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1.  Acute effects of trichloroethylene on blood concentrations and performance decrements in rats and their relevance to humans. 
This study was designed to clarify the nature of effects of trichloroethylene (TCE) on the central nervous system, and to determine the critical concentrations in blood associated with specific behavioural changes. This was achieved by a follow up of the whole time course of TCE intoxication during and after exposure. The effects of a single four hour exposure to TCE on signalled bar press shock avoidance in rats were tested by methods previously applied to investigate the acute neurobehavioural effects of exposure to toluene. Even low exposure to TCE induced shock avoidance performance decrements in rats. Rats exposed to 250 ppm TCE showed a significant decrease both in the total number of lever presses and in avoidance responses at 140 minutes of exposure compared with controls. The rats did not recover their pre-exposure performance until 140 minutes after the exhaustion of TCE vapour. Exposures in the range 250 ppm to 2000 ppm TCE for four hours produced concentration related decreases in the avoidance response rate. No apparent acceleration of the reaction time was seen during exposure to 1000 or 2000 ppm TCE. The latency to a light signal was somewhat prolonged during the exposure to 2000 to 4000 ppm TCE. It is estimated that there was depression of the central nervous system with slight performance decrements and the corresponding blood concentration was 40 micrograms/ml during exposure. Depression of the central nervous system with anaesthetic performance decrements was produced by a blood TCE concentration of about 100 micrograms/ml. These results showed effects of TCE on the central nervous system that were considered to be a function of both the exposure concentration and the duration of exposure, which are closely related to the TCE concentration in blood.
PMCID: PMC1012166  PMID: 8507600
2.  Elevated urinary levels of kidney injury molecule-1 among Chinese factory workers exposed to trichloroethylene 
Carcinogenesis  2012;33(8):1538-1541.
Epidemiological studies suggest that trichloroethylene (TCE) exposure may be associated with renal cancer. The biological mechanisms involved are not exactly known although nephrotoxicity is believed to play a role. Studies on TCE nephrotoxicity among humans, however, have been largely inconsistent. We studied kidney toxicity in Chinese factory workers exposed to TCE using novel sensitive nephrotoxicity markers. Eighty healthy workers exposed to TCE and 45 comparable unexposed controls were included in the present analyses. Personal TCE exposure measurements were taken over a 2-week period before urine collection. Ninety-six percent of workers were exposed to TCE below the current US Occupational Safety and Health Administration permissible exposure limit (100 ppm 8h TWA), with a mean (SD) of 22.2 (35.9) ppm. Kidney injury molecule-1 (KIM-1) and Pi-glutathione S transferase (GST) alpha were elevated among the exposed subjects as compared with the unexposed controls with a strong exposure-response association between individual estimates of TCE exposure and KIM-1 (P < 0.0001). This is the first report to use a set of sensitive nephrotoxicity markers to study the possible effects of TCE on the kidneys. The findings suggest that at relatively low occupational exposure levels a toxic effect on the kidneys can be observed. This finding supports the biological plausibility of linking TCE exposure and renal cancer.
Abbreviations:GSTglutathione-S-transferaseKIM-1kidney injury molecule-1NAGN-acetyl-beta-(d)-glucosaminidaseOVMorganic vapour monitoringTCEtrichloroethyleneVEGFvascular endothelial growth factor.
PMCID: PMC3499056  PMID: 22665366
3.  Threshold of trichloroethylene contamination in maternal drinking waters affecting fetal heart development in the rat. 
Environmental Health Perspectives  2003;111(3):289-292.
Halogenated hydrocarbons such as trichloroethylene (TCE) are among the most common water supply contaminants in the United States and abroad. Epidemiologic studies have found an association but not a cause-and-effect relation between halogenated hydrocarbon contamination and increased incidence of congenital cardiac malformations or other defective birth outcomes. Avian and rat studies demonstrated statistically significant increases in the number of congenital cardiac malformations in those treated with high doses of TCE, either via intrauterine pump or in maternal drinking water, compared with controls. This study attempts to determine if there is a threshold dose exposure to TCE above which the developing heart is more likely to be affected. Sprague-Dawley rats were randomly placed in test groups and exposed to various concentrations of TCE (2.5 ppb, 250 ppb, 1.5 ppm, 1,100 ppm) in drinking water or distilled water (control group) throughout pregnancy. The percentage of abnormal hearts in the treated groups ranged from 0 to 10.48%, with controls having 2.1% abnormal hearts, and the number of litters with fetuses with abnormal hearts ranged from 0 to 66.7%, and the control percentage was 16.4%. The data from this study indicate not only that there is a statistically significant probability overall of a dose response to increasing levels of TCE exposure, but also that this trend begins to manifest at relatively low levels of exposure (i.e., < 250 ppb). Maternal rats exposed to more than this level of TCE during pregnancy showed an associated increased incidence of cardiac malformations in their developing rat fetuses.
PMCID: PMC1241384  PMID: 12611656
4.  Evaluation of the psychophysiological functions in humans exposed to trichloroethylene 
Salvini, M., Binaschi, S., and Riva, M. (1971).Brit. J. industr. Med.,28, 293-295. Evaluation of the psychophysiological functions in humans exposed to trichloroethylene. To provide data on the psychophysiological efficiency of human beings exposed to solvent vapour currently used in the industry the effects of trichloroethylene (TCE) were evaluated by exposing six male university students to an average vapour concentration of 110 p.p.m. for two s4-hour exposures, separated by a 1½-hour interval. Each subject was examined on two different days, on one day undertaking a set of tests in an atmosphere contaminated with TCE vapours and on another day in a `control' atmosphere which did not contain TCE.
