2
Phthalate Exposure Assessment in Humans

As mentioned in Chapter 1, phthalates1 are chemicals used as plasticizers in polymers to impart flexibility and durability to a multitude of everyday products and for their solvent properties in other products. Phthalates may be classified into two groups based on molecular weight. Accordingly, low-molecular-weight phthalates (ester side-chain lengths, one to four carbons) include DMP, DEP, DBP, and DIBP, and high-molecular-weight phthalates (ester side-chain lengths, five or more carbons) include DEHP, DOP, and DINP.

This chapter briefly describes what is known about phthalate exposures in humans and includes an overview of important sources and routes of exposures; some human exposure levels, including those of susceptible or highly exposed populations; and metabolism and pharmacokinetics. Many questions remain unanswered about cumulative exposures to phthalates throughout the life span, relative contributions of various sources of exposure to the phthalate body burden over time, and mixed exposures that may include phthalates or other chemicals that may elicit common adverse outcomes. Despite those limitations, the existing information on human exposure to phthalates can be used to help determine whether cumulative risk assessment should be conducted for phthalates. This chapter provides the context for the discussion of cumulative risk assessment and is not meant to be a quantitative exposure assessment of any particular phthalate or the chemical class as a whole.

PHTHALATE SOURCES AND ROUTES OF EXPOSURE

Phthalates used as plasticizers in polymers are not chemically bound to the polymers and therefore readily leach, migrate, or off-gas from the polymers, particularly when phthalate-containing products are exposed to high tempera-

1

As stated in Chapter 1, the term phthalates used in this report refers to diesters of 1,2-benzenedicarboxylic acid, the o-phthalates.



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2 Phthalate Exposure Assessment in Humans As mentioned in Chapter 1, phthalates1 are chemicals used as plasticizers in polymers to impart flexibility and durability to a multitude of everyday prod- ucts and for their solvent properties in other products. Phthalates may be classi- fied into two groups based on molecular weight. Accordingly, low-molecular- weight phthalates (ester side-chain lengths, one to four carbons) include DMP, DEP, DBP, and DIBP, and high-molecular-weight phthalates (ester side-chain lengths, five or more carbons) include DEHP, DOP, and DINP. This chapter briefly describes what is known about phthalate exposures in humans and includes an overview of important sources and routes of exposures; some human exposure levels, including those of susceptible or highly exposed populations; and metabolism and pharmacokinetics. Many questions remain unanswered about cumulative exposures to phthalates throughout the life span, relative contributions of various sources of exposure to the phthalate body bur- den over time, and mixed exposures that may include phthalates or other chemi- cals that may elicit common adverse outcomes. Despite those limitations, the existing information on human exposure to phthalates can be used to help de- termine whether cumulative risk assessment should be conducted for phthalates. This chapter provides the context for the discussion of cumulative risk assess- ment and is not meant to be a quantitative exposure assessment of any particular phthalate or the chemical class as a whole. PHTHALATE SOURCES AND ROUTES OF EXPOSURE Phthalates used as plasticizers in polymers are not chemically bound to the polymers and therefore readily leach, migrate, or off-gas from the polymers, particularly when phthalate-containing products are exposed to high tempera- 1 As stated in Chapter 1, the term phthalates used in this report refers to diesters of 1,2- benzenedicarboxylic acid, the o-phthalates. 21

