The role of trichloroacetic acid and peroxisome proliferation in the differences in carcinogenicity of perchloroethylene in the mouse and rat

Odum, J.; Green, T.; Foster, John R.; Hext, Paul M.

doi:10.1016/0041-008x(88)90232-3

Cited by 62 publications

(30 citation statements)

References 27 publications

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“…We homogenized the remaining hepatic tissue with a teflon-glass homogenizer in SET buffer (0.25 M sucrose, 5.4 mM EDTA 20 mM Tris-HCl, pH7.4) and prepared peroxisomal fractions (20). Microsomal fractions were prepared by centrifugation of the postperoxisomal supernatant at 105,000 g for 1 hr.…”

Section: Animalsmentioning

confidence: 99%

Prediction of rodent nongenotoxic carcinogenesis: evaluation of biochemical and tissue changes in rodents following exposure to nine nongenotoxic NTP carcinogens.

Elcombe

Odum

Foster

et al. 2002

Environ Health Perspect

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We studied nine presumed nongenotoxic rodent carcinogens, as defined by the U.S. National Toxicology Program (NTP), to determine their ability to induce acute or subacute biochemical and tissue changes that may act as useful predictors of nongenotoxic rodent carcinogenesis. The chemicals selected included six liver carcinogens (two of which are peroxisome proliferators), three thyroid gland carcinogens, and four kidney carcinogens. We administered the chemicals (diethylhexyl phthalate, cinnamyl anthranilate, chlorendic acid, 1,4-dichlorobenzene, monuron, ethylene thiourea, diethyl thiourea, trimethyl thiourea, and d-limonene to the same strains of mice and rats used in the original NTP bioassays (nine chemicals to rats and seven to mice). Selected tissues (liver, thyroid gland, and kidney) were collected from groups of animals at 7, 28, and 90 days for evaluation. Tissue changes selected for study were monitored for all of the test groups, irrespective of the specificity of the carcinogenic responses observed in those tissues. This allowed us to assess both the carcinogen specificity and the carcinogen sensitivity of the events being monitored. We studied relative weight, cell labeling indices, and pathologic changes such as hypertrophy in all tissues; a range of cytochrome P450 enzymes and palmitoyl coenzyme A oxidase in the liver; changes in the levels of plasma total triiodothyronine, total thyroxine, and thyroid-stimulating hormone (TSH) as markers of thyroid gland function; and hyaline droplet formation, tubular basophilia, and the formation of granular casts in the kidney. There were no single measurements that alerted specifically to the carcinogenicity of the agents to the rodent liver, thyroid gland, or kidney. However, in the majority of cases, the chemical induction of cancer in a tissue was preceded by a range of biochemical/morphologic changes, most of which were moderately specific for a carcinogenic outcome, and some of which were highly specific for it (e.g., increases in TSH in the thyroid gland and increases in relative liver weight in the mouse). The only measurements that failed to correlate usefully with carcinogenicity were the induction of liver enzymes (with the exception of the enzymes associated with peroxisome proliferation). Most of the useful markers were evident at the early times studied (7 days and 28 days), but no overall best time for the measurement of all markers was identified. The judicious choice of markers and evaluation times can aid the detection of potential nongenotoxic rodent carcinogens.

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Section: Animalsmentioning

confidence: 99%

Prediction of rodent nongenotoxic carcinogenesis: evaluation of biochemical and tissue changes in rodents following exposure to nine nongenotoxic NTP carcinogens.

Elcombe

Odum

Foster

et al. 2002

Environ Health Perspect

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“…Green et al, (1998) reported that treatment of male F344 rats with the large doses of TCE produced a marked and sustained formic aciduria which is associated with acidification of the urine. Urinary pH falls after TCE treatment by about half a pH unit, but no further, this is presumably due to buffering of the urinary pH by increased ammonium ion excretion (Liesivuori and Savolainen, 1987;Green et al, 1988). Most importantly Green and co-worker's (1998) showed that the formic acid excreted in the urine of TCE-treated rats is not a metabolite of TCE, indicating that it occurs as a result of perturbation of endogenous cellular metabolism Following a single dose of TCE the formic aciduria was still present 72h after dosing, which is in agreement with Green et al, (1998) who reported it reached a maximum by 48h with a half-life of 4-5 days.…”

