected markers. Echocardiography of exposed embryos showed reduced cardiac function with both TCE and Benfluorex. Cardiac contraction was reduced by 29% and 23%, respectively at 10 ppb. The effects of TCE and Benfluorex on autocrine regulation of HNF4a, selected markers and cardiac function argue for a functional interaction of TCE and HNF4a. Further, the dose-sensitive shift between inhibition and induction of marker expression may explain the nonmonotonic-like dose response observed with TCE exposure in the heart.

Trichloroethylene and Parkinson's Disease: Risk Assessment.

This study was conducted to investigate the mechanism of action and extent of selective dopaminergic neurodegeneration caused by exposure to trichloroethylene (TCE) leading to the endogenous formation of the neurotoxin 1-trichloromethyl-1,2,3,4-tetrahydro-β-carboline (TaClo) in rodents. Beginning at 3months of age, male C57BL/6 mice received oral TCE dissolved in vehicle for 8months. Dopaminergic neuronal loss was assessed by nigral tyrosine hydroxylase (TH) immunoreactivity. Selective dopaminergic neurodegeneration was determined based on histological analysis of non-dopaminergic neurons in the brain. Behavioral assays were evaluated using open field activity and rotarod tests. Mitochondrial complex I activity, oxidative stress markers, and microglial activation were also examined in the substantia nigra. The level of TaClo was detected using HPLC-electrospray ionization tandem mass spectrometry. Dopaminergic neurotoxicity of TaClo was determined in midbrain organotypic cultures from rat pups. Following 8months of TCE treatment, there was a progressive and selective loss of 50% of the dopaminergic neurons in mouse substantia nigra (SN) and about 50% loss of dopamine and 72% loss of 3,4-dihydroxyphenylacetic acid in the striatum, respectively. In addition, motor deficits, mitochondrial impairment, oxidative stress, and inflammation were measured. TaClo content was quantified in the brain after TCE treatment. In organotypic cultures, TaClo rather than TCE induced dopaminergic neuronal loss, similar to MPP+. TCE exposure may stimulate the endogenous formation of TaClo, which is responsible for dopaminergic neurodegeneration. However, even prolonged administration of TCE was insufficient for producing a greater than 50% loss of nigral dopamine neurons, indicating that additional co-morbid factors would be needed for mimicking the profound loss of dopamine neurons seen in Parkinson's disease.

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 (β = 0.13, P-value = 3.6 × 10−5), glutamine (β = 0.08, P-value = 0.0013), cystine (β = 0.75, P-value = 0.0022), methylthioadenosine (β = −1.6, P-value = 0.0043), taurine (β = −2.4, P-value = 0.0011) and chenodeoxycholic acid (β = −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.

This study investigates the association between occupational exposure to trichloroethylene (TCE) and kidney cancer, as this correlation has been questioned. The incidence of cancers was studied in a dynamic cohort of 997 male workers who for many years had been occupationally exposed to TCE. 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. The present study supports the view that TCE is a kidney carcinogen.

Abstract 840: Occupational exposure to trichloroethylene and LINE-1 methylation

Abstract Trichloroethylene (TCE) is a volatile chlorinated organic compound that is commonly used in industrial settings as a degreaser. Epidemiologic studies suggest that TCE exposure is associated with an increased risk of kidney cancer and may also be associated with non-Hodgkin lymphoma. However, the mechanisms for these associations are still not clear. To evaluate the relationship between occupational exposure to trichloroethylene (TCE) and LINE-1 methylation, a measure of global methylation, we conducted a cross-sectional molecular epidemiology study of 79 workers exposed to TCE and 81 comparable unexposed controls in Guangdong, China. Personal air exposure measurements and urine samples were collected prior to phlebotomy. The urine TCE metabolite, trichloroacetic acid (TCA), was measured by liquid chromatography electrospray ionization tandem mass spectrometry in urine samples and LINE-1 methylation was assessed by pyrosequencing DNA isolated from peripheral blood. LINE-1 methylation levels [median (range) in percent] were 78.40 (75.80-81.20) in controls, 77.80 (76.10-81.00) in lower exposed, and 77.50 (74.20-80.20) in higher exposed workers based on median urine TCA level (p trend = 0.012). These results suggest that TCE may be associated with a decrease in global methylation measured by the LINE-1 assay. Gene-specific methylation is currently being conducted to follow up these findings. Citation Format: Wei Hu, Luoping Zhang, Christopher Kim, Xiaojiang Tang, Sungkyoon Kim4, Bryan Bassig, Wei-Jie Seow, Min Shen, Chuangyi Qiu, Yechen Ge, Boris Reiss, Mark Purdue, Lee Moore, Laiyu Li, Fei Yue, Hanlin Huang, Martyn T. Smith, Roel Vermeulen, Nathaniel Rothman, Qing Lan. Occupational exposure to trichloroethylene and LINE-1 methylation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 840. doi:10.1158/1538-7445.AM2015-840

