Next Generation Risk Assessment Of Androgens And Estrogens

To assure safe levels of human exposure to chemicals, in toxicological risk assessment advances are made to shift from using animal-based to animal-free testing strategies. This is fuelled by ethical, economic, and legislative issues and the scientific rationale that experimental animals do not adequately represent the human body and animal test guidelines may not cover human pathologies. In Next Generation Risk Assessment (NGRA), the development and use of non-animal based new approach methodologies (NAMs) aims not to predict chemical-induced pathologies in animals but to assure human safety, eliminating the need for animal data. The aim of this thesis to perform NGRA to inform human-relevant safe levels of chemical exposure, integrating in vitro-in silico approaches for chemicals with putative (anti)androgenic and/or estrogenic effects. NGRA can use the Dietary Comparator Ratio (DCR) to evaluate the safety of a defined exposure to a compound with an identified mode of action. The DCR compares the Exposure Activity Ratio (EAR) for the compound of interest, to the EAR of an established safe level of human exposure to a comparator compound with the same mode of action. A DCR ≤ 1 indicates the exposure evaluated is safe. It was aimed to define adequate and safe comparator compound exposures for evaluation of endocrine effects. 3,3-Diindolylmethane (DIM), from cruciferous vegetables, and the anti-androgenic drug bicalutamide (BIC) were used to evaluate anti-androgenic effects and the EAR values for these comparator compounds were defined using an in vitro androgenic reporter gene assay. The isoflavone genistein (GEN) was used to evaluate estrogenic effects and its EAR value was set using in vitro estrogenic proliferation and reporter gene assays. The EAR values of DIM and BIC were evaluated using physiologically based kinetic (PBK) modelling and comparison to in vivo reported safe and therapeutic-active levels, respectively. The EAR values of GEN were evaluated by comparison with in vivo reported safe internal levels of GEN following different diets. The adequacy of the comparator EAR values was further evaluated by comparing the generated DCRs of a series of test compound exposures to actual knowledge of their safety regarding in vivo anti-androgenicity or estrogenicity. Exposure scenarios of nine anti-androgenic pesticides, phenols, and drugs and of 12 estrogenic hormones, phytoestrogens, pesticides, phenols, parabens, phthalates, and drugs were included. Results obtained supported the use of the in vitro bioactivity assay-derived comparator EARs for DCR-based NGRA for putative anti-androgenic and estrogenic compounds. This further validates the DCR approach as an important animal free tool in NGRA and will further support the safety assessment of endocrine acting substances. Another NGRA strategy was explored aiming at including hepatic biotransformation by providing a proof of principle for PBK modelling-facilitated quantitative in vitro to in vivo extrapolation (QIVIVE) using a toxic equivalency factor (TEF) approach. In the PBK modelling-facilitated QIVIVE of the selected anti-androgenic model compound flutamide (FLU), its in vitro AR-CALUX derived concentration-response curve was translated to the corresponding in vivo dose-response curves, either excluding or including the activity of its more anti-androgenic active metabolite hydroxyflutamide (HF). It was demonstrated that including the bioactivity of the active metabolite in PBK modelling-facilitated QIVIVE provides a better and more appropriate point of departure (PoD) to assure human safe exposure levels to the parent compound, whereas excluding the activity of the metabolite will potentially result in an underestimation of the corresponding risk. Finally, a two-chamber co-culture system with human liver and reporter cells was developed to assess androgenic responses in the absence and presence of a biotransformation system. The androgenic response of testosterone (T) and 5α-dihydrotestosterone (DHT), which are hepatically detoxified, were assessed using the AR-CALUX or AR-INDIGO assay in the absence or presence of 3D HepaRG microtissues, that exhibit active hepatic metabolism. Androstenedione, which is an inactivated metabolite, was formed following incubation of T with the 3D HepaRG microtissues which translated in the co-culture system to a significantly reduced T mediated induction of the AR response in both reporter gene assays in the presence of 3D HepaRG microtissues. A similar 3D HepaRG microtissues dependent reduction in the DHT induced AR response was observed in line with the hepatic inactivation of DHT by a similar biotransformation step. The two-chamber co-culture system with human liver and reporter cells may thus provide a screening tool to identify chemicals for which hepatic metabolism affects their bioactivity and thus should be included when setting the PoD of the parent compound. In conclusion, the DCR approach provides an appropriate NAM for the safety assessment of human chemical exposures to anti-androgenic and estrogenic compounds. Furthermore, biologically active metabolites should be taken into account in the PBK modelling-facilitated QIVIVE for evaluating the safety of a parent compound. Lastly, the two-chamber co-culture system with human liver and reporter cells is a new technology that will allow the identification of hepatic metabolites affecting the in vitro bioactivity of a parent compound. Taken together, it is concluded that the NGRA strategies presented in this thesis are appropriate and of value for human safety assessment of exposure to (anti)androgens and estrogens in an animal free in silico/in vitro 3R compliant way.

