Towards translating in vitro measures of thyroid hormone system disruption to in vivo responses in the pregnant rat via a biologically based dose response (BBDR) model.

Despite the number of in vitro assays that have been recently developed to identify chemicals that interfere with the hypothalamic-pituitary-thyroid axis (HPT), the translation of those in vitro results into in vivo responses (in vitro to in vivo extrapolation, IVIVE) has received limited attention from the modeling community. To help advance this field a steady state biologically based dose response (BBDR) model for the HPT axis was constructed for the pregnant rat on gestation day (GD) 20. The BBDR HPT axis model predicts plasma levels of thyroid stimulating hormone (TSH) and the thyroid hormones, thyroxine (T4) and triiodothyronine (T3). Thyroid hormones are important for normal growth and development of the fetus. Perchlorate, a potent inhibitor of thyroidal uptake of iodide by the sodium iodide symporter (NIS) protein, was used as a case study for the BBDR HPT axis model. The inhibitory blocking of the NIS by perchlorate was associated with dose-dependent steady state decreases in thyroid hormone production in the thyroid gland. The BBDR HPT axis model predictions for TSH, T3, and T4 plasma concentrations in pregnant Sprague Dawley (SD) rats were within 2-fold of observations for drinking water perchlorate exposures ranging from 10 to 30,000 µg/kg/d. In Long Evans (LE) pregnant rats, for both control and perchlorate drinking water exposures, ranging from 85 to 82,000 µg/kg/d, plasma thyroid hormone and TSH concentrations were predicted within 2 to 3.4- fold of observations. This BBDR HPT axis model provides a successful IVIVE template for thyroid hormone disruption in pregnant rats.

Predicting nonlinear relationships between external and internal concentrations with physiologically based pharmacokinetic modeling.

Although external concentrations are more readily quantified and often used as the metric for regulating and mitigating exposures to environmental chemicals, the toxicological response to an environmental chemical is more directly related to its internal concentrations than the external concentration. The processes of absorption, distribution, metabolism, and excretion (ADME) determine the quantitative relationship between the external and internal concentrations, and these processes are often susceptible to saturation at high concentrations, which can lead to nonlinear changes in internal concentrations that deviate from proportionality. Using generic physiologically-based pharmacokinetic (PBPK) models, we explored how saturable absorption or clearance influence the shape of the internal to external concentration (IEC) relationship. We used the models for hypothetical chemicals to show how differences in kinetic parameters can impact the shape of an IEC relationship; and models for styrene and caffeine to explore how exposure route, frequency, and duration impact the IEC relationships in rat and human exposures. We also analyzed available plasma concentration data for 2,4-dichlorophenoxyacetic acid to demonstrate how a PBPK modeling approach can be an alternative to common statistical methods for analyzing dose proportionality. A PBPK modeling approach can be a valuable tool used in the early stages of a chemical safety assessment program to optimize the design of longer-term animal toxicity studies or to interpret study results.

Characterizing biopersistence potential of the metabolite 5:3 fluorotelomer carboxylic acid after repeated oral exposure to the 6:2 fluorotelomer alcohol.

Our previous report on pharmacokinetic (PK) evaluation of 6:2 fluorotelomer alcohol (6:2 FTOH) examined the biopersistence potential of its metabolites based on data published from single inhalation and occupational 6:2 FTOH exposure studies. We calculated internal exposure estimates of three key metabolites of 6:2 FTOH, of which 5:3 fluorotelomer carboxylic acid (5:3 acid) had the highest internal exposure and the slowest clearance. No oral repeated 6:2 FTOH exposure data were available at the time to fully characterize the biopersistence potential of the metabolite 5:3 acid. We recently received additional data on 6:2 FTOH and 5:3 acid, which included a 90-day toxicokinetic study report on repeated oral 6:2 FTOH exposure to rats. We reviewed the study and analyzed the reported 5:3 acid concentrations in plasma, liver, and fat using one-compartment PK modeling and calculated elimination rate constants (kel), elimination half-lives (t1/2) and times to steady state (tss) of 5:3 acid at three 6:2 FTOH doses. Our results showed that tss of 5:3 acid in plasma and evaluated tissues were approximately close to 1 year, such that the majority of highest values were observed at the lowest 6:2 FTOH dose, indicating its association with the biopersistence of 6:2 FTOH. The results of our PK analysis are the first to characterize biopersistence potential of the 5:3 acid after repeated oral exposure to the parent compound 6:2 FTOH based on steady state PK parameters, and therefore, may have an impact on future study designs when conducting toxicity assays for such compounds.

