Non-linearities in the pharmacokinetics of di-(2-ethylhexyl) phthalate and metabolites in male rats

Sjöberg, Per J. R.; Bondesson, Ulf; Hammarlund, Margareta

doi:10.1007/bf00348312

Cited by 23 publications

(4 citation statements)

References 24 publications

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“…In our study, the plasma testosterone concentration and relative weight of the seminal vesicle increased in the low-dose DEHP group and therefore the low-observed-effect level (LOEL) was 1.0 mg/kg, but Akingbemi et al 14) reported the LOEL of DEHP affecting steroidogenesis to be 10 mg/kg and the no-observed-effect level (NOEL) 1 mg/kg. Although there is no report about metabolites produced after inhalation of DEHP, higher concentrations of MEHHP and MEOHP were found in plasma following intravenous infusions of DEHP in rats 38) and the level of MEHP was lower after intravenous exposure than after oral 25-50% 0 (0%) 1 (17%) 1 (17%) 4 (marked) 50-75% 1 (17%) 0 (0%) 0 (0%) 5 (severe) > 75% 0 (0%) 0 (0%) 0 (0%) administration 21) . After inhalation of DEHP, the plasma concentrations of MEHHP and MEOHP may be higher than those after oral administration.…”

Section: Discussionmentioning

confidence: 91%

The Effects of Subacute Inhalation of Di (2‐ethylhexyl) Phthalate (DEHP) on the Testes of Prepubertal Wistar Rats

Kurahashi

Kondo

Omura

et al. 2005

Journal of Occupational Health

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The Effects of Subacute Inhalation of Di (2-ethylhexyl) Phthalate (DEHP) on the Testes of Prepubertal Wistar Rats: Norie KURAHASHI, et al. Department of Public Health, Hokkaido UniversityGraduate School of Medicine-In animal studies using oral dosing for short periods, di (2-ethylhexyl) phthalate (DEHP) is well known for its reproductive toxicity, especially for its testicular toxicity. However, extending the period of DEHP exposure in prepubertal rats resulted in significant increases in testosterone. This suggests that the reproductive effect of DEHP might be associated with the timing and the term of exposure. Moreover, the route of exposure may induce differences in its effect because tissue levels of metabolites of DEHP after inhalation are thought to be different from those after oral administration. We researched the effects of inhalation of DEHP on testes of prepubertal rats. Our results showed that inhalation of DEHP by 4-wk-old male Wistar rats at doses of 5 or 25 mg/m 3 , 6 h per day, for 4 and 8 wk significantly increased the concentration of plasma testosterone and weight of seminal vesicles. However, the concentration of luteinizing hormone (LH), follicular stimulating hormone (FSH) and the expression of mRNAs of androgen biosynthesis enzyme, cytochrome P450 cholesterol side-chain-cleavage enzyme (P450scc), 3β-hydroxysteroid dehydrogenase (3β-HSD), cytochrome P450 17α-hydroxylase/17, 20 lyase (CYP17) and aromatase (CYP19) did not change. Rats with precocious testes did not increase in any of the DEHP groups. We also found that the estimated effective dose in this study was less than those reported in previous studies which used oral dosing. Our study showed that inhaled DEHP increased plasma testosterone concentrations in prepubertal rats and suggested that their effects were more sensitive to inhalation of DEHP than oral dosing. , and it is widely found in food and the environment. A recent investigation by Blount et al. 2) demonstrated that the urinary levels of phthalates in humans are much higher than generally expected. Although DEHP has a relatively low vapor pressure, it appears to be a common air contaminant and is globally present 3) . The release of DEHP directly into the atmosphere is the most important mode of entry into the environment 3) . Absorption of DEHP from the atmosphere is most likely to occur by inhalation since the dermal absorption of DEHP in rats is low 4) . The concentration of DEHP in Canada for the general population has been documented to be 3 µg/m 3 5). Uhde et al. 6) reported that the maximum DEHP concentration in a room with wallcoverings coated by polyvinyl chloride was 0.94 µg/m 3 . In another study, the median concentration of DEHP in 27 houses was reported as 0.11 µg/m 3 7) . In the air inside cars, DEHP has been found at levels ranging from 1 to 34 µg/m 3 1) . Thus, the entire general population might have inhalation exposure to DEHP. Children and adolescents are generally recognized as being particularly at risk for greater exposure to environme...