Section: Discussionmentioning

confidence: 99%

Trichloroethylene-induced formic aciduria: Effect of dose, sex and strain of rat

2013

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Yaqoob, N, Evans, AR and Lock, EATrichloroethylene-induced formic aciduria: effect of dose, sex and strain of rat.http://researchonline.ljmu.ac.uk/1383/ Article LJMU has developed LJMU Research Online for users to access the research output of the University more effectively. Copyright © and Moral Rights for the papers on this site are retained by the individual authors and/or other copyright owners. Users may download and/or print one copy of any article(s) in LJMU Research Online to facilitate their private study or for non-commercial research. You may not engage in further distribution of the material or use it for any profit-making activities or any commercial gain.The version presented here may differ from the published version or from the version of the record. Please see the repository URL above for details on accessing the published version and note that access may require a subscription. AbstractThe industrial solvent trichloroethylene (TCE) has been reported to increase the excretion of formic acid in the urine of male Fischer 344 (F-344) rats following large oral doses. We have examined the dose-response relationship for formic aciduria in male and female Fischer 344 rats, the effect of some known metabolites of TCE and examined the response in male Wistar rats to help understand its relevance to renal toxicity. We report that doses of TCE as low as 8mg/kg for 3 days to both male and female F344 rats produced formic aciduria. The formic aciduria was time-dependent being more marked after 3 doses compared to one dose in male F344 rats and to a lesser extent in female F344 rats. TCE administration to male Wistar rats produced less formic aciduria than in male F344 rats, indicating a strain difference in response.As TCE is primarily metabolized by cytochrome P450 2E1, Wistar rats were administered inducers of cytochrome P450 2E1 followed by TCE, this increased formic acid excretion to a concentration similar to that observed in male F344 rats, indicating a role for P450.Administration of the major metabolites of TCE, trichloroethanol and trichloroacetic acid to male F344 rats also produced a marked and sustained formic aciduria, while the metabolite of TCE formed via glutathione conjugation had no effect on formic acid excretion. The mechanism whereby this response occurs is currently not understood, but the formic acid excreted is not a metabolite of TCE, but appears to be due to interference with the metabolic utilization of formate by a down stream metabolite of TCE. Over the three days of the studies no histopathological evidence of kidney toxicity was observed in F344 rats given TCE, indicating that the perturbation of formate metabolism does not lead to acute renal injury.3

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“…In a previously published study, inhalation exposure to PERC resulted in dose-related liver congestion in rats, with 8/20, 10/20, and 15/19 rats affected at 400, 800, and 1600 ppm, respectively, with no liver effects observed at 200 ppm (NTP, 1986). In another inhalation study, mice and rats were exposed to 200 ppm of PERC for 28 days, or 400 ppm for 14, 21, or 28 days; centrilobular hepatocellular vacuolization was induced in mice and rats developed centrilobular hepatocellular hypertrophy (Odum et al, 1988). Although the kidney has also been reported as a target organ for PERC, effects are typically noted at concentrations higher than those that induce liver effects after intermediate exposure durations (Berman et al, 1995;ATSDR, 1997a).…”

Section: Discussionmentioning

confidence: 99%

Assessment of the immunotoxic potential of trichloroethylene and perchloroethylene in rats following inhalation exposure

Boverhof

Krieger

Hotchkiss

et al. 2012

Journal of Immunotoxicology

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The role of trichloroacetic acid and peroxisome proliferation in the differences in carcinogenicity of perchloroethylene in the mouse and rat

Cited by 62 publications

References 27 publications

Prediction of rodent nongenotoxic carcinogenesis: evaluation of biochemical and tissue changes in rodents following exposure to nine nongenotoxic NTP carcinogens.

Prediction of rodent nongenotoxic carcinogenesis: evaluation of biochemical and tissue changes in rodents following exposure to nine nongenotoxic NTP carcinogens.

Trichloroethylene-induced formic aciduria: Effect of dose, sex and strain of rat

Assessment of the immunotoxic potential of trichloroethylene and perchloroethylene in rats following inhalation exposure

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