The Experts below are selected from a list of 213 Experts worldwide ranked by ideXlab platform
Neil R. Pumford - One of the best experts on this subject based on the ideXlab platform.
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Environmental contaminant Trichloroethylene promotes autoimmune disease and inhibits T-cell apoptosis in MRL(+/+) mice.
Journal of Immunotoxicology, 2006Co-Authors: Kathleen M. Gilbert, Neil R. Pumford, Sarah J. BlossomAbstract:The ability of environmental contaminant Trichloroethylene to alter immune function and promote autoimmunity was tested in female MRL+/+ mice. MRL+/+ mice exposed to occupationally relevant doses of Trichloroethylene in their drinking water for 32 weeks developed autoantibodies and pathological evidence of autoimmune hepatitis. The ability of Trichloroethylene (TCE) to promote autoimmunity was associated with the expansion of activated (CD44hi CD62Llo) CD4+ T-lymphocytes that produced increased levels of the pro-inflammatory cytokine interferon (IFN)-γ. Activated T-lymphocytes can accumulate if activation-induced apoptosis is suppressed. Consequently, the effect of TCE on apoptosis in CD4+ T-lymphocytes was investigated. These experiments were conducted with TCE and one of the major oxidative metabolites of Trichloroethylene, namely trichloroacetaldehyde hydrate (TCAH). CD4+ T-lymphocytes isolated from MRL+/+ mice exposed to TCE or TCAH in their drinking water for 4 weeks were resistant to activation-indu...
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environmental contaminant Trichloroethylene promotes autoimmune disease and inhibits t cell apoptosis in mrl mice
Journal of Immunotoxicology, 2006Co-Authors: Kathleen M. Gilbert, Neil R. Pumford, Sarah J. BlossomAbstract:The ability of environmental contaminant Trichloroethylene to alter immune function and promote autoimmunity was tested in female MRL+/+ mice. MRL+/+ mice exposed to occupationally relevant doses of Trichloroethylene in their drinking water for 32 weeks developed autoantibodies and pathological evidence of autoimmune hepatitis. The ability of Trichloroethylene (TCE) to promote autoimmunity was associated with the expansion of activated (CD44hi CD62Llo) CD4+ T-lymphocytes that produced increased levels of the pro-inflammatory cytokine interferon (IFN)-γ. Activated T-lymphocytes can accumulate if activation-induced apoptosis is suppressed. Consequently, the effect of TCE on apoptosis in CD4+ T-lymphocytes was investigated. These experiments were conducted with TCE and one of the major oxidative metabolites of Trichloroethylene, namely trichloroacetaldehyde hydrate (TCAH). CD4+ T-lymphocytes isolated from MRL+/+ mice exposed to TCE or TCAH in their drinking water for 4 weeks were resistant to activation-indu...
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Inhibition of CYP2E1 Reverses CD4+ T-Cell Alterations in Trichloroethylene-Treated MRL+/+ Mice
Toxicological sciences : an official journal of the Society of Toxicology, 2000Co-Authors: Joseph M. Griffin, Kathleen M. Gilbert, Neil R. PumfordAbstract:Trichloroethylene is an organic solvent that is primarily used as a degreasing agent for metals. There is increasing evidence in both humans and animal models that Trichloroethylene promotes the development of autoimmunity, but little is known about the mechanisms that mediate the effect of Trichloroethylene on the immune system. Metabolic activation of Trichloroethylene is considered an obligatory pathway for other known toxicities such as hepatotoxicity, nephrotoxicity, and carcinogenicity. Trichloroethylene is metabolized by the cytochromes P450, primarily cytochrome P450 2E1 (CYP2E1). To investigate whether metabolism by CYP2E1 is required for immunomodulation, we treated autoimmune prone MRL+/+ mice with Trichloroethylene in the drinking water for 4 weeks, in the presence or absence of diallyl sulfide, a specific inhibitor of CYP2E1. Using an antibody that recognizes proteins covalently modified by a reactive metabolite of Trichloroethylene; two immunoreactive proteins were detected in liver microsomes from Trichloroethylene-treated mice. Formation of these Trichloroethylene-protein adducts, an indicator of metabolic activation, was completely inhibited in animals that were concomitantly treated with Trichloroethylene and diallyl sulfide. The level of CYP2E1 apoprotein in liver microsomes was significantly reduced in the presence of diallyl sulfide. The enhanced mitogen-induced proliferative capacity of T cells from Trichloroethylene-treated MRL+/+ mice was inhibited if the mice were also treated with diallyl sulfide. In addition, the reduction in interleukin-4 levels secreted by activated CD4 + T cells from Trichloroethylene-treated mice was reversed if the mice were also treated with diallyl sulfide. Taken collectively, metabolism of Trichloroethylene by CYP2E1 is responsible, at least in part, for the CD4 + T cell alterations associated with exposure to this environmental toxicant.
