Development of a physiologically based pharmacokinetic model for bisphenol A in pregnant mice

Kawamoto, Yuko; Matsuyama, Wakoto; Wada, Masahiro; Hishikawa, Junko; Chan, Melissa P. L.; Nakayama, Aki; Morisawa, Shinsuke

doi:10.1016/j.taap.2007.06.023

Cited by 35 publications

(15 citation statements)

References 31 publications

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“…A few PBTK models have been developed for describing the toxicokinetics of BPA in rats (Shin et al 2004), pregnant mice (Kawamoto et al 2007), adult humans (Teeguarden et al 2005), and children < 2 years of age (Edginton and Ritter 2009). First, Shin et al (2004) developed a PBTK model involving vein, artery, lung, liver, spleen, kidneys, heart, testes, muscle, brain, adipose tissue, and small intestines for predicting tissue distribution and kinetics of BPA in rats.…”

Section: Utility Of Physiologically Based Toxicokinetic Models Of Bpamentioning

confidence: 99%

Urinary, Circulating, and Tissue Biomonitoring Studies Indicate Widespread Exposure to Bisphenol A

Vandenberg

Chahoud

Heindel

et al. 2010

Environ Health Perspect

1,063

609

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BackgroundBisphenol A (BPA) is one of the highest-volume chemicals produced worldwide, and human exposure to BPA is thought to be ubiquitous. Thus, there are concerns that the amount of BPA to which humans are exposed may cause adverse health effects. Importantly, results from a large number of biomonitoring studies are at odds with the results from two toxicokinetic studies.ObjectiveWe examined several possibilities for why biomonitoring and toxicokinetic studies could come to seemingly conflicting conclusions.Data sourcesWe examined > 80 published human biomonitoring studies that measured BPA concentrations in human tissues, urine, blood, and other fluids, along with two toxicokinetic studies of human BPA metabolism.Data extraction and synthesisThe > 80 biomonitoring studies examined included measurements in thousands of individuals from several different countries, and these studies overwhelmingly detected BPA in individual adults, adolescents, and children. Unconjugated BPA was routinely detected in blood (in the nanograms per milliliter range), and conjugated BPA was routinely detected in the vast majority of urine samples (also in the nanograms per milliliter range). In stark contrast, toxicokinetic studies proposed that humans are not internally exposed to BPA. Some regulatory agencies have relied solely on these toxicokinetic models in their risk assessments.ConclusionsAvailable data from biomonitoring studies clearly indicate that the general population is exposed to BPA and is at risk from internal exposure to unconjugated BPA. The two toxicokinetic studies that suggested human BPA exposure is negligible have significant deficiencies, are directly contradicted by hypothesis-driven studies, and are therefore not reliable for risk assessment purposes.

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Section: Utility Of Physiologically Based Toxicokinetic Models Of Bpamentioning

confidence: 99%

Urinary, Circulating, and Tissue Biomonitoring Studies Indicate Widespread Exposure to Bisphenol A

Vandenberg

Chahoud

Heindel

et al. 2010

Environ Health Perspect

1,063

609

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“…There is no discrete target organ at the NOAEL in the key study in rats, as the endpoint is reduced body weight. A preliminary PBPK model for the mouse has been developed (Kawamoto et al, 2007), but it "was not successful to predict the time course of Downloaded by [Tulane University] at 05:30 03 January 2015 concentration." At the mouse LOAEL, there is evidence for the liver and kidney as target organs; however, the most sensitive endpoint in mice is minimal hepatocellular hypertrophy.…”

Section: Uncertainty Factor Selectionmentioning

confidence: 99%

Derivation of a Bisphenol a Oral Reference Dose (RfD) and Drinking-Water Equivalent Concentration∗

