Academic journal article Environmental Health Perspectives

Dose Reconstruction of Di(2-Ethylhexyl) Phthalate Using a Simple Pharmacokinetic Model

Academic journal article Environmental Health Perspectives

Dose Reconstruction of Di(2-Ethylhexyl) Phthalate Using a Simple Pharmacokinetic Model

Article excerpt

Phthalates, diesters of phthalic acid, are a class of industrial chemicals extensively used as softeners of plastics, solvents in perfumes, and additives to many personal care and consumer products such as hairsprays, lubricants, and insect repellents (David et al. 2001; Koch and Calafat 2009). Di(2-ethylhexyl) phthalate (DEHP) is used primarily as a plasticizer for polyvinyl chloride and can be found in a variety of products, such as floor or wall coverings, vinyl gloves, toys and child care articles, materials that have contact with foods, and medical devices (Schettler 2006).

Several phthalates, including DEHP, di-n-butyl phthalate, diisobutyl phthalate, and butyl benzyl phthalate, have been identified as endocrine disruptors in animal studies (National Research Council 2008). In the body, phthalates rapidly hydrolyze to their respective monoesters; some monoesters are further metabolized by phase I and/or phase II reactions. For phthalates with short alkyl side chains, monoesters represent the major human metabolites. In contrast, for phthalates with longer alkyl chains, including DEHP, the main metabolites are the products of [omega]-, [omega]-1, and [beta]-oxidations of the alkyl chain (Koch and Calafat 2009). All phthalate metabolites are excreted in the urine or feces within a few hours; excretion is complete within 1 or 2 days (Koch and Calafat 2009).

Two approaches have been used to quantify human exposures to DEHP and other phthalates. One relies on the biomonitoring of DEHP metabolites in urine to back calculate the daily intake of DEHP. For example, researchers have used biomonitoring data from the United States (Kohn et al. 2000; Lorber et al. 2010), Germany (Koch et al. 2003; Wittassek et al. 2007), and other countries (Fujimaki et al. 2006; Huang et al. 2006) to characterize general population exposures. The other approach uses DEHP concentrations in exposure media (e.g., air, food, dust) and exposure contact rates to estimate daily intakes. This approach has been used in two studies, one using worldwide exposure media data (Clark et al. 2011) and the other using European exposure data (Wormuth et al. 2006). Both approaches arrived at similar intakes of DEHP in adults, ranging from about 2 to 10 [micro]g/kg-day. These researchers concluded that, for the general population, diet explained the bulk of exposure to DEHP.

For the present study, we used a third approach to assess general population exposures to DEHP. This approach relies on having precise times of urination and urine volumes, along with urinary concentrations of DEHP metabolites. We used a calibrated simple pharmacokinetic model for DEHP (Lorber et al. 2010) in conjunction with these data to "reconstruct" the dose necessary to have resulted in the observed metabolite concentrations.


Biomonitoring data set. We used data collected from four adult men and four adult women, 24-59 years of age, who provided the full volume and time of all urinary void events for 1 week in October-November 2005. Each participant provided diary information that included when and what the participant ate and drank, time spent driving and putting gasoline in the car, and time spent in other activities that might influence the presence of DEHP metabolites and other contaminants in urine. Because we had no information about the participants' body weights, we assumed body weights of 70 kg for men and 60 kg for women. The study design has been described in detail previously (Li et al. 2010; Preau et al. 2010; Ye et al. 2011). The institutional review board of the Centers for Disease Control and Prevention (CDC) approved the original study; the present study was exempted, and all participants provided written informed consent at the time of the original study.

The data set comprised 56 person-days of data (8 people x 7 days) and included 427 distinct urine samples. These samples have previously been analyzed for several polycyclic aromatic hydrocarbon (PAH) metabolites (Li et al. …

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