Environmental Chemicals in Breast Milk and Formula: Exposure and Risk Assessment Implications.

BACKGROUND: Human health risk assessment methods have advanced in recent years to more accurately estimate risks associated with exposure during childhood. However, predicting risks related to infant exposures to environmental chemicals in breast milk and formula remains challenging. OBJECTIVES: Our goal was to compile available information on infant exposures to environmental chemicals in breast milk and formula, describe methods to characterize infant exposure and potential for health risk in the context of a risk assessment, and identify research needed to improve risk analyses based on this type of exposure and health risk information. METHODS: We reviewed recent literature on levels of environmental chemicals in breast milk and formula, with a focus on data from the United States. We then selected three example publications that quantified infant exposure using breast milk or formula chemical concentrations and estimated breast milk or formula intake. The potential for health risk from these dietary exposures was then characterized by comparison with available health risk benchmarks. We identified areas of this approach in need of improvement to better characterize the potential for infant health risk from this critical exposure pathway. DISCUSSION: Measurements of chemicals in breast milk and formula are integral to the evaluation of risk from early life dietary exposures to environmental chemicals. Risk assessments may also be informed by research investigating the impact of chemical exposure on developmental processes known to be active, and subject to disruption, during infancy, and by analysis of exposure-response data specific to the infant life stage. Critical data gaps exist in all of these areas. CONCLUSIONS: Better-designed studies are needed to characterize infant exposures to environmental chemicals in breast milk and infant formula as well as to improve risk assessments of chemicals found in both foods. https://doi.org/10.1289/EHP1953.

Infant Dietary Exposures to Environmental Chemicals and Infant/Child Health: A Critical Assessment of the Literature.

BACKGROUND: The benefits of breastfeeding to the infant and mother have been well documented. It is also well known that breast milk contains environmental chemicals, and numerous epidemiological studies have explored relationships between background levels of chemicals in breast milk and health outcomes in infants and children. OBJECTIVES: In this paper, we examine epidemiological literature to address the following question: Are infant exposures to background levels of environmental chemicals in breast milk and formula associated with adverse health effects? We critically review this literature a) to explore whether exposure-outcome associations are observed across studies, and b) to assess the literature quality. METHODS: We reviewed literature identified from electronic literature searches. We explored whether exposure-outcome associations are observed across studies by assessing the quality (using a modified version of a previously published quality assessment tool), consistency, and strengths and weaknesses in the literature. The epidemiological literature included cohorts from several countries and examined infants/children either once or multiple times over weeks to years. Health outcomes included four broad categories: growth and maturation, morbidity, biomarkers, and neurodevelopment. RESULTS: The available literature does not provide conclusive evidence of consistent or clinically relevant health consequences to infants exposed to environmental chemicals in breast milk at background levels. CONCLUSIONS: It is clear that more research would better inform our understanding of the potential for health impacts from infant dietary exposures to environmental chemicals. A critical data gap is a lack of research on environmental chemicals in formula and infant/child health outcomes. https://doi.org/10.1289/EHP1954.

Use of a simple pharmacokinetic model to study the impact of breast-feeding on infant and toddler body burdens of PCB 153, BDE 47, and DDE.

Several studies have examined the role of breast milk consumption in the buildup of environmental chemicals in infants, and have concluded that this pathway elevates infant body burdens above what would occur in a formula-only diet. Unique data from Australia provide an opportunity to study this finding using simple pharmacokinetic (PK) models. Pooled serum samples from infants in the general population provided data on PCB 153, BDE 47, and DDE at 6-month increments from birth until 4 years of age. General population breast-feeding scenarios for Australian conditions were crafted and input into a simple PK model which predicted infant serum concentrations over time. Comparison scenarios of background exposures to characterize formula-feeding were also crafted. It was found that the models were able to replicate the rise in measured infant body burdens for PCB 153 and DDE in the breast-feeding scenarios, while the background scenarios resulted in infant body burdens substantially below the measurements. The same was not true for BDE 47, however. Both the breast-feeding and background scenarios substantially underpredicted body burden measurements. Two possible explanations were offered: that exposure to higher BDE congeners would debrominate and form BDE 47 in the body, and/or, a second overlooked exposure pathway for PBDEs might be the cause of high infant and toddler body burdens. This pathway was inhalation due to the use of PBDEs as flame retardants in bedding materials. More research to better understand and quantify this pathway, or other unknown pathways, to describe infant and toddler exposures to PBDEs is needed.