Use of a physiologically-based pharmacokinetic model to explore the potential disparity in nicotine disposition between adult and adolescent nonhuman primates.

The widespread use and high abuse liability of tobacco products has received considerable public health attention, in particular for youth, who are vulnerable to nicotine addiction. In this study, adult and adolescent squirrel monkeys were used to evaluate age-related metabolism and pharmacokinetics of nicotine after intravenous administration. A physiologically-based pharmacokinetic (PBPK) model was created to characterize the pharmacokinetic behaviors of nicotine and its metabolites, cotinine, trans-3'-hydroxycotinine (3'-OH cotinine), and trans-3'-hydroxycotinine glucuronide (3'-OH cotinine glucuronide) for both adult and adolescent squirrel monkeys. The PBPK nicotine model was first calibrated for adult squirrel monkeys utilizing in vitro nicotine metabolic data, plasma concentration-time profiles and cumulative urinary excretion data for nicotine and metabolites. Further model refinement was conducted when the calibrated adult model was scaled to the adolescents, because adolescents appeared to clear nicotine and cotinine more rapidly relative to adults. More specifically, the resultant model parameters representing systemic clearance of nicotine and cotinine for adolescent monkeys were approximately two- to three-fold of the adult values on a per body weight basis. The nonhuman primate PBPK model in general captured experimental observations that were used for both model calibration and evaluation, with acceptable performance metrics for precision and bias. The model also identified differences in nicotine pharmacokinetics between adolescent and adult nonhuman primates which might also be present in humans.

Pharmacokinetics of oseltamivir phosphate and oseltamivir carboxylate in non-pregnant and pregnant rhesus monkeys.

Oseltamivir is an antiviral drug approved to treat influenza in humans. Although the dosing regimen of this drug is well established for non-pregnant patients, it is not clear if the significant physiological alterations associated with pregnancy affect the pharmacokinetics of oseltamivir and, thus, warrant different dosing regimens to assure efficacy. In this study, we investigated the suitability of rhesus macaques as an animal model for studying oseltamivir pharmacokinetics during all trimesters of pregnancy in comparison to pre-pregnant conditions. Specifically, we compared the pharmacokinetics of oseltamivir and its pharmacologically active metabolite oseltamivir carboxylate in rhesus monkeys after intravenous and nasogastric administration of 2.5 mg oseltamivir phosphate/kg body weight given prior to and during the first, second, and third trimesters of pregnancy. Pregnancy had only a modest effect upon the pharmacokinetic parameters of oseltamivir and oseltamivir carboxylate. Monkeys treated intravenously in the third trimester had a reduction in Vd and CL, compared to non-pregnant monkeys. These changes did not occur in the other two trimesters. Pregnant monkeys treated intravenously had 20-25% decrease in AUC0-∞ of oseltamivir carboxylate and a corresponding increase in Vd and CL. Pregnant monkeys treated nasogastrically with oseltamivir phosphate demonstrated a pattern that recapitulated intravenous dosing. Taken together these data indicate that rhesus monkeys are an acceptable model for studying drug-pregnancy interactions.

PBPK model reporting template for chemical risk assessment applications.

Physiologically-based pharmacokinetic (PBPK) modeling analysis does not stand on its own for regulatory purposes but is a robust tool to support drug/chemical safety assessment. While the development of PBPK models have grown steadily since their emergence, only a handful of models have been accepted to support regulatory purposes due to obstacles such as the lack of a standardized template for reporting PBPK analysis. Here, we expand the existing guidances designed for pharmaceutical applications by recommending additional elements that are relevant to environmental chemicals. This harmonized reporting template can be adopted and customized by public health agencies receiving PBPK model submission, and it can also serve as general guidance for submitting PBPK-related studies for publication in journals or other modeling sharing purposes. The current effort represents one of several ongoing collaborations among the PBPK modeling and risk assessment communities to promote, when appropriate, incorporating PBPK modeling to characterize the influence of pharmacokinetics on safety decisions made by regulatory agencies.