Differential immunotoxicity induced by two different windows of developmental trichloroethylene exposure.

Developmental exposure to environmental toxicants may induce immune system alterations that contribute to adult stage autoimmune disease. We have shown that continuous exposure of MRL+/+ mice to trichloroethylene (TCE) from gestational day (GD) 0 to postnatal day (PND) 49 alters several aspects of CD4+ T cell function. This window of exposure corresponds to conception-adolescence/young adulthood in humans. More narrowly defining the window of TCE developmental exposure causes immunotoxicity that would establish the stage at which avoidance and/or intervention would be most effective. The current study divided continuous TCE exposure into two separate windows, namely, gestation only (GD0 to birth (PND0)) and early-life only (PND0-PND49). The mice were examined for specific alterations in CD4+ T cell function at PND49. One potentially long-lasting effect of developmental exposure, alterations in retrotransposon expression indicative of epigenetic alterations, was found in peripheral CD4+ T cells from both sets of developmentally exposed mice. Interestingly, certain other effects, such as alterations in thymus cellularity, were only found in mice exposed to TCE during gestation. In contrast, expansion of memory/activation cell subset of peripheral CD4+ T cells were only found in mice exposed to TCE during early life. Different windows of developmental TCE exposure can have different functional consequences.

379 Occupational exposure to trichloroethylene and risk of non-Hodgkin lymphoma and its major subtypes: a pooled interlymph analysis

ObjectivesTo test the association between occupational exposure to trichloroethylene (TCE) and risk of non Hodgkin lymphoma (NHL), we conducted a pooled analysis of four international case-control studies.Methods Studies were selected...

Occupational exposure to trichloroethylene and risk of non-Hodgkin lymphoma and its major subtypes: a pooled IinterLlymph analysis

ObjectivesWe evaluated the association between occupational exposure to trichloroethylene (TCE) and risk of non-Hodgkin lymphoma (NHL) in a pooled analysis of four international case-control studies.MethodsOverall, the pooled study population included...

Epigenetic alterations may regulate temporary reversal of CD4(+) T cell activation caused by trichloroethylene exposure.

Previous studies have shown that short-term (4 weeks) or chronic (32 weeks) exposure to trichloroethylene (TCE) in drinking water of female MRL+/+ mice generated CD4(+) T cells that secreted increased levels of interferon (IFN)-γ and expressed an activated (CD44(hi)CD62L(lo)) phenotype. In contrast, the current study of subchronic TCE exposure showed that midway in the disease process both of these parameters of CD4(+) T cell activation were reversed. This phase of the disease process may represent an attempt by the body to counteract the inflammatory effects of TCE. The decrease in CD4(+) T cell production of IFN-γ following subchronic TCE exposure could not be attributed to skewing toward a Th2 or Th17 phenotype or to an increase in Treg cells. Instead, the suppression corresponded to alterations in markers used to assess DNA methylation, namely increased expression of retrotransposons Iap (intracisternal A particle) and Muerv (murine endogenous retrovirus). Also observed was an increase in the expression of Dnmt1 (DNA methyltransferase-1) and decreased expression of several genes known to be downregulated by DNA methylation, namely Ifng, Il2, and Cdkn1a. CD4(+) T cells from a second study in which MRL+/+ mice were treated for 17 weeks with TCE showed a similar increase in Iap and decrease in Cdkn1a. In addition, DNA collected from the CD4(+) T cells in the second study showed TCE-decreased global DNA methylation. Thus, these results described the biphasic nature of TCE-induced alterations in CD4(+) T cell function and suggested that these changes represented potentially reversible alterations in epigenetic processes.