Estimated tris(1,3-dichloro-2-propyl) phosphate exposure levels for US infants suggest potential health risks.

Tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) has been widely used as a flame retardant and is commonly detected in environmental samples. Biomonitoring studies relying on urinary metabolite levels (i.e. bis(1,3-dichloro-2-propyl) phosphate (BDCIPP)) demonstrate widespread exposure, but TDCIPP intake is unknown. Intake data area critical component of meaningful risk assessments and are needed to elucidate the potential health impacts of TDCIPP exposure. Using biomonitoring data, we estimated TDCIPP intake for infants. Infants aged 2-18 months were recruited from central, North Carolina (n=43, recruited 2014-2015), and spot urine samples were analyzed for BDCIPP. TDCIPP intake rates were estimated using daily urine excretion and the fraction of TDCIPP excreted as BDCIPP in urine. Daily TDCIPP intake estimates ranged from 0.01-15.03 µg/kg-day for children included in our assessment, with some variation depending on model assumptions. The U.S. Consumer Products Safety Commission (CPSC) previously established an acceptable daily intake of 5µg/kg-day for non-cancer health risks. Depending on modeling assumptions, we found that 2-9% percent of infants had TDCIPP intake estimates above this threshold. Our results indicate that current TDCIPP exposure levels could pose health risks for highly exposed infants.

Linking a dermal permeation and an inhalation model to a simple pharmacokinetic model to study airborne exposure to di(n-butyl) phthalate.

Six males clad only in shorts were exposed to high levels of airborne di(n-butyl) phthalate (DnBP) and diethyl phthalate (DEP) in chamber experiments conducted in 2014. In two 6 h sessions, the subjects were exposed only dermally while breathing clean air from a hood, and both dermally and via inhalation when exposed without a hood. Full urine samples were taken before, during, and for 48 h after leaving the chamber and measured for key DnBP and DEP metabolites. The data clearly demonstrated high levels of DnBP and DEP metabolite excretions while in the chamber and during the first 24 h once leaving the chamber under both conditions. The data for DnBP were used in a modeling exercise linking dose models for inhalation and transdermal permeation with a simple pharmacokinetic model that predicted timing and mass of metabolite excretions. These models were developed and calibrated independent of these experiments. Tests included modeling of the "hood-on" (transdermal penetration only), "hood-off" (both inhalation and transdermal) scenarios, and a derived "inhalation-only" scenario. Results showed that the linked model tended to duplicate the pattern of excretion with regard to timing of peaks, decline of concentrations over time, and the ratio of DnBP metabolites. However, the transdermal model tended to overpredict penetration of DnBP such that predictions of metabolite excretions were between 1.1 and 4.5 times higher than the cumulative excretion of DnBP metabolites over the 54 h of the simulation. A similar overprediction was not seen for the "inhalation-only" simulations. Possible explanations and model refinements for these overpredictions are discussed. In a demonstration of the linked model designed to characterize general population exposures to typical airborne indoor concentrations of DnBP in the United States, it was estimated that up to one-quarter of total exposures could be due to inhalation and dermal uptake.

Exposure assessment of adult intake of bisphenol A (BPA) with emphasis on canned food dietary exposures.

Bisphenol A (BPA) is a high-volume, synthetic compound found in epoxy resins and plastics used in food packaging. Food is believed to be a major source of BPA intake. In this study, we measured the concentration of BPA in convenience samplings of foodstuffs purchased in Dallas, Texas. Sampling entailed collection of 204 samples of fresh, frozen, and canned foods in two rounds in 2010. BPA was positive in 73% of the canned food samples, while it was found in only 7% of non-canned foods at low concentrations. The results of this food sampling program were used to calculate adult dietary intakes of BPA. A pathway approach combined food intakes, a "canned fraction" parameter which described what portion of total intake of that food came from canned products, and measured food concentrations. Dietary intakes were calculated as 12.6 ng/kg-day, of which 12.4 ng/kg-day was from canned foods. Canned vegetable intakes alone were 11.9 ng/kg-day. This dietary intake was compared to total intakes of BPA estimated from urine measurements of the National Health and Nutrition Examination Survey (NHANES). Total adult central tendency intakes ranged from 30 to 70 ng/kg-day for NHANES cycles between 2005 and 2010. Three possibilities were explored to explain the difference between these two approaches for intake estimation. Not all foods which may have been canned, particularly canned beverages such as soft drinks, were sampled in our food sampling program. Second, non-food pathways of exposure may be important for adults, including thermal paper exposures, and dust and air exposures. Finally, our canned food concentrations may not be adequately representative of canned foods in the United States; they were found to be generally lower compared to canned food concentrations measured in six other worldwide food surveys including three in North America. Our finding that canned food concentrations greatly exceeded non-canned concentrations was consistent with other studies, and underscores the importance of canned foods in the overall exposure of adults of BPA.

