title: Kinetics of di(2-ethylhexyl) phthalate (DEHP) and mono(2-ethylhexyl) phthalate in blood and of DEHP metabolites in urine of male volunteers after single ingestion of ring-deuterated DEHP.
abstract: The plasticizer di(2-ethylhexyl) phthalate (DEHP) is suspected to induce antiandrogenic effects in men via its metabolite mono(2-ethylhexyl) phthalate (MEHP). However, there is only little information on the kinetic behavior of DEHP and its metabolites in humans. The toxikokinetics of DEHP was investigated in four male volunteers (28-61y) who ingested a single dose (645±20μg/kg body weight) of ring-deuterated DEHP (DEHP-D(4)). Concentrations of DEHP-D(4), of free ring-deuterated MEHP (MEHP-D(4)), and the sum of free and glucuronidated MEHP-D(4) were measured in blood for up to 24h; amounts of the monoesters MEHP-D(4), ring-deuterated mono(2-ethyl-5-hydroxyhexyl) phthalate and ring-deuterated mono(2-ethyl-5-oxohexyl) phthalate were determined in urine for up to 46h after ingestion. The bioavailability of DEHP-D(4) was surprisingly high with an area under the concentration-time curve until 24h (AUC) amounting to 50% of that of free MEHP-D(4). The AUC of free MEHP-D(4) normalized to DEHP-D(4) dose and body weight (AUC/D) was 2.1 and 8.1 times, that of DEHP-D(4) even 50 and 100 times higher than the corresponding AUC/D values obtained earlier in rat and marmoset, respectively. Time courses of the compounds in blood and urine of the volunteers oscillated widely. Terminal elimination half-lives were short (4.3-6.6h). Total amounts of metabolites in 22-h urine are correlated linearly with the AUC of free MEHP-D(4) in blood, the parameter regarded as relevant for risk assessment.
authors.affiliation: Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany. kessler@helmholtz-muenchen.de
authors.forename: Winfried
authors.initials: W
authors.lastname: Kessler
authors.forename: Wanwiwa
authors.initials: W
authors.lastname: Numtip
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Völkel
authors.forename: Elcim
authors.initials: E
authors.lastname: Seckin
authors.forename: György A
authors.initials: GA
authors.lastname: Csanády
authors.forename: Christian
authors.initials: C
authors.lastname: Pütz
authors.forename: Dominik
authors.initials: D
authors.lastname: Klein
authors.forename: Hermann
authors.initials: H
authors.lastname: Fromme
authors.forename: Johannes G
authors.initials: JG
authors.lastname: Filser
mesh_terms: D000328:Adult; D019540:Area Under Curve; D001711:Biotransformation; D001835:Body Weight; D003903:Deuterium; D004051:Diethylhexyl Phthalate / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine; D004305:Dose-Response Relationship, Drug; D020719:Glucuronides / Q000097:blood / Q000652:urine; D006207:Half-Life; D006801:Humans; D007202:Indicators and Reagents; D007700:Kinetics; D008297:Male; D008875:Middle Aged
chemical_list: D020719:Glucuronides; D007202:Indicators and Reagents; D003903:Deuterium; D004051:Diethylhexyl Phthalate; C016599:mono-(2-ethylhexyl)phthalate