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Occupational and Environmental Medicine Oct 2022There has been concern over the possible risk of autoimmune diseases from exposure to trichloroethylene (TCE), an industrial solvent and common pollutant near hazardous...
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.
Topics: Animals; Antibodies, Antinuclear; Autoimmune Diseases; Biological Products; Cross-Sectional Studies; Humans; Mice; Occupational Exposure; Trichloroethylene
PubMed: 35504721
DOI: 10.1136/oemed-2022-108266 -
Reproductive Toxicology (Elmsford, N.Y.) Apr 2022Residential and occupational exposures to the industrial solvents perchloroethylene (PERC) and trichloroethylene (TCE) present public health concerns. In humans,...
Residential and occupational exposures to the industrial solvents perchloroethylene (PERC) and trichloroethylene (TCE) present public health concerns. In humans, maternal PERC and TCE exposures can be associated with adverse birth outcomes. Because PERC and TCE are biotransformed to toxic metabolites and placental dysfunction can contribute to adverse birth outcomes, the present study compared the toxicity of key PERC and TCE metabolites in three in vitro human placenta models. We measured cell viability and caspase 3 + 7 activity in the HTR-8/SVneo and BeWo cell lines, and caspase 3 + 7 activity in first trimester villous explant cultures. Cultures were exposed for 24 h to 5-100 µM S-(1,2-dichlorovinyl)-L-cysteine (DCVC) and S-(1,2,2-trichlorovinyl)-L-cysteine (TCVC), or 5-200 µM trichloroacetate (TCA) and dichloroacetate (DCA). DCVC significantly reduced cell viability and increased caspase 3 + 7 activity in HTR-8/SVneo cells at a lower concentration (20 µM) compared with concentrations toxic to BeWo cells and villous explants. Similarly, TCVC reduced cell viability and increased caspase 3 + 7 activity in HTR-8/SVneo cells but not in BeWo cells. TCA and DCA had only negligible effects on HTR-8/SVneo or BeWo cells. This study advances understanding of potential risks of PERC and TCE exposure during pregnancy by identifying metabolites toxic in placental cells and tissues.
Topics: Cysteine; Female; Humans; Placenta; Pregnancy; Solvents; Tetrachloroethylene; Trichloroethylene
PubMed: 35304307
DOI: 10.1016/j.reprotox.2022.03.003 -
Environmental Health Perspectives May 2000Although humans vary in their response to chemicals, comprehensive measures of susceptibility have generally not been incorporated into human risk assessment. The U.S.... (Review)
Review
Although humans vary in their response to chemicals, comprehensive measures of susceptibility have generally not been incorporated into human risk assessment. The U.S. EPA dose-response-based risk assessments for cancer and the RfD/RfC (reference dose-reference concentration) approach for noncancer risk assessments are assumed to protect vulnerable human subgroups. However, these approaches generally rely on default assumptions and do not consider the specific biological basis for potential susceptibility to a given toxicant. In an effort to focus more explicitly on this issue, this article addresses biological factors that may affect human variability and susceptibility to trichloroethylene (TCE), a widely used halogenated industrial solvent. In response to Executive Order 13045, which requires federal agencies to make protection of children a high priority in implementing their policies and to take special risks to children into account when developing standards, this article examines factors that may affect risk of exposure to TCE in children. The influence of genetics, sex, altered health state, coexposure to alcohol, and enzyme induction on TCE toxicity are also examined.
Topics: Biotransformation; Carcinogens, Environmental; Genetic Variation; Humans; Neoplasms; Reproduction; Trichloroethylene
PubMed: 10807552
DOI: 10.1289/ehp.00108s2201 -
Biomolecules Apr 2022Particulate methane monooxygenase (pMMO), a membrane-bound enzyme having three subunits (α, β, and γ) and copper-containing centers, is found in most of the...