Development of a multi-compartment pharmacokinetic model to characterize the exposure to Hexamoll® DINCH®.

We developed and calibrated a multi compartment pharmacokinetic (PK) model to predict urinary concentrations after oral exposure of four specific DINCH metabolites: MINCH, OH-MINCH, cx-MINCH, and oxo-MINCH. This descriptive model has 4 compartments: a "stomach" (SC) compartment, a "holding" (HC) compartment, a "blood" (BC) compartment and a "bladder" (BLC) compartment. DINCH is assumed to first deposit into the SC, with transfer split between the HC and the BC. Unmetabolized DINCH from the HC then transfers to the BC. The DINCH metabolism is assumed to occur in the BC before excretion via the BLC. At each urination event, all the metabolite mass in the BLC is excreted. The model was calibrated using published urine metabolite data from 3 different male volunteers, each orally dosed with 50mg DINCH. Full urine voids were taken for 48 h after dosage. The predicted values showed a good agreement with the observed urinary DINCH metabolite concentrations, with a Spearman correlation coefficient exceeding 0.7 for all oxidized metabolites. We showed the importance of a holding reservoir. Without it, a good agreement could not be found. We applied the model to a set of 24-h general population samples measured for DINCH metabolites. The model was unable to duplicate the ratio of metabolites seen in the 24-h samples. Two possibilities were offered to explain the difference: the exposure pattern in the general population did not match the oral exposure in the dosing experiments, or the long-term toxicokinetics of DINCH was not captured in the 48-h controlled dosing experiments.

Reconstruction of bisphenol A intake using a simple pharmacokinetic model.

Bisphenol A (BPA) is used in the manufacture of a range of consumer products, and human biomonitoring studies suggest that exposure to BPA is nearly ubiquitous. We constructed and calibrated a simple pharmacokinetic model to predict urinary concentrations of BPA based on a known initial dose. This descriptive (rather than physiologically based) model has three compartments: "stomach/liver," "blood," and "bladder." We calibrated and validated the model parameters using blood and urine measurements from nine volunteers who consumed 5 mg of d16-BPA. We then applied the model to a second group of eight persons, who supplied full volumes of urine over 7 consecutive days and a diary identifying times and types of food and beverage consumed, to "reconstruct" the time and mass of BPA intakes. These reconstructed daily intakes ranged on average from 60 to 100 ng/kg-day, within the range of, but slightly higher than, those surmised from other studies. About two-thirds of intakes occurred within an hour of reported food or drink consumption, supporting the hypothesis that diet is the main pathway of exposure to BPA. However, one-third of all reconstructed intakes took place outside this time window, suggesting that other sources of BPA exposure may also be relevant.

Changes in epidemiologic associations with different exposure metrics: a case study of phthalate exposure associations with body mass index and waist circumference.