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22 Phthalates and Cumulative Risk Assessment: The Tasks Ahead tures. Low-molecular-weight phthalates—including DMP, DEP, and DBP—are used in a variety of personal-hygiene and cosmetic products, such as nail polish to minimize chipping and fragrances as scent stabilizers (ATSDR 1995, 2001; NICNAC 2008). High-molecular-weight phthalates—including DEHP, DINP, and DOP—are used in plastic tubing, food packaging and processing materials, containers, vinyl toys, vinyl floor coverings, and building products (ATSDR 1997, 2002; ECB 2003; Kueseng et al. 2007). Medical supplies and devices may contain phthalates, as may some medications (for example, medications with enteric coatings) (Hauser et al. 2004). Table 2-1 lists some common phthalates and examples of their uses. Phthalate exposures may occur through ingestion, inhalation, dermal ab- sorption, and parenteral administration. The relative contributions of the expo- sures to the total body burden at various ages are not known. BIOMARKERS OF EXPOSURE Both animal and human studies demonstrate that exposure may occur throughout the life span, from the developing fetus through early infancy, child- hood, and beyond. Phthalates can cross the placenta (Saillenfait et al. 1998; Fennell et al. 2004), have been measured in amniotic fluid in human studies (Silva et al. 2004), are present in breast milk (Parmar et al. 1985; Dostal et al. 1987), and can be measured in urine at all ages (CDC 2003, 2005; Sathyanara- yana et al. 2008). Human exposure to phthalates is assessed most frequently by measuring urinary polar metabolites. Urinary excretion of polar molecules is efficient, and their urinary concentration is generally 5-20 times that in lipid-rich body com- partments. For example, the urinary concentrations of MEHP, MIBP, MEP, and MBP were 20-100 times those in blood or milk (Högberg et al. 2008). Recent advances in urinary phthalate biomarkers have led to the measurement of the oxidized metabolites; measuring these metabolites eliminates the potential prob- lems of contamination inherent in measuring the parent compounds and their monoesters. The utility of other biologic matrices—such as blood, breast milk, and seminal plasma—for assessing human exposure remains largely unknown because there are few data. The incorporation of those novel matrices into hu- man studies necessitates the measurement of oxidized metabolites to avoid prob- lems with contamination by the ubiquitous parent diesters. Exposure of the U.S. and German population to at least 10 phthalates has been demonstrated by measurement of their urinary metabolites as shown in Table 2-2. Other reports generally have found exposures similar to or consistent with those in Table 2-2 with respect to age, sex, and racial or ethnic variations. Except for MEP, urinary metabolites in U.S. children, males, Hispanics, and blacks are generally somewhat higher than those in adults shown in Table 2-2 (CDC 2005).

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23 Phthalate Exposure Assessment in Humans TABLE 2-1 Common Phthalates and Examples of Uses Phthalate Uses DMP Insect repellent, plastic DEP Shampoo, scents, soap, lotion, cosmetics, industrial solvent, medica- tions DBP Adhesives, caulk, cosmetics, industrial solvent, medications DIBP Adhesives, caulk, cosmetics, industrial solvent BBP Vinyl flooring, adhesives, sealants, industrial solvent DCHP Stabilizer in rubber, polymers DEHP Soft plastic, including tubing, toys, home products, food containers, food packaging DOP Soft plastic DINP Soft plastics, replacement for DEHP In Germany, concentrations of MBP and of DEHP metabolites decreased over the period 1988-2003 (Wittassek et al. 2007). In the United States, MBP concentrations also decreased over the period 1999-2002; however, no decline was noted for MEHP (CDC 2003, 2005). Data released by the National Health and Nutrition Examination Survey (NHANES) demonstrate exposure to multiple phthalates in most people (CDC 2003, 2005). Data from Wittassek et al. (2007) and Sathyanarayana et al. (2008) also indicate exposure to multiple phthalates. Infant and Childhood Exposure NHANES data show that concentrations of urinary phthalate metabolites in children 6-11 years old were higher than those in adolescents and adults (CDC 2005). Several studies support the Centers for Disease Control and Pre- vention’s findings that children have higher urinary concentrations than adults of DBP, BBP, and DEHP (Brock et al. 2002; Koch et al. 2004, 2005a). Differences between children and adults in the amount of urine produced per unit body weight and in body surface area may contribute to differences in urinary concen- trations of specific metabolites. Whether the observed differences in urinary concentrations between children and adults result from differences in exposure or metabolism or both is unclear. In a recent study (Sathyanarayana et al. 2008), urine samples from infants were found to have detectable concentrations of mul- tiple urinary phthalate metabolites, which suggested that exposure to multiple phthalates is common even early in life. Studies of urine samples of pregnant women (Adibi et al. 2008; Wolff et al. 2008) have suggested that fetuses may also be exposed to multiple phthalates.