A case-control study of occupational exposure to trichloroethylene and non-Hodgkin lymphoma.

BackgroundPrevious epidemiologic findings suggest an association between exposure to trichloroethylene (TCE), a chlorinated solvent primarily used for vapor degreasing of metal parts, and non-Hodgkin lymphoma (NHL).ObjectivesWe investigated the association between occupational TCE exposure and NHL within a population-based case–control study using detailed exposure assessment methods.MethodsCases (n = 1,189; 76% participation rate) and controls (n = 982; 52% participation rate) provided information on their occupational histories and, for selected occupations, on possible workplace exposure to TCE using job-specific interview modules. An industrial hygienist assessed potential TCE exposure based on this information and a review of the TCE industrial hygiene literature. We computed odds ratios (ORs) and 95% confidence intervals (CIs) relating NHL and different metrics of estimated TCE exposure, categorized using tertiles among exposed controls, with unexposed subjects as the reference group.ResultsWe observed associations with NHL for the highest tertiles of estimated average weekly exposure (23 exposed cases; OR = 2.5; 95% CI, 1.1–6.1) and cumulative exposure (24 exposed cases; OR = 2.3; 95% CI, 1.0–5.0) to TCE. Tests for trend with these metrics surpassed or approached statistical significance (p-value for trend = 0.02 and 0.08, respectively); however, we did not observe dose–response relationships across the exposure levels. Overall, neither duration nor intensity of exposure was associated with NHL, although we observed an association with the lowest tertile of exposure duration (OR = 2.1; 95% CI, 1.0–4.7).ConclusionsOur findings offer additional support for an association between high levels of exposure to TCE and increased risk of NHL. However, we cannot rule out the possibility of confounding from other chlorinated solvents used for vapor degreasing and note that our exposure assessment methods have not been validated.

Mammalian cytochrome CYP2E1 triggered differential gene regulation in response to trichloroethylene (TCE) in a transgenic poplar

Trichloroethylene (TCE) is an important environmental contaminant of soil, groundwater, and air. Studies of the metabolism of TCE by poplar trees suggest that cytochrome P450 enzymes are involved. Using poplar genome microarrays, we report a number of putative genes that are differentially expressed in response to TCE. In a previous study, transgenic hybrid poplar plants expressing mammalian cytochrome P450 2E1 (CYP2E1) had increased metabolism of TCE. In the vector control plants for this construct, 24 h following TCE exposure, 517 genes were upregulated and 650 genes were downregulated over 2-fold when compared with the non-exposed vector control plants. However, in the transgenic CYP2E1 plant, line 78, 1,601 genes were upregulated and 1,705 genes were downregulated over 2-fold when compared with the non-exposed transgenic CYP2E1 plant. It appeared that the CYP2E1 transgenic hybrid poplar plants overexpressing mammalian CYP2E1 showed a larger number of differentially expressed transcripts, suggesting a metabolic pathway for TCE to metabolites had been initiated by activity of CYP2E1 on TCE. These results suggest that either the over-expression of the CYP2E1 gene or the abundance of TCE metabolites from CYP450 2E1 activity triggered a strong genetic response to TCE. Particularly, cytochrome p450s, glutathione S-transferases, glucosyltransferases, and ABC transporters in the CYP2E1 transgenic hybrid poplar plants were highly expressed compared with in vector controls.