The use of human biomonitoring data to characterize exposure to environmental contaminants in epidemiology studies has expanded greatly in recent years. Substantial variability in effect measures may arise when using different exposure metrics for a given contaminant, and it is often not clear which metric is the best surrogate for the 'causal' or 'true' exposure. Here we evaluated variability and potential bias in epidemiologic associations resulting from the use of different phthalate exposure metrics in the 2009-2010 National Health and Nutrition Examination Survey (NHANES). We examined associations between urinary phthalate metabolites and the outcomes of body mass index (BMI) and waist circumference (WC). We examined each of the following NHANES-derived exposure metrics for metabolites of individual phthalates: molar excretion rate (nmol/min), molar amount (nmol), molar concentration (nmol/mL, with and without additional model adjustment for creatinine), creatinine corrected molar concentration (nmol/g creatinine), and reconstructed daily phthalate intake (nmol/kg/day). In order to investigate potential biasing effect of each metric, we first assumed that daily intake of the parent phthalate is the causal exposure. We then constructed a simulated population based on the 2009-2010 NHANES, and randomly assigned each individual a di-2-ethylhexyl phthalate (DEHP) intake dose based on a published distribution, but independent of any other factor. Accordingly, all associations between these randomly assigned intake doses and individuals' BMI and WC should be null. Next, demographic data in the NHANES were incorporated into a pharmacokinetic model to predict urinary molar excretions of five DEHP metabolites based on the randomly assigned DEHP intake. The predicted molar excretions were then used to calculate the same exposure metrics listed above. Three exposure metrics (randomly generated intake, excretion rate, urine concentration) showed no significant associations with BMI, which supports the null hypothesis stated above. In contrast, metrics adjusted for creatinine showed a significant negative correlation, and reconstructed daily intake showed a significant positive correlation, indicating the introduction of bias away from the true (i.e., null) association. Interestingly, trends in the simulation analysis were similar to those seen in the observed NHANES data. Our findings show that, at least in this example case, the choice of exposure metric can introduce significant bias of varying magnitude and direction into the calculation of epidemiologic associations.

Generation of hazard indices for cumulative exposure to phthalates for use in cumulative risk assessment.

Exposures to multiple chemicals may contribute to increased risk of similar adverse effects. Cumulative risk may be estimated using a hazard index (HI), the sum of individual hazard quotients (HQ, ratio of exposure to the reference value). We demonstrate the HI approach for five phthalates: di(2-ethylhexyl) phthalate (DEHP), di-n-butyl phthalate (DBP), diisobutyl phthalate (DiBP), diisononyl phthalate (DiNP), and butyl benzyl phthalate (BBP). Phthalate exposure for the US general population is estimated using urine metabolite levels from NHANES, extrapolating to ingested 'dose' using the creatinine correction approach. We used two sets of reference values: European Union Tolerable Daily Intakes and Denmark Environmental Protection Agency Derived No Effect Levels. We also investigated the use of an alternate reference value for DEHP, derived from a recent study on male reproductive system development. HQs and HIs were calculated for the total population ages 6years and older, as well as for men and women of approximate reproductive age (18-39 years), and children (6-11 years). Median HQs ranged from <0.01 for BBP, to ∼0.1 (using established values) or ∼2 (using an alternate value) for DEHP. Median HIs were <0.30 (95th percentiles just >1.0), and were driven by DEHP and DBP exposures.

Development and application of simple pharmacokinetic models to study human exposure to di-n-butyl phthalate (DnBP) and diisobutyl phthalate (DiBP).

In a published controlled dosing experiment, a single individual consumed 5mg each of labeled di-n-butyl phthalate (DnBP) and diisobutyl phthalate (DiBP) on separate occasions and tracked metabolites in his blood and urine over 48h. Data from this study were used to structure and calibrate simple pharmacokinetic (PK) models for these two phthalates, which predict urine and blood metabolite concentrations with a given phthalate intake scenario (times and quantities). The calibrated models were applied to a second published experiment in which 5 individuals fasted over the course of a 48-h weekend (bottled water only), and their full urine voids were captured and measured for DnBP and DiBP metabolites. One goal of this model application was to confirm the validity of the calibrated models - their validity would be demonstrated if a profile of intakes could be found which adequately duplicated the metabolite concentrations measured in the urine. A second goal was to study patterns of exposure for this group. It was found that all metabolites could be duplicated very well with individual-specific "best-fit" intake scenarios, with one exception. It appears that the model predicted much lower concentrations of the metabolite, 3carboxy-mono-propylphthalate (MCPP), than were observed in all individuals. Modeled as a metabolite of DnBP, this suggests that DnBP was not the major source of MCPP in the urine. For all 5 individuals, the reconstructed dose profiles of the two phthalates were similar: about 6 small bolus doses per day and an intake of about 0.5µg/kg-day. The intakes did not appear to be associated with diary-reported activities (personal hygiene and medication) of the participants. The modeled frequent intakes suggested one (or both) of two possibilities: ongoing exposures such as an inhalation exposure, or no exposure but rather an ongoing release of body stores of the phthalate metabolites from past exposures.

