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Environmental Health Perspectives May 2000Trichloroethylene (TCE) pharmacokinetics have been studied in experimental animals and humans for over 30 years. Compartmental and physiologically based pharmacokinetic... (Review)
Review
Trichloroethylene (TCE) pharmacokinetics have been studied in experimental animals and humans for over 30 years. Compartmental and physiologically based pharmacokinetic (PBPK) models have been developed for the uptake, distribution, and metabolism of TCE and the production, distribution, metabolism, and elimination of P450-mediated metabolites of TCE. TCE is readily taken up into systemic circulation by oral and inhalation routes of exposure and is rapidly metabolized by the hepatic P450 system and to a much lesser degree, by direct conjugation with glutathione. Recent PBPK models for TCE and its metabolites have focused on the major metabolic pathway for metabolism of TCE (P450-mediated metabolic pathway). This article briefly reviews selected published compartmental and PBPK models for TCE. Trichloroacetic acid (TCA) is considered a principle metabolite responsible for TCE-induced liver cancer in mice. Liver cancer in mice was considered a critical effect by the U.S. Environmental Protection Agency for deriving the current maximum contaminant level for TCE in water. In the literature both whole blood and plasma measurements of TCA are reported in mice and humans. To reduce confusion about disparately measured and model-predicted levels of TCA in plasma and whole blood, model-predicted outcomes are compared for first-generation (plasma) and second-generation (whole blood) PBPK models published by Fisher and colleagues. Qualitatively, animals and humans metabolize TCE in a similar fashion, producing the same metabolites. Quantitatively, PBPK models for TCE and its metabolites are important tools for providing dosimetry comparisons between experimental animals and humans. TCE PBPK models can be used today to aid in crafting scientifically sound public health decisions for TCE.
Topics: Animals; Cytochrome P-450 Enzyme System; Hazardous Substances; Humans; Oxidation-Reduction; Trichloroacetic Acid; Trichloroethylene
PubMed: 10807557
DOI: 10.1289/ehp.00108s2265 -
International Journal of Environmental... Jul 2021Pesticide adjuvants (PAs) denote the general term for auxiliaries in pesticide preparations except for the active components. Toluene, chloroform, and trichloroethylene...
Pesticide adjuvants (PAs) denote the general term for auxiliaries in pesticide preparations except for the active components. Toluene, chloroform, and trichloroethylene are the three most commonly used PAs as organic solvents. The residues of the three chemicals in the process of production and application of pesticides may endanger the ecosystem. In the present study, the mutagenicity of toluene, chloroform, and trichloroethylene as well the mixture of the three chemicals was tested by the reverse mutation test (Ames test) with TA97, TA98, TA100, and TA102 strains in the system with and without rat liver microsomal preparations (S9). The four tester strains have been used for more than 40 years to detect mutagenic compounds in chemicals, cosmetics, and environmental samples. The mutagenicity was detected on tester strains in the separated experiment from the three chemicals. The addition of S9 decreased the mutation ratios of toluene to four strains, except for the TA100 strain, but increased the mutation ratios of chloroform to four strains except for the TA98 strain. Trichloroethylene caused positive mutagenicity to become negative on the TA102 strain. In the mixed experiment, positive effects were detected only on the TA102 strain in the absence of S9. The addition of S9 increased the mutagenicity except for the TA102 strain. The mixture of toluene, chloroform, and trichloroethylene showed antagonism in mutagenicity to tester strains, except for the TA102 strain without S9. However, the mixture showed a synergistic effect to tester strains after adding S9 except for the TA98 strain.
Topics: Animals; Chloroform; Ecosystem; Mutagenicity Tests; Mutagens; Pesticides; Rats; Toluene; Trichloroethylene
PubMed: 34360388
DOI: 10.3390/ijerph18158095 -
Toxicology Jan 2023Numerous Superfund sites are contaminated with the volatile organic chemical trichloroethylene (TCE). In women, exposure to TCE in pregnancy is associated with reduced...