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Section: Discussionmentioning

confidence: 91%

The Effects of Subacute Inhalation of Di (2‐ethylhexyl) Phthalate (DEHP) on the Testes of Prepubertal Wistar Rats

Kurahashi

Kondo

Omura

et al. 2005

Journal of Occupational Health

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“…Given single infusions of a DEHP emulsion in doses of 5, 50 or 500 mg/kg to rats, nonlinear increases in the AUCs of DEHP and MEHP indicated saturation in the formation as well as the elimination of the potentially toxic metabolite MEHP [31]. Testosterone production and gene endpoints in the fetal testis have been considered as the critical effect in some phthalate risk assessments, and thus the dose-response relationship for the effects of DEHP on the synthesis and production of testosterone in the fetal rat testis has been investigated [32].…”

Section: Resultsmentioning

confidence: 99%

Determination and Pharmacokinetics of Di-(2-ethylhexyl) Phthalate in Rats by Ultra Performance Liquid Chromatography with Tandem Mass Spectrometry

Chang-Liao¹,

Hou²,

Chang³

et al. 2013

Molecules

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Di-(2-ethylhexyl) phthalate (DEHP) is used to increase the flexibility of plastics for industrial products. However, the illegal use of the plasticizer DEHP in food and drinks has been reported in Taiwan in 2011. In order to assess the exact extent of the absorption of DEHP via the oral route, the aim of this study is to develop a reliable and validated ultra performance liquid chromatography with tandem mass spectrometry (UPLC-MS/MS) method to evaluate the oral bioavailability of DEHP in rats. The optimal chromatographic separation of DEHP and butyl benzyl phthalate (BBP; used as internal standard) were achieved on a C 18 column. The mobile phase was consisted of 5 mM ammonium acetatemethanol (11:89, v/v) with a flow rate of 0.25 mL/min. The monitoring ion transitions were m/z 391.4 → 149.0 for DEHP and m/z 313.3 → 149.0 for BBP. The mean matrix effects of DEHP at low, medium and high concentrations were 94.5 ± 5.7% and 100.1 ± 2.3% OPEN ACCESSMolecules 2013, 18 11453 in plasma and feces homogenate samples, respectively. In conclusion, the validated UPLC-MS/MS method is suitable for analyzing the rat plasma sample of DEHP and the oral bioavailability of DEHP was about 7% in rats.

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“…Recent studies by Gray et al [21]on the addition of DEHP to liver and testicular cell culture indicate that DEHP has to be metabolized before it will exert any effect. Data obtained by several workers indicate that these metabolites of DEHP are responsible for the biological effects observed on administration of DEHP [22, 23]. Sjöberg et al [20]indicated that these metabolites, rather than DEHP itself, accumulate in the tissues.…”

Section: Discussionmentioning

confidence: 99%

Decrease in the Concentration of Vitamin E in Blood and Tissues Caused by Di(2-Ethylhexyl) Phthalate, a Commonly Used Plasticizer in Blood Storage Bags and Medical Tubing

Manojkumar¹,

Nair²,

Santhosh³

et al. 1998

Vox Sanguinis

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Background and Objectives: Significant amounts of di(2-ethylhexyl) phthlate (DEHP) leach into blood stored in DEHP-plasticized PVC bags. The aim of this study was to find out whether DEHP at these low levels has any effect on the concentration of vitamin E, an antioxidant which affords protection against free radical damage. Materials and Methods: DEHP was administered in low doses (150–750 μg/100 g body weight) to rats intraperitoneally and the concentration of vitamin E in the liver and testes was measured. Concentration of vitamin E was also measured in blood stored in glass bottles in the presence and absence of DEHP and in blood stored in DEHP-plasticized PVC bags. Results: A decrease in the concentration of vitamin E was observed in all cases. Administration of vitamin E to rats and incorporation of vitamin E in the additive solution in the case of blood prevented this decrease. Conclusion: DEHP even at very low doses caused a decrease in the concentration of vitamin E in liver and tests of rats given this substance. Blood stored in DEHP-plasticized bags also showed a decrease in the concentration of vitamin E.

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Non-linearities in the pharmacokinetics of di-(2-ethylhexyl) phthalate and metabolites in male rats

Cited by 23 publications

References 24 publications

The Effects of Subacute Inhalation of Di (2‐ethylhexyl) Phthalate (DEHP) on the Testes of Prepubertal Wistar Rats

The Effects of Subacute Inhalation of Di (2‐ethylhexyl) Phthalate (DEHP) on the Testes of Prepubertal Wistar Rats

Determination and Pharmacokinetics of Di-(2-ethylhexyl) Phthalate in Rats by Ultra Performance Liquid Chromatography with Tandem Mass Spectrometry

Decrease in the Concentration of Vitamin E in Blood and Tissues Caused by Di(2-Ethylhexyl) Phthalate, a Commonly Used Plasticizer in Blood Storage Bags and Medical Tubing

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