Particulate methane monooxygenase (pMMO), a membrane-bound enzyme having three subunits (α, β, and γ) and copper-containing centers, is found in most of the methanotrophs that selectively catalyze the oxidation of methane into methanol. Active sites in the pMMO of OB3b were determined by docking the modeled structure with ethylbenzene, toluene, 1,3-dibutadiene, and trichloroethylene. The docking energy between the modeled pMMO structure and ethylbenzene, toluene, 1,3-dibutadiene, and trichloroethylene was -5.2, -5.7, -4.2, and -3.8 kcal/mol, respectively, suggesting the existence of more than one active site within the monomeric subunits due to the presence of multiple binding sites within the pMMO monomer. The evaluation of tunnels and cavities of the active sites and the docking results showed that each active site is specific to the radius of the substrate. To increase the catalysis rates of methane in the pMMO of OB3b, selected amino acid residues interacting at the binding site of ethylbenzene, toluene, 1,3-dibutadiene, and trichloroethylene were mutated. Based on screening the strain energy, docking energy, and physiochemical properties, five mutants were downselected, B:Leu31Ser, B:Phe96Gly, B:Phe92Thr, B:Trp106Ala, and B:Tyr110Phe, which showed the docking energy of -6.3, -6.7, -6.3, -6.5, and -6.5 kcal/mol, respectively, as compared to the wild type (-5.2 kcal/mol) with ethylbenzene. These results suggest that these five mutants would likely increase methane oxidation rates compared to wild-type pMMO.
Topics: Catalysis; Copper; Methane; Methylosinus trichosporium; Toluene; Trichloroethylene
PubMed: 35454149
DOI: 10.3390/biom12040560 -
Pharmacology & Therapeutics Jan 2014The chlorinated solvent trichloroethylene (TCE) is a ubiquitous environmental pollutant. The carcinogenic hazard of TCE was the subject of a 2012 evaluation by a Working... (Review)
Review
The chlorinated solvent trichloroethylene (TCE) is a ubiquitous environmental pollutant. The carcinogenic hazard of TCE was the subject of a 2012 evaluation by a Working Group of the International Agency for Research on Cancer (IARC). Information on exposures, relevant data from epidemiologic studies, bioassays in experimental animals, and toxicity and mechanism of action studies was used to conclude that TCE is carcinogenic to humans (Group 1). This article summarizes the key evidence forming the scientific bases for the IARC classification. Exposure to TCE from environmental sources (including hazardous waste sites and contaminated water) is common throughout the world. While workplace use of TCE has been declining, occupational exposures remain of concern, especially in developing countries. The strongest human evidence is from studies of occupational TCE exposure and kidney cancer. Positive, although less consistent, associations were reported for liver cancer and non-Hodgkin lymphoma. TCE is carcinogenic at multiple sites in multiple species and strains of experimental animals. The mechanistic evidence includes extensive data on the toxicokinetics and genotoxicity of TCE and its metabolites. Together, available evidence provided a cohesive database supporting the human cancer hazard of TCE, particularly in the kidney. For other target sites of carcinogenicity, mechanistic and other data were found to be more limited. Important sources of susceptibility to TCE toxicity and carcinogenicity were also reviewed by the Working Group. In all, consideration of the multiple evidence streams presented herein informed the IARC conclusions regarding the carcinogenicity of TCE.
Topics: Animals; Carcinogens, Environmental; Humans; Mutagens; Neoplasms; Risk Factors; Solvents; Trichloroethylene
PubMed: 23973663
DOI: 10.1016/j.pharmthera.2013.08.004 -
Environmental Science and Pollution... Aug 2022Exposure to light at night, pineal gland impairment, and the environmental pollutant trichloroethylene (TCE) have serious implications for health and contribute to...