On each of the two days two sets of test were performed at 8.30 a.m. and at 6 p.m. The following tests were performed: perception test with tachistoscopic presentation, Wechsler Memory Scale, complex reaction time test, and manual dexterity test. A crossed scheme analysis was used. In all the tests performed a statistically very significant decrease in performance ability was seen; the greatest decrease occurred during the more complex tests. The suggested TLV for TCE (100 p.p.m) appears to be very close to the average concentration capable of interfering with psychophysiological efficiency, even in the absence of other undesirable subjective and objective manifestations.
PMCID: PMC1069504  PMID: 5557850
5.  Occupational exposure to trichloroethylene is associated with a decline in lymphocyte subsets and soluble CD27 and CD30 markers 
Carcinogenesis  2010;31(9):1592-1596.
Occupational cohort and case–control studies suggest that trichloroethylene (TCE) exposure may be associated with non-Hodgkin lymphoma (NHL) but findings are not consistent. There is a need for mechanistic studies to evaluate the biologic plausibility of this association. We carried out a cross-sectional molecular epidemiology study of 80 healthy workers that used TCE and 96 comparable unexposed controls in Guangdong, China. Personal exposure measurements were taken over a three-week period before blood collection. Ninety-six percent of workers were exposed to TCE below the current US Occupational Safety and Health Administration Permissible Exposure Limit (100 p.p.m. 8 h time-weighted average), with a mean (SD) of 22.2 (36.0) p.p.m. The total lymphocyte count and each of the major lymphocyte subsets including CD4+ T cells, CD8+ T cells, natural killer (NK) cells and B cells were significantly decreased among the TCE-exposed workers compared with controls (P < 0.05), with evidence of a dose-dependent decline. Further, there was a striking 61% decline in sCD27 plasma level and a 34% decline in sCD30 plasma level among TCE-exposed workers compared with controls. This is the first report that TCE exposure under the current Occupational Safety and Health Administration workplace standard is associated with a decline in all major lymphocyte subsets and sCD27 and sCD30, which play an important role in regulating cellular activity in subsets of T, B and NK cells and are associated with lymphocyte activation. Given that altered immunity is an established risk factor for NHL, these results add to the biologic plausibility that TCE is a possible lymphomagen.
PMCID: PMC2930801  PMID: 20530238
6.  Trichloroethylene Metabolism in the Rat Ovary Reduces Oocyte Fertilizability 
Chemico-biological interactions  2007;170(1):20-30.
Exposure to trichloroethylene (TCE, an environmental toxicant) reduced oocyte fertilizability in the rat. In vivo, TCE may be metabolized by cytochrome P450 dependent oxidation or glutathione conjugation in the liver or kidneys, respectively. Cytochrome P450 dependent oxidation is the higher affinity pathway. The primary isoform of cytochrome P450 to metabolize TCE in the liver, cytochrome P450 2E1, is present in the rodent ovary. Ovarian metabolism of TCE by the oxidative pathway and the production of reactive oxygen species may occur given the presence of the metabolizing enzyme. The objectives of this study were to define the sensitive interval of oocyte growth to TCE exposure, and to determine if TCE exposure resulted in the formation of ovarian protein carbonyls, an indicator of oxidative damage. Rats were exposed to TCE in drinking water (0.45% TCE (v/v) in 3% Tween) or 3% Tween (vehicle-control) during three 4–5 day intervals of oocyte development preceding ovulation. Oocytes from TCE-exposed females were less fertilizable compared with vehicle-control oocytes. Immunohistochemical labeling of ovaries and Western blotting of ovarian proteins demonstrated TCE treatment induced a greater incidence of protein carbonyls compared with vehicle controls. Protein carbonyl formation in the ovary is consistent with TCE metabolism by the cytochrome P450 pathway. Oxidative damage following ovarian TCE metabolism or the presence of TCE metabolites may contribute to reduced oocyte fertilizability. In summary, these results indicate maturing oocytes are susceptible to very short in vivo exposures to TCE.
PMCID: PMC2085368  PMID: 17673192
Ovary; In vitro fertilization; Oocyte; Trichloroethylene metabolism
7.  Metabolic changes and DNA hypomethylation in cerebellum are associated with behavioral alterations in mice exposed to trichloroethylene postnatally 
Toxicology and applied pharmacology  2013;269(3):263-269.
Previous studies demonstrated that low-level postnatal and early life exposure to the environmental contaminant, trichloroethylene (TCE), in the drinking water of MRL+/+ mice altered glutathione redox homeostasis and increased biomarkers of oxidative stress indicating a more oxidized state. Plasma metabolites along the interrelated transmethylation pathway were also altered indicating impaired methylation capacity. Here we extend these findings to further characterize the impact of TCE exposure in mice exposed to water only or two doses of TCE in the drinking water (0, 2, and 28 mg/kg/day) postnatally from birth until 6 weeks of age on redox homeostasis and biomarkers of oxidative stress in the cerebellum. In addition, pathway intermediates involved in methyl metabolism and global DNA methylation patterns were examined in cerebellar tissue. Because the cerebellum is functionally important for coordinating motor activity, including exploratory and social approach behaviors, these parameters were evaluated in the present study. Mice exposed to 28 mg/kg/day TCE exhibited increased locomotor activity over time as compared with control mice. In the novel object exploration test, these mice were more likely to enter the zone with the novel object as compared to control mice Similar results were obtained in a second test when an unfamiliar mouse was introduced into the testing arena. The results show for the first time that postnatal exposure to TCE causes key metabolic changes in the cerebellum that may contribute to global DNA methylation deficits and behavioral alterations in TCE-exposed mice.
