Abstract
Human metabolism of di(2-ethylhexyl)phthalate (DEHP) was studied after a single oral dose of 48.1 mg to a male volunteer. To avoid interference by background exposure the D4-ring-labelled DEHP analogue was dosed. Excretion of three metabolites, mono(2-ethyl-5-hydroxyhexyl)phthalate (5OH-MEHP), mono(2-ethyl-5-oxohexyl)phthalate (5oxo-MEHP) and mono(2-ethylhexyl)phthalate (MEHP), was monitored for 44 h in urine and for 8 h in serum. Peak concentrations of all metabolites were found in serum after 2 h and in urine after 2 h (MEHP) and after 4 h (5OH-MEHP and 5oxo-MEHP). While the major metabolite in serum was MEHP, the major metabolite in urine was 5OH-MEHP, followed by 5oxo-MEHP and MEHP. Excretion in urine followed a multi-phase elimination model. After an absorption and distribution phase of 4 to 8 h, half-life times of excretion in the first elimination phase were approximately 2 h with slightly higher half-life times for 5OH- and 5oxo-MEHP. Half-life times in the second phase—beginning 14 to 18 h post dose—were 5 h for MEHP and 10 h for 5OH-MEHP and 5oxo-MEHP. In the time window 36 to 44 h, no decrease in excreted concentrations of 5OH- and 5oxo-MEHP was observed. In the first elimination phase (8 to 14 h post dose), mean excretion ratios of MEHP to 5oxo-MEHP and MEHP to 5OH-MEHP were 1 to 1.8 and 1 to 3.1. In the second elimination phase up to 24 h post dose mean excretion ratios of MEHP to 5oxo-MEHP to 5OH-MEHP were 1 to 5.0 to 9.3. The excretion ratio of 5OH-MEHP to 5oxo-MEHP remained constant through time at 1.7 in the mean. After 44 h, 47% of the DEHP dose was excreted in urine, comprising MEHP (7.3%), 5OH-MEHP (24.7%) and 5oxo-MEHP (14.9%).
Similar content being viewed by others
References
Akingbemi BT, Youker RT, Sottas CM, Ge R, Katz E, Klinefelter GR, Zirkin BR, Hardy MP (2001) Modulation of rat Leydig cell steroidogenic function by di(2-ethylhexyl)phthalate. Biol Reprod 65:1252–1259
Albro PW, Corbett JT, Schroeder JL, Jordan ST, Matthews HB (1982a) Pharmacokinetics, interactions with macromolecules and species differences in metabolism of DEHP. Environ Health Perspect 45:19–25
Anderson WA, Castle L, Scotter MJ, Massey RC, Springall C (2001) A biomarker approach to measuring human dietary exposure to certain phthalate diesters. Food Addit Contam 18:1068–1074
Arcadi FA, Costa C, Imperatore C, Marchese A, Rapisardi A, Salemi M, Trimarchi GR, Costa G (1998) Oral toxicity of bis(2-ethylhexyl)phthalate during pregnancy and suckling in the Long-Evans rat. Food Chem Toxicol 35:963–970
ATSDR, Agency for Toxic Substances and Disease Registry (1993) Toxicological profile for di(2-ethylhexyl)phthalate. Update (Final report, ATSDR/TP-92/05). ATSDR, Public Health Service, U.S. Department of Health and Human Services. NTIS Accession no. PB93-182400, Atlanta, Georgia, p 171
Barr DB, Silva MJ, Kato K, Reidy JA, Malek NA, Hurtz D, Sadowski M, Needham LL, Calafat AM (2003) Assessing human exposure to phthalates using monoesters and their oxidized metabolites as biomarkers. Environ Health Perspect 111:1148–1151
Blount BC, Silva MJ, Caudill SP, Needham LL, Pirkle JL, Sampson EJ, Lucier GW, Jackson RJ, Brock JW (2000) Levels of seven urinary phthalate metabolites in a human reference population. Environ Health Perspect 108:979–982
Butte W, Hofmann W, Hostrup O, Schmidt A, Walker G (2001) Endocrine disrupting chemicals in house dust: results of a representative monitoring (in German). Gefahrst Reinh Luft:19–23
Cammack JN, White RD, Gordon D, Gass J, Hecker L, Conine D, Bruen US, Friedman M, Echols C, Yeh TY, Wilson DM (2003) Evaluation of reproductive development following intravenous and oral exposure to DEHP in male neonatal rats. Int J Toxicol 22:159–174