Willhite

Ball

McLellan

2008

Journal of Toxicology and Environmental Health, Part B

183

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Human exposure to bisphenol A (BPA) is due to that found in the diet, and BPA and its metabolites were detected at parts per billion (or less) concentrations in human urine, milk, saliva, serum, plasma, ovarian follicular fluid, and amniotic fluid. Adverse health effects in mice and rats may be induced after parenteral injection or after massive oral doses. Controlled ingestion trials in healthy adult volunteers with 5 mg d16-BPA were unable to detect parent BPA in plasma despite exquisitely sensitive (limit of detection = 6 nM) methods, but by 96 h 100% of the administered dose was recovered in urine as the glucuronide. The extensive BPA glucuronidation following ingestion is not seen after parenteral injection; only the parent BPA binds plasma proteins and estrogen receptors (ER). The hypothesis that BPA dose-response may be described by a J- or U-shape curve was not supported by toxicogenomic data collected in fetal rat testes and epididymes (after repeated parenteral exposure at 2-400,000 microg/kg-d), where a clear monotonic dose-response both in the numbers of genes and magnitude of individual gene expression was evident. There is no clear indication from available data that the BPA doses normally consumed by humans pose an increased risk for immunologic or neurologic disease. There is no evidence that BPA poses a genotoxic or carcinogenic risk and clinical evaluations of 205 men and women with high-performance liquid chromatography (HPLC)-verified serum or urinary BPA conjugates showed (1) no objective signs, (2) no changes in reproductive hormones or clinical chemistry parameters, and (3) no alterations in the number of children or sons:daughters ratio. Results of benchmark dose (BMD10 and BMDL10) calculations and no-observed-adverse-effect level (NOAEL) inspections of all available and reproducible rodent studies with oral BPA found BMD and NOAEL values all greater than the 5 mg/kg-d NOAELs from mouse and rat multigeneration reproduction toxicity studies. While allometric and physiologically based pharmacokinetic (PBPK) models were constructed for interspecies scaling of BPA and its interaction with ER, multigeneration feeding studies with BPA at doses spanning 5 orders of magnitude failed to identify signs of developmental toxicity or adverse changes in reproductive tract tissues; the 5-mg/kg-d NOAELs identified for systemic toxicity in rats and mice were less than the oral NOAELs for reproductive toxicity. Thus, it is the generalized systemic toxicity of ingested BPA rather than reproductive, immunologic, neurobehavioral, or genotoxic hazard that represents the point of departure. Using U.S. Environmental Protection Agency (EPA) uncertainty factor guidance and application of a threefold database uncertainty factor (to account for the fact that the carcinogenic potential of transplacental BPA exposure has yet to be fully defined and comprehensive neurobehavioral and immunotoxicologic evaluations of BPA by relevant routes and at relevant doses have yet to be completed) to the administered dose NOAEL resu...

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“…By contrast, the Chapel Hill Report forewarned of negative, and potentially irreversible, outcomes in humans (Vandenberg et al, 2009; vom Saal et al, 2007). Rodent model and human studies show that BPA can be transferred across the placenta (Balakrishnan et al, 2010; Ikezuki et al, 2002; Kawamoto et al, 2007; Nishikawa et al, 2010) and through the milk (Deceuninck et al, 2015; Kurebayashi et al, 2005; Tateoka, 2014; Zimmers et al, 2014), although not all studies agree that this is a substantial route of exposure (Doerge et al, 2011; Doerge et al, 2010b). Fetal rodents possess limited ability to metabolize BPA (Doerge et al, 2011; Doerge et al, 2010a; Ikezuki et al, 2002; Kawamoto et al, 2007; Nishikawa et al, 2010), and therefore higher internal concentrations of bioactive BPA may result compared to adults.…”

Section: Introductionmentioning

confidence: 99%

Effects of developmental exposure to bisphenol A on spatial navigational learning and memory in rats: A CLARITY-BPA study

Johnson

Javurek

Painter

et al. 2016

Hormones and Behavior

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Bisphenol A (BPA) is a ubiquitous industrial chemical used in the production of a wide variety of items. Previous studies suggest BPA exposure may result in neuro-disruptive effects; however, data are inconsistent across animal and human studies. As part of the Consortium Linking Academic and Regulatory Insights on BPA Toxicity (CLARITY-BPA), we sought to determine whether female and male rats developmentally exposed to BPA demonstrated later spatial navigational learning and memory deficits. Pregnant NCTR Sprague-Dawley rats were orally dosed from gestational day 6 to parturition, and offspring were directly orally dosed until weaning (postnatal Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. ) and a 0.5 μg/kg/day ethinyl estradiol (EE)-reference estrogen dose. At adulthood, 1/sex/litter was tested for seven days in the Barnes maze. The 2500 BPA group sniffed more incorrect holes on day 7 than those in the control, 2.5 BPA, and EE groups. The 2500 BPA females were less likely than control females to locate the escape box in the allotted time (P value= 0.04). Although 2.5 BPA females exhibited a prolonged latency, the effect did not reach significance (P value = 0.06), whereas 2.5 BPA males showed improved latency compared to control males (P value = 0.04), although the significance of this result is uncertain. No differences in serum testosterone concentration were detected in any male or female treatment groups. Current findings suggest developmental exposure of rats to BPA may disrupt aspects of spatial navigational learning and memory. HHS Public Access

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Development of a physiologically based pharmacokinetic model for bisphenol A in pregnant mice

Cited by 35 publications

References 31 publications

Urinary, Circulating, and Tissue Biomonitoring Studies Indicate Widespread Exposure to Bisphenol A

Urinary, Circulating, and Tissue Biomonitoring Studies Indicate Widespread Exposure to Bisphenol A

Derivation of a Bisphenol a Oral Reference Dose (RfD) and Drinking-Water Equivalent Concentration∗

Effects of developmental exposure to bisphenol A on spatial navigational learning and memory in rats: A CLARITY-BPA study

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