RESUMO
BACKGROUND: Given its hormonal activity, bisphenol S (BPS) as a substitute for bisphenol A (BPA) could actually increase the risk of endocrine disruption if its toxicokinetic (TK) properties, namely its oral availability and systemic persistency, were higher than those of BPA. OBJECTIVES: The TK behavior of BPA and BPS was investigated by administering the two compounds by intravenous and oral routes in piglet, a known valid model for investigating oral TK. METHODS: Experiments were conducted in piglets to evaluate the kinetics of BPA, BPS, and their glucuronoconjugated metabolites in plasma and urine after intravenous administration of BPA, BPS, and BPS glucuronide (BPSG) and gavage administration of BPA and BPS. A population semiphysiologically based TK model describing the disposition of BPA and BPS and their glucuronides was built from these data to estimate the key TK parameters that drive the internal exposure to active compounds. RESULTS: The data indicated that almost all the BPS oral dose was absorbed and transported into the liver where only 41% of BPS was glucuronidated, leading to a systemic bioavailability of 57.4%. In contrast, only 77% of the oral dose of BPA was absorbed and underwent an extensive first-pass glucuronidation either in the gut (44%) or in the liver (53%), thus accounting for the low systemic bioavailability of BPA (0.50%). Due to the higher systemic availability of BPS, in comparison with BPA, and its lower plasma clearance (3.5 times lower), the oral BPS systemic exposure was on average about 250 times higher than for BPA for an equal oral molar dose of the two compounds. CONCLUSION: Given the similar digestive tracts of pigs and humans, our results suggest that replacing BPA with BPS will likely lead to increased internal exposure to an endocrine-active compound that would be of concern for human health. https://doi.org/10.1289/EHP4599.
Assuntos
Compostos Benzidrílicos/farmacocinética , Poluentes Ambientais/farmacocinética , Fenóis/farmacocinética , Sulfonas/farmacocinética , Sus scrofa/metabolismo , Administração Intravenosa , Administração Oral , Animais , Disponibilidade Biológica , Feminino , Masculino , ToxicocinéticaRESUMO
The minipig continues to build a reputation as a viable alternative large animal model to predict humans in dermatology and toxicology studies. Therefore, it is essential to describe and predict the pharmacokinetics in that species to speed up the clinical candidate selection. Essential input parameters in whole-body physiologically based pharmacokinetic models are the tissue-to-plasma partition coefficients and the resulting volume of distribution at steady-state (Vss). Mechanistic in vitro- and in silico-based models used for predicting these parameters of tissue distribution of drugs refer to the tissue composition-based model (TCM). Robust TCMs were initially developed for some preclinical species (e.g., rat and dog) and human; however, there is currently no model available for the minipig. Therefore, the objective of this present study was to develop a TCM for the minipig and to estimate the corresponding tissue composition data. Drug partitioning into the tissues was predominantly governed by lipid and protein binding effects in addition to drug solubilization and pH gradient effects in the aqueous phase on both sides of the biological membranes; however, some more complex tissue distribution processes such as drug binding to the collagen-laminin material in dermis and a restricted drug partitioning into membranes of tissues for compounds that are amphiphilic and contain sulfur atom(s) were also challenged. The model was validated by predicting Vss and the dermis-to-plasma partition coefficients (Kp-dermis) of 68 drugs. The prediction of Kp-dermis was extended to humans for comparison with the minipig. The results indicate that the extended TCM provided generally good agreements with observations in the minipig showing that it is also applicable to this preclinical species. In general, up to 86% and 100% of the predicted Vss values are respectively within 2-fold and 3-fold errors compared to the experimentally determined values, whereas these numbers are 78% and 94% for Kp-dermis when the anticipated outlier compounds are not included. Binding data to dermis are comparable between minipigs and humans. Overall, this study is a first step toward developing a mechanistic TCM for the minipig, with the aim of increasing the use of physiologically based pharmacokinetic models of drugs for that species in addition to rats, dogs, and humans because such models are used in preclinical and clinical transdermal studies.