Physiology of the Neonatal Gastrointestinal System Relevant to the Disposition of Orally Administered Medications.

A thorough knowledge of the newborn (age, birth to 1 month postpartum) infant's gastrointestinal tract (GIT) is critical to the evaluation of the absorption, distribution, metabolism, and excretion (ADME) of orally administered drugs in this population. Developmental changes in the GIT during the newborn period are important for nutrient uptake as well as the disposition of orally administered medications. Some aspects of gastrointestinal function do not mature until driven by increased dietary complexity and nutritional demands later in the postnatal period. The functionalities present at birth, and subsequent maturation, can also impact the ADME parameters of orally administered compounds. This review will examine some specific contributors to the ADME processes in human neonates, as well as what is currently understood about the drivers for their maturation. Key species differences will be highlighted, with a focus on laboratory animals used in juvenile toxicity studies. Because of the gaps and inconsistencies in our knowledge, we will also highlight areas where additional study is warranted to better inform the appropriate use of medicines specifically intended for neonates.

Food ingredient safety evaluation: Utility and relevance of toxicokinetic methods.

The use of toxicokinetic (TK) data is becoming more prevalent in the evaluation of food ingredient safety as more TK information is being incorporated in safety data packages. Data demonstrating "1) the extent of absorption, 2) tissue distribution, 3) pathways and rates of metabolism, and 4) rate(s) of elimination" of food ingredients and their metabolites of intermediate and high toxicological potential may be useful for planning and designing toxicity studies, selecting doses for toxicity studies, addressing species differences, and understanding the potential modes of action to evaluate their safety. TK data reported in the literature or generated from mechanistic TK studies can be analyzed using mathematical methods, including compartment and noncompartment TK methods, whose predictions can enhance interpretation of observed effects. Because of recent advancements, several approaches have been developed to improve sensitivity of analyses of available TK data and reduce uncertainty for evaluating safety of food ingredients. An example of advanced TK methods is physiologically-based TK (PBTK) modeling that incorporates physiological/biochemical parameters into a TK framework to predict internal exposure. In this review, we discuss the utility of some TK methods and explore their relevance and potential value for food ingredient safety evaluation. We also describe the strengths and limitations of these TK methods and discuss current challenges and opportunities for expanding their application for evaluating safety of food ingredients. This review represents a state of science report, and not a guidance document, on the utility and relevance of TK methods for the safety evaluation of food ingredients.

Using mathematical modeling to infer the valence state of arsenicals in tissues: A PBPK model for dimethylarsinic acid (DMAV) and dimethylarsinous acid (DMAIII) in mice.

Chronic exposure to inorganic arsenic (iAs), a contaminant of water and food supplies, is associated with many adverse health effects. A notable feature of iAs metabolism is sequential methylation reactions which produce mono- and di-methylated arsenicals that can contain arsenic in either the trivalent (III) or pentavalent (V) valence states. Because methylated arsenicals containing trivalent arsenic are more potent toxicants than their pentavalent counterparts, the ability to distinguish between the +3 and +5 valence states is a crucial property for physiologically based pharmacokinetic (PBPK) models of arsenicals to possess if they are to be of use in risk assessment. Unfortunately, current analytic techniques for quantifying arsenicals in tissues disrupt the valence state; hence, pharmacokinetic studies in animals, used for model calibration, only reliably provide data on the sum of the +3 and +5 valence forms of a given metabolite. In this paper we show how mathematical modeling can be used to overcome this obstacle and present a PBPK model for the dimethylated metabolite of iAs, which exists as either dimethylarsinous acid, (CH3)2AsIIIOH (abbreviated DMAIII) or dimethylarsinic acid, (CH3)2AsV(O)OH (abbreviated DMAV). The model distinguishes these two forms and sets a lower bound on how much of an organ's DMA burden is present in the more reactive and toxic trivalent valence state. We conjoin the PBPK model to a simple model for DMAIII-induced oxidative stress in liver and use this extended model to predict cytotoxicity in liver in response to the high oral dose of DMAV. The model incorporates mechanistic details derived from in vitro studies and is iteratively calibrated with lumped-valence-state PK data for intravenous or oral dosing with DMAV. Model formulation leads us to predict that orally administered DMAV undergoes extensive reduction in the gastrointestinal (GI) tract to the more toxic trivalent DMAIII.

