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

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

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 breastfeeding 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. Published by Elsevier Ltd

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