Centers for Disease Control and Prevention (2003) Second national report on human exposure to environmental chemicals. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Environmental Health, Division of Laboratory Sciences, Atlanta, Georgia 30341–3724; NCEH pub no. 20716
CSTEE, Scientific Committee on Toxicity, Ecotoxicity and the Environment (1998) Opinion on phthalate migration from soft PVC toys and child-care articles. Data made available on the 16th of June 1998, opinion expressed at the 6th CSTEE plenary meeting, Brussels, 26/27 November 1998
Dalgaard M, Nellemann C, Lam HR, Sorensen IK, Ladefoged O (2001) The acute effects of mono(2-ethylhexyl)phthalate (MEHP) on testes of prepubertal Wistar rats. Tox Lett 122:69–79
Daniel JW, Bratt H (1974) The absorption, metabolism and tissue distribution of di(ethylhexyl)phthalate in rats. Toxicology 2:51–65
David RM (2000) Exposure to phthalate esters. Environ Health Perspect 108:A440
Deutsche Forschungsgemeinschaft, DFG (2002) Di(2-ethylhexyl)phthalat (DEHP). In: Greim H (ed) Gesundheitsschädliche Arbeitsstoffe—Toxikologisch-arbeitsmedizinische Begründungen von MAK-Werten. 35. Ergänzungslieferung, Wiley-VCH, Weinheim
Dirven HA, van den Broek PH, Jongeneelen FJ (1993) Determination of four metabolites of the plasticizer di(2-ethylhexyl)phthalate in human urine samples. Int Arch Occup Environ Health 64:555–560
Duty SM, Silva MJ, Barr DB, Brock JW, Ryan L, Chen Z, Herrick RF, Christiani DC, Hauser R (2003a) Phthalate exposure and human semen parameters. Epidemiology 14:269–277
Duty SM, Singh NP, Silva MJ, Barr DB, Brock JW, Ryan L, Herrick RF, Christiani DC, Hauser R (2003b) The relationship between environmental exposures to phthalates and DNA damage in human sperm using the neutral comet assay. Environ Health Perspect 111:1164–1169
European Commission, EU (2002) Opinion on medical devices containing DEHP plasticised PVC; neonates and other groups possibly at risk from DEHP toxicity. Adopted by the Scientifc Committee on Medical Products and Medical Devices on 26 September 2002. Doc SANCO/SCMPMD/2002/0010Final. Health and Consumer Protection Directorate General
FDA, U.S. Food and Drug Administration (2001) Safety assessment of di(2-ethylhexyl)phthalate (DEHP) released from medical devices. Center for Devices and Radiological Health, FDA, 12709 Twinbrook Parkway, Rockville, MD 20852, USA
Fisher JS, Macpherson S, Marchetti N, Sharpe RM (2003) Human ‘testicular dysgenesis syndrome’: a possible model using in-utero exposure of the rat to dibutyl phthalate. Hum Reprod 18:1383–1394
Gilsing H-D, Angerer J, Prescher D (2002) Monophthalates with oxidized C5-carbon in the ester chain: a simple synthetic access to two major metabolites of bis-(2-ethylhexyl)-phthalate. Monatsh Chem 133:1147–1155
Gray LE Jr, Ostby J, Furr J, Price M, Veeramachaneni DN, Parks L (2000) Perinatal exposure to the phthalates DEHP, BBP and DINP, but not DEP, DMP or DOTP, alters sexual differentiation of the male rat. Toxicol Sci 58:350–365
Kavlock R, Boeckelheide K, Chapin R, Cunningham M, Faustman E, Foster P, et al (2002) NTP Center for the Evaluation of Risks to Human Reproduction: phthalates expert panel report on the reproductive and developmental toxicity of di(2-ethylhexyl)phthalate. Reprod Toxicol 16:529–653
Koch HM, Gonzalez-Reche LM, Angerer J (2003a) On-line cleanup by multidimensional LC-ESI-MS/MS for high throughput quantification of primary and secondary phthalate metabolites in human urine. J Chromatogr B 784:169–182
