title: In vitro metabolites of di-2-ethylhexyl adipate (DEHA) as biomarkers of exposure in human biomonitoring applications.
abstract: Di-2-ethylhexyl adipate (DEHA) is a common plasticizer used in food packaging. At high doses, DEHA can cause adverse health effects in rats. Although the potential for human exposure to DEHA is high, no DEHA specific biomarkers are identified for human biomonitoring. Using human liver microsomes, we investigated the in vitro phase I metabolism of DEHA and its hydrolytic metabolite mono-2-ethylhexyl adipate (MEHA) and, for comparison purposes, of the analogous di-2-ethylhexyl phthalate (DEHP) and its hydrolytic metabolite mono-2-ethylhexyl phthalate. We unequivocally identified MEHA, a DEHA specific biomarker, and adipic acid, a nonspecific biomarker, using authentic standards. On the basis of their mass spectrometric fragmentation patterns, we tentatively identified two other DEHA specific metabolites: mono-2-ethylhydroxyhexyl adipate (MEHHA) and mono-2-ethyloxohexyl adipate (MEOHA), analogous to the oxidative metabolites of DEHP. Interestingly, although adipic acid was the major in vitro metabolite of DEHA, the analogous phthalic acid was not the major in vitro metabolite of DEHP. Our preliminary data for 144 adults with no known exposure to DEHA suggests that adipic acid is also the main in vivo urinary metabolite, while MEHA, MEHHA, and MEOHA are only minor metabolites. Therefore, the use of these specific metabolites for assessing the exposure of DEHA may be limited to highly exposed populations.
authors.affiliation: Division of Laboratory Sciences, National Center for Environmental Health, Centers for Disease Control and Prevention , Atlanta, Georgia 30341, United States.
authors.forename: Manori J
authors.initials: MJ
authors.lastname: Silva
authors.forename: Ella
authors.initials: E
authors.lastname: Samandar
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Ye
authors.forename: Antonia M
authors.initials: AM
authors.lastname: Calafat
mesh_terms: D000272:Adipates / Q000737:chemistry / Q000378:metabolism* / Q000652:urine; D000328:Adult; D000818:Animals; D015415:Biomarkers / Q000378:metabolism / Q000652:urine; D002851:Chromatography, High Pressure Liquid; D004051:Diethylhexyl Phthalate / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism / Q000652:urine; D004781:Environmental Exposure; D004784:Environmental Monitoring; D006801:Humans; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000378:metabolism; D010084:Oxidation-Reduction; D010968:Plasticizers / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*; D051381:Rats
chemical_list: D000272:Adipates; D015415:Biomarkers; D010968:Plasticizers; C013966:dioctyl adipate; C029900:adipic acid; D004051:Diethylhexyl Phthalate; C016599:mono-(2-ethylhexyl)phthalate
references.citation: J Toxicol Sci. 2009;34 Suppl 1:SP101-9
references.pmid: 19265276
references.citation: J Chromatogr B Analyt Technol Biomed Life Sci. 2012 May 1;895-896:123-30
references.pmid: 22503746
references.citation: Environ Int. 2007 Nov;33(8):1012-20
references.pmid: 17610953
references.citation: Environ Res. 2013 Oct;126:159-63
references.pmid: 23777640
references.citation: Int J Hyg Environ Health. 2007 Jan;210(1):9-19
references.pmid: 17182279
references.citation: Arch Toxicol. 2004 Mar;78(3):123-30
references.pmid: 14576974
references.citation: Int J Androl. 2006 Feb;29(1):155-65; discussion 181-5
references.pmid: 16466535
references.citation: Food Chem Toxicol. 1993 Sep;31(9):609-14
references.pmid: 8406236
references.citation: Biomarkers. 2006 Jan-Feb;11(1):1-13
references.pmid: 16484133
references.citation: Toxicol Appl Pharmacol. 1975 Jun;32(3):566-76
references.pmid: 1154415
references.citation: IARC Monogr Eval Carcinog Risks Hum. 2000;77:149-75
references.pmid: 11100400
references.citation: Food Chem Toxicol. 1994 Jan;32(1):1-5
references.pmid: 8132159
references.citation: Environ Health Perspect. 2006 Aug;114(8):1158-61
references.pmid: 16882519
references.citation: Toxicology. 1981;22(3):223-33
references.pmid: 7340012
references.citation: J Chromatogr B Analyt Technol Biomed Life Sci. 2007 Dec 1;860(1):106-12
references.pmid: 17997365