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24 TABLE 2-2 Urinary Phthalate Metabolites in Large Studies in United States and Germany Concentration, µg/La CDC 2005 Wittassek et al. 2007 Silva et al. 2007a NHANES, United States Germany United States 2001-2002 1988-2003 2003-2004 Spot Urine Sample 24-h Urine Sample Spot Urine Sample N = 1,647, over 20 y old N = 634, 20-29 y old N = 129, Adults Parent Compound Metabolite 50th % 95th % 50th % 95th % 50th % 95th % DMP MMP 1.40 9.10 – – – – DEP MEP 181 2,720 – – – – DBP MBP 19.1 95.4 112 604 – – DIBP MIBP 2.4 16.3 34.5 176 – – BBP MBZP 13.8 99.7 7.4 50.4 – – DCHP MCHP < LOD 0.500 – – – – DEHP MECPP 26.9 98.8 – – – – MEHHP 17.7 175 21.0 77.2 – – MEOHP 12.2 115 16.7 57.5 – – MEHP 4.10 39.5 7.6 33.6 – – DOP MCPP 2.60 12.0 – – – – MOP < LOD < LOD – – – – DINP MINP < LOD < LOD – – – – MHINP – – 2.0 11.9 MOINP – – 1.0 5.6 – –

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DIDP MCINP – – – – 4.4 104.4 MHIDP – – – – 4.9 70.6 MOIDP – – – – 1.2 15.0 MIDP – – – – < LOD < LOD a –, data not obtained; LOD, limit of detection. Note: LODs vary by study and by analyte but are generally less than 1 µg/L. 25

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26 Phthalates and Cumulative Risk Assessment: The Tasks Ahead Several factors are unique to infants and children and may affect exposure to multiple phthalates. Differences in urinary concentrations of phthalates among infants, children, and adults may reflect different sources and routes of intake. Ingestion is thought to be a primary pathway of exposure to some phthal- ates, especially those in food packaging (Shea et al. 2003; Kueseng et al. 2007). Infants and young children consume more calories per kilogram of body weight and consume relatively more dairy and other fatty foods, such as milk and infant formulas, which have been found to contain phthalates (Sorensen 2006). Infants and toddlers also demonstrate age-appropriate mouthing behaviors that poten- tially increase their exposures to phthalates in children’s toys and other products made with plasticized polymers. Indoor air is another source of exposure to phthalates from a variety of sources, including aerosols generated from polyvinyl chloride household prod- ucts, such as vinyl flooring and shower curtains, and indoor deodorants (Adibi et al. 2003; Rudel et al. 2003). Infants and young children have higher specific respiratory rates than adults (Etzel and Balk 2003; EPA 2006) and thus have potentially higher specific exposures via inhalation. In summary, infants’ and children’s physiology, developmental stages, and age-appropriate behaviors all may increase exposure to phthalates. Conse- quently, they may be especially vulnerable to phthalate exposures during critical stages of growth and development. Highly Exposed Populations Highly exposed people have urinary metabolite concentrations that often exceed those at the 95th percentile of the general population (Table 2-3). Widely recognized as potentially highly exposed are neonates receiving medical treat- ments, such as transfusions (Shea et al. 2003; Green et al. 2005). Neonates in the intensive care unit experience high exposures because many medical devices are made of polyvinyl chloride plastics that may contain phthalates (Sjoberg et al. 1985; Green et al. 2005); thus, for neonates and others using parenteral devices, this is another important route to consider. Some medications contain phthalates in their coatings or delivery systems (Hauser et al. 2005) and may contribute to high exposures of children, pregnant women, and others taking these medica- tions. METABOLISM, PHARMACOKINETICS, AND IMPLICATIONS FOR POSSIBLE SUSCEPTIBILITY Mammalian absorption and metabolism of phthalates (see Figure 2-1) are rapid; initial de-esterification of one alkyl linkage occurs in the saliva or the gut after oral intake. The resulting monoesters have one carboxylic acid and one

