Trichloroethylene-Induced Mouse Lung Tumors: Studies of the Mode of Action and Comparisons between Species

Green, T.; Mainwaring, Guy; Foster, John R.

doi:10.1093/toxsci/37.2.125

Cited by 13 publications

(29 citation statements)

References 8 publications

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“…The previous conclusion in the last U.S. Environmental Protection Agency risk assessment for TCE (33) (43,44), and this has been attributed to the accumulation of CH, which occurs because the subsequent steps in the metabolism of CH are much slower than the conversion of TCE to CH (45). Besides having a slow rate of subsequent metabolism of CH, the rate of formation of CH in mouse lung is markedly higher than that in either rat or human lung (44).…”

Section: Descrption Ofoxidative Pathways Oftce Metabolismmentioning

confidence: 77%

“…Besides having a slow rate of subsequent metabolism of CH, the rate of formation of CH in mouse lung is markedly higher than that in either rat or human lung (44). CH CH reduction to TCOH has been reported to be inhibited by ethanol, and it was suggested that this reaction is, therefore, catalyzed by alcohol dehydrogenase (47,48 (59) identified DCA, in addition to TCA, TCOH, and TCOG, as a metabolite of CH in children, for whom CH is still used therapeutically as a sedative-hypnotic agent.…”

Section: Descrption Ofoxidative Pathways Oftce Metabolismmentioning

confidence: 90%

“…A situation where differential activities of the enzymes of the oxidative pathway of TCE metabolism markedly affect the distribution of metabolites and the toxicity is that of CH accumulation in mouse lungs (44,45). Clara cells of mouse lungs have relatively high P450 activity but have low activities of alcohol dehydrogenase and UDP-glucuronosyltransferase.…”

Section: Descrption Ofoxidative Pathways Oftce Metabolismmentioning

confidence: 99%

“…Blood samples were taken by cardiac puncture and were analyzed by gas chromatography. AUC were determined graphically up to the final time point taken (TCE: 7.5 hr in rats, 11 hr in mice; CH: 15 hr in rats, 10 hr in mice; TCOH: 18 hr in rats, 8 hr in mice; TCA: 40 hr in rats, 44 hr in mice). For TCA in mice, two major peaks of blood concentration were observed.…”

mentioning

confidence: 99%

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Metabolism of trichloroethylene.

Lash

Fisher

Lipscomb

et al. 2000

Environ Health Perspect

250

246

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A major focus in the study of metabolism and disposition of trichloroethylene (TCE) is to identify metabolites that can be used reliably to assess flux through the various pathways of TCE metabolism and to identify those metabolites that are causally associated with toxic responses. Another important issue involves delineation of sex-and species-dependent differences in biotransformation pathways. Defining these differences can play an important role in the utility of laboratory animal data for understanding the pharmacokinetics and pharmacodynamics of TCE in humans. Sex-, species-, and strain-dependent differences in absorption and distribution of TCE may play some role in explaining differences in metabolism and susceptibility to toxicity from TCE exposure. The majority of differences in susceptibility, however, are likely due to sex-, species-, and strain-dependent differences in activities of the various enzymes that can metabolize TCE and its subsequent metabolites. An additional factor that plays a role in human health risk assessment for TCE is the high degree of variability in the activity of certain enzymes. TCE undergoes metabolism by two major pathways, cytochrome P450 (P450)-dependent oxidation and conjugation with glutathione (GSH). Key P450-derived metabolites of TCE that have been associated with specific target organs, such as the liver and lungs, include chloral hydrate, trichloroacetate, and dichloroacetate. Metabolites derived from the GSH conjugate of TCE, in contrast, have been associated with the kidney as a target organ. Specifically, metabolism of the cysteine conjugate of TCE by the cysteine conjugate ,B Iyase generates a reactive metabolite that is nephrotoxic and may be nephrocarcinogenic. Although the P450 pathway is a higher activity and higher affinity pathway than the GSH conjugation pathway, one should not automatically conclude that the latter pathway is only important at very high doses. A synthesis of this information is then presented to assess how experimental data, from either animals or from in vitro studies, can be extrapolated to humans for risk assessment.

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Section: Descrption Ofoxidative Pathways Oftce Metabolismmentioning

confidence: 77%

Section: Descrption Ofoxidative Pathways Oftce Metabolismmentioning

confidence: 90%

Section: Descrption Ofoxidative Pathways Oftce Metabolismmentioning

confidence: 99%

mentioning

confidence: 99%

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Metabolism of trichloroethylene.