A sensitivity analysis using alternative toxic equivalency factors to estimate U.S. dietary exposures to dioxin-like compounds.

EPA recommends sensitivity analyses when applying the toxic equivalency factor (TEF) method to evaluate exposures to dioxin-like compounds (DLCs). Applying the World Health Organization's (WHO) 2005 TEF values and estimating average U.S. daily dietary intakes of 25 DLCs from eight food categories, we estimate a toxic equivalency (TEQ) intake of 23 pg/day. Among DLCs, PCB 126 (26%) and 1,2,3,7,8-PeCDD (23%) dominate TEQ intakes. Among food categories, milk (14%), other dairy (28%), beef (25%), and seafood (18%) most influenced TEQ intakes. We develop two approaches to estimate alternative TEF values. Based on WHO's assumption regarding TEF uncertainty, Approach1 estimates upper and lower TEFs for each DLC by multiplying and dividing, respectively, its individual TEF by ± half a log. Based on compiled empirical ranges of relative potency estimates, Approach2 uses percentile values for individual TEFs. Total TEQ intake estimates using the lower and upper TEFs based on Approach1 were 8 and 68 pg TEQ/day, respectively. The 25th and 75th percentile TEFs from Approach2 yielded 12 and 28 pg TEQ/day, respectively. The influential DLCs and food categories remained consistent across alternative TEFs, except at the 90th percentile using Approach2. We highlight the need for developing underlying TEF probability distributions.

Phthalate concentrations and dietary exposure from food purchased in New York State.

BACKGROUND: Phthalates have been found in many personal care and industrial products, but have not previously been reported in food purchased in the United States. Phthalates are ubiquitous synthetic compounds and therefore difficult to measure in foods containing trace levels. Phthalates have been associated with endocrine disruption and developmental alteration. OBJECTIVES: Our goals were to report concentrations of phthalates in U.S. food for the first time, specifically, nine phthalates in 72 individual food samples purchased in Albany, New York, and to compare these findings with other countries and estimate dietary phthalate intake. METHODS: A convenience sample of commonly consumed foods was purchased from New York supermarkets. Methods were developed to analyze these foods using gas chromatography-mass spectroscopy. Dietary intakes of phthalates were estimated as the product of the food consumption rate and concentration of phthalates in that food. RESULTS: The range of detection frequency of individual phthalates varied from 6% for dicyclohexyl phthalate (DCHP) to 74% for di-2-ethylhexyl phthalate (DEHP). DEHP concentrations were the highest of the phthalates measured in all foods except beef [where di-n-octyl phthalate (DnOP) was the highest phthalate found], with pork having the highest estimated mean concentration of any food group (mean 300 ng/g; maximum, 1,158 ng/g). Estimated mean adult intakes ranged from 0.004 µg/kg/day for dimethyl phthalate (DMP) to 0.673 µg/kg/day for DEHP. CONCLUSIONS: Phthalates are widely present in U.S. foods. While estimated intakes for individual phthalates in this study were more than an order of magnitude lower than U.S. Environmental Protection Agency reference doses, cumulative exposure to phthalates is of concern and a more representative survey of U.S. foods is indicated.

Identifying sources of phthalate exposure with human biomonitoring: results of a 48h fasting study with urine collection and personal activity patterns.

Human biomonitoring studies measuring phthalate metabolites in urine have shown widespread exposure to phthalates in the general population. Diet is thought to be a principle route of exposure to many phthalates. Therefore, we studied urinary phthalate metabolite patterns over a period of strict fasting and additionally recorded personal activity patterns with a diary to investigate non-dietary routes of exposure. Five individuals (3 female, 2 male, 27-47 years of age) fasted on glass-bottled water only over a 48-h period. All urine void events were captured in full, and measured for metabolites of the high molecular weight (HMW) di-(2-ethylhexyl) phthalate (DEHP), di-isononyl phthalate (DINP) and di-isodecyl phthalate (DiDP), and the low molecular weight (LMW) di-n-butyl phthalate (DnBP), di-iso-butyl phthalate (DiBP), butylbenzyl phthalate (BBzP), dimethyl phthalate (DMP), and diethyl phthalate (DEP). In all, 21 metabolites were measured in a total of 118 urine events, including events before and after the fasting period. At the onset of the study all phthalate metabolite concentrations were consistent with levels found in previous general population studies. Metabolites of the HMW phthalates (DEHP, DiNP and DiDP) showed a rapid decline to levels 5-10 times lower than initial levels within 24h of the fast and remained low thereafter. After food consumption resumed, levels rose again. By contrast, metabolites of the LMW phthalates including DMP, DEP, BBzP, DnBP and DiBP showed a cyclical pattern of rising and declining concentrations suggestive of ongoing non-food exposures. Furthermore, metabolites of most of the LMW phthalates (BBzP, DnBP and DiBP) tracked each other remarkably well, suggesting concurrent exposures. Diary entries could not help explain exposure sources for these phthalates, with one exception: rises in MEP concentrations around males' showers suggest personal care products as a major source of DEP. Exposure to HMW phthalates in this cohort appears to be driven by dietary intake, while non-dietary routes such as use of personal care products and ubiquitous sources including dust and indoor air appear to explain exposure to LMW phthalates.