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TABLE 2-3 Urinary Phthalate Metabolite Concentrations after Exceptional Exposures and Comparison Medians from Available NHANES or European Union Data Metabolite Concentrations in NHANES or EU Medians Exposure Urine (µg/L) [95th %] (µg/L) Reference Enteric-coated medication taken MBP 16,868 MBP 19.3 [95]a Hauser et al. 2004 orally for 3 mo (n = 1 male) MEP 444 MEP 171 [3,050]a MEHP 3 MEHP 4.3 [38]a MBZP 9 MBZP 16 [122]a Intravenous tubing for platelet MEHP 388 MEHP 7.6 [34]b Koch et al. 2005b donation, maximum measured 4 h MEHHP 822 MEHHP 21 [77]b after donation (n = 1 male) MEOHP 729 MEOHP 16.7 [58]b MECPP 577 MECPP 26.9 [99]b Neonatal intensive care unit, 33 MEHP 129c MEHP 4.4 [30]d Calafat et al. 2004 samples from infants exposed for MEHHP 2,221c MEHHP 32.9 [210]d over 2 wk (n = 6) MEOHP 1,697c MEOHP 22.6 [142]d Infants in neonatal intensive care MEHP 22 (75th % = 71)c MEHP 4.4 [30]d Weuve et al. 2006 unit (n = 54) MEHHP 267 (75th % = 644)c MEHHP 32.9 [210]d MEOHP 256 (75th % = 628)c MEOHP 22.6 [142]d MBP 18 (75th % = 45)c MBP 32.4 [157]d MBZP 41 (75th % = 131)c MBZP 37 [226]d Plastisol workers after shift (n = 25) MEHP 56e MEHP 4.3 [38]a Gaudin et al. 2008 MECPP 104e a U.S. males over 25 years old from NHANES 2001-2002 (CDC 2005). b German adults 20-29 years old (Wittassek et al. 2007). c Median values, unless otherwise stated. d U.S. children 6-11 years old from NHANES 2001-2002 (CDC 2005). No data are available on neonates. e Medians before shift, 16 µg/L (MEHP) and 38 µg/L (MECPP), which were slightly higher than in controls. 27

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28 Phthalates and Cumulative Risk Assessment: The Tasks Ahead Monoester Free Metabolites, Metabolite Phthalate Phthalate Oxidized Glucuronides, Metabolite Sulfates Monoester Diester Metabolites P450s Lipase, UDP-GT, (side-chain Esterase Sulfotransferase oxidation) FIGURE 2-1 Phthalate metabolism. UDP-GT, uridine 5′-diphosphate-glucu- ronosyltransferase. ester substituent with a side chain of one or more carbons. Monoesters are the main detected metabolites of the low-molecular-weight phthalates, such as DEP and DBP (Silva et al. 2007b; Wittassek and Angerer 2008). However, phthalate monoesters with five or more carbons in the ester side chain (for example, MEHP, MOP, and MNP) are efficiently transformed further to oxidized metabo- lites arising mainly from ω-oxidation at the terminal or penultimate carbon of the alkyl ester side chain (for example, MECCP and MEOHP for DEHP; see Figure 2-2). For esters with side chains of five or more carbons, the oxidized metabolites are the primary metabolites found in urine. The proportions of nu- merous oxidized metabolites vary among parent phthalates (see Table 1-1). The first-round ω-oxidation products dominate for MEHP, but MOP and MNP can lose additional two-carbon units sequentially via ß-oxidation at the ester termi- nal side chain. Thus, the longer the alkyl side chain, the greater variety of oxi- dized metabolites (Wittassek and Angerer 2008). As a result, little monoester from the high-molecular-weight phthalates is detected, typically less than 10% of the absorbed dose (Barr et al. 2003; Koch et al. 2003). Monoesters and oxidized metabolites are excreted free or conjugated as glucuronides—and to a small extent sulfates—and mainly in urine (Silva et al. 2003; Kato et al. 2004; CDC 2005; Calafat et al. 2006; Silva et al. 2007a). How- ever, the low-molecular-weight phthalate metabolites, such as MEP and MBP, are eliminated quickly, yielding a large proportion of the free nonpolar mono- esters, whereas the more polar oxidized metabolites have a greater proportion of conjugated monoesters (Silva et al. 2006). For most phthalates, urinary mono- ester concentrations may not constitute a major fraction of absorbed dose. For example, the primary metabolite of DBP is MBP (about 90%), whereas less than 10% of metabolites of long-chain phthalates are monoesters. Specifically, MECPP is the primary metabolite of DEHP (greater than 25%), MHINP is the primary DINP metabolite (greater than 20%), and MHPHP is the primary DPHP metabolite (greater than 15%) (Wittassek and Angerer 2008). Therefore, human exposure to the low-molecular-weight phthalates can be adequately assessed with urinary monoesters, but exposure to the high-molecular-weight phthalates, such as DEHP and DINP, have been underestimated by measuring only mono- esters and failing to account for other metabolites.