Numerous Superfund sites are contaminated with the volatile organic chemical trichloroethylene (TCE). In women, exposure to TCE in pregnancy is associated with reduced birth weight. Our previous study reported that TCE exposure in pregnant rats decreased fetal weight and elevated oxidative stress biomarkers in placentae, suggesting placental injury as a potential mechanism of TCE-induced adverse birth outcomes. In this study, we investigated if co-exposure with the antioxidant N-acetylcysteine (NAC) attenuates TCE exposure effects on RNA expression. Timed-pregnant Wistar rats were exposed orally to 480 mg TCE/kg/day on gestation days 6-16. Exposure of 200 mg NAC/kg/day alone or as a pre/co-exposure with TCE occurred on gestation days 5-16 to stimulate antioxidant genes prior to TCE exposure. Tissue was collected on gestation day 16. In male and female placentae, we evaluated TCE- and/or NAC-induced changes to gene expression and pathway enrichment analyses using false discovery rate (FDR) and fold-change criteria. In female placentae, exposure to TCE caused significant differential expression 129 genes while the TCE+NAC altered 125 genes, compared with controls (FDR< 0.05 + fold-change >1). In contrast, in male placentae TCE exposure differentially expressed 9 genes and TCE+NAC differentially expressed 35 genes, compared with controls (FDR< 0.05 + fold-change >1). NAC alone did not significantly alter gene expression in either sex. Differentially expressed genes observed with TCE exposure were enriched in mitochondrial biogenesis and oxidative phosphorylation pathways in females whereas immune system pathways and endoplasmic reticulum stress pathways were differentially expressed in both sexes (FDR<0.05). TCE treatment was differentially enriched for genes regulated by the transcription factors ATF6 (both sexes) and ATF4 (males only), indicating a cellular condition triggered by misfolded proteins during endoplasmic reticulum stress. This study demonstrates novel genes and pathways involved in TCE-induced placental injury and showed antioxidant co-treatment largely did not attenuate TCE exposure effects.
Topics: Female; Male; Rats; Pregnancy; Animals; Trichloroethylene; Acetylcysteine; Rats, Wistar; Antioxidants; Placenta
PubMed: 36396003
DOI: 10.1016/j.tox.2022.153371 -
Environmental Health Perspectives May 2000Trichloroethylene (TCE) is both acutely toxic and carcinogenic to the mouse lung following exposure by inhalation. In contrast, it is not carcinogenic in the rat lung... (Review)
Review
Trichloroethylene (TCE) is both acutely toxic and carcinogenic to the mouse lung following exposure by inhalation. In contrast, it is not carcinogenic in the rat lung and is markedly less toxic following acute exposure. Toxicity to the mouse lung is confined almost exclusively to the nonciliated Clara cell and is characterized by vacuolation and increases in cell replication. Chloral, a metabolite of TCE that accumulates in Clara cells and has been shown to be the cause of the toxicity, also causes aneuploidy in some test systems. Cytotoxicity, increased cell division, and aneuploidy are known risk factors in the development of cancer and provide a plausible mode of action for TCE as a mouse lung carcinogen. All acute and chronic effects of TCE on the mouse lung are believed to be a direct consequence of high cytochrome P450 activity and impaired metabolism of chloral in Clara cells. Comparisons between species suggest that the ability of the human lung to metabolize TCE is approximately 600-fold less than that in the mouse. In addition, the human lung differs markedly from the mouse lung in the number and morphology of its Clara cells. Thus, the large quantitative differences between the metabolic capacity of the mouse lung and the human lung, together with the species differences in the number and morphology of lung Clara cells, suggest that the risks to humans are minimal and that other tumor sites should take precedent over the lung when assessing the potential risks to humans exposed to TCE.
Topics: Animals; Carcinogens, Environmental; Humans; Lung; Lung Neoplasms; Neoplasms, Experimental; Species Specificity; Trichloroethylene
PubMed: 10807556
DOI: 10.1289/ehp.00108s2261 -
Environmental Health Perspectives Jun 1995Chlorinated solvents and their natural transformation products are the most frequently observed groundwater contaminants in the United States. In situ bioremediation... (Review)
Review
Chlorinated solvents and their natural transformation products are the most frequently observed groundwater contaminants in the United States. In situ bioremediation using anaerobic or aerobic co-metabolic processes is a promising means of cleaning up contaminated aquifers. Studies show that under natural conditions trichloroethylene can be anaerobically degraded to dichloroethylene, vinyl chloride, and ethylene. Pilot scale field studies of in situ aerobic co-metabolic transformations have shown that indigenous microbes grown on phenol are more effective at degrading trichloroethylene and cis-1,2-dichloroethylene than microbes grown on methane. Modeling studies support field observations and indicate that the removal of trichloroethylene and cis-dichloroethylene results from the biostimulation of an indigenous microbial population. Field tests and modeling studies indicate that, at high TCE concentration, degradation becomes stoichiometrically limited.
