Phthalates: metabolism and exposure

Abstract

IntroductionPhthalates are mostly used as plasticizers in PVC products. Annually more than 1 000 000 tonnes of phthalates are consumed in Western Europe (AgPU, 2006). Among the most important phthalates are di-n-butyl phthalate (DnBP), diisobutyl phthalate (DiBP), butylbenzyl phthalate (BBzP), di(2-ethylhexyl) phthalate (DEHP), diisononyl phthalate (DiNP), diisodecyl phthalate (DiDP) and di(2-propylheptyl) phthalate (DPHP). As ubiquitous environmental contaminants phthalates are taken up by the general population. This has raised concern because phthalates are considered to be endocrine-disrupting chemicals. It is supposed that phthalates and other endocrine-disrupting chemicals might have contributed to adverse trends in reproductive medicine, which show an increase in testicular cancer and hypospadias as well as a decrease in sperm counts (Sharpe & Irvine, 2004). Human phthalate metabolism: single oral dose experimentsDi(2-ethylhexyl) phthalate For many years DEHP was the most important PVC plasticizer. Therefore, we decided to study intensively human metabolism of DEHP. For this purpose a healthy male volunteer at the age of 61 took three different oral doses of isotopically labelled DEHP -about 5, 29 and 650 lg ⁄ kg body weight (Koch et al., 2004a(Koch et al., , 2005a. By using D4-ring-labelled DEHP interference by the omnipresent background exposure to DEHP was avoided. After 24 h the urinary excretion rate for the sum of five metabolites, namely mono-(2-ethylhexyl) phthalate (MEHP), mono-(2-ethyl-5-hydroxyhexyl) phthalate (5OH-MEHP), mono-(2-ethyl-5-oxohexyl) phthalate (5oxo-MEHP), mono(2-ethyl-5-carboxypentyl) phthalate (5cx-MEPP), and mono[2-(carboxymethyl)hexyl] phthalate (2cx-MMHP), was between 65 and 70% for all three doses. This outcome was in contrast to previous studies, which had hypothesized that a great amount of DEHP is excreted with faeces (Schmid & Schlatter, 1985). After 2 days more than 65% of the highest dose 1 taken up were excreted as the sum of the four oxidative metabolites, whereas only 7.3% was excreted as MEHP (Table 1). We found that urinary DEHP excretion follows a multi-phase elimination model. In the second elimination phase MEHP showed the shortest half-life with 5 h, whereas for 2cx-MMHP a half-life of around 24 h was estimated. Interestingly, there were two maximum concentrations SummaryIn human metabolism studies we found that after oral application of di(2-ethylhexyl) phthalate (DEHP), diisononyl phthalate (DiNP) and di(2-propylheptyl) phthalate (DPHP), at least 74, 44 and 34%, respectively, are excreted via urine. In contrast to the short chain phthalates, their oxidized products, not the simple monoesters, were found to be the main metabolites. Based on urinary phthalate metabolite concentrations we estimated in 102 German subjects between 6 and 80 years of age median daily intakes (lg ⁄ kg ⁄ day) of 2.7 for DEHP, 2.1 for di-nbutyl phthalate, 1.5 for diisobutyl phthalate, 0.6 for DiNP, and 0.3 for butylbenzyl phthalate. In general, children have higher exposures compared...

Estimated daily intake of phthalates in occupationally exposed groups

“…DBP daily intake estimates for workers in our two highest DBP-exposed sectors, phthalate manufacturing, and rubber gasket (GM ¼ 17 mg/kg/day, each), were 4-to 20-fold higher than estimates for a subset of U.S. adults and children in NHANES 99 (GM ¼ 0.90 mg/kg/day) (Clark et al, 2003), U.S. pregnant women (median ¼ 0.84 mg/kg/day) (Marsee et al, 2006), German children (median ¼ 4.07 mg/kg/day) and German adults and children (median ¼ 2.1 mg/kg/day) (Wittassek and Angerer, 2008); however, our highest individual DBP intake estimate (76 mg/ kg/day) was lower than for some people using medications with coatings containing DBP (Herna´ndez-Diaz et al, 2009) DEHP daily intake has been estimated using different DEHP metabolites (Calafat and McKee, 2006;Koch et al, 2006Koch et al, , 2005bWeuve et al, 2006;Wittassek and Angerer, 2008). DEHP intake estimates (based on MEOHP only) reported for infants in a neonatal intensive care unit (Weuve et al, 2006) (median ¼ 325 mg/kg/day) and for premature neonates (Calafat and McKee, 2006) (GM ¼ 1256 mg/kg/ day) were 1-2 orders of magnitude higher than for workers in our most highly exposed sector (PVC film, GM ¼ 16 mg/kg/ day, based on MEOHP only, data not shown).…”

“…DEHP intake estimates (based on MEOHP only) reported for infants in a neonatal intensive care unit (Weuve et al, 2006) (median ¼ 325 mg/kg/day) and for premature neonates (Calafat and McKee, 2006) (GM ¼ 1256 mg/kg/ day) were 1-2 orders of magnitude higher than for workers in our most highly exposed sector (PVC film, GM ¼ 16 mg/kg/ day, based on MEOHP only, data not shown). In PVC film and PVC compounding, DEHP intake estimates (based on MEHP3) were B2-6-fold higher than in German adults and children (Koch et al, 2006;Wittassek and Angerer, 2008), but approximately half that of platelet donors highly exposed to DEHP leaching from PVC materials used during apheresis (Koch et al, 2005b).…”

“…Biomarker-based estimates of phthalate daily intake are available for adults and children in the United States, Germany, Korea, Japan, and Taiwan (David, 2000;Kohn et al, 2000;Koo et al, 2002;Clark et al, 2003;Itoh et al, 2005;Koo and Lee 2005;Itoh et al, 2007;Koch et al, 2007Koch et al, , 2006Koch et al, , 2003bWittassek et al, 2007;Chen et al, 2008;Wittassek and Angerer, 2008), for pregnant women (Marsee et al, 2006) and for infants in neonatal intensive care units (Calafat and McKee, 2006;Weuve et al, 2006); however, phthalate daily intake estimates for occupationally exposed groups are lacking. In 2003-2005, the National Institute for Occupational Safety and Health (NIOSH) conducted a preliminary study of phthalate exposures among 156 workers in eight industry sectors where materials containing diethyl phthalate (DEP), dibutyl phthalate (DBP), and di(2-ethylhexyl) phthalate (DEHP) were manufactured or used as part of the workers' regular job duties.…”

Human body burdens of chemicals used in plastic manufacture

“…For these calculations, the extrapolation from using urinary concentration data collected from one spot urine sample to reflect the 24 h exposure has the highest uncertainty, although all proposed approaches to account for this fact (e.g. urine volume or creatinine correction) produce similar results (David 2000;Kohn et al 2000;Koch et al 2003aWittassek & Angerer 2008). Furthermore, dose calculations based on spot urine samples and on 24 h urine samples produced very comparable results (Wittassek et al 2007a).…”

Exposure Marker Discovery of Phthalates Using Mass Spectrometry

“…74,75,82) Using custom synthesized reference standards of speci c oxidized metabolites of DINP, DIDP and, we are now able to assess human exposure to these phthalates. 61,74,75,[82][83][84][85] Table 1 summarizes selected phthalates and their respective metabolites (as biomarkers of exposure) that are currently being investigated in …”