The carcinogenicity of dietary di(2‐ethylhexyl) phthalate (DEHP) in fischer 344 rats and B6C3F<sub>1</sub>mice

Kluwe, William M.; Haseman, Joseph K.; Douglas, J. F.; Huff, James

doi:10.1080/15287398209530296

Cited by 212 publications

(74 citation statements)

References 28 publications

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“…DISCUSSION The decreased body weight gain of DEHP-treated mice of both sexes in all models was ascribed to the toxicity of DEHP. This is because the lower body weight gain was not due to lower feed intake and because the increased incidences of nonneoplastic lesions characteristic for toxicity of DEHP were found in the high-dose groups of all models in 1 or both sexes in the kidneys (12), and in the testes (12,15). The statistically increased water intake that was recorded in all DEHP-and p-cresidine-treated mice compared to controls could be due to the ingestion of the test compunds.…”

Section: Positive Controlmentioning

confidence: 99%

“…Of the remaining rodent carcinogenicity studies, 4 in rats (4,5,12,18) and 2 in mice (6,12) demonstrated a statistically signi cant increase in liver tumors. In a NTP mouse study (12,16), the incidence of treated animals with hepatic carcinomas was statistically signi cantly greater than that in the controls for males ingesting diet with 6,000 ppm DEHP and females ingesting diets with 3,000 or 6,000 ppm DEHP. Furthermore, the combined incidence of animals with hepatocellular carcinomas and adenomas was statistically signi cantly greater than that in controls for males ingesting diet with 3,000 ppm DEHP.…”

Section: Positive Controlmentioning

confidence: 99%

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Assessment of Carcinogenicity of Di(2-ethylhexyl phthalate in a Short-Term Assay Using Xpa-/- and Xpa-/ - /p53+/-Mice

et al. 2002

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The potential of X pa / and X pa / / p53 / mice for short-term carcinogenicity assays was evaluated with di(2-ethylhexyl)phthalate (DEHP). Groups of 15 male and female Xpa / mice, received diets containing 0, 1,500, 3,000, or 6,000 ppm DEHP, and wild-type (WT) and X pa / / p53 / mice 0 or 6,000 ppm DEHP for 39 weeks. X pa / , X pa / / p53 / , and WT males, fed 2,500 ppm p-cresidine, served as a positive control. In all models, the survival was not altered by DEHP. Increased incidences of nonneoplasti c lesions were recorded in testes and kidneys with no apparent difference between the models. The only liver tumors in all models were adenomas in males with no statistically signi cantly increased incidence. For p-cresidine, the survival was decreased ( p < 0.05) only in transgenic models. Statistically signi cantly increased incidences of nonneoplasti c lesions were recorded in the liver, urinary bladder, and nasal cavity in all models, and in kidneys in transgenic models. The only tumors with statistically signi cantly increased incidence were liver adenomas in transgenic models (XPA: 1 vs 7; 'XPA/p53': 0 vs 12; WT: 0 vs 5, p 0.053) and urinary bladder carcinomas in XPA/p53 model (0 vs 7). The negative carcinogeni c response to DEHP and the positive response to p-cresidine support the expected sensitivity to genotoxic carcinogens in these transgenic models.

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Section: Positive Controlmentioning

confidence: 99%

Section: Positive Controlmentioning

confidence: 99%

Assessment of Carcinogenicity of Di(2-ethylhexyl phthalate in a Short-Term Assay Using Xpa-/- and Xpa-/ - /p53+/-Mice

et al. 2002

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“…There have been many reports on the hepatotoxicity, testicular atrophy, teratogenicity and carcinogenicity as related to PEs. [1][2][3][4][5][6] Recently, di-n-butyl phthalate (DBP) and di-(2-ethylhexyl) phthalate (DEHP) have in particular been attracting attention as being suspects in disrupting the endocrine system. [7][8][9][10] PEs are considered to be biodegradable and having low bioaccumulation.…”

mentioning

confidence: 99%

Phthalate Esters Detected in Various Water Samples and Biodegradation of the Phthalates by Microbes Isolated from River Water.

Hashizume

Nanya

Toda

et al. 2002

Biological & Pharmaceutical Bulletin

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Phthalate esters (PEs), especially di-n-butyl phthalate (DBP) and di-(2-ethylhexyl) phthalate (DEHP) were detected in various water samples such as river water, well water and tap water. On degradation tests of PEs, Tempaku River water degraded almost 100% of diethyl phthalate (DEP), di-isobutyl phthalate and DBP, and approximately 70% of DEHP. All eight isolates from Tempaku River water (R1-R7, D1) did not degrade dimethyl phthalate (DMP), but showed biodegrading ability for the other PEs. The DBP-degrading ability was particularly high for the isolates R1-R3 and D1 of Acinetobacter lwoffii. Crude enzyme solutions prepared from bacterial cells of these isolates showed a higher degrading activity for DEHP compared with that for microbiallydegradable DBP. Particularly high DEHP-degrading activity was found for crude enzyme solutions of the isolate D1. As metabolites from the river water and bacterial isolates, DMP and an unknown diester were produced from DEP. DMP, DEP, monomethyl phthalate, monobutyl phthalate (MBP) and an unknown diester were produced from DBP. DBP, DEP, DMP and an unknown diester were produced from DEHP. As metabolites by the crude enzyme solutions, DMP, MBP and an unknown diester derivative were produced from DBP. DBP, mono-(2-ethylhexyl) phthalate and an unknown diester derivative were produced from DEHP. Diesters with shortened alkyl carbon chains were also found as metabolites by the isolates and their crude enzyme solutions. The results suggest that the alkyl chains in the diesters are also decomposed in addition to monoester formation from DBP or DEHP at the first step reported for animals and some types of bacteria.