Topics: Bacteria, Aerobic; Bacteria, Anaerobic; Biodegradation, Environmental; Hydrocarbons, Chlorinated; Models, Biological; Pilot Projects; Solvents; Trichloroethylene
PubMed: 8565895
DOI: 10.1289/ehp.95103s4101 -
Environmental Health Perspectives May 2000This article focuses on the various models for kidney toxicity due to trichloroethylene (TCE) and its glutathione-dependent metabolites, in particular... (Review)
Review
This article focuses on the various models for kidney toxicity due to trichloroethylene (TCE) and its glutathione-dependent metabolites, in particular S-(1,2-dichlorovinyl)-l-cysteine. Areas of controversy regarding the relative importance of metabolic pathways, species differences in toxic responses, rates of generation of reactive metabolites, and dose-dependent phenomena are highlighted. The first section briefly reviews information on the incidence and risk factors of kidney cancer in the general U.S. population. Epidemiological data on incidence of kidney cancer in male workers exposed occupationally to TCE are also summarized. This is contrasted with cancer bioassay data from laboratory animals, that highlights sex and species differences and, consequently, the difficulties in making risk assessments for humans based on animal data. The major section of the article considers proposed modes of action for TCE or its metabolites in kidney, including peroxisome proliferation, alpha(2u)-globulin nephropathy, genotoxicity, and acute and chronic toxicity mechanisms. The latter comprise oxidative stress, alterations in calcium ion homeostasis, mitochondrial dysfunction, protein alkylation, cellular repair processes, and alterations in gene expression and cell proliferation. Finally, the status of risk assessment for TCE based on the kidneys as a target organ and remaining questions and research needs are discussed.
Topics: Animals; Biological Assay; Carcinogens, Environmental; Disease Models, Animal; Humans; Incidence; Kidney; Kidney Neoplasms; Mutagens; Trichloroethylene; United States
PubMed: 10807554
DOI: 10.1289/ehp.00108s2225 -
Environmental Health Perspectives May 2000Strategies are needed for assessing the risks of exposures to airborne toxicants that vary over concentrations and durations. The goal of this project was to describe... (Review)
Review
Strategies are needed for assessing the risks of exposures to airborne toxicants that vary over concentrations and durations. The goal of this project was to describe the relationship between the concentration and duration of exposure to inhaled trichloroethylene (TCE), a representative volatile organic chemical, tissue dose as predicted by a physiologically based pharmacokinetic model, and neurotoxicity. Three measures of neurotoxicity were studied: hearing loss, signal detection behavior, and visual function. The null hypothesis was that exposure scenarios having an equivalent product of concentration and duration would produce equal toxic effects, according to the classic linear form of Haber's Rule ((italic)C(/italic) times t = k), where C represents the concentration, t, the time (duration) of exposure, and k, a constant toxic effect. All experiments used adult male, Long-Evans rats. Acute and repeated exposure to TCE increased hearing thresholds, and acute exposure to TCE impaired signal detection behavior and visual function. Examination of all three measures of neurotoxicity showed that if Haber's Rule were used to predict outcomes across exposure durations, the risk would be overestimated when extrapolating from shorter to longer duration exposures, and underestimated when extrapolating from longer to shorter duration exposures. For the acute effects of TCE on behavior and visual function, the estimated concentration of TCE in blood at the time of testing correlated well with outcomes, whereas cumulative exposure, measured as the area under the blood TCE concentration curve, did not. We conclude that models incorporating dosimetry can account for differing exposure scenarios and will therefore improve risk assessments over models considering only parameters of external exposure.
Topics: Animals; Brain; Environmental Exposure; Humans; Nervous System; Neurotoxins; Osmolar Concentration; Time Factors; Trichloroethylene
PubMed: 10807561
DOI: 10.1289/ehp.00108s2317 -
British Journal of Industrial Medicine Oct 1966The physical and chemical characteristics of trichlorethylene are discussed together with its uses in industry and medical practice. Chemical and physical methods of the... (Review)
Review
The physical and chemical characteristics of trichlorethylene are discussed together with its uses in industry and medical practice. Chemical and physical methods of the estimation of trichlorethylene in air have been described, including the use of gas detector tubes, which today is the method most commonly employed. The metabolism of trichlorethylene was systematically investigated by Butler (1948), who in animals established the identity of the main metabolites appearing in the urine, Powell (1945a, b) having also done this in human subjects. The excretion of these metabolites has since been repeatedly investigated, but the intermediate breakdown products within the body as well as the organ mainly responsible still remain uncertain. The acute toxicity of trichlorethylene, manifested preponderantly by central nervous system effects, came to be recognized during the second decade of this century, not long after its introduction as a substitute for benzol as a degreasant in Germany during the First World War. The recognition of a possible chronic toxic effect, characterized by a mild psycho-organic syndrome, came much later and is still not universally accepted. Damage to the trigeminal nerve after closed-circuit trichlorethylene anaesthesia was observed soon after its introduction as a general anaesthetic 30 to 40 years ago, and it was shown to be due to breakdown to dichloracetylene in carbon dioxide absorbers. The pure substance seems otherwise not to have a specific effect on this nerve. The balance of opinion, based on human observations and on animal experiments, is against a severe toxic effect on the liver, although individual cases of liver damage in industrial workers have been reported. The sudden fatal collapse of young workers during mild exercise has on rare occasions been described, there being in most cases an element of heavy exposure. Investigations on man and animals indicate that pure trichlorethylene has no severe effect on other systems of the body. Maximum permissible levels for trichlorethylene in air were reduced from 400 p.p.m. in 1947 to 200 p.p.m., and in 1961 there was a further reduction to 100 p.p.m., which, except in the Soviet Union, is at present accepted in most parts of the world.