PMCID: PMC3670756  PMID: 23566951
cerebellum; trichloroethylene; locomotor behavior; oxidative stress; methylation
8.  Coexposure to Mercury Increases Immunotoxicity of Trichloroethylene 
Toxicological Sciences  2010;119(2):281-292.
We have shown previously that chronic (32 weeks) exposure to occupationally relevant concentrations of the environmental pollutant trichloroethylene (TCE) induced autoimmune hepatitis (AIH) in autoimmune-prone MRL+/+ mice. In real-life, individuals are never exposed to only one chemical such as TCE. However, very little is known about the effects of chemical mixtures on the immune system. The current study examined whether coexposure to another known immunotoxicant, mercuric chloride (HgCl2), altered TCE-induced AIH. Female MRL+/+ mice were treated for only 8 weeks with TCE (9.9 or 186.9 mg/kg/day in drinking water) and/or HgCl2 (260 μg/kg/day, sc). Unlike mice exposed to either TCE or HgCl2 alone, mice exposed to both toxicants for 8 weeks developed significant liver pathology commensurate with early stages of AIH. Disease development in the coexposed mice was accompanied by a unique pattern of anti-liver and anti-brain antibodies that recognized, among others, a protein of approximately 90 kDa. Subsequent immunoblotting showed that sera from the coexposed mice contained antibodies specific for heat shock proteins, a chaperone protein targeted by antibodies in patients with AIH. Thus, although TCE can promote autoimmune disease following chronic exposure, a shorter exposure to a binary mixture of TCE and HgCl2 accelerated disease development. Coexposure to TCE and HgCl2 also generated a unique liver-specific antibody response not found in mice exposed to a single toxicant. This finding stresses the importance of including mixtures in assessments of chemical immunotoxicity.
PMCID: PMC3023566  PMID: 21084432
mercury; trichloroethylene; MRL+/+ mice; Co-exposure; liver; autoimmune hepatitis; CD4+ T cells cytokines; autoimmunity
9.  Urinary excretion of total trichloro-compounds, trichloroethanol, and trichloroacetic acid as a measure of exposure to trichloroethylene and tetrachloroethylene 
Ikeda, M., Ohtsuji, H., Imamura, T., and Komoike, Y. (1972).Brit. J. industr. Med.,29, 328-333. Urinary excretion of total trichloro-compounds, trichloroethanol, and trichloroacetic acid as a measure of exposure to trichloroethylene and tetrachloroethylene. To investigate the relation between trichloroethylene and tetrachloroethylene concentrations in working environments and metabolite concentrations in urine, a series of surveys was conducted at 17 workshops where the vapour concentration in the air of each workshop was relatively constant. Urine samples collected from 85 male workers were analysed for total trichloro-compounds (TTC), and trichloroacetic acid (TCA). Trichloroethanol (TCE) was estimated by difference. Statistical analyses of the data revealed that the urinary concentrations of both TTC and TCE were proportional to the atmospheric concentration of trichloroethylene. The concentration of TCA was also related to the vapour concentration up to 50 p.p.m. but not at higher concentrations. Further calculations suggested that only one-third of the trichloroethylene absorbed through the lungs was excreted in the urine during working time.
In tetrachloroethylene exposure, urinary metabolite levels increased until the atmospheric concentration of the solvent reached 50 to 100 p.p.m., but little increase occurred at higher concentration. This observation was further confirmed by experimental exposure of rats. The toxicological significance of changes in the metabolism of the two solvents is discussed in relation to the possible necessity of reducing the threshold limit value from the current value of 100 p.p.m.
PMCID: PMC1009432  PMID: 5044605
10.  Excretion of Trichloroethylene Metabolites in Human Urine 
Five healthy subjects were exposed to known concentrations of trichloroethylene (T.R.I.) for five hours. The amount retained was calculated. The excretion of the metabolites monochloroacetic acid (M.C.A.), trichloroacetic acid (T.C.A.), and trichloroethanol (T.C.E.) in the urine was measured over the next seven to 14 days. Metabolites excreted represented an average of 73% of the dose of T.R.I. retained (M.C.A. 4%, T.C.A. 19%, T.C.E. 50%). The amount and speed of excretion of metabolites in one experiment was increased by giving glucose and insulin. The diurnal variation in the excretion of T.C.A. is emphasized.
After the vapour of T.R.I. has been inhaled the metabolites T.C.A., and M.C.A. are excreted in the urine. Trichloroacetic acid was first detected in canine and human urine by Barrett and Johnston (1939) and Barrett, Cunningham, and Johnston (1939), trichloroethanol was found in canine urine by Butler (1948) and in human urine by Souček and Vlachová (1954). These authors also found monochloroacetic acid to be excreted.