Koch HM, Rossbach B, Dexler H, Angerer J (2003b) Internal exposure of the general population to DEHP and other phthalates—determination of secondary and primary phthalate monoester metabolites in urine. Environ Res 93: 177–185
Koch HM, Drexler H, Angerer J (2003c) An estimation of the daily intake of Di(2-ethylhexyl)phthalate (DEHP) and other phthalates in the general population. Int J Hyg Environ Health 206:77–83
Kohn MC, Parham F, Masten SA, Portier CJ, Shelby MD, Brock JW, Needham LL (2000) Human exposure estimates for phthalates. Environ Health Perspect 108:A440–442
Lamb JC 4th, Chapin RE, Teague J, Lawton AD, Reel JR (1987) Reproductive effects of four phthalic acid esters in the mouse. Toxicol Appl Pharmacol 88:255–269
Lorz PM, Towae FK, Enke W, Jäckh R, Bhargava N (2002) Phthalic acid and derivatives. In: Wiley-VCH (ed) Ullmann’s encyclopedia of industrial chemistry, release 2003, 7th edn online. Wiley-VCH, Weinheim. DOI: 10.1002/14356007.a20_181
Meek ME, Chan PK (1994) Bis(2-ethylhexyl)phthalate: evaluation of risks to health from environmental exposure in Canada. J Environ Sci Health Part C 12:179–194
Moore RW, Rudy TA, Lin TM, Ko K, Peterson RE (2001) Abnormalities of sexual development in male rats with in utero and lactational exposure to the antiandrogenic plasticizer di(2-ethylhexyl) phthalate. Environ Health Perspect 109:229–237
Park JD, Habeebu SSM, Klaassen CD (2002) Testicular toxicity of di-(2-ethylhexyl)phthalate in young Sprague-Dawley rats. Toxicology 171:105–115
Parks LG, Ostby JS, Lambright CR, Abbott BD, Klinefelter GR, Barlow NJ, Gray LE Jr (2000) The plasticizer diethylhexyl phthalate induces malformations by decreasing fetal testosterone synthesis during sexual differentiation in the male rat. Toxicol Sci 58:339–349
Peck CC, Albro PW (1982) Toxic potential of the plasticizer di(2-ethylhexyl) phthalate in the context of its disposition and metabolism in primates and man. Environ Health Perspect 45:11–17
Petersen JH, Breindahl T (2000) Plasticizers in total diet samples, baby food and infant formulae. Food Addit Contam 17:133–141
Poon R, Lecavallier P, Mueller P, Valli VE, Procter BG, Chu I (1997) Subchronic oral toxicity of di-n-octylphthalate and di(2-ethylhexyl)phthalaten in the rat. Food Chem Toxicol 35:225–239
Rippen G (ed) (2000) Handbuch Umweltchemikalien, Di(2-ethylhexyl)phthalat, 3rd edn, Suppl 51. Ecomed, Landsberg
Sharpe RM (2001) Hormones and testis development and the possible adverse effects of environmental chemicals. Toxicol Lett 120:221–232
Schmid P, Schlatter C (1985) Excretion and metabolism of di(2-ethylhexyl)phthalate in man. Xenobiotica 15:251–256
Sjoberg P, Lindquist NG, Montin G, Ploen L (1985) Effects of repeated intravenous infusions of the plasticizer di-(2-ethylhexyl) phthalate in young male rats. Arch Toxicol 58:78–83
Sjoberg P, Bondesson U, Gray TJ, Ploen L (1986) Effects of di-(2-ethylhexyl) phthalate and five of its metabolites on rat testis in vivo and in vitro. Acta Pharmacol Toxicol (Copenh) 58:225–233
Skakkebaek NE (2002) Endocrine disrupters and testicular dysgenesis syndrome. Horm Res 57 [Suppl 2]:43
Acknowledgements
We especially thank the DFG (German Research Foundation) for their financial support of the project (no. AN 107/16/1).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Koch, H.M., Bolt, H.M. & Angerer, J. Di(2-ethylhexyl)phthalate (DEHP) metabolites in human urine and serum after a single oral dose of deuterium-labelled DEHP. Arch Toxicol 78, 123–130 (2004). https://doi.org/10.1007/s00204-003-0522-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00204-003-0522-3