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Trichloroethylene accelerates an autoimmune response by Th1 T cell activation in MRL+/+ mice
Immunopharmacology, 2000Co-Authors: Joseph M. Griffin, Kathleen M. Gilbert, Sarah J. Blossom, Stephanie K. Jackson, Neil R. PumfordAbstract:Trichloroethylene (1,1,2-trichloroethene) is a major environmental contaminant. There is increasing evidence relating exposure to Trichloroethylene with autoimmunity. To investigate potential mechanisms, we treated the autoimmune-prone MRL+/+ mice with Trichloroethylene in the drinking water at 0, 2.5 or 5.0 mg/ml and sacrificed them at 4, 8 and 22 weeks. As early as 4 weeks of treatment, Western blot analysis showed a dose-dependent increase in the level of Trichloroethylene-modified proteins, indicating that a reactive metabolite of Trichloroethylene was formed. Significant increases in antinuclear antibodies (ANA) and total serum immunoglobulins were found following 4–8 weeks of Trichloroethylene treatment, indicating that Trichloroethylene was accelerating an autoimmune response. Investigation into possible mechanisms of this autoimmune response revealed that Trichloroethylene treatment dramatically increased the expression of the activation marker CD44 on splenic CD4+ T cells at 4 weeks. In addition, splenic T cells from mice treated for 4 weeks with Trichloroethylene secreted more IFN-γ and less IL-4 than control T cells, consistent of a T-helper type 1 (Th1) type immune or inflammatory response. A specific immune response directed against dichloroacetylated proteins was found at 22 weeks of Trichloroethylene treatment. Taken collectively, the results suggest that Trichloroethylene treatment accelerated an autoimmune response characteristic of MRL+/+ mice in association with nonspecific activation of Th1 cells. In addition, long-term treatment with Trichloroethylene led to the initiation of a Trichloroethylene-specific immune response.
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Trichloroethylene ACTIVATES CD4+ T CELLS: POTENTIAL ROLE IN AN AUTOIMMUNE RESPONSE*
Drug metabolism reviews, 1999Co-Authors: Kathleen M. Gilbert, Joseph M. Griffin, Neil R. PumfordAbstract:Trichloroethylene is an industrial solvent and has become a major environmental contaminant. Autoimmune-prone MRL +/+ mice were treated for up to 22 weeks with Trichloroethylene in the drinking water (0, 2.5, and 5.0 mg/mL) in order to study the immunoregulatory effects of this environmental toxicant. After only 4 weeks of treatment, Trichloroethylene was shown to promote the expansion of CD4+ T cells that expressed a memory/activation phenotype (i.e., CD44hi CD45RBlo) and secreted high levels of IFN-gamma, but not IL-4. In addition, Trichloroethylene treatment accelerated the development of an autoimmune response in the MRL +/+ mice as evidenced by an earlier appearance of antinuclear antibodies and increased levels of total IgG2a. MRL +/+ mice treated with Trichloroethylene for 22 weeks also contained antibodies specific for Trichloroethylene adducts, suggesting the activation of Trichloroethylene-specific T cells. The results suggest that Trichloroethylene can stimulate antigen nonspecific as well as specific T cells that are capable of promoting autoimmunity in genetically predisposed individuals.
Bernard W. Stewart - One of the best experts on this subject based on the ideXlab platform.
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Trichloroethylene and cancer: a carcinogen on trial.