Exposure to light at night, pineal gland impairment, and the environmental pollutant trichloroethylene (TCE) have serious implications for health and contribute to illness, including liver cancer. The adverse effect of the association of continuous exposure to light with decreased melatonin levels and TCE-induced toxicity is not disclosed in target organs. This work explored the role of light and pineal impairment in increasing susceptibility to liver toxicity and cancer upon exposure to TCE. Male albino mice were divided into groups as follows: control group (12-h light/12-h dark cycle), constant light (24-h light), pinealectomized (Pnx) mice, sham surgically treated group, TCE-treated groups subjected to two doses (500 and 1000 mg/kg) at two different light regimens, and combination of Pnx and TCE-treated mice kept at a 12-h light/12-h dark cycle. Melatonin levels were significantly decreased in both Pnx mice and TCE-treated animals at both light regimens. Aspartate transaminase, alanine aminotransferase, activities, and serum bilirubin levels were significantly elevated, whereas albumin levels were markedly decreased in Pnx mice, TCE-treated mice, and the combination group. Histopathological investigations reflected changes in liver function parameters indicating liver injury and induction of cancer. These effects were accompanied by significant increase of the liver cancer biomarker alpha-fetoprotein and the expression of the metastatic markers CD44, TGFβ-1, and VEGF, along with increased oxidative stress indicators and inflammatory cytokines (IL-6, IL-1β, and TNF-α) in both Pnx and TCE-treated mice and the combination group at both light regimens. Taken together, our findings indicated that low melatonin levels, exposure to constant light, and the combination of both factors increases susceptibility to the toxic and carcinogenic effects of TCE on the liver.
Topics: Animals; Chemical and Drug Induced Liver Injury; Liver; Liver Neoplasms; Male; Melatonin; Mice; Pineal Gland; Pinealectomy; Solvents; Trichloroethylene
PubMed: 35419691
DOI: 10.1007/s11356-022-19976-4 -
Toxicology Nov 2018Trichloroethylene (TCE) and tetrachloroethylene (PCE) are structurally similar chemicals that are metabolized through oxidation and glutathione conjugation pathways.... (Comparative Study)
Comparative Study
Trichloroethylene (TCE) and tetrachloroethylene (PCE) are structurally similar chemicals that are metabolized through oxidation and glutathione conjugation pathways. Both chemicals have been shown to elicit liver and kidney toxicity in rodents and humans; however, TCE has been studied much more extensively in terms of both metabolism and toxicity. Despite their qualitative similarities, quantitative comparison of tissue- and strain-specific metabolism of TCE and PCE has not been performed. To fill this gap, we conducted a comparative toxicokinetic study where equimolar single oral doses of TCE (800 mg/kg) or PCE (1000 mg/kg) were administered to male mice of C57BL/6J, B6C3F1/J, and NZW/LacJ strains. Samples of liver, kidney, serum, brain, and lung were obtained for up to 36 h after dosing. For each tissue, concentrations of parent compounds, as well as their oxidative and glutathione conjugation metabolites were measured and concentration-time profiles constructed. A multi-compartment toxicokinetic model was developed to quantitatively compare TCE and PCE metabolism. As expected, the flux through oxidation metabolism pathway predominated over that through conjugation across all mouse strains examined, it is 1,200-3,800 fold higher for TCE and 26-34 fold higher for PCE. However, the flux through glutathione conjugation, albeit a minor metabolic pathway, was 21-fold higher for PCE as compared to TCE. The degree of inter-strain variability was greatest for oxidative metabolites in TCE-treated and for glutathione conjugation metabolites in PCE-treated mice. This study provides critical data for quantitative comparisons of TCE and PCE metabolism, and may explain the differences in organ-specific toxicity between these structurally similar chemicals.
Topics: Animals; Brain; Kidney; Liver; Lung; Male; Mice; Models, Biological; Solvents; Species Specificity; Tetrachloroethylene; Tissue Distribution; Trichloroethylene
PubMed: 30053492
DOI: 10.1016/j.tox.2018.07.012 -
Environmental Health Perspectives Nov 2022Both trichloroethylene (TCE) and tetrachloroethylene (PCE) are high-priority chemicals subject to numerous human health risk evaluations by a range of agencies....
Reanalysis of Trichloroethylene and Tetrachloroethylene Metabolism to Glutathione Conjugates Using Human, Rat, and Mouse Liver Models to Improve Precision in Risk Characterization.
BACKGROUND
Both trichloroethylene (TCE) and tetrachloroethylene (PCE) are high-priority chemicals subject to numerous human health risk evaluations by a range of agencies. Metabolism of TCE and PCE determines their ultimate toxicity; important uncertainties exist in quantitative characterization of metabolism to genotoxic moieties through glutathione (GSH) conjugation and species differences therein.
OBJECTIVES
This study aimed to address these uncertainties using novel liver models, interspecies comparison, and a sensitive assay for quantification of GSH conjugates of TCE and PCE, -(1,2-dichlorovinyl)glutathione (DCVG) and -(1,2,2-trichlorovinyl) glutathione (TCVG), respectively.