A new Bayesian joint model for longitudinal count data with many zeros, intermittent missingness, and dropout with applications to HIV prevention trials.

In longitudinal clinical trials, it is common that subjects may permanently withdraw from the study (dropout), or return to the study after missing one or more visits (intermittent missingness). It is also routinely encountered in HIV prevention clinical trials that there is a large proportion of zeros in count response data. In this paper, a sequential multinomial model is adopted for dropout and subsequently a conditional model is constructed for intermittent missingness. The new model captures the complex structure of missingness and incorporates dropout and intermittent missingness simultaneously. The model also allows us to easily compute the predictive probabilities of different missing data patterns. A zero-inflated Poisson mixed-effects regression model is assumed for the longitudinal count response data. We also propose an approach to assess the overall treatment effects under the zero-inflated Poisson model. We further show that the joint posterior distribution is improper if uniform priors are specified for the regression coefficients under the proposed model. Variations of the g-prior, Jeffreys prior, and maximally dispersed normal prior are thus established as remedies for the improper posterior distribution. An efficient Gibbs sampling algorithm is developed using a hierarchical centering technique. A modified logarithm of the pseudomarginal likelihood and a concordance based area under the curve criterion are used to compare the models under different missing data mechanisms. We then conduct an extensive simulation study to investigate the empirical performance of the proposed methods and further illustrate the methods using real data from an HIV prevention clinical trial.

60 Minutes for health: examining the feasibility and acceptability of a low-resource behavioral intervention designed to promote retention in HIV care.

Sustained retention in HIV medical care is a key health behavior for the long-term health of people living with HIV (PLWH). Approximately 60% of PLWH in the U.S. are poorly retained in HIV care, yet to date, the few available evidence-based retention-promoting interventions are resource and time intensive to implement. The current study describes the feasibility and acceptability of a theory-based retention-promoting intervention designed to meet the needs of a busy clinical care setting. 60 Minutes for Health reflects a low-resource single-session intervention, implemented by a health educator, to PLWH who have had a recent gap in care (≥6-months) in the past 18-months. Intervention content was informed by a situated application of the Information Motivation Behavioral Skills Model and delivered using a Motivational Interviewing-based format. The intervention uses a workbook to guide a series of activities that: (1) Identify and reduce misinformation guiding HIV care attendance. (2) Enhance motivation to maintain care via personal health goals. (3) Build skills for coping with emotional distress related to living with HIV. (4) Increase self-efficacy for navigating the logistics of maintaining care amidst competing priorities. A small feasibility pilot of this intervention protocol was conducted to assess its potential to improve retention in care and to obtain estimates for a larger-scale efficacy trial. Participants were randomized to the 60-minute intervention session (n = 8), or a theory-based time-and-attention control session focused on diet and nutrition (n = 8). Medical records were abstracted to evaluate changes in participants' retention in care status at 12- and 24-months post-intervention. Findings suggest the intervention is both feasible and acceptable to implement with poorly retained PLWH in a clinic setting. Post-intervention a larger proportion of intervention participants were retained in care (12-months: 87.5%, 24-months: 62.5%), compared control participants (12-months: 50.0%, 24-months: 25.0%). Future work should aim to evaluate a larger-scale efficacy trial.

Bayesian Modeling and Inference for Nonignorably Missing Longitudinal Binary Response Data with Applications to HIV Prevention Trials.