This book provides a comprehensive overview of endocrinology of the male reproductive system, explaining how it works and how, sometimes, it fails to work. World-class specialists present state of the art knowledge on all aspects, including anatomy, physiology, molecular biology, genetics, pathophysiology, clinical manifestations of testicular diseases, endocrine aspects of andrological and sexual diseases, and therapy. Extensive consideration is given to sexual development, testicular function, the clinical approach to disorders of male reproduction, male hypogonadism, sexual dysfunction, and male infertility. In addition, sociodemographic, psychological, and ethical aspects of male reproductive disorders are discussed. The book is intended as a major reference for endocrinologists, andrologists, and sexologists, as well as basic and clinical scientists. It is published as part of the SpringerReference program, which delivers access to living editions constantly updated through a dynamic peer-review publishing process.

Male Reproductive Function gives an up-to-date review on the physiology and disease processes associated with the male reproductive system. The first few chapters describe the regulation of the functions of the testis and the integration of its components: germ cells, Sertoli cells and Leydig cells. This is followed by a description of puberty and aging, and the disorders or dysfunction that may be associated with these physiological processes. Discussions on the current methods for the diagnosis and treatment of male hypogonadism, male infertility and male sexual dysfunction follow, with detailed descriptions of types of androgen replacement and the benefits and risks of such treatment. The book concludes with the development of male contraception and the possible influence of the environment on the male reproductive system. Male Reproductive Function represents a conglomeration of the efforts of experts in andrology from all over the world, both in basic cellular/molecular biology as well as in clinical science and practice. This book is suitable for endocrinologists, urologists, general internists, gynecologists and other students in the field of male reproduction.

The decade that has passed since publication of the second edition of this textbook has not only witnessed a tremendous increase in knowledge within the ? eld of and- logy, but also seen the ? eld itself achieve a newfound status within the medical p- fession. Knowledge and status have been of mutual bene? t to the ? eld and the growing critical mass of diagnostic and therapeutic possibilities have caused andrology to be recognized as a medical subspecialty in some countries such as Germany, Poland, and Estonia. The European Academy of Andrology (EAA) served as a pacemaker for this development and continues to strive for establishment of andrology as a clinical ? eld. Well-designed curricula and qualifying examinations have contributed to the of? cial recognition of andrology as a speciality. This recognition of the ? eld helps patients with andrological problems to ? nd the specialist they seek. This textbook summarizes the current state of knowledge in the ? eld of andrology. It is a source of knowledge to all those who are or want to become andrologists. In addition, as andrology is clearly an interdisciplinary ? eld, this book may serve as a compendium and source of reference for all those physicians and biologists active in neighboring areas, who want to obtain an overview of andrology and who require information on special problems. The extensive references are timely and up to date.

Since Dr. Brizendine wrote The Female Brain ten years ago, the response has been overwhelming. This New York Times bestseller has been translated into more than thirty languages, has sold nearly a million copies between editions, and has most recently inspired a romantic comedy starring Whitney Cummings and Sofia Vergara. And its profound scientific understanding of the nature and experience of the female brain continues to guide women as they pass through life stages, to help men better understand the girls and women in their lives, and to illuminate the delicate emotional machinery of a love relationship. Why are women more verbal than men? Why do women remember details of fights that men can’t remember at all? Why do women tend to form deeper bonds with their female friends than men do with their male counterparts? These and other questions have stumped both sexes throughout the ages. Now, pioneering neuropsychiatrist Louann Brizendine, M.D., brings together the latest findings to show how the unique structure of the female brain determines how women think, what they value, how they communicate, and who they love. While doing research as a medical student at Yale and then as a resident and faculty member at Harvard, Louann Brizendine discovered that almost all of the clinical data in existence on neurology, psychology, and neurobiology focused exclusively on males. In response to the overwhelming need for information on the female mind, Brizendine established the first clinic in the country to study and treat women’s brain function. In The Female Brain, Dr. Brizendine distills all her findings and the latest information from the scientific community in a highly accessible book that educates women about their unique brain/body/behavior. The result: women will come away from this book knowing that they have a lean, mean, communicating machine. Men will develop a serious case of brain envy.

Part of Water Quality Set - Buy all four books and save over 30% on buying separately! Bioanalytical Tools in Water Quality Assessment reviews the application of bioanalytical tools to the assessment of water quality including surveillance monitoring. The types of water included range from wastewater to drinking water, including recycled water, as well as treatment processes and advanced water treatment. Bioanalytical Tools in Water Quality Assessment not only demonstrates applications but also fills in the background knowledge in toxicology/ecotoxicology needed to appreciate these applications. Each chapter summarises fundamental material in a targeted way so that information can be applied to better understand the use of bioanalytical tools in water quality assessment. Bioanalytical tools in Water Quality Assessment can be used by lecturers teaching academic and professional courses and also by risk assessors, regulators, experts, consultants, researchers and managers working in the water sector. It can also be a reference manual for environmental engineers, analytical chemists, and toxicologists. Authors: Beate Escher, National Research Centre for Environmental Toxicology (EnTox), The University of Queensland, Australia, Frederic Leusch, Smart Water Research Facility (G51), Griffith