A number of quantitative studies of the formation of the metabolites of T.R.I. have been made. Most interest has been taken in trichloroacetic acid. The prolonged excretion (10 to 14 days) of T.C.A. even after a single exposure to T.R.I. is striking (Barrett et al., 1939; Forssman, 1945; Forssman and Ahlmark, 1946; Souček and Pavelková, 1953). The excretion of the sodium salt of T.C.A. introduced into the organism is equally slow (Powell, 1945; Ahlmark and Forssman, 1949) and has not been satisfactorily explained. Fabre (1949) and Fabre and Truhaut (1952) assumed that it became linked to the red cells but experiments in vitro by Souček (1955) did not confirm this view although linkage to the plasma proteins was considered possible (Souček, 1954).
The gradual increase of the T.C.A. concentration in the plasma and urine for some time after the end of the exposure to T.R.I. is similarly unexplained. Ahlmark and Forssman (1949, 1951) found the excretion of T.C.A. began two to four hours after the beginning of exposure but Souček, Teisinger, and Pavelková (1952) showed that it could be detected within a few minutes. Thereafter it is agreed that the concentration of the T.C.A. in the urine rises to a maximum at 24 to 48 hours and subsequently decreases exponentially for a number of days.
The amount of T.C.A. formed from retained T.R.I. appears to vary with the species. In dogs the T.C.A. excreted accounts for 5-8% of the T.R.I. (Barrett et al., 1939); in rats for 4% (Forssman and Holmquist, 1953); in rabbits for 0·5% (Bartoniček and Souček, 1959). In man higher values have been found: 6-16% (Ahlmark and Forssman, 1951); 7-27% (Souček et al., 1952); 13% (Grandjean, Manchinger, Turrian, Haas, Knoepfel, and Rosenmund, 1955).
Trichloroethanol was shown by Butler (1949) to be eliminated in dogs mainly bound to glucuronic acid, and the amount excreted was three to four times that of T.C.A. The relationship of T.C.A. to T.C.E. has been found in man to be 1: 2 to 1: 4 (Souček and Vlachová, 1954); 1: 2 to 1: 7 (Teisinger, Stýblová, and Vlachová, 1955); 1: 0·5 to 1: 5 (Bardoděj and Krivucová, 1958).
In this paper we have investigated the quantitative relationships of the formation, and the course of elimination in the urine of all three trichloroethylene derivatives following inhalation of its vapour.
PMCID: PMC1037993  PMID: 13832993
11.  Trichloroethylene-Induced Gene Expression and DNA Methylation Changes in B6C3F1 Mouse Liver 
PLoS ONE  2014;9(12):e116179.
Trichloroethylene (TCE), widely used as an organic solvent in the industry, is a common contaminant in air, soil, and water. Chronic TCE exposure induced hepatocellular carcinoma in mice, and occupational exposure in humans was suggested to be associated with liver cancer. To understand the role of non-genotoxic mechanism(s) for TCE action, we examined the gene expression and DNA methylation changes in the liver of B6C3F1 mice orally administered with TCE (0, 100, 500 and 1000 mg/kg b.w. per day) for 5 days. After 5 days TCE treatment at a dose level of 1000 mg/kg b.w., a total of 431 differentially expressed genes were identified in mouse liver by microarray, of which 291 were up-regulated and 140 down-regulated. The expression changed genes were involved in key signal pathways including PPAR, proliferation, apoptosis and homologous recombination. Notably, the expression level of a number of vital genes involved in the regulation of DNA methylation, such as Utrf1, Tet2, DNMT1, DNMT3a and DNMT3b, were dysregulated. Although global DNA methylation change was not detected in the liver of mice exposed to TCE, the promoter regions of Cdkn1a and Ihh were found to be hypo- and hypermethylated respectively, which correlated negatively with their mRNA expression changes. Furthermore, the gene expression and DNA methylation changes induced by TCE were dose dependent. The overall data indicate that TCE exposure leads to aberrant DNA methylation changes, which might alter the expression of genes involved in the TCE-induced liver tumorgenesis.
PMCID: PMC4280179  PMID: 25549359
12.  Occupational Exposure to Trichloroethylene and Serum Concentrations of IL-6, IL-10, and TNF-alpha 
To evaluate the immunotoxicity of trichloroethylene (TCE), we conducted a cross-sectional molecular epidemiology study in China of workers exposed to TCE. We measured serum levels of IL-6, IL-10, and TNF-α, which play a critical role in regulating various components of the immune system, in 71 exposed workers and 78 unexposed control workers. Repeated personal exposure measurements were taken in workers before blood collection using 3 M organic vapor monitoring badges. Compared to unexposed workers, the serum concentration of IL-10 in workers exposed to TCE was decreased by 70% (P = 0.001) after adjusting for potential confounders. Further, the magnitude of decline in IL-10 was >60% and statistically significant in workers exposed to <12 ppm as well as in workers with exposures ≥ 12 ppm of TCE, compared to unexposed workers. No significant differences in levels of IL-6 or TNF-α were observed among workers exposed to TCE compared to unexposed controls. Given that IL-10 plays an important role in immunologic processes, including mediating the Th1/Th2 balance, our findings provide additional evidence that TCE is immunotoxic in humans.
