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 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.

TABLE 2-1

Common Phthalates and Examples of Uses.

Phthalate exposures may occur through ingestion, inhalation, dermal absorption, and parenteral administration. The relative contributions of the exposures 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, childhood, 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; Sathyanarayana 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 compartments. 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 problems 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 human studies necessitates the measurement of oxidized metabolites to avoid problems 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).

TABLE 2-2

Urinary Phthalate Metabolites in Large Studies in United States and Germany.

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.

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 treatments, 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 medications.

TABLE 2-3

Urinary Phthalate Metabolite Concentrations after Exceptional Exposures and Comparison Medians from Available NHANES or European Union Data.

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 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 metabolites 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 numerous 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 terminal side chain. Thus, the longer the alkyl side chain, the greater variety of oxidized 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).

FIGURE 2-1

Phthalate metabolism. UDP-GT, uridine 5′-diphosphate-glucuronosyltransferase.

FIGURE 2-2

DEHP metabolism. Source: Adapted from Silva et al. 2006. Reprinted with permission; copyright 2006, Toxicology.

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). However, the low-molecular-weight phthalate metabolites, such as MEP and MBP, are eliminated quickly, yielding a large proportion of the free nonpolar monoesters, whereas the more polar oxidized metabolites have a greater proportion of conjugated monoesters (Silva et al. 2006). For most phthalates, urinary monoester 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 monoesters and failing to account for other metabolites.

Oxidized metabolites have several important advantages as biomarkers of exposure. First, phthalates are ubiquitous in the environment. They often contaminate 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 monoester 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 implications 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, exposure-assessment strategies aimed at risk assessment may need to choose whether to focus on specific metabolites or on the total body burden as reflecting exposure to the parent phthalates.

There are as yet unexplained interindividual differences in metabolic capacity 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 concentrations 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 amniotic 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 variability in exposure related to age, race, sex, and other factors may provide a better 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) did not find a correlation between DEHP in house dust and urinary concentrations of DEHP metabolites. Phthalate metabolism is qualitatively similar among species, beginning with formation of the monoester, which can be excreted unchanged, 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 metabolism 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 developed 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 amniotic fluid. Thus, the model provides a means of extrapolating rat fetal dose from different phthalate exposure biomarkers in various compartments or biologic matrices. The DBP model has also been extrapolated for use in the human by adjusting the physiologic parameters and scaling chemical-specific parameters 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 chemical-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 observations 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 biomarkers 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 similar 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)

The findings on DBP and DEHP from experimental pharmacokinetic models in various life stages and species based on known physiologic differences, although relying on few data, suggest that the approach may also be useful for describing the disposition of other phthalates in the rat and human. Such information on disposition is needed for both quantitative and qualitative evaluation of the array of human phthalate exposures. Future goals should include development 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 usually 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 phthalate 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 intriguing 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 amniotic 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 concentrations and understand the relationship between metabolite concentrations in am 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 pregnant 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 metabolism 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 potentially include the fetus and child, whose exposure and metabolism may differ from those of the adult and impart differences in risk. Despite our increased understanding, important unresolved issues remain; research needs are described in Chapter 6 of this report.

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Footnotes

1

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