And Toxicokinetics of Selected Exogenous and Endogenous Estrogens: a Review of the Data and Identification of Knowledge Gaps
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http://informahealthcare.com/txc ISSN:1040-8444 (print), 1547-6898 (electronic) Crit Rev Toxicol, 2014; Early Online: 1–29 © 2014 Informa Healthcare USA, Inc. DOI: 10.3109/10408444.2014.930813 REVIEW ARTICLE Pharmaco- and toxicokinetics of selected exogenous and endogenous estrogens: A review of the data and identification of knowledge gaps Donald R. Mattison1,2, Nataliya Karyakina1, Michael Goodman3, and Judy S. LaKind4,5,6 1Risk Sciences International, Ottawa, ON, Canada, 2McLaughlin Centre for Population Health Risk Assessment, University of Ottawa, Ottawa, ON, Canada, 3Department of Epidemiology, Emory University School of Public Health, Atlanta, Georgia, USA, 4LaKind Associates, LLC, Catonsville, Maryland, USA, 5Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, Maryland, USA, and 6Department of Pediatrics, Milton S. Hershey Medical Center, Penn State College of Medicine, Hershey, Pennsylvania, USA Abstract Keywords Chemicals with estrogenic activity are derived from many different natural and synthetic bisphenol A, conjugated estrogens, daidzein, processes and products, including endogenous production (e.g., estradiol, conjugated estro- daidzin, estradiol, ethinyl estradiol, equol, gens), drugs (e.g., ethinyl estradiol, conjugated estrogens), plants used as foods (phytoestrogens genistein, genistin, pharmacokinetics, such as genistein, daidzein, S-equol), and man-made chemicals (xenoestrogens such as bisphenol pharmacodynamics, physiologically based A). Human exposure to low doses of endogenous estrogens, estrogenic drugs, phytoestrogens, pharmacokinetics and xenoestrogens has the potential to improve health or disrupt normal endocrine activity, as well as impact the diverse systems with which estrogens interact, including the cardiovascular system, and lipid and carbohydrate metabolism. Mechanisms of action and diversity of adverse History and non-adverse effects following human exposure to low doses of estrogen active chemicals Received 23 October 2013 (EACs, defined as chemicals which interact with an estrogen receptor [ER]) are poorly under- Revised 1 June 2014 stood. This review summarizes our current understanding of the pharmacological action Accepted 1 June 2014 with a focus on pharmacokinetics (PK) and toxicokinetics (TK) of several representative EACs in Published online 7 August 2014 both physiological and pathological processes. The goal of this review is to assess the current state-of-the-science on: (i) the potential for EACs to interfere with endocrine activity, (ii) factors For personal use only. which contribute to endocrine-related clinical outcomes, and (iii) existing knowledge gaps. While classical PK approaches (compartmental or non-compartmental) can be used to characterize absorption, distribution, metabolism, and elimination of EACs, many of the detailed pharmaco- logical characteristics necessary to understand benefit-risk balance have not yet been clarified. Pharmacological complexities mirror the complexity of determining whether and under what conditions exposure to estrogens in drugs, foods or to xenoestrogenic chemicals are beneficial or harmful to human health. Table of Contents Elimination ... ... ... .. ... ... ... .. ... ... ... .. ... ... ... .. 8 Introduction ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 2 Mechanism of action... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 9 Literature search and review ... ... ... .. ... ... ... .. ... ... ... .. 2 Summary ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 9 Critical Reviews in Toxicology Downloaded from informahealthcare.com by 108.3.173.129 on 08/06/14 Background information on estrogens selected Knowledge gaps . ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 9 for this review. ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 3 PBPK model for estradiol. ... ... ... ... ... ... ... ... ... ... ... ... ... ... ...10 Endogenous and therapeutic estrogens ... ... ... ... ... ... ... ... ... ... 5 PBPK model for E2—knowledge gaps ... ... ... ... ... ... ... ... ... ...10 17b-Estradiol ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 5 Endogenous and therapeutic estrogens: Ethinyl estradiol . ... ... ...10 Ethinyl estradiol... