Measurement of eight urinary metabolites of di(2-ethylhexyl) phthalate as biomarkers for human exposure assessment

Abstract

Human metabolism of di(2-ethylhexyl) phthalate (DEHP) is complex and yields mono(2-ethylhexyl) phthalate (MEHP) and numerous oxidative metabolites. The oxidative metabolites, mono(2-ethyl-5-oxohexyl) phthalate (MEOHP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono(2-ethyl-5-carboxypentyl) phthalate (MECPP) and mono(2-carboxymethylhexyl) phthalate (MCMHP), have been considered to be better biomarkers for DEHP exposure assessment than MEHP because urinary levels of these metabolites are generally higher than MEHP, and their measurements are not subject to contamination. The urinary levels of the above metabolites, and of three other recently identified DEHP oxidative metabolites, mono(2-ethyl-3-carboxypropyl) phthalate (MECPrP), mono-2-(1-oxoethylhexyl) phthalate (MOEHP), and mono(2-ethyl-4-carboxybutyl) phthalate (MECBP), were measured in 129 adults. MECPP, MCMHP and MEHHP were present in all the samples analysed. MEHP and the other oxidative metabolites were detected less frequently: MEOHP (99%), MECBP (88%), MECPrP (84%), MEHP (83%) and MOEHP (77%). The levels of all DEHP metabolites were highly correlated (p<0.0001) with each other, confirming a common parent. The ? and ?-1 oxidative metabolites (MECPP, MCMHP, MEHHP and MEOHP) comprised 87.1% of all metabolites measured, and thus are most likely the best biomarkers for DEHP exposure assessment. The percentage of the unglucuronidated free form excreted in urine was higher for the ester linkage carboxylated DEHP metabolites compared with alcoholic and ketonic DEHP metabolites. The percentage of the unglucuronidated free form excreted in urine was higher for the DEHP metabolites with a carboxylated ester side-chain compared with alcoholic and ketonic metabolites. Further, differences were found between the DEHP metabolite profile between this adult population and that of six neonates exposed to high doses of DEHP through extensive medical treatment. In the neonates, MEHP represented 0.6% and MECPP 65.5% of the eight DEHP metabolites measured compared to 6.6% (MEHP) and 31.8% (MECPP) in the adults. Whether the observed differences reflect differences in route/duration of the exposure, age and/or health status of the individuals is presently unknown.

Human body burdens of chemicals used in plastic manufacture

“…In recent years, research on the oxidative metabolism of phthalates, which initially was largely limited to DEHP and di-n-octyl phthalate, two phthalates with a defined chemical composition (Anderson et al 2001;Koch et al 2004aKoch et al , 2005bPreuss et al 2005;Silva et al 2005Silva et al , 2006bCalafat et al 2006), has made considerable progress. As a result of this research, detailed toxicokinetic data exist on rodent and human metabolism, including metabolic conversion factors, distribution and elimination kinetics, and interspecies comparisons.…”

A simple pharmacokinetic model to characterize exposure of Americans to Di-2-ethylhexyl phthalate

“…In the study which is used to calibrate the model of this paper, they also measure two additional metabolites: mono (2-ethyl-5-carboxypentyl) phthalate, or 5cx-MEPP, and mono(2-(carboxymethyl)hexyl) phthalate, or 2cx-MMHP (Koch et al, 2005a). These metabolites have even longer half-lives of elimination than the above-oxidized metabolites and, furthermore, 5cx-MEPP has been shown to be the major urinary metabolite of DEHP (Silva et al, 2006).…”

“…Phthalates are excreted mostly within hours, with excretion completed within a day or two; half-lives in the body for parent and identified metabolites are in the range of hours. For phthalates with short alkyl chains, monoesters represent the major human metabolite, but in the case of phthalates with long alkyl chains, including DEHP, di-isonyl phthalate (DINP), and diisodecyl phthalate (DIDP), the monoesters are further metabolized via o-, o-1, and b-oxidations of the alkyl chain (ATSDR, 2002;Koch et al, 2006;Silva et al, 2006Silva et al, , 2007Wittassek et al, 2007a, b).…”

Mono-(2-ethylhexyl) phthalate stimulates basal steroidogenesis by a cAMP-independent mechanism in mouse gonadal cells of both sexes

“…The general population is exposed to DEHP primarily through inhalation and ingestion (Silva et al 2006). The major metabolite of DEHP, mono-(2-ethylhexyl) phthalate (MEHP), is thought to be the active agent in testicular (Sjoberg et al 1986) as well as ovarian toxicity (Davis et al 1994b).…”