Dose reconstruction of di(2-ethylhexyl) phthalate using a simple pharmacokinetic model.

BACKGROUND: Di(2-ethylhexyl) phthalate (DEHP), used primarily as a plasticizer for polyvinyl chloride, is found in a variety of products. Previous studies have quantified human exposure by back calculating intakes based on DEHP metabolite concentrations in urine and by determining concentrations of DEHP in exposure media (e.g., air, food, dust). OBJECTIVES: To better understand the timing and extent of DEHP exposure, we used a simple pharmacokinetic model to "reconstruct" the DEHP dose responsible for the presence of DEHP metabolites in urine. METHODS: We analyzed urine samples from eight adults for four DEHP metabolites [mono(2-ethylhexyl) phthalate, mono(2-ethyl-5-hydroxyhexyl) phthalate, mono(2-ethyl-5-oxohexyl) phthalate, and mono(2-ethyl-5-carboxypentyl) phthalate]. Participants provided full volumes of all voids over 1 week and recorded the time of each void and information on diet, driving, and outdoor activities. Using a model previously calibrated on a single person self-dosed with DEHP in conjunction with the eight participants' data, we used a simple trial-and-error method to determine times and doses of DEHP that resulted in a best fit of predicted and observed urinary concentrations of the metabolites. RESULTS: The average daily mean and median reconstructed DEHP doses were 10.9 and 5.0 µg/kg-day, respectively. The highest single modeled dose of 60 µg/kg occurred when one study participant reported consuming coffee and a bagel with egg and sausage that was purchased at a gas station. About two-thirds of all modeled intake events occurred near the time of reported food or beverage consumption. Twenty percent of the modeled DEHP exposure occurred between 2200 hours and 0500 hours. CONCLUSIONS: Dose reconstruction using pharmacokinetic models-in conjunction with biomonitoring data, diary information, and other related data-can provide a powerful means to define timing, magnitude, and possible sources of exposure to a given contaminant.

Population variability of phthalate metabolites and bisphenol A concentrations in spot urine samples versus 24- or 48-h collections.

Human exposure to phthalates and bisphenol A (BPA) can be assessed through urinary biomonitoring, but methods to infer daily intakes assume that spot sample concentrations are comparable to daily average concentrations. We evaluate this assumption using human biomonitoring data from Germany and the United States (US). The German data comprised three regional studies with spot samples and one with full-day samples analyzed for phthalate metabolites. The US data included: a study on DEHP metabolites and BPA involving eight persons supplying all urine voids (from which 24-h samples were constructed) for seven consecutive days; NHANES spot sample data on DEHP metabolites and BPA; and a regional study of children with 48-h samples analyzed for BPA. In the German data, measures of central tendency differed, but spot and 24-h samples showed generally comparable variance including 95th percentiles and maxima equidistant from central tendency measures. In contrast, the US adult data from the eight-person study showed similar central tendencies for phthalate metabolites and BPA, but generally greater variability for the spot samples, including higher 95th percentiles and maxima. When comparing children's BPA concentrations in NHANES spot and 48-h samples, distributions showed similar central tendency and variability. Overall, spot urinary concentrations of DEHP metabolites and BPA have variability roughly comparable with corresponding 24-h average concentrations obtained from a comparable population, suggesting that spot samples can be used to characterize population distributions of intakes. However, the analysis also suggests that caution should be exercised when interpreting the high end of spot sample data sets.