Assuntos
Derme/metabolismo , Preparações Farmacêuticas/metabolismo , Plasma/metabolismo , Distribuição Tecidual/fisiologia , Animais , Dermatologia/métodos , Cães , Humanos , Modelos Biológicos , Fenômenos Físicos , Ligação Proteica/fisiologia , Ratos , Suínos , Porco MiniaturaRESUMO
The investigation of interspecies differences in bisphenol A (BPA) pharmacokinetics (PK) may be useful for translating findings from animal studies to humans, identifying major processes involved in BPA clearance mechanisms, and predicting BPA PK parameters in man. For the first time, a large range of species in terms of body weight, from 0.02 kg (mice) to 495 kg (horses) was used to predict BPA clearance in man by an allometric approach. BPA PK was evaluated after intravenous administration of BPA in horses, sheep, pigs, dogs, rats and mice. A non-compartmental analysis was used to estimate plasma clearance and steady state volume of distribution and predict BPA PK parameters in humans from allometric scaling. In all the species investigated, BPA plasma clearance was high and of the same order of magnitude as their respective hepatic blood flow. By an allometric scaling, the human clearance was estimated to be 1.79 L/min (equivalent to 25.6 mL/kg.min) with a 95% prediction interval of 0.36 to 8.83 L/min. Our results support the hypothesis that there are highly efficient and hepatic mechanisms of BPA clearance in man.
Assuntos
Compostos Benzidrílicos/farmacocinética , Tamanho Corporal , Poluentes Ambientais/farmacocinética , Modelos Biológicos , Fenóis/farmacocinética , Administração Intravenosa , Animais , Compostos Benzidrílicos/administração & dosagem , Compostos Benzidrílicos/sangue , Cães , Poluentes Ambientais/administração & dosagem , Poluentes Ambientais/sangue , Feminino , Meia-Vida , Eliminação Hepatobiliar , Cavalos , Humanos , Circulação Hepática , Masculino , Taxa de Depuração Metabólica , Camundongos , Fenóis/administração & dosagem , Fenóis/sangue , Ratos Wistar , Carneiro Doméstico , Especificidade da Espécie , Sus scrofaRESUMO
BACKGROUND: Bisphenol A (BPA) risk assessment is currently hindered by the rejection of reported higher-than-expected plasma BPA concentrations in humans after oral ingestion. These are deemed incompatible with the almost complete hepatic first-pass metabolism of BPA into its inactive glucurono-conjugated form, BPA glucuronide (BPAG). OBJECTIVES: Using dogs as a valid model, we compared plasma concentrations of BPA over a 24-hr period after intravenous, orogastric, and sublingual administration in order to establish the absolute bioavailability of BPA administered sublingually and to compare it with oral bioavailability. METHODS: Six dogs were sublingually administered BPA at 0.05 mg/kg and 5 mg/kg. We compared the time course of plasma BPA concentrations with that obtained in the same dogs after intravenous administration of the same BPA doses and after a 20-mg/kg BPA dose administrated by orogastric gavage. RESULTS: The data indicated that the systemic bioavailability of BPA deposited sublingually was high (70-90%) and that BPA transmucosal absorption from the oral cavity led to much higher BPA internal exposure than obtained for BPA absorption from the gastrointestinal tract. The concentration ratio of BPAG to BPA in plasma was approximately 100-fold lower following sublingual administration than after orogastric dosing, distinguishing the two pathways of absorption. CONCLUSIONS: Our findings demonstrate that BPA can be efficiently and very rapidly absorbed through the oral mucosa after sublingual exposure. This efficient systemic entry route of BPA may lead to far higher BPA internal exposures than known for BPA absorption from the gastrointestinal tract.
Assuntos
Compostos Benzidrílicos/farmacocinética , Poluentes Ambientais/farmacocinética , Glucuronídeos/farmacocinética , Fenóis/farmacocinética , Administração Oral , Administração Sublingual , Animais , Compostos Benzidrílicos/sangue , Disponibilidade Biológica , Cromatografia Líquida de Alta Pressão , Cães , Poluentes Ambientais/sangue , Feminino , Glucuronídeos/sangue , Masculino , Espectrometria de Massas , Fenóis/sangueRESUMO
The putative thyroid-disrupting properties of bisphenol A (BPA) highlight the need for an evaluation of fetal exposure and its consequence on the mother/newborn thyroid functions in models relevant to human. The goals of this study were to characterize in sheep a relevant model for human pregnancy and thyroid physiology, the internal exposures of the fetuses and their mothers to BPA and its main metabolite BPA-glucuronide (Gluc), and to determine to what extent it might be associated with thyroid disruption. Ewes were treated with BPA [5 mg/(kg · d) sc] or vehicle from d 28 until the end of pregnancy. Unconjugated BPA did not appear to accumulate in pregnant ewes, and its concentration was similar in the newborns and their mothers (0.13 ± 0.02 and 0.18 ± 0.03 nmol/ml in cord and maternal blood, respectively). In amniotic fluid and cord blood, BPA-Gluc concentrations were about 1300-fold higher than those of BPA. Total T(4) concentrations were decreased in BPA-treated pregnant ewes and in the cord and the jugular blood of their newborns (30% decrease). A similar difference was observed for free T(4) plasma concentrations in the jugular blood of the newborns. Our results show in a long-gestation species with a similar regulatory scheme of thyroid function as humans that BPA in utero exposure can be associated with hypothyroidism in the newborns. If such an effect were to be confirmed for a more relevant exposure scheme to BPA, this would constitute a major issue for BPA risk assessment.