Lash

Fisher

Lipscomb

et al. 2000

Environ Health Perspect

250

246

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“…Glucuronidation of TCOH produces TCOH glucuronide, which is secreted into bile and then into the small intestine, hydrolyzed back to TCOH in the gut, reabsorbed, and is then available for conversion to TCA (Bull, 2000). Humans are efficient at glucuronidating TCOH relative to rodents, although impaired ability for glucuronidation reactions is relatively frequent in the human population (Templin et al, 1993;Green et al, 1997). Recent studies indicated that dichloroacetyl chloride is generated from TCE oxide and can be trapped with lysine to form N ⑀ -dichloroacetyllysine (Cai and Guengerich, 1999).…”

mentioning

confidence: 99%

Identification of Trichloroethylene and Its Metabolites in Human Seminal Fluid of Workers Exposed to Trichloroethylene

Forkert¹,

Lash²,

Tardif³

et al. 2003

Drug Metab Dispos

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ABSTRACT:We have investigated the potential of the male reproductive tract to accumulate trichloroethylene (TCE) and its metabolites, including chloral, trichloroethanol (TCOH), trichloroacetic acid (TCA), and dichloroacetic acid (DCA). Human seminal fluid and urine samples from eight mechanics diagnosed with clinical infertility and exposed to TCE occupationally were analyzed. In in vivo experimental studies, TCE and its metabolites were determined in epididymis and testis of mice exposed to TCE (1000 ppm) by inhalation for 1 to 4 weeks. In other studies, incubations of monkey epididymal microsomes were performed in the presence of TCE and NADPH. Our results showed that seminal fluid from all eight subjects contained TCE, chloral, and TCOH. DCA was present in samples from two subjects, and only one contained TCA. TCA and/or TCOH were also identified in urine samples from only two subjects. TCE, chloral, and TCOH were detected in murine epididymis after inhalation exposure with TCE for 1 to 4 weeks. Levels of TCE and chloral were similar throughout the entire exposure period. TCOH levels were similar at 1 and 2 weeks but increased significantly after 4 weeks of TCE exposure. Chloral was identified in microsomal incubations with TCE in monkey epididymis. CYP2E1, a P450 that metabolizes TCE, was localized in human and monkey epididymal epithelium and testicular Leydig cells. These results indicated that TCE is metabolized in the reproductive tract of the mouse and monkey. Furthermore, TCE and its metabolites accumulated in seminal fluid, and suggested associations between production of TCE metabolites, reproductive toxicity, and impaired fertility.

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Isopropyl benzene (cumene) [MAK Value Documentations, 2013]

Jahnke

Hamann²,

Laube³

et al. 2016

The MAK‐Collection for Occupational Health and Safety

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The German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area has re‐evaluated isopropyl benzene to derive a maximum concentration at the work place (MAK value), considering all toxicity endpoints. Available publications are described in detail. Isopropyl benzene caused adenomas in the nose of rats, and in mice adenomas and carcinomas in the lungs and adenomas in the liver. Genotoxic effects do not seem to be responsible for the carcinogenicity. Concerning the lung tumours of mice, it is assumed that ring hydroxylated metabolites stimulate cell proliferation, which can lead to tumour formation. In humans, the metabolism of aromatic molecules in the respiratory tissues is not yet clarified in detail and therefore carcinogenic effects of isopropyl benzene in humans cannot be excluded. Isopropyl benzene is therefore classified in Carcinogen Category 3B. Isopropyl benzene is not genotoxic, therefore, the derivation of a MAK value is possible. In agreement with the procedures used by the Commission, a MAK value of 10 ml/m 3 was set, derived from a calculated BMDL of 35 ml/m 3 for liver weight increase in the 14‐week study with rats and from the calculated BMDL of 42 ml/m 3 for nasal adenomas in the 2‐year study in rats. On the basis of the mainly systemic effects, the classification in Peak Limitation Category II is retained. The half‐life in humans is considerably longer than 2 hours, so that the excursion factor of 4 is also retained. No foetotoxic or teratogenic effects were found in rats and rabbits up to 1200 and 2300 ml/m 3 , respectively. As the difference between the NOAEC for developmental toxicity and the MAK value is sufficiently large, damage to the embryo or foetus is unlikely when the MAK value is observed. The assignment to Pregnancy Group C is confirmed. Skin contact may contribute significantly to systemic toxicity and the designation with an “H” notation is retained. Sensitisation is not expected based on the result of a maximisation test.

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Trichloroethylene-Induced Mouse Lung Tumors: Studies of the Mode of Action and Comparisons between Species

Cited by 13 publications

References 8 publications

Metabolism of trichloroethylene.

Metabolism of trichloroethylene.

Identification of Trichloroethylene and Its Metabolites in Human Seminal Fluid of Workers Exposed to Trichloroethylene

Isopropyl benzene (cumene) [MAK Value Documentations, 2013]

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