The Medical Journal of Australia, 2001Co-Authors: Bernard W. StewartAbstract:: The organic solvent Trichloroethylene has been used in dry cleaning, as an industrial degreasing agent and as a solvent for oils and resins; large numbers of workers have been exposed to Trichloroethylene, mainly by inhalation. Trichloroethylene has been categorised as a Group 2A carcinogen (probably carcinogenic to humans) by the International Agency for Research on Cancer (World Health Organization) and a Category 2 carcinogen (to be regarded as carcinogenic to humans) by the Australian National Industrial Chemicals Notification and Assessment Scheme. The Administrative Appeals Tribunal was asked to determine the validity of classifying Trichloroethylene as a Category 2 rather than a Category 3 (data inadequate for making a satisfactory assessment) carcinogen. In the AAT's determination, relevant epidemiological evidence was not taken into account because such evidence concerned tumour sites apart from the kidney (the site of tumour induction by Trichloroethylene in rats). This mode of evaluation is fundamentally different from that used by the International Agency for Research on Cancer. The precedent set by the consideration of carcinogenicity data in this case could have significant implications for classification of other putative carcinogens
Richat Abbas - One of the best experts on this subject based on the ideXlab platform.
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A human physiologically based pharmacokinetic model for Trichloroethylene and its metabolites, trichloroacetic acid and free trichloroethanol.
Toxicology and applied pharmacology, 1998Co-Authors: Jeffrey W. Fisher, Deirdre A. Mahle, Richat AbbasAbstract:Nine male and eight female healthy volunteers were exposed to 50 or 100 ppm Trichloroethylene vapors for 4 h. Blood, urine, and exhaled breath samples were collected for development of a physiologically based pharmacokinetic (PBPK) model for Trichloroethylene and its two major P450-mediated metabolites, trichloroacetic acid and free trichloroethanol. Blood and urine were analyzed for Trichloroethylene, chloral hydrate, free trichloroethanol and trichloroethanol glucuronide, and trichloroacetic acid. Plasma was analyzed for dichloroacetic acid. Trichloroethylene was also measured in exhaled breath samples. Trichloroethylene, free trichloroethanol, and trichloroacetic acid were found in blood samples of all volunteers and only trace amounts of dichloroacetic acid (4–12 ppb) were found in plasma samples from a few volunteers. Trichloroethanol glucuronide and trichloroacetic acid were found in urine of all volunteers. No chloral hydrate was detected in the volunteers. Gender-specific PBPK models were developed with fitted urinary rate constant values for each individual Trichloroethylene exposure to describe urinary excretion of trichloroethanol glucuronide and trichloroacetic acid. Individual urinary excretion rate constants were necessary to account for the variability in the measured cumulative amount of metabolites excreted in the urine. However, the average amount of trichloroacetic acid and trichloroethanol glucuronide excreted in urine for each gender was predicted using mean urinary excretion rate constant values for each sex. A four-compartment physiological flow model was used for the metabolites (lung, liver, kidney, and body) and a six-compartment physiological flow model was used for Trichloroethylene (lung, liver, kidney, fat, and slowly and rapidly perfused tissues). Metabolic capacity (Vmaxc) for oxidation of Trichloroethylene was estimated to be 4 mg/kg/h in males and 5 mg/kg/h in females. Metabolized Trichloroethylene was assumed to be converted to either free trichloroethanol (90%) or trichloroacetic acid (10%). Free trichloroethanol was glucuronidated forming trichloroethanol glucuronide or converted to trichloroacetic acid via back conversion of trichloroethanol to chloral (trichloroacetaldehyde). Trichloroethanol glucuronide and trichloroacetic acid were then excreted in urine. Gender-related pharmacokinetic differences in the uptake and metabolism of Trichloroethylene were minor, but apparent. In general, the PBPK models for the male and female volunteers provided adequate predictions of the uptake of Trichloroethylene and distribution of Trichloroethylene and its metabolites, trichloroacetic acid and free trichloroethanol. The PBPK models for males and females consistently overpredicted exhaled breath concentrations of Trichloroethylene immediately following the TCE exposure for a 2- to 4-h period. Further research is needed to better understand the biological determinants responsible for the observed variability in urinary excretion of trichloroethanol glucuronide and trichloroacetic acid and the metabolic pathway resulting in formation of dichloroacetic acid.