PMCID: PMC4360987  PMID: 23798002
trichloroethylene; immunotoxicity; IL-10; TNF-α; IL-6; occupational exposure
13.  Alterations in serum immunoglobulin levels in workers occupationally exposed to trichloroethylene 
Carcinogenesis  2012;34(4):799-802.
Trichloroethylene (TCE) has been associated with a variety of immunotoxic effects and may be associated with an increased risk of non-Hodgkin lymphoma (NHL). Altered serum immunoglobulin (Ig) levels have been reported in NHL patients and in animals exposed to TCE. Recently, we reported that occupational exposure to TCE is associated with immunosuppressive effects and immune dysfunction, including suppression of B-cell counts and activation, even at relatively low levels. We hypothesized that TCE exposure would also affect Ig levels in humans. We measured serum levels of IgG, IgM and IgE, by enzyme-linked immunosorbent assay, in TCE-exposed workers (n = 80) and unexposed controls (n = 45), matched by age and gender, in a cross-sectional, molecular epidemiology study of occupational exposure to TCE in Guangdong, China. Exposed workers had about a 17.5% decline in serum levels of IgG compared with unexposed controls (P = 0.0002). Similarly, serum levels of IgM were reduced by about 38% in workers exposed to TCE compared with unexposed controls (P < 0.0001). Serum levels of both IgG and IgM were significantly decreased in workers exposed to TCE levels below 12 p.p.m., the median exposure level. Adjustment for B-cell counts had minimal impact on our findings. IgE levels were not significantly different between exposed and control subjects. These results provide further evidence that TCE is immunotoxic at relatively low exposure levels and provide additional biologic plausibility for the reported association of TCE with NHL.
PMCID: PMC3616671  PMID: 23276795
14.  Ovarian Gene Expression is Stable after Exposure to Trichloroethylene 
Toxicology letters  2007;177(1):59-65.
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.
PMCID: PMC2747470  PMID: 18249509
Trichloroethylene; Ovary; Gene expression; Protein expression; Oocyte plasma membrane
15.  Effects of chronic exposure to low doses of trichloroethylene on steroid hormone and insulin levels in normal men. 
The aim of this study was to examine the serum levels of insulin and some adrenal steroid hormones in men chronically exposed to low doses of trichloroethylene (TCE). A total of 85 workers participated in this study. Each worker had urine collected and analyzed for trichloroacetic acids (UTCA) on the same day that a blood sample was taken for analyses of serum testosterone, sex hormone-binding globulin (SHBG), androstenedione, cortisol, aldosterone, and insulin. The mean concentration of environmental TCE was 29.6 ppm and the mean UTCA was 22.4 mg/g creatinine (range 0.8-136.4). TCE exposure did not cause any significant changes to the adrenal steroid hormone productions. The results showed that UTCA was significantly correlated to serum insulin levels. Insulin and SHBG responded in tandem, with the highest levels found in workers exposed to TCE for less than 2 years; levels of both parameters were significantly lowered in those exposed for more than 2 years. A triphasic response in insulin levels to TCE, which depended on the duration of exposure, was noted. Initial exposure caused an acute rise in insulin levels. This was followed by a fall to normal levels in those exposed 2-4 years and then a slight rise in those exposed for more than 6 years. The mechanism for this pattern of response to TCE exposure is yet unknown.
PMCID: PMC1532938  PMID: 9417767
16.  In silico toxicology: simulating interaction thresholds for human exposure to mixtures of trichloroethylene, tetrachloroethylene, and 1,1,1-trichloroethane. 
Environmental Health Perspectives  2002;110(10):1031-1039.
In this study, we integrated our understanding of biochemistry, physiology, and metabolism of three commonly used organic solvents with computer simulation to present a new approach that we call "in silico" toxicology. Thus, we developed an interactive physiologically based pharmacokinetic (PBPK) model to predict the individual kinetics of trichloroethylene (TCE), perchloroethylene (PERC), and methylchloroform (MC) in humans exposed to differently constituted chemical mixtures of the three solvents. Model structure and parameterization originate from the literature. We calibrated the single-compound PBPK models using published data and described metabolic interactions within the chemical mixture using kinetic constants estimated in rats. The mixture model was used to explore the general pharmacokinetic profile of two common biomarkers of exposure, peak TCE blood levels and total amount of TCE metabolites generated, in rats and humans. Assuming that a 10% change in the biomarkers corresponds to a significant health effect, we calculated interaction thresholds for binary and ternary mixtures of TCE, PERC, and MC. Increases in the TCE blood levels led to higher availability of the parent compound for glutathione conjugation, a metabolic pathway associated with kidney toxicity/carcinogenicity. The simulated change in production rates of toxic conjugative metabolites exceeded 17% for a corresponding 10% increase in TCE blood concentration, indicating a nonlinear risk increase due to combined exposures to TCE. Evaluation of metabolic interactions and their thresholds illustrates a unique application of PBPK modeling in risk assessment of occupational exposures to chemical mixtures.
PMCID: PMC1241030  PMID: 12361929
17.  Lack of formic acid production in rat hepatocytes and human renal proximal tubule cells exposed to chloral hydrate or trichloroacetic acid 
Toxicology  2006;230(2-3):234-243.