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DEHP mono(2-ethyl-6-hydroxyhexyl) phthalate mono(2-ethyl-5-hydroxyhexyl) phthalate mono(2-ethylhexyl) phthalate mono(2-(1-hydroxyethyl)hexyl) mono(2-ethyl-5-carboxypentyl) phthalate mono(2-ethyl-5-oxohexyl) phthalate mono(2-(2-hydroxyethyl)hexyl) phthalate phthalate mono(2-ethyl-4-hydroxy- mono(2-(1-oxyethyl)hexyl) phthalate 5-carboxypentyl) phthalate mono(2-carboxymethylhexyl) phthalate mono(2-ethyl-4-carboxybutyl) phthalate mono(2-(1-hydroxyethyl)-5-carboxypentyl) phthalate mono(2-ethyl-4-oxo- 5-carboxypentyl) phthalate mono(2-ethyl-3-carboxypropyl) phthalate mono(2-(1-hydroxyethyl)-4-carboxybutyl) phthalate FIGURE 2-2 DEHP metabolism. Source: Adapted from Silva et al. 2006. Reprinted with permission; copyright 2006, Toxicology. 29

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30 Phthalates and Cumulative Risk Assessment: The Tasks Ahead Oxidized metabolites have several important advantages as biomarkers of exposure. First, phthalates are ubiquitous in the environment. They often con- taminate biospecimens, becoming precursors of monoesters that can be formed by endogenous esterases (as in serum in a vacutainer) or by chemical hydrolysis or photolysis during the course of sample collection, storage, and analysis. In contrast, the oxidized metabolites can be formed in vivo only from the mono- ester and only via hepatic metabolism; therefore, they do not arise from external contamination. A second advantage is that they have longer half-lives than the monoesters, which are either rapidly excreted or quickly oxidized. Accordingly, the oxidized metabolites may be more reflective of average exposure than the rapidly excreted monoesters, at least in the case of phthalates with ester side chains of five or more carbons. The complex pharmacokinetics of various phthalates may have implica- tions for toxicity in that some metabolites have more potent biologic activity than others. For example, the monoesters are thought to be those most relevant to androgen insufficiency (Shono et al. 2000; Kai et al. 2005). Therefore, expo- sure-assessment strategies aimed at risk assessment may need to choose whether to focus on specific metabolites or on the total body burden as reflecting expo- sure to the parent phthalates. There are as yet unexplained interindividual differences in metabolic ca- pacity at each step of phthalate metabolism, which may account for some of the differences seen in urinary metabolites by age, sex, race, and other demographic factors. Such differences may explain the observation that the urinary concentra- tions of oxidized metabolites are more prevalent in children than in adults (Koch et al. 2004; CDC 2005; Koch et al. 2005a). Neonates show a striking difference, with urinary MECPP concentrations being higher proportionally than in older subjects (Koch et al. 2006). Conversely, the lack of oxidized metabolites in am- niotic fluid might be explained by immature expression of some enzymes, such as esterases, and oxidation, glucuronidation, and sulfation enzymes by fetuses. At this time, however, it is not known which specific enzymes are involved in phthalate metabolism in humans (McCarver and Hines 2002; Shea et al. 2003; Blake et al. 2005). Differences in metabolism may have potential implications for risk. Therefore, improved knowledge concerning the biologic basis of vari- ability in exposure related to age, race, sex, and other factors may provide a bet- ter understanding of differences in susceptibility to phthalate toxicity. PHARMACOKINETIC MODELS OF PHTHALATES The phthalates on which pharmacokinetic data are most extensive are DBP and DEHP. Human absorption of phthalates is efficient after oral exposure and can occur after dermal exposure (Koch et al. 2006; Janjua et al. 2007). Evidence is sparser with respect to respiratory intake. Adibi et al. (2008) reported positive correlations between air measurements of BBP, DIBP, and DEP and urinary concentrations of MBZP, MIBP, and MEP, respectively, but Becker et al. (2004)