M. V. Prabhakara Rao - One of the best experts on this subject based on the ideXlab platform.
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Excess volumes and viscosities of binary mixtures of Trichloroethylene with branched alcohols
Fluid Phase Equilibria, 1997Co-Authors: D. Venkatesulu, P. Venkatesu, M. V. Prabhakara RaoAbstract:Abstract Excess volumes (VE) and viscosities (η) of binary liquid mixtures of Trichloroethylene with branched alcohols have been measured as a function of composition at 303.15 K. The branched alcohols include 2-propanol, 2-methyl-1-propanol, 3-methyl-1-butanol, 2-butanol and 2-methyl-2-propanol. Further, the deviation in viscosities (Δlnη) have been computed from viscosity data. The VE values are positive in mixtures of Trichloroethylene with 2-propanol, 2-butanol, 2-methyl-2-propanol and an inversion of sign from negative to positive is observed in the mixtures of Trichloroethylene with 2-methyl-1-propanol and 3-methyl-1-butanol. The values of Δlnη are negative in all the mixtures except at lower mole fraction of Trichloroethylene in the system Trichloroethylene with 3-methyl-1-butanol.
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Excess volumes of 2-alkoxyethanols with Trichloroethylene and tetrachloroethylene
Journal of Chemical & Engineering Data, 1992Co-Authors: D. Venkatesulu, M. V. Prabhakara RaoAbstract:Excess volumes of binary liquid mixtures of Trichloroethylene and tetrachloroethylene with 2-methoxyethanol, 2-ethoxyethanol, and 2-butoxyethanol have been measured at 909.15 and 919.15 K with a dilatometer. Excess volumes are positive over the entire range of composition for the systems Trichloroethylene+2-methoxyethanol and tetrachloroethylene+2-methoxyethanol,+2-ethoxyethanol, and+2-butoxyethanol and change sign from negative to positive for the remaining two systems, Trichloroethylene+2-ethoxyethanol and+2-butoryethanol
Jorgen H Olsen - One of the best experts on this subject based on the ideXlab platform.
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Cancer Risk among Workers at Danish Companies using Trichloroethylene: A Cohort Study
American Journal of Epidemiology, 2003Co-Authors: Ole Raaschou-nielsen, Joseph K Mclaughlin, Jytte M. Christensen, Johnni Hansen, Robert E Tarone, Henrik A Kolstad, Jorgen H OlsenAbstract:Trichloroethylene is an animal carcinogen with limited evidence of carcinogenicity in humans. Cancer incidence between 1968 and 1997 was evaluated in a cohort of 40,049 blue-collar workers in 347 Danish companies with documented Trichloroethylene use. Standardized incidence ratios for total cancer were 1.1 (95% confidence interval (CI): 1.04, 1.12) in men and 1.2 (95% CI: 1.14, 1.33) in women. For non-Hodgkin’s lymphoma and renal cell carcinoma, the overall standardized incidence ratios were 1.2 (95% CI: 1.0, 1.5) and 1.2 (95% CI: 0.9, 1.5), respectively; standardized incidence ratios increased with duration of employment, and elevated standardized incidence ratios were limited to workers first employed before 1980 for non-Hodgkin’s lymphoma and before 1970 for renal cell carcinoma. The standardized incidence ratio for esophageal adenocarcinoma was 1.8 (95% CI: 1.2, 2.7); the standardized incidence ratio was higher in companies with the highest probability of Trichloroethylene exposure. In a subcohort of 14,360 presumably highly exposed workers, the standardized incidence ratios for non-Hodgkin’s lymphoma, renal cell carcinoma, and esophageal adenocarcinoma were 1.5 (95% CI: 1.2, 2.0), 1.4 (95% CI: 1.0, 1.8), and 1.7 (95% CI: 0.9, 2.9), respectively. The present results and those of previous studies suggest that occupational exposure to Trichloroethylene at past higher levels may be associated with elevated risk for non-Hodgkin’s lymphoma. Associations between Trichloroethylene exposure and other cancers are less consistent. adenocarcinoma; biliary tract neoplasms; esophageal neoplasms; kidney neoplasms; liver neoplasms; lymphoma, non-Hodgkin; occupations; Trichloroethylene