Missing data are frequently encountered in longitudinal clinical trials. To better monitor and understand the progress over time, one must handle the missing data appropriately and examine whether the missing data mechanism is ignorable or nonignorable. In this article, we develop a new probit model for longitudinal binary response data. It resolves a challenging issue for estimating the variance of the random effects, and substantially improves the convergence and mixing of the Gibbs sampling algorithm. We show that when improper uniform priors are specified for the regression coefficients of the joint multinomial model via a sequence of one-dimensional conditional distributions for the missing data indicators under nonignorable missingness, the joint posterior distribution is improper. A variation of Jeffreys prior is thus established as a remedy for the improper posterior distribution. In addition, an efficient Gibbs sampling algorithm is developed using a collapsing technique. Two model assessment criteria, the deviance information criterion (DIC) and the logarithm of the pseudomarginal likelihood (LPML), are used to guide the choices of prior specifications and to compare the models under different missing data mechanisms. We report on extensive simulations conducted to investigate the empirical performance of the proposed methods. The proposed methodology is further illustrated using data from an HIV prevention clinical trial.

Physiologically based pharmacokinetic modeling of human exposure to perfluorooctanoic acid suggests historical non drinking-water exposures are important for predicting current serum concentrations.

Manufacturing of perfluorooctanoic acid (PFOA), a synthetic chemical with a long half-life in humans, peaked between 1970 and 2002, and has since diminished. In the United States, PFOA is detected in the blood of >99% of people tested, but serum concentrations have decreased since 1999. Much is known about exposure to PFOA in drinking water; however, the impact of non-drinking water PFOA exposure on serum PFOA concentrations is not well characterized. The objective of this research is to apply physiologically based pharmacokinetic (PBPK) modeling and Monte Carlo analysis to evaluate the impact of historic non-drinking water PFOA exposure on serum PFOA concentrations. In vitro to in vivo extrapolation was utilized to inform descriptions of PFOA transport in the kidney. Monte Carlo simulations were incorporated to evaluate factors that account for the large inter-individual variability of serum PFOA concentrations measured in individuals from North Alabama in 2010 and 2016, and the Mid-Ohio River Valley between 2005 and 2008. Predicted serum PFOA concentrations were within two-fold of experimental data. With incorporation of Monte Carlo simulations, the model successfully tracked the large variability of serum PFOA concentrations measured in populations from the Mid-Ohio River Valley. Simulation of exposure in a population of 45 adults from North Alabama successfully predicted 98% of individual serum PFOA concentrations measured in 2010 and 2016, respectively, when non-drinking water ingestion of PFOA exposure was included. Variation in serum PFOA concentrations may be due to inter-individual variability in the disposition of PFOA and potentially elevated historical non-drinking water exposures.

Exclusive breast-feeding promotion among HIV-infected women in South Africa: an Information-Motivation-Behavioural Skills model-based pilot intervention.

OBJECTIVE: Exclusive breast-feeding (EBF) provides optimal nutrition for infants and mothers. The practice of EBF while adhering to antiretroviral medication decreases the risk of mother-to-child transmission of HIV from approximately 25 % to less than 5 %. Thus the WHO recommends EBF for the first 6 months among HIV-infected women living in resource-limited settings; however, EBF rates remain low. In the present study our aim was to design and implement a pilot intervention promoting EBF among HIV-infected women. DESIGN: The Information-Motivation-Behavioural Skills (IMB) model was applied in a brief motivational interviewing counselling session that was tested in a small randomized controlled trial. SETTING: Pietermaritzburg, South Africa, at two comparable rural public health service clinics. SUBJECTS: Sixty-eight HIV-infected women in their third trimester were enrolled and completed baseline interviews between June and August 2014. Those randomized to the intervention arm received the IMB-based pilot intervention directly following baseline interviews. Follow-up interviews occurred at 6 weeks postpartum. RESULTS: While not significantly different between trial arms, high rates of intention and practice of EBF at 6-week follow-up were reported. Findings showed high levels of self-efficacy being significantly predictive of breast-feeding initiation and duration regardless of intervention arm. CONCLUSIONS: Future research must account for breast-feeding self-efficacy on sustaining breast-feeding behaviour and leverage strategies to enhance self-efficacy in supportive interventions. Supporting breast-feeding behaviour through programmes that include both individual-level and multi-systems components targeting the role of health-care providers, family and community may create environments that value and support EBF behaviour.