Trichloroethylene Causes Generalized Hypersensitivity Skin Disorders Complicated by Hepatitis

Idiosyncratic generalized skin disorders complicated by hepatitis, which resemble severe drug hypersensitivities, occur sporadically in workers exposed to trichloroethylene (TCE) in China. However, it has been a matter of controversy whether the solvent itself, not its impurities or stabilizers, can cause hypersensitivity reactions or not. This study aimed to characterize the exposure of hospitalized patients and their healthy colleagues. TCE metabolites were measured in urine of 19 hospitalized patients suffering from the disorders. To assess the exposure of patients' healthy colleagues, on-site surveys were conducted in 6 factories where the disorders occurred and in 2 control factories without such occurrences despite TCE use. Urinalysis of the patients detected trichloroacetic acid (TCA) in all of them. Its average concentration in the end-of-shift urine was estimated to be 206 mg/l. On-site survey of healthy exposed workers revealed that the maximum urinary TCA concentrations and the maximum time-weighted average concentrations of personal TCE exposure were 318-1,617 mg/l and 164-2,330 mg/m(3), respectively. There was no common impurity in TCE used in the factories. These results suggested that TCE itself caused the skin hypersensitivity disorders, and that the disorders occurred in factories where TCE metabolites could be extensively accumulated, possibly due to long working hours. Since the lowest TCA concentration in the end-of-shift urine of the patients was estimated to be 72-80 mg/l, it is recommended to control TCE exposure to keep the urinary TCA concentration below 50 mg/l to reduce the disease risk.

Ovarian gene expression is stable after exposure to trichloroethylene

Exposure of female rats to trichloroethylene (TCE), an environmental toxicant commonly found in ground and surface waters throughout the United States, reduces the fertilizability of oocytes produced by these females compared with oocytes from control females. Localization of cytochrome P450 2E1 and glutathione s-transferase α, TCE-metabolizing enzymes, in the ovary suggests TCE metabolism occurs in the ovary. The production of bioactive TCE metabolites in the ovary may alter female reproductive function by altering ovarian gene transcription and/or protein expression and function. The purpose of the present study was to examine ovarian gene transcription after exposure of female rats to 0.45% TCE (v/v) in 3% Tween. Control rats received 3% Tween. Microarray analysis after 1 and 5 days of exposure indicated ovarian gene transcription was maintained during TCE exposure with the possible exception of a very few genes. Although conclusions for these few genes were ambiguous from the microarray analysis due to the minimal but statistically significant reductions, quantitative real time RT-PCR (qRT-PCR) analysis indicated expression of these genes was unaltered after TCE exposure. Protein analysis confirmed qRT-PCR results. This study suggests TCE-induced reductions in oocyte fertilizability are independent of currently detectable alterations in ovarian gene expression.

Occupational trichloroethylene exposure as a cause of idiosyncratic generalized skin disorders and accompanying hepatitis similar to drug hypersensitivities

Workers exposed to trichloroethylene (TCE) rarely show severe generalized skin disorders and accompanying hepatitis which resemble drug hypersensitivities. The disorders are completely different from solvent-induced irritating contact dermatitis, and their serious consequences have become one of the critical occupational health issues recently in Asia. The present review sheds light on the analogous relationship between the reported patients' clinical manifestations and those of severe drug rash, and provides a comprehensive picture of the disorder occurrences among TCE-exposed workers to date. All literature published in English and ad hoc publications in local languages were reviewed. The patients typically showed rash on the extremities, face, neck or trunk with/without fever 2 weeks to 2 months after commencement of occupational TCE exposure. Reported cutaneous manifestations were classified into two hypersensitivity categories, i.e. hypersensitivity syndrome and erythema multiforme/Stevens-Johnson syndrome/toxic epidermal necrolysis. Based on this categorization, 124 (52%) cases were classified as the former and 115 (48%) as the latter. According to the two spectra, the prevalence of each clinical finding of TCE-related skin disorders was close to that in drug hypersensitivities except for disease incidence and the prevalence of fever, hepatitis, and lymphadenopathy. Occurrences of the disorders have been reported from the USA, Japan, Spain, Singapore, China, Korea, Thailand, and the Philippines. The case reports from industrialized countries were mostly published up to 1990, whereas cases from Asian industrializing countries appeared thereafter. The TCE-related generalized skin disorders are important not only in terms of the number of disease occurrences and severity but from the viewpoint of drug hypersensitivity. Systematic collection of clinical information is necessary in cases diagnosed by the same criteria as those used for drug hypersensitivities. Detailed exposure assessments are also required to establish preventive strategies in these countries.