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Phthalate Exposure Assessment in Humans 31 did not find a correlation between DEHP in house dust and urinary concentra- tions of DEHP metabolites. Phthalate metabolism is qualitatively similar among species, beginning with formation of the monoester, which can be excreted un- changed, glucuronidated, sulfated, or further oxidized (Albro et al. 1984; Pollack et al. 1985a,b; Koch et al. 2006; Clewell et al. 2008). However, the rates of me- tabolism and proportions of the various metabolites vary by species and by diester structure, especially the length and saturation of the alkyl side chain of the diester as described above. Physiologically based pharmacokinetic (PBPK) models have been devel- oped for the two better studied phthalates, DBP and DEHP. Keys et al. (1999, 2000) first developed PBPK models to evaluate the role of various transport processes in the clearance of MBP and MEHP in the adult male rat. The models accurately describe plasma MBP and MEHP kinetics after administration of the phthalates. More recently, a PBPK model was developed for disposition of DBP in the adult, pregnant, and fetal rat (Clewell et al. 2008). This model describes the time course of urinary, plasma, bile, and fecal clearance of DBP, MBP (the biologically active metabolite), and the glucuronide and oxidized metabolites after single (oral or intravenous) or repeated (oral) DBP exposures at 1-500 mg/kg. With the model, it is possible to estimate fetal MBP exposure from other exposure metrics, including external dose, maternal plasma and urine, and am- niotic fluid. Thus, the model provides a means of extrapolating rat fetal dose from different phthalate exposure biomarkers in various compartments or bio- logic matrices. The DBP model has also been extrapolated for use in the human by adjusting the physiologic parameters and scaling chemical-specific parame- ters allometrically. Preliminary results reported in an abstract (Campbell et al. 2007) indicated that the model was able to predict MBP concentrations in the urine of human adults given controlled doses of DBP without changing chemi- cal-specific parameters; this suggested that the metabolism of DBP to MBP and of MBP to MBP-glucuronide is similar in the rat and human at human-relevant doses. In particular, the kinetics of free MBP and MBP-glucuronide are well described by the allometric scaling. The DBP gestation model has also been applied to DEHP, a phthalate with different kinetics from DBP (Clewell et al., 2007). In vitro data and in vivo ob- servations were used to adjust the chemical-specific model parameters, and data on plasma, tissue, and excreta MEHP concentrations in the adult, pregnant, and fetal rat after DEHP administration (Kessler et al. 2004) were used to test the model. The predictive models can be evaluated by using cross-sectional data on rats and humans, which allow a crude comparison of phthalate exposure bio- markers in amniotic fluid, urine, and maternal and fetal serum. The data suggest that concentrations in maternal and fetal serum are similar to those in amniotic fluid, and all three compartments have lower concentrations than those in urine (Silva et al. 2004; Calafat et al. 2006; Silva et al. 2007b). The estimates are simi- lar to those in reports of other polar environmental biomarkers in amniotic fluid, urine, and blood (Engel et al. 2006; Foster et al. 2002; CDC 2005)

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32 Phthalates and Cumulative Risk Assessment: The Tasks Ahead The findings on DBP and DEHP from experimental pharmacokinetic models in various life stages and species based on known physiologic differ- ences, although relying on few data, suggest that the approach may also be use- ful for describing the disposition of other phthalates in the rat and human. Such information on disposition is needed for both quantitative and qualitative evalua- tion of the array of human phthalate exposures. Future goals should include de- velopment of models that can provide reasonable estimates of the concentrations of “active phthalates” in the fetus or mother after mixed exposures. AMNIOTIC FLUID: THE FETAL COMPARTMENT Amniotic fluid can be used to estimate fetal exposure and consists largely of fetal urine, especially late in gestation (Gabbe et al. 2007). There is only one published study on phthalate metabolites in human amniotic fluid, which is based on 54 anonymously collected samples. Amniotic fluid concentrations of MEP, MBP, and MEHP exceeded the limit of detection in 93%, 39%, and 24% of samples, respectively (Silva et al. 2004). MBZP was detected in only one sample. The oxidized DEHP metabolites MEHHP and MEOHP, which are usu- ally found in higher concentrations than MEHP in maternal urine (Barr et al. 2003), were not detected in amniotic fluid. Similarly, in rats, free MEHP and MBP were the predominant metabolites in amniotic fluid (Calafat et al. 2006), but oxidized metabolites were not measured. Paired urine samples from the women providing amniotic fluid samples were not available. Nevertheless, the concentrations of MEP, MBP, and MEHP in amniotic fluid were generally lower than median urinary concentrations from NHANES 1999-2000 (NCHS 2008). Because uridine diphosphate glucuronosyl- transferase isoenzymes are not fully expressed until after birth (Coughtrie et al. 1988; de Wildt et al. 1999), the fetus may be unable to glucuronidate the phthal- ate monoesters; in turn, clearance from the fetal compartment may be slower. The lack of detectable DEHP oxidized metabolites in the human amniotic fluid samples (no measurements were made in the rat study) raises several in- triguing issues. It may indicate that the fetus is unable to oxidatively metabolize MEHP because of immature P450 enzymes. Alternatively, the presence of MEHP without the oxidized metabolites may indicate contamination of the am- niotic fluid with DEHP during collection or storage and then hydrolysis to MEHP in the amniotic fluid. Alternatively, it is possible that passive transfer of maternal oxidized metabolites across the placental barrier is not efficient or that they are excreted so rapidly that the resulting low serum concentrations lead to little transfer. Indeed, rat studies suggest that maternal DEHP dose is correlated with urinary and amniotic fluid concentrations of MEHP and MEHHP but that relationships are not linear (Calafat et al. 2006). Because it is difficult—and not generally possible—to obtain amniotic fluid, apart from clinical procedures or at delivery, there is a need for human studies to determine metabolite concentra- tions and understand the relationship between metabolite concentrations in am-