A biokinetic model for nickel released from cardiovascular devices.

Many alloys used in cardiovascular device applications contain high levels of nickel, which if released in sufficient quantities, can lead to adverse health effects. While nickel release from these devices is typically characterized through the use of in-vitro immersion tests, it is unclear if the rate at which nickel is released from a device during in-vitro testing is representative of the release rate following implantation in the body. To address this uncertainty, we have developed a novel biokinetic model that combines a traditional toxicokinetic compartment model with a physics-based model to estimate nickel release from an implanted device. This model links the rate of in-vitro nickel release from a cardiovascular device to serum nickel concentrations, an easily measured endpoint, to estimate the rate and extent of in-vivo nickel release from an implanted device. The model was initially parameterized using data in the literature on in-vitro nickel release from a nickel-containing alloy (nitinol) and baseline serum nickel levels in humans. The results of this first step were then used to validate specific components of the model. The remaining unknown quantities were fit using serum values reported in patients following implantation with nitinol atrial occluder devices. The model is not only consistent with levels of nickel in serum and urine of patients following treatment with the atrial occluders, but also the optimized parameters in the model were all physiologically plausible. The congruity of the model with available data suggests that it can provide a framework to interpret nickel biomonitoring data and use data from in-vitro nickel immersion tests to estimate in-vivo nickel release from implanted cardiovascular devices.

Rapid Electron Beam Writing of Topologically Complex 3D Nanostructures Using Liquid Phase Precursor.

Advancement of focused electron beam-induced deposition (FEBID) as a versatile direct-write additive nanoscale fabrication technique has been inhibited by poor throughput, limited choice of precursors, and restrictions on possible 3D topologies. Here, we demonstrate FEBID using nanoelectrospray liquid precursor injection to grow carbon and pure metal nanostructures via direct decomposition and electrochemical reduction of the relevant precursors, achieving growth rates 10(5) times greater than those observed in standard gas-phase FEBID. Initiating growth at the free surface of a liquid pool enables fabrication of complex 3D carbon nanostructures with strong adhesion to the substrate. Deposition of silver microstructures at similar growth rates is also demonstrated as a promising avenue for future development of the technique.

Application of physiologically-based pharmacokinetic modeling to explore the role of kidney transporters in renal reabsorption of perfluorooctanoic acid in the rat.

Renal elimination and the resulting clearance of perfluorooctanoic acid (PFOA) from the serum exhibit pronounced sex differences in the adult rat. The literature suggests that this is largely due to hormonally regulated expression of organic anion transporters (OATs) on the apical and basolateral membranes of the proximal tubule cells that facilitate excretion and reabsorption of PFOA from the filtrate into the blood. Previously developed PBPK models of PFOA exposure in the rat have not been parameterized to specifically account for transporter-mediated renal elimination. We developed a PBPK model for PFOA in male and female rats to explore the role of Oat1, Oat3, and Oatp1a1 in sex-specific renal reabsorption and excretion of PFOA. Descriptions of the kinetic behavior of these transporters were extrapolated from in vitro studies and the model was used to simulate time-course serum, liver, and urine data for intravenous (IV) and oral exposures in both sexes. Model predicted concentrations of PFOA in the liver, serum, and urine showed good agreement with experimental data for both male and female rats indicating that in vitro derived physiological descriptions of transporter-mediated renal reabsorption can successfully predict sex-dependent excretion of PFOA in the rat. This study supports the hypothesis that sex-specific serum half-lives for PFOA are largely driven by expression of transporters in the kidney and contribute to the development of PBPK modeling as a tool for evaluating the role of transporters in renal clearance.

Development of a physiologically based pharmacokinetic model for assessment of human exposure to bisphenol A.