The industrial solvent trichloroethylene (TCE) and its major metabolites have been shown to cause formic aciduria in male rats. We have examined whether chloral hydrate (CH) and trichloroacetic acid (TCA), known metabolites of TCE, produce an increase in formic acid in vitro in cultures of rat hepatocytes or human renal proximal tubule cells (HRPTC). The metabolism and cytotoxicity of CH was also examined to establish that the cells were metabolically active and not compromised by toxicity. Rat hepatocytes and HRPTC were cultured in serum-free medium and then treated with 0.3–3mM CH for 3 days or 0.03–3mM CH for 10 days respectively and formic acid production, metabolism to trichloroethanol (TCE-OH) and TCA and cytotoxicity determined. No increase in formic acid production in rat hepatocytes or HRPTC exposed to CH was observed over and above that due to chemical degradation, neither was formic acid production observed in rat hepatocytes exposed to TCA. HRPTC metabolised CH to TCE-OH and TCA with a 12-fold greater capacity to form TCE-OH versus TCA. Rat hepatocytes exhibited a 1.6-fold and 3-fold greater capacity than HRPTC to form TCE-OH and TCA respectively. CH and TCA were not cytotoxic to rat hepatocytes at concentrations up to 3mM/day for 3 days. With HRPTC, one sample showed no cytotoxicity to CH at concentrations up to 3mM/day for 10 days, while in another cytotoxicity was seen at 1mM/day for 3 days. In summary, increased formic acid production was not observed in rat hepatocytes or HRPTC exposed to TCE metabolites, suggesting that the in vivo response cannot be modelled in vitro. CH was toxic to HRPTC at millimolar concentrations/day over 10 days, while glutathione derived metabolites of TCE were toxic at micromolar concentrations/day over 10 days (Lock et al., 2006) supporting the view that glutathione derived metabolites are likely to be responsible for nephrotoxicity.
PMCID: PMC2645029  PMID: 17161896
Trichloroethylene; chloral hydrate; trichloroethanol; trichloroacetic acid; formic acid; human renal proximal tubule cells; rat hepatocytes
18.  Trichloroethylene Exposure during Cardiac Valvuloseptal Morphogenesis Alters Cushion Formation and Cardiac Hemodynamics in the Avian Embryo 
Environmental Health Perspectives  2006;114(6):842-847.
It is controversial whether trichloroethylene (TCE) is a cardiac teratogen. We exposed chick embryos to 0, 0.4, 8, or 400 ppb TCE/egg during the period of cardiac valvuloseptal morphogenesis (2–3.3 days’ incubation). Embryo survival, valvuloseptal cellularity, and cardiac hemodynamics were evaluated at times thereafter. TCE at 8 and 400 ppb/egg reduced embryo survival to day 6.25 incubation by 40–50%. At day 4.25, increased proliferation and hypercellularity were observed within the atrioventricular and outflow tract primordia after 8 and 400 ppb TCE. Doppler ultrasound revealed that the dorsal aortic and atrioventricular blood flows were reduced by 23% and 30%, respectively, after exposure to 8 ppb TCE. Equimolar trichloroacetic acid (TCA) was more potent than TCE with respect to increasing mortality and causing valvuloseptal hypercellularity. These results independently confirm that TCE disrupts cardiac development of the chick embryo and identifies valvuloseptal development as a period of sensitivity. The hypercellular valvuloseptal profile is consistent with valvuloseptal heart defects associated with TCE exposure. This is the first report that TCA is a cardioteratogen for the chick and the first report that TCE exposure depresses cardiac function. Valvuloseptal hypercellularity may narrow the cardiac orifices, which reduces blood flow through the heart, thereby compromising cardiac output and contributing to increased mortality. The altered valvuloseptal formation and reduced hemodynamics seen here are consistent with such an outcome. Notably, these effects were observed at a TCE exposure (8 ppb) that is only slightly higher than the U.S. Environmental Protection Agency maximum containment level for drinking water (5 ppb).
PMCID: PMC1480523  PMID: 16759982
cardiac cushions; chick embryo; Doppler ultrasound; heart development; proliferation; trichloroethylene
19.  A comparative study of the excretion of Fujiwara reaction-positive substances in urine of humans and rodents given trichloro- or tetrachloro-derivatives of ethane and ethylene 
Ikeda, M., and Ohtsuji, H. (1972).Brit. J. industr. Med.,29, 99-104. A comparative study or the excretion of Fujiwara reaction-positive substances in urine of humans and rodents given trichloro- or tetrachloro-derivatives of ethane and ethylene. 1,1,1-Trichloroethane, 1,1,2- trichloroethane, 1,1,1,2-tetrachloroethane, 1,1,2,2-tetrachloroethane, trichloroethylene, and tetrachloroethylene were administered to rats and mice as vapours at 200 p.p.m. for 8 hours and urine was collected for 48 hours. The urine was analysed by the Fujiwara reaction for total trichlorocompounds (TTC), trichloroacetic acid (TCA), and trichloroethanol (TCE). All compounds except 1,1,2-trichloroethane yielded substantial TCA and TCE but 1,1,1,2-tetrachloroethane and trichloroethylene much more than the rest. The results obtained during two periods of 48 hours after intraperitoneal injection were similar. The variations in the amounts of metabolites are shown to be consistent with the vapour pressures of the solvents (compounds with high vapour pressures are lost from the lungs before being metabolized) and with their known chemical properties, according to which 1,1,1-trichlorocompounds should yield TCE and TCA readily, whereas 1,1,2-chlorocompounds should not.