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 5 Absorption ... ... ... .. ... ... ... .. ... ... ... .. ... ... ... .. .10 Conjugated estrogens ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 5 Distribution. ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ...11 Phytoestrogens (isoflavones) ... ... ... .. ... ... ... .. ... ... ... 6 Metabolism. ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ...11 Genistein. ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 6 Elimination ... ... ... .. ... ... ... .. ... ... ... .. ... ... ... .. .11 Daidzein ... ... ... .. ... ... ... .. ... ... ... .. ... ... ... .. ... 6 Mechanism of action... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ...11 S-equol ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 6 Summary ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ...11 Xenoestrogen: Bisphenol A ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 6 Knowledge gaps . ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ...12 Pharmacokinetics of estrogenic compounds. ... ... ... ... ... ... ... ... ... 6 Endogenous and therapeutic estrogens: Conjugated Endogenous and therapeutic estrogens: 17ß-Estradiol ... ... ... .. 6 estrogens ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ...12 Absorption and distribution ... ... ... ... ... ... ... ... ... ... ... ... ... ... 7 Absorption ... ... ... .. ... ... ... .. ... ... ... .. ... ... ... .. .12 Metabolism. ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 8 Distribution. ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ...13 Metabolism. ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ...13 Address for correspondence: Dr Judy S. LaKind, LaKind Associates, Elimination ... ... ... .. ... ... ... .. ... ... ... .. ... ... ... .. .13 LLC, 106 Oakdale Avenue, Catonsville, 21228 Maryland, USA. Mechanism of action... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ...13 Tel: 1-410-788-8639. Fax: 1-410-788-8639. E-mail: lakindassoc@ Summary ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ...13 gmail.com Knowledge gaps . ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ...13 2 D. R. Mattison et al. Crit Rev Toxicol, 2014; Early Online: 1–29 Phytoestrogens: Genistein, daidzein... ... ... ... ... ... ... ... ... ... ... ...14 and PD), as well as the influence of such important factors as Absorption ... ... ... .. ... ... ... .. ... ... ... .. ... ... ... .. .14 sex, age, hormonal status, and the features of exposure such Distribution. ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ...14 Metabolism. ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ...14 as timing, dose, and duration, it will be difficult to interpret Elimination ... ... ... .. ... ... ... .. ... ... ... .. ... ... ... .. .15 the health-based information that is appearing in the epide- Mechanism of action... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ...15 miological and experimental clinical literature. Phytoestrogens: S-equol ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ...15 The goal of this review is to assess the current state-of- Absorption ... ... ... .. ... ... ... .. ... ... ... .. ... ... ... .. .16 the-science on: (i) the potential for EACs to interfere with Distribution. ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ...16 Metabolism. ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ...16 endocrine activity, (ii) factors which contribute to endocrine- Excretion. ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ...16 related clinical outcomes, and (iii) existing knowledge gaps. Mechanism of action... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ...16 While classical PK approaches (compartmental or non- Summary ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ...16 compartmental) can be used to characterize absorption, dis- Knowledge gaps . ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ...17 tribution, metabolism, and elimination of EACs, many of the PBPK model for genistein ... ... ... ... ... ... ... ... ... ... ... ... ... ... ...17 Genistein PBPK knowledge gaps ... ... ... ... ... ... ... ... ... ... ... ...17 detailed pharmacological characteristics necessary to under- Xenoestrogens: Bisphenol A ... ... ... ... ... ... ... ... ... ... ... ... ... ... ...18 stand benefit-risk balance have not yet been clarified. This Absorption ... ... ... .. ... ... ... .. ... ... ... .. ... ... ... .. .18 review is not meant to be exhaustive; rather, we have chosen Distribution. ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ...18 to highlight concepts which summarize our current