A previously developed physiologically based pharmacokinetic (PBPK) model for bisphenol A (BPA) in adult rhesus monkeys was modified to characterize the pharmacokinetics of BPA and its phase II conjugates in adult humans following oral ingestion. Coupled with in vitro studies on BPA metabolism in the liver and the small intestine, the PBPK model was parameterized using oral pharmacokinetic data with deuterated-BPA (d6-BPA) delivered in cookies to adult humans after overnight fasting. The availability of the serum concentration time course of unconjugated d6-BPA offered direct empirical evidence for the calibration of BPA model parameters. The recalibrated PBPK adult human model for BPA was then evaluated against published human pharmacokinetic studies with BPA. A hypothesis of decreased oral uptake was needed to account for the reduced peak levels observed in adult humans, where d6-BPA was delivered in soup and food was provided prior to BPA ingestion, suggesting the potential impact of dosing vehicles and/or fasting on BPA disposition. With the incorporation of Monte Carlo analysis, the recalibrated adult human model was used to address the inter-individual variability in the internal dose metrics of BPA for the U.S. general population. Model-predicted peak BPA serum levels were in the range of pM, with 95% of human variability falling within an order of magnitude. This recalibrated PBPK model for BPA in adult humans provides a scientific basis for assessing human exposure to BPA that can serve to minimize uncertainties incurred during extrapolations across doses and species.

24-hour human urine and serum profiles of bisphenol A: Evidence against sublingual absorption following ingestion in soup.

Extensive first-pass metabolism of ingested bisphenol A (BPA) in the gastro-intestinal tract and liver restricts blood concentrations of bioactive BPA to <1% of total BPA in humans and non-human primates. Absorption of ingested BPA through non-metabolizing tissues of the oral cavity, recently demonstrated in dogs, could lead to the higher serum BPA concentrations reported in some human biomonitoring studies. We hypothesized that the extensive interaction with the oral mucosa by a liquid matrix, like soup, relative to solid food or capsules, might enhance absorption through non-metabolizing oral cavity tissues in humans, producing higher bioavailability and higher serum BPA concentrations. Concurrent serum and urine concentrations of d6-BPA, and its glucuronide and sulfate conjugates, were measured over a 24hour period in 10 adult male volunteers following ingestion of 30µg d6-BPA/kg body weight in soup. Absorption of d6-BPA was rapid (t1/2=0.45h) and elimination of the administered dose was complete 24h post-ingestion, evidence against any tissue depot for BPA. The maximum serum d6-BPA concentration was 0.43nM at 1.6h after administration and represented <0.3% of total d6-BPA. Pharmacokinetic parameters, pharmacokinetic model simulations, and the significantly faster appearance half-life of d6-BPA-glucuronide compared to d6-BPA (0.29h vs 0.45h) were evidence against meaningful absorption of BPA in humans through any non-metabolizing tissue (<1%). This study confirms that typical exposure to BPA in food produces picomolar to subpicomolar serum BPA concentrations in humans, not nM concentrations reported in some biomonitoring studies.

Development of a physiologically-based pharmacokinetic model of 2-phenoxyethanol and its metabolite phenoxyacetic acid in rats and humans to address toxicokinetic uncertainty in risk assessment.

2-Phenoxyethanol (PhE) has been shown to induce hepatotoxicity, renal toxicity, and hemolysis at dosages ≥ 400 mg/kg/day in subchronic and chronic studies in multiple species. To reduce uncertainty associated with interspecies extrapolations and to evaluate the margin of exposure (MOE) for use of PhE in cosmetics and baby products, a physiologically-based pharmacokinetic (PBPK) model of PhE and its metabolite 2-phenoxyacetic acid (PhAA) was developed. The PBPK model incorporated key kinetic processes describing the absorption, distribution, metabolism and excretion of PhE and PhAA following oral and dermal exposures. Simulations of repeat dose rat studies facilitated the selection of systemic AUC as the appropriate dose metric for evaluating internal exposures to PhE and PhAA in rats and humans. Use of the PBPK model resulted in refinement of the total default UF for extrapolation of the animal data to humans from 100 to 25. Based on very conservative assumptions for product composition and aggregate product use, model-predicted exposures to PhE and PhAA resulting from adult and infant exposures to cosmetic products are significantly below the internal dose of PhE observed at the NOAEL dose in rats. Calculated MOEs for all exposure scenarios were above the PBPK-refined UF of 25.