Excretion of metabolites from men exposed intermittently to vapours of tetrachloroethylene and trichloroethylene were also studied. Both gave enough TCE and TCA, but trichloroethylene gave considerably more, in accordance with its relative instability to oxidation.
PMCID: PMC1009358  PMID: 5060252
20.  Postnatal exposure to trichloroethylene alters glutathione redox homeostasis, methylation potential, and neurotrophin expression in the mouse hippocampus 
Neurotoxicology  2012;33(6):1518-1527.
Previous studies have shown that continuous exposure throughout gestation until the juvenile period to environmentally-relevant doses of trichloroethylene (TCE) in the drinking water of MRL+/+ mice promoted adverse behavior associated with glutathione depletion in the cerebellum indicating increased sensitivity to oxidative stress. The purpose of this study was to extend our findings and further characterize the impact of TCE exposure on redox homeostasis and biomarkers of oxidative stress in the hippocampus, a brain region prone to oxidative stress. Instead of a continuous exposure, the mice were exposed to water only or two environmentally relevant doses of TCE in the drinking water postnatally from birth until 6 weeks of age. Biomarkers of plasma metabolites in the transsulfuration pathway and the transmethylation pathway of the methionine cycle were also examined. Gene expression of neurotrophins was examined to investigate a possible relationship between oxidative stress, redox imbalance and neurotrophic factor expression with TCE exposure. Our results show that hippocampi isolated from male mice exposed to TCE showed altered glutathione redox homeostasis indicating a more oxidized state. Also observed was a significant, dose dependent increase in glutathione precursors. Plasma from the TCE treated mice showed alterations in metabolites in the transsulfuration and transmethylation pathways indicating redox imbalance and altered methylation capacity. 3-Nitrotyrosine, a biomarker of protein oxidative stress, was also significantly higher in plasma and hippocampus of TCE-exposed mice compared to controls. In contrast, expression of key neurotrophic factors in the hippocampus (BDNF, NGF, and NT-3) was significantly reduced compared to controls. Our results demonstrate that low-level postnatal and early life TCE exposure modulates neurotrophin gene expression in the mouse hippocampus and may provide a mechanism for TCE-mediated neurotoxicity.
PMCID: PMC3383874  PMID: 22421312
trichloroethylene; glutathione; hippocampus; neurotrophins; oxidative stress
21.  Trichloroethylene Hypersensitivity Syndrome Is Potentially Mediated through Its Metabolite Chloral Hydrate 
PLoS ONE  2015;10(5):e0127101.
We documented previously the entity of trichloroethylene (TCE) hypersensitivity syndrome (THS) in occupational workers.
To identify the culprit causative compound, determine the type of hypersensitivity of THS, and establish a screening test for subjects at risk of THS.
TCE and its main metabolites chloral hydrate (CH), trichloroethanol (TCOH) and trichloroacetic acid (TCA) were used as allergens at different concentrations in skin patch tests. The study included 19 case subjects diagnosed with occupational THS, 22 control healthy workers exposed to TCE (exposure >12 weeks), and 20 validation new workers exposed to TCE for <12 weeks free of THS. All subjects were followed-up for 12 weeks after the patch test.
The highest patch test positive rate in subjects with THS was for CH, followed by TCOH, TCA and TCE. The CH patch test positive rate was 100% irrespective of CH concentrations (15%, 10% and 5%). The TCOH patch test positive rate was concentration-dependent (89.5%, 73.7% and 52.6% for 5%, 0.5% and 0.05%, respectively). Lower patch test positive rates were noted for TCA and TCE. All patch tests (including four allergens) were all negative in each of the 22 control subjects. None of the subjects of the validation group had a positive 15% CH patch test.
Chloral hydrate seems to be the culprit causative compound of THS and type IV seems to be the major type of hypersensitivity of THS. The CH patch test could be potentially useful for screening workers at risk of THS.
PMCID: PMC4447350  PMID: 26020924
22.  Cometabolic degradation of trichloroethylene by Pseudomonas cepacia G4 in a chemostat with toluene as the primary substrate. 
Pseudomonas cepacia G4 is capable of cometabolic degradation of trichloroethylene (TCE) if the organism is grown on certain aromatic compounds. To obtain more insight into the kinetics of TCE degradation and the effect of TCE transformation products, we have investigated the simultaneous conversion of toluene and TCE in steady-state continuous culture. The organism was grown in a chemostat with toluene as the carbon and energy source at a range of volumetric TCE loading rates, up to 330 mumol/liter/h. The specific TCE degradation activity of the cells and the volumetric activity increased, but the efficiency of TCE conversion dropped when the TCE loading was elevated from 7 to 330 mumol/liter/h. At TCE loading rates of up to 145 mumol/liter/h, the specific toluene conversion rate and the molar growth yield of the cells were not affected by the presence of TCE. The response of the system to varying TCE loading rates was accurately described by a mathematical model based on Michaelis-Menten kinetics and competitive inhibition. A high load of 3,400 mumol of TCE per liter per h for 12 h caused inhibition of toluene and TCE conversion, but reduction of the TCE load to the original nontoxic level resulted in complete recovery of the system within 2 days. These results show that P. cepacia can stably and continuously degrade toluene and TCE simultaneously in a single-reactor system without biomass retention and that the organism is more resistant to high concentrations and shock loadings of TCE than Methylosinus trichosporium OB3b.