Assuntos
Compostos Benzidrílicos/toxicidade , Exposição Materna/efeitos adversos , Fenóis/toxicidade , Glândula Tireoide/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Feminino , Gravidez , Ovinos , Glândula Tireoide/metabolismo , Tiroxina/sangueRESUMO
BACKGROUND: Bisphenol A (BPA) is a widely produced endocrine-disrupting chemical. Diet is a primary route of exposure, but internal exposure (serum concentrations) in animals and humans has been measured only after single oral bolus administration. OBJECTIVE: We compared serum concentrations of BPA over a 24-hr period after oral bolus administration or ad libitum feeding in mice and assessed for buildup with dietary exposure. METHODS: Adult female mice were administered [dimethyl-d6]-BPA (BPA-d6) as a single oral bolus (20 mg/kg body weight) or fed a diet containing 100 mg BPA-d6/kg feed weight ad libitum for 1 week. Serum concentrations were analyzed using isotope dilution liquid chromatography coupled with electrospray tandem mass spectrometry and compared between exposure groups over the first 23 hr and after 7 days of dietary exposure. RESULTS: Maximum concentration (Cmax) for BPA-d6 during the first 24 hr was reached at 1 hr and 6 hr for oral bolus and diet groups, respectively. Relative BPA-d6 bioavailability (unconjugated BPA-d6) was higher in diet-exposed mice than in the bolus group despite a relative lower absorption, a phenomenon consistent with an inhibitory effect of food on first-pass hepatic metabolism. In mice with ongoing dietary exposure, unconjugated BPA-d6 was higher on day 7 than on day 1. CONCLUSIONS: This is the first report of serum BPA concentrations in an animal model exposed to this chemical via the diet. Although bolus administration of BPA-d6 led to peak concentrations within 1 hr, Cmax for diet-exposed mice was delayed for several hours. However, bolus administration underestimates bioavailable serum BPA concentrations in animals-and presumably humans-than would result from dietary exposure. Exposure via diet is a more natural continuous exposure route than oral bolus exposure and is thus a better predictor of BPA concentrations in chronically exposed animals and humans.
Assuntos
Disruptores Endócrinos/sangue , Disruptores Endócrinos/farmacocinética , Fenóis/sangue , Fenóis/farmacocinética , Administração Oral , Animais , Compostos Benzidrílicos , Disponibilidade Biológica , Cromatografia Líquida/veterinária , Dieta/veterinária , Disruptores Endócrinos/administração & dosagem , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Fenóis/administração & dosagem , Espectrometria de Massas em Tandem/veterináriaRESUMO
The model of the prepubertal ovariectomized lamb was selected as a sensitive model to characterize the estrogenic effects of bisphenol A (BPA) on the hypothalamo-pituitary axis (HPA). In a first experiment, the disrupting effect of BPA and of 17-beta estradiol (E2), administered as a constant 54-h iv infusion, on luteinizing hormone (LH) pulsatility was quantified. The results showed that the inhibitory effect of BPA and E2 on LH secretion appeared to follow a dual mechanism: a rapid (about 1 h) suppressive effect for high exposure and an effect observed with a period of latency (about 48 h) probably of genomic origin and observed for lower E2 and BPA levels. For E2, the disrupting dose was 0.14 microg/(kg x d), corresponding to a plasma concentration of 2 pg/ml; for BPA, the lowest observed disrupting plasma concentration was 38 ng/ml, a value only 10-fold higher than the human plasma concentration routinely reported in biomonitoring surveys. In a second experiment, we showed that after 7 weeks of BPA treatment, there was no BPA accumulation and no evidence of an alteration in the HPA responsiveness to BPA. Finally, our results showed that directly considering plasma concentrations, the ratio of the BPA disrupting plasma concentration in lambs over the observed human plasma concentration is only 10, whereas if the dose is considered, it could be concluded that the BPA disrupting dose in lamb is conservatively 50-fold higher than the currently recommended Tolerable Daily Intake of 50 microg/(kg x d).