METHODS
Liver models used herein were suspension, 2-D culture, and micropatterned coculture (MPCC) with primary human, rat, and mouse hepatocytes, as well as human induced pluripotent stem cell (iPSC)-derived hepatocytes (iHep).
RESULTS
We found that, although efficiency of metabolism varied among models, consistent with known differences in their metabolic capacity, formation rates of DCVG and TCVG generally followed the patterns , and primary . Data derived from MPCC were most consistent with estimates from physiologically based pharmacokinetic models calibrated to data.
DISCUSSION
For TCE, the new data provided additional empirical support for inclusion of GSH conjugation-mediated kidney effects as critical for the derivation of noncancer toxicity values. For PCE, the data reduced previous uncertainties regarding the extent of TCVG formation in humans; this information was used to update several candidate kidney-specific noncancer toxicity values. Overall, MPCC-derived data provided physiologically relevant estimates of GSH-mediated metabolism of TCE and PCE to reduce uncertainties in interspecies extrapolation that constrained previous risk evaluations, thereby increasing the precision of risk characterizations of these high-priority toxicants. https://doi.org/10.1289/EHP12006.
Topics: Humans; Rats; Mice; Animals; Trichloroethylene; Tetrachloroethylene; Induced Pluripotent Stem Cells; Glutathione; Liver
PubMed: 36445294
DOI: 10.1289/EHP12006 -
Experimental Biology and Medicine... Jul 2011At birth, the mammalian ovary contains a finite number of primordial follicles, which once depleted, cannot be replaced. Xenobiotic exposures can destroy primordial... (Review)
Review
At birth, the mammalian ovary contains a finite number of primordial follicles, which once depleted, cannot be replaced. Xenobiotic exposures can destroy primordial follicles resulting in premature ovarian failure and, consequently, early entry into menopause. A number of chemical classes can induce premature ovarian failure, including environmental, chemotherapeutic and industrial exposures. While our knowledge on the mechanistic events that occur in the ovary with chemical exposures is increasing, our understanding of the ovary's capacity to metabolize such compounds is less established. This review will focus on three chemicals for which information on ovarian metabolism is known: trichloroethylene, 7,12-dimethylbenz[a]anthracene and 4-vinylcyclohexene. The current state of understanding of ovarian bioactivation and detoxification processes for each will be described.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Cyclohexenes; Female; Inactivation, Metabolic; Ovary; Primary Ovarian Insufficiency; Trichloroethylene; Xenobiotics
PubMed: 21616964
DOI: 10.1258/ebm.2011.011051 -
Environmental Health Perspectives May 2000This article reviews exposure information available for trichloroethylene (TCE) and assesses the magnitude of human exposure. The primary sources releasing TCE into the... (Review)
Review
This article reviews exposure information available for trichloroethylene (TCE) and assesses the magnitude of human exposure. The primary sources releasing TCE into the environment are metal cleaning and degreasing operations. Releases occur into all media but mostly into the air due to its volatility. It is also moderately soluble in water and can leach from soils into groundwater. TCE has commonly been found in ambient air, surface water, and groundwaters. The 1998 air levels in microg/m(3) across 115 monitors can be summarized as follows: range = 0.01-3.9, mean = 0.88. A California survey of large water utilities in 1984 found a median concentration of 3.0 microg/L. General population exposure to TCE occurs primarily by inhalation and water ingestion. Typical average daily intakes have been estimated as 11-33 microg/day for inhalation and 2-20 microg/day for ingestion. A small portion of the population is expected to have elevated exposures as a result of one or more of these pathways: inhalation exposures to workers involved in degreasing operations, ingestion and inhalation exposures occurring in homes with private wells located near disposal/contamination sites, and inhalation exposures to consumers using TCE products in areas of poor ventilation. More current and more extensive data on TCE levels in indoor air, water, and soil are needed to better characterize the distribution of background exposures in the general population and elevated exposures in special subpopulations.
Topics: Body Burden; Environmental Exposure; Humans; Trichloroethylene; United States
PubMed: 10807565
DOI: 10.1289/ehp.00108s2359