Urinary DEHP metabolites and fasting time in NHANES.

Exposure assessment analyses conducted in Europe have concluded that the primary pathway of exposure to di(2-ethylhexyl) phthalate (DEHP) is through the diet. The purpose of this study is to evaluate whether urinary DEHP metabolite data from the 2007-2008 National Health and Nutritional Examination Survey (NHANES) demonstrate relationships with reported food-fasting time consistent with diet as the predominant exposure pathway. Previous controlled-dosing data demonstrate that DEHP metabolite concentrations in urine first rise and then decline over time, with first-order elimination becoming evident at about 6 h post exposure. Regression of the concentrations of four key DEHP metabolites vs reported fasting times between 6 and 18 h in adults resulted in apparent population-based urinary elimination half-lives, consistent with those previously determined in a controlled-dosing experiment, supporting the importance of the dietary pathway for DEHP. For fasting times less than about 6 h, sampling session (morning, afternoon, or evening) affected the measured metabolite concentrations. Evening samples showed the highest metabolite concentrations, supporting a hypothesis of recent daily dietary exposures from multiple meals, whereas morning and afternoon samples for fasting times less than 6 h were similar and somewhat lower than evening samples, consistent with less-substantial early day dietary exposure. Variations in children's bodyweight-normalized creatinine excretion and food intake rates contribute to a strong inverse relationship between urinary DEHP metabolite concentrations and age under age 18. Finally, a previously published pharmacokinetic model for DEHP demonstrates that time since previous urinary void, a parameter not measured in NHANES, is predicted to result in non-random effects on measured urinary concentrations.

Simple intake and pharmacokinetic modeling to characterize exposure of Americans to perfluoroctanoic acid, PFOA.

Models for assessing intakes of perfluorooctanoic acid, PFOA, are described and applied. One model is based on exposure media concentrations and contact rates. This model is applied to general population exposures for adults and 2-year old children. The other model is a simple one-compartment, first-order pharmacokinetic (PK) model. Parameters for this model include a rate of elimination of PFOA and a blood volume of distribution. The model was applied to data from the National Health and Nutritional Examination Survey, NHANES, to backcalculate intakes. The central tendency intake estimate for adults and children based on exposure media concentrations and contact rates were 70 and 26 ng/day, respectively. The central tendency adult intake derived from NHANES data was 56 and 37 ng/day for males and females, respectively. Variability and uncertainty discussions regarding the intake modeling focus on lack of data on direct exposure to PFOA used in consumer products, precursor compounds, and food. Discussions regarding PK modeling focus on the range of blood measurements in NHANES, the appropriateness of the simple PK model, and the uncertainties associated with model parameters. Using the PK model, the 10th and 95th percentile long-term average adult intakes of PFOA are 15 and 130 ng/day.

A critical evaluation of the creatinine correction approach: can it underestimate intakes of phthalates? A case study with di-2-ethylhexyl phthalate.

The creatinine correction approach has been used to estimate daily intake for contaminants whose primary route of elimination is through urine. This method is challenged using the phthalate di-2-ethylhexyl phthalate (DEHP) as an example. An alternate prediction approach based on human experimental metabolism and urinary excretion data on DEHP was developed. This alternate model was developed from urine measurements of four metabolites of DEHP from two individuals partaking in different experiments, for up to 44 h after known exposures. Particular attention was paid to the changing ratios of the metabolites over time: they took a certain form when exposure was in the "near" (the past few hours) versus the "distant" (24 h or more) past. The creatinine correction approach was applied to measurements of the same four metabolites from 18 individuals in the National Health And Nutrition Evaluation Survey (NHANES) 2003/2004. The alternate model was also applied to these individuals, and the results were compared. Predictions using the two methods were similar or the creatinine correction predicted higher concentrations when the ratio suggested that the DEHP exposure was "near" in time, but the alternate approach predicted intakes that were an order of magnitude higher when the ratios suggested that the intake was "distant". As much as 25% of all NHANES measurements contain metabolites whose key ratio suggest that exposure was "distant". Uncertainties notwithstanding, the analysis in this article suggests that the creatinine correction approach should be used cautiously for DEHP and possibly other contaminants with similar exposure characteristics: rapid metabolism with metabolite urine elimination half-lives on the order of hours, and exposure patterns that may not be continuous and ongoing.