PMCID: PMC201811  PMID: 7524444
23.  Altered Cardiac Function and Ventricular Septal Defect in Avian Embryos Exposed to Low-Dose Trichloroethylene 
Toxicological Sciences  2009;113(2):444-452.
Trichloroethylene (TCE) is the most frequently reported organic groundwater contaminant in the United States. It is controversial whether gestational TCE exposure causes congenital heart defects. The basis for TCE’s proposed cardiac teratogenicity is not well understood. We previously showed that chick embryos exposed to 8 ppb TCE during cardiac morphogenesis have reduced cardiac output and increased mortality. To further investigate TCE’s cardioteratogenic potential, we exposed in ovo chick embryos to TCE and evaluated the heart thereafter. Significant mortality was observed following TCE exposures of 8–400 ppb during a narrow developmental period (Hamburger-Hamilton [HH] stages 15–20, embryo day ED2.3–3.5) that is characterized by myocardial expansion, secondary heart looping, and endocardial cushion formation. Of the embryos that died, most did so between ED5.5 and ED6.5. Echocardiography of embryos at ED5.5 found that TCE-exposed hearts displayed significant functional and morphological heterogeneity affecting heart rate, left ventricular mass, and wall thickness. Individual embryos were identified with cardiac hypertrophy as well as with hypoplasia. Chick embryos exposed to 8 ppb TCE at HH17 that survived to hatch exhibited a high incidence (38%, p < 0.01, n = 16) of muscular ventricular septal defects (VSDs) as detected by echocardiography and confirmed by gross dissection; no VSDs were found in controls (n = 14). The TCE-induced VSDs may be secondary to functional impairments that alter cardiac hemodynamics and subsequent ventricular foramen closure, an interpretation consistent with recent demonstrations that TCE impairs calcium handling in cardiomyocytes. These data demonstrate that TCE is a cardiac teratogen for chick.
PMCID: PMC2807037  PMID: 19910388
trichloroethylene; biphasic dose response; cardiac teratogen; chick embryo; ventricular septal defects; echocardiography
24.  Impact of trichloroethylene and toluene on nitrogen cycling in soil. 
Applied and Environmental Microbiology  1997;63(10):4015-4019.
The effects of trichloroethylene (TCE) and toluene on soil nitrogen-cycling activities were examined. Ammonium oxidation potential (AOP) was reduced after incubation with as little as 1 microgram of TCE ml-1, and the effects were generally greater when toluene was present and increased with longer exposure. Arginine ammonification potential and denitrification enzyme activity were constant regardless of TCE concentration or the presence of toluene, while nitrite oxidation potential (NOP) exhibited variable sensitivity. KCl-extractable ammonium levels increased dramatically after exposure to 30 and 60 micrograms of TCE ml-1 in the presence of toluene, whereas gamma-irradiated or sodium azide-treated soil incubated with the same concentrations of TCE and toluene showed no increase. Alfalfa-amended soils showed similar decreases in AOP and increases in extractable ammonium during incubation with 60 micrograms of TCE ml-1 and 20 micrograms of toluene ml-1, although most probable number estimates of the ammonium oxidizer population showed no difference between exposed and unexposed soil. AOP and extractable ammonium returned slowly to control levels after 28 days of incubation in the presence of TCE and toluene. Activity assays to which various TCE and toluene concentrations were added indicated that AOP and NOP were relatively more sensitive to these compounds than was arginine ammonification potential. These results indicate that the soil microbial populations responsible for nitrogen cycling exhibit different sensitivities to TCE and toluene and that they may be more susceptible to adverse effects than previously thought.
PMCID: PMC168714  PMID: 9327567
25.  Aerobic Degradation of Trichloroethylene by Co-Metabolism Using Phenol and Gasoline as Growth Substrates 
Trichloroethylene (TCE) is a common groundwater contaminant of toxic and carcinogenic concern. Aerobic co-metabolic processes are the predominant pathways for TCE complete degradation. In this study, Pseudomonas fluorescens was studied as the active microorganism to degrade TCE under aerobic condition by co-metabolic degradation using phenol and gasoline as growth substrates. Operating conditions influencing TCE degradation efficiency were optimized. TCE co-metabolic degradation rate reached the maximum of 80% under the optimized conditions of degradation time of 3 days, initial OD600 of microorganism culture of 0.14 (1.26 × 107 cell/mL), initial phenol concentration of 100 mg/L, initial TCE concentration of 0.1 mg/L, pH of 6.0, and salinity of 0.1%. The modified transformation capacity and transformation yield were 20 μg (TCE)/mg (biomass) and 5.1 μg (TCE)/mg (phenol), respectively. Addition of nutrient broth promoted TCE degradation with phenol as growth substrate. It was revealed that catechol 1,2-dioxygenase played an important role in TCE co-metabolism. The dechlorination of TCE was complete, and less chlorinated products were not detected at the end of the experiment. TCE could also be co-metabolized in the presence of gasoline; however, the degradation rate was not high (28%). When phenol was introduced into the system of TCE and gasoline, TCE and gasoline could be removed at substantial rates (up to 59% and 69%, respectively). This study provides a promising approach for the removal of combined pollution of TCE and gasoline.
PMCID: PMC4057779  PMID: 24857922
trichloroethylene; co-metabolism; phenol; combined pollution; gasoline

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