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Phthalate Exposure Assessment in Humans 33 niotic fluid and maternal urine samples. Two recent reports (Adibi et al. 2008; Wolff et al. 2008) indicate that the urinary concentrations of phthalates in preg- nant women are consistent with the previously published NHANES data on women of reproductive age. CONCLUSIONS Our understanding of important sources of, routes of exposure to, and me- tabolism of phthalates in humans has increased over the last decade. Recent data have shown widespread human exposure to multiple phthalates from a multitude of sources. Studies have also identified high-exposure groups that may be more vulnerable to the effects of phthalates and their metabolites. Those groups poten- tially include the fetus and child, whose exposure and metabolism may differ from those of the adult and impart differences in risk. Despite our increased un- derstanding, important unresolved issues remain; research needs are described in Chapter 6 of this report. REFERENCES Adibi, J.J., F.P. Perera, W. Jedrychowski, D.E. Camann, D. Barr, R. Jacek, and R.M. Whyatt. 2003. Prenatal exposures to phthalates among women in New York City and Krakow, Poland. Environ. Health Perspect. 111(14):1719-1722. Adibi, J.J., R.M. Whyatt, P.L. Williams, A.M. Calafat, D. Camann, R. Herrick, H. Nel- son, H.K. Bhat, F.P. Perera, M.J. Silva, and R. Hauser. 2008. Characterization of phthalate exposure among pregnant women assessed by repeat air and urine sam- ples. Environ. Health Perspect. 116(4):467-473. Albro, P.W., K. Chae, R. Philpot, J.T. Corbett, J. Schroeder, and S. Jordan. 1984. In vitro metabolism of mono-2-ethylhexyl phthalate by microsomal enzymes. Similarity to omega- and (omega-1) oxidation of fatty acids. Drug Metab. Dispos. 12(6):742- 748. ATSDR (Agency for Toxic Substances and Disease Registry). 1995. Toxicological Pro- file for Diethyl Phthalate. U.S. Department of Health and Human Services, Public Health Service, Agency for Toxic Substances and Disease Registry, Atlanta, GA. June 1995 [online]. Available: http://www.atsdr.cdc.gov/toxprofiles/tp73.pdf [ac- cessed Sept. 22, 2008]. ATSDR (Agency for Toxic Substances and Disease Registry). 1997. Toxicological Pro- file for Di-n-Octylphthalate. U.S. Department of Health and Human Services, Pub- lic Health Service, Agency for Toxic Substances and Disease Registry, Atlanta, GA. September 1997 [online]. Available: http://www.atsdr.cdc.gov/toxprofiles/ tp95.pdf [accessed Sept. 22, 2008]. ATSDR (Agency for Toxic Substances and Disease Registry). 2001. Toxicological Pro- file for Di-n-Butyl Phthalate. U.S. Department of Health and Human Services, Public Health Service, Agency for Toxic Substances and Disease Registry, At- lanta, GA. September 2001 [online]. Available: http://www.atsdr.cdc.gov/tox profiles/tp135.pdf [accessed Sept. 22, 2008]. ATSDR (Agency for Toxic Substances and Disease Registry). 2002. Toxicological Pro- file for Di(2-ethylhexyl)phthalate. U.S. Department of Health and Human Ser-

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