Topics: Humans; Occupational Medicine; Trichloroethylene
PubMed: 5332897
DOI: No ID Found -
Environmental Health Perspectives May 2000A physiologically based pharmacokinetic (PBPK) model was developed that provides a comprehensive description of the kinetics of trichloroethylene (TCE) and its... (Review)
Review
A physiologically based pharmacokinetic (PBPK) model was developed that provides a comprehensive description of the kinetics of trichloroethylene (TCE) and its metabolites, trichloroethanol (TCOH), trichloroacetic acid (TCA), and dichloroacetic acid (DCA), in the mouse, rat, and human for both oral and inhalation exposure. The model includes descriptions of the three principal target tissues for cancer identified in animal bioassays: liver, lung, and kidney. Cancer dose metrics provided in the model include the area under the concentration curve (AUC) for TCA and DCA in the plasma, the peak concentration and AUC for chloral in the tracheobronchial region of the lung, and the production of a thioacetylating intermediate from dichlorovinylcysteine in the kidney. Additional dose metrics provided for noncancer risk assessment include the peak concentrations and AUCs for TCE and TCOH in the blood, as well as the total metabolism of TCE divided by the body weight. Sensitivity and uncertainty analyses were performed on the model to evaluate its suitability for use in a pharmacokinetic risk assessment for TCE. Model predictions of TCE, TCA, DCA, and TCOH concentrations in rodents and humans are in good agreement with a variety of experimental data, suggesting that the model should provide a useful basis for evaluating cross-species differences in pharmacokinetics for these chemicals. In the case of the lung and kidney target tissues, however, only limited data are available for establishing cross-species pharmacokinetics. As a result, PBPK model calculations of target tissue dose for lung and kidney should be used with caution.
Topics: Animals; Carcinogens, Environmental; Humans; Models, Biological; Risk Assessment; Sensitivity and Specificity; Trichloroethylene
PubMed: 10807559
DOI: 10.1289/ehp.00108s2283 -
BMC Public Health Dec 2023The laundry and dry cleaning industries are critical for maintaining cleanliness and hygiene in our daily lives. However, they have also been identified as sources of... (Review)
Review
BACKGROUND
The laundry and dry cleaning industries are critical for maintaining cleanliness and hygiene in our daily lives. However, they have also been identified as sources of hazardous chemical exposure for workers, leading to potentially severe health implications. Despite mounting evidence that solvents like perchloroethylene and trichloroethylene are carcinogenic, they remain commonly used in the industry. Additionally, while alternative solvents are increasingly being utilized in response to indications of adverse health and environmental effects, there remains a significant gap in our understanding of the potential risks associated with exposure to these new agents.
METHODS
This study aims to identify gaps in the literature concerning worker exposure to contemporary toxic chemicals in the laundry and dry cleaning industry and their associated carcinogenic risks. A scoping review of peer-reviewed publications from 2012 to 2022 was conducted to achieve this objective, focusing on studies that detailed chemical exposures, sampling methods, and workers within the laundry and dry cleaning sector.
RESULTS
In this scoping review, 12 relevant papers were assessed. A majority (66%) examined perchloroethylene exposure, with one notable finding revealing that biomarkers from dry cleaners had significant micronuclei frequency and DNA damage, even when exposed to PCE at levels below occupational exposure limits. Similarly, another study supported these results, finding an increase in early DNA damage among exposed workers. Separate studies on TCE and benzene presented varied exposure levels and health risks, raising concern due to their IARC Group 1 carcinogen classification. Information on alternative solvents was limited, highlighting gaps in health outcome data, exposure guidelines, and carcinogenic classifications.
CONCLUSION
Research on health outcomes, specifically carcinogenicity from solvent exposure in dry cleaning, is limited, with 66% of studies not monitoring health implications, particularly for emerging solvents. Further, findings indicated potential DNA damage from perchloroethylene, even below set occupational limits, emphasizing the need to reevaluate safety limits. As alternative solvents like butylal and high-flashpoint hydrocarbons become more prevalent, investigations into the effects of their exposure are necessary to safeguard workers' health. This scoping review is registered with the Open Science Framework, registration DOI: https://doi.org/10.17605/OSF.IO/Q8FR3 .
Topics: Humans; Tetrachloroethylene; Occupational Exposure; Solvents; Hydrocarbons; Trichloroethylene; Neoplasms
PubMed: 38129859
DOI: 10.1186/s12889-023-17306-y