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“…DEHP is known as one of the substances called peroxisome proliferators, which induce increased peroxisome formation and drug metabolizing enzyme activities in the livers of rats [13]. In 1978, DEHP was found in two-year carcinogenicity bioassays performed in the National Toxicology Program (NTP) to be a hepatocarcinogen in Fischer 344 rats and B6C3F 1 mice [12]. In addition, clofibrate, that is also one of the peroxisome proliferators, is known to induce hepatocellular tumors in rats and mice [16].…”

Section: Discussionmentioning

confidence: 99%

Susceptibility of Liver Proliferative Lesions in Heterozygous p53 Deficient CBA Mice to Various Carcinogens.

Uehara

Kashida

Watanabe

et al. 2002

The Journal of Veterinary Medical Science

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ABSTRACT. To investigate the liver tumorigenic sensitivity to various carcinogens in heterozygous p53 deficient [p53 (+/-)] CBA mice and their wild-type littermates [p53 (+/+) mice], 71 p53 (+/-) and 74 p53 (+/+) CBA mice (male, 6-12 weeks of age) were given diet containing 4,000 or 0 ppm flumequine (FL) for 26 weeks or a single intraperitoneal injection of 5 mg/kg body weights dimethylnitros amine (DMN) at start of the study in Exp. 1, diet containing 6,000 or 0 ppm di(2-ethylhexyl)-phthalate (DEHP) for 26 weeks in Exp. 2, or diet containing 12,000, 6,000 or 0 ppm phenolphthalein (PhP) for 26 weeks in Exp. 3. All surviving animals of these groups were killed after completion of treatment of the test substances for 26 weeks. In the FL groups, the incidences of hepatocellular altered f oci in p53 (+/-) mice, the multiplicities of those in p53 (+/-) and p53 (+/+) mice were significantly increased as compared to the corresponding control groups. The incidences and multiplicities of altered foci in the DMN groups were higher than those in the corresponding control groups in p53 (+/-) and p53 (+/+) mice, but no significant differences were indicated between the groups. There were no significant differences in the incidences, multiplicities and proliferating cell nuclear antigen labeling indices of altered foci in the FL or DMN groups between p53 (+/-) and p53 (+/+) mice. There were no significant differences in the incidences and multiplicities of altered foci between the DEHP or PhP and control groups. The present results suggest that p53 gene knocked out heterozygously does not enhance the chemical hepatocarcinogenesis in CBA mice. KEY WORDS: dimethylnitrosamine, di(2-ethylhexyl)-phthalate, flumequine, phenolphthalein, p53 (+/-) CBA mouse.

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The carcinogenicity of dietary di(2‐ethylhexyl) phthalate (DEHP) in fischer 344 rats and B6C3F₁mice

Cited by 212 publications

References 28 publications

Assessment of Carcinogenicity of Di(2-ethylhexyl phthalate in a Short-Term Assay Using Xpa-/- and Xpa-/ - /p53+/-Mice

Assessment of Carcinogenicity of Di(2-ethylhexyl phthalate in a Short-Term Assay Using Xpa-/- and Xpa-/ - /p53+/-Mice

Phthalate Esters Detected in Various Water Samples and Biodegradation of the Phthalates by Microbes Isolated from River Water.

Susceptibility of Liver Proliferative Lesions in Heterozygous p53 Deficient CBA Mice to Various Carcinogens.

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The carcinogenicity of dietary di(2‐ethylhexyl) phthalate (DEHP) in fischer 344 rats and B6C3F1mice

Cited by 212 publications

References 28 publications

Assessment of Carcinogenicity of Di(2-ethylhexyl phthalate in a Short-Term Assay Using Xpa-/- and Xpa-/ - /p53+/-Mice

Assessment of Carcinogenicity of Di(2-ethylhexyl phthalate in a Short-Term Assay Using Xpa-/- and Xpa-/ - /p53+/-Mice

Phthalate Esters Detected in Various Water Samples and Biodegradation of the Phthalates by Microbes Isolated from River Water.

Susceptibility of Liver Proliferative Lesions in Heterozygous p53 Deficient CBA Mice to Various Carcinogens.

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The carcinogenicity of dietary di(2‐ethylhexyl) phthalate (DEHP) in fischer 344 rats and B6C3F₁mice