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.

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.

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.

Screening level assessment of risks due to dioxin emissions from burning oil from the BP Deepwater Horizon Gulf of Mexico spill.

Between April 28 and July 19 of 2010, the U.S. Coast Guard conducted in situ oil burns as one approach used for the management of oil spilled after the explosion and subsequent sinking of the BP Deepwater Horizon platform in the Gulf of Mexico. The purpose of this paper is to describe a screening level assessment of the exposures and risks posed by the dioxin emissions from these fires. Using upper estimates for the oil burn emission factor, modeled air and fish concentrations, and conservative exposure assumptions, the potential cancer risk was estimated for three scenarios: inhalation exposure to workers, inhalation exposure to residents on the mainland, and fish ingestion exposures to residents. U.S. EPA's AERMOD model was used to estimate air concentrations in the immediate vicinity of the oil burns and NOAA's HYSPLIT model was used to estimate more distant air concentrations and deposition rates. The lifetime incremental cancer risks were estimated as 6 × 10(-8) for inhalation by workers, 6 × 10(-12) for inhalation by onshore residents, and 6 × 10(-8) for fish consumption by residents. For all scenarios, the risk estimates represent upper bounds and actual risks would be expected to be less.

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.

Survey of dioxin-like compounds in dairy feeds in the United States.

The United States Environmental Protection Agency (USEPA) has completed a survey of dioxin-like compounds (including 17 dioxin and furan (CDD/F) congeners and 12 coplanar polychlorinated biphenyl (PCBs) congeners) in dairy feeds from 10 dairy research facilities around the United States, sampling the overall mixtures and the major and minor feed components. Low levels of dioxin were found in all feed mixtures with an average concentration of 0.05 pg/g (ppt) toxic equivalent (TEQ) dry weight. This is lower than previously found in dairy feeds by about a factor of 4. While it is possible that generally lower levels of dioxins in the environment in recent years may explain this result, examinations of the data suggest that the oven drying used to prepare the wet feed samples could have resulted in a loss of dioxins from the feed materials. The percentage of the total TEQ due to CDD/Fs was about four times that of PCBs. Leafy vegetations in the feed (the silages and the hays) had concentrations about twice as high as nonleafy, protected vegetation of the feeds (the ground or meal corn, cottonseed, and others). Minor components did not significantly influence the final feed mixture concentration of dioxin TEQ. However, in one of the feed mixtures, a minor component with a high concentration of 38.5 ppt TEQ effectively doubled the concentration of the overall feed mixture.

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.

Hershey Medical Center Technical Workshop Report: optimizing the design and interpretation of epidemiologic studies for assessing neurodevelopmental effects from in utero chemical exposure.

Neurodevelopmental disabilities affect 3-8% of the 4 million babies born each year in the U.S. alone, with known etiology for less than 25% of those disabilities. Numerous investigations have sought to determine the role of environmental exposures in the etiology of a variety of human neurodevelopmental disorders (e.g., learning disabilities, attention deficit-hyperactivity disorder, intellectual disabilities) that are manifested in childhood, adolescence, and young adulthood. A comprehensive critical examination and discussion of the various methodologies commonly used in investigations is needed. The Hershey Medical Center Technical Workshop: Optimizing the design and interpretation of epidemiologic studies for assessing neurodevelopmental effects from in utero chemical exposure provided such a forum for examining these methodologies. The objective of the Workshop was to develop scientific consensus on the key principles and considerations for optimizing the design and interpretation of epidemiologic studies of in utero exposure to environmental chemicals and subsequent neurodevelopmental effects. (The Panel recognized that the nervous system develops post-natally and that critical periods of exposure can span several developmental life stages.) Discussions from the Workshop Panel generated 17 summary points representing key tenets of work in this field. These points stressed the importance of: a well-defined, biologically plausible hypothesis as the foundation of in utero studies for assessing neurodevelopmental outcomes; understanding of the exposure to the environmental chemical(s) of interest, underlying mechanisms of toxicity, and anticipated outcomes; the use of a prospective, longitudinal cohort design that, when possible, runs for periods of 2-5 years, and possibly even longer, in an effort to assess functions at key developmental epochs; measuring potentially confounding variables at regular, fixed time intervals; including measures of specific cognitive and social-emotional domains along with non-cognitive competence in young children, as well as comprehensive measures of health; consistency of research design protocols across studies (i.e., tests, covariates, and analysis styles) in an effort to improve interstudy comparisons; emphasis on design features that minimize introduction of systematic error at all stages of investigation: participant selection, data collection and analysis, and interpretation of results; these would include (but not be limited to) reducing selection bias, using double-blind designs, and avoiding post hoc formulation of hypotheses; a priori data analysis strategies tied to hypotheses and the overall research design, particularly for methods used to characterize and address confounders in any neurodevelopmental study; actual quantitative measurements of exposure, even if indirect, rather than methods based on subject recall; careful examination of standard test batteries to ensure that the battery is tailored to the age group as well as what is known about the specific neurotoxic effects on the developing nervous system; establishment of a system for neurodevelopmental surveillance for tracking the outcomes from in utero exposure across early developmental time periods to determine whether central nervous system injuries may be lying silent until developmentally challenged; ongoing exploration of computerized measures that are culturally and linguistically sensitive, and span the age range from birth into the adolescent years; routine incorporation of narrative in manuscripts concerning the possibility of spurious (i.e., false positive and false negative) test results in all research reportage (this can be facilitated by detailed, transparent reporting of design, covariates, and analyses so that others can attempt to replicate the study); forthright, disciplined, and intellectually honest treatment of the extent to which results of any study are conclusive--that is, how generalizable the results of the study are in terms of the implications for the individual study participants, the community studied, and human health overall; confinement of reporting to the actual research questions, how they were tested, and what the study found, and avoiding, or at least keeping to a minimum, any opinions or speculation concerning public health implications; education of clinicians and policymakers to critically read scientific reports, and to interpret study findings and conclusions appropriately; and recognition by investigators of their ethical duty to report negative as well as positive findings, and the importance of neither minimizing nor exaggerating these findings.

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.

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.

Infant exposure to dioxin-like compounds in breast milk.

We used a one-compartment, first-order pharmacokinetic model to predict the infant body burden of dioxin-like compounds that results from breast-feeding. Validation testing of the model showed a good match between predictions and measurements of dioxin toxic equivalents (TEQs) in breast-fed infants, and the exercise highlighted the importance of the assumption of the rate of dissipation of TEQs in the infant. We evaluated five nursing scenarios: no nursing (i.e., formula only), and nursing for 6 weeks, 6 months, 1 year, and 2 years. We assumed that an infant weighs 3.3 kg at birth and is exposed to a total of 800 pg TEQ/day by consumption of breast milk, leading to an estimated body weight-based dose of 242 pg TEQ/kg-day, which drops to 18 pg TEQ/kg-day after 1 year. This decline is due to declines in dioxin concentration in mother's milk and infant body weight increases. This range is significantly higher, on a body-weight basis, than adult TEQ exposure, which has been estimated to average about 1 pg TEQ/kg-day. For the nursing scenarios of >or= 6 months, we predict that body burdens (expressed as a body lipid concentration) peak at around 9 weeks at 44 ppt TEQ lipid. We predict that the body burden of the formula-fed infants will remain below 10 ppt TEQ lipid during the first year. These results compare to the current adult average body burden of 25 ppt TEQ lipid. We also found that an infant who had been breast-fed for 1 year had an accumulated dose 6 times higher than a 1-year-old infant who had not been breast-fed. For a 70-year lifetime, individuals who had been breast-fed had an accumulated dose 3-18% higher than individuals who had not been breast-fed.

A pharmacokinetic model for estimating exposure of Americans to dioxin-like compounds in the past, present, and future.

Empirical evidence suggests that exposure of Americans to dioxin-like compounds was low during the early decades of the 20th century, then increased during the 1940s and 1950s, reaching a peak in the 1960s and 1970s, and progressively decreased to lower levels in the 1980s and 1990s. Such evidence includes dioxin analysis of carbon-dated sediment cores of lakes and rivers, preserved meat samples from different decades of the 20th century, and limited body burden measurements of dioxin-like compounds. Pinsky and Lorber (1998) summarized studies measuring 2,3,7,8-TCDD in blood and adipose tissue, and found a range of 10-20 pg/g (ppt) lipid during the 1970s, and 2-10 ppt lipid during the 1980s. This study reviews body burdens of dioxin toxic equivalents, TEQs, to find a range from approximately 50 to 80 ppt lipid during the 1970s, 30-50 ppt lipid during the 1980s, and 10-20 ppt lipid during the 1990s (TEQs comprised of the 17 dioxin and furan congeners only). Pinsky and Lorber (1998) investigated historical exposure trends for 2,3,7,8-TCDD by using a single-compartment, first-order pharmacokinetic model. The current study extends this prior effort by modeling dioxin TEQs instead of the single compound, 2,3,7,8-TCDD. TEQs are modeled as though they were a single compound, in contrast to an approach where the individual dioxin and furan congeners are modeled separately. It was found that body burdens of TEQs during the 1970s, 1980s and 1990s could be modeled by assuming a historical dose which began the century at low levels of approximately 0.5 pg TEQ/kg/day, rose during the middle decades of the 20th century to over 6 pg TEQ/kg/day, and declined to current levels of approximately 0.5 pg TEQ/kg/day. Trends in individual and population body burdens of TEQs are also investigated using this PK modeling framework. A key uncertainty of this effort - assuming that TEQs behave as though they were a single compound - is discussed and analyzed.

Investigation of the potential release of polychlorinated dioxins and furans from PCP-treated utility poles.

The United States (US) Environmental Protection Agency (EPA) estimated that the use of technical grade pentachlorophenol (PCP) between 1970 and 1995 to treat wood was approximately 400,000 metric tons in the US, and that between 4800 and 36,000 g of 2,3,7,8-tetrachlorodibenzo-p-dioxin toxic equivalents (TEQs) were incorporated annually in treated wood. The EPA has been unable, however, to estimate the rate of release of polychlorinated dibenzo-p-dioxins and dibenzofurans (CDD/Fs) from treated utility poles into the environment. There is some evidence that CDD/Fs leach from treated poles into the surrounding soils, but these studies do not allow for the calculation of a rate of release from this mechanism. Another possible release mechanism is the volatilization of dioxins into the atmosphere, but there are no data to demonstrate, much less quantify, this release. While not directly measuring the release of dioxins from treated utility poles into the environment, this study was designed to examine the potential for such release. The general approach taken was to collect PCP-treated poles of varying ages, to remove and analyze multiple samples from each pole cross-section, and to compare the spatial distribution of CDD/F congeners among poles of different ages. Evidence of concentration-depth profile changes over time may provide insight into the potential for dioxins to migrate through and then out of PCP-treated utility poles. It was found that the CDD/F concentrations were consistently higher in the outer portions of the poles than the center. This trend tends to be most marked in older poles and for the lower chlorinated congeners. The trend for dioxins to concentrate in the outer portions of the pole over time suggest migration within the poles, and this migration may result in some environmental release. Other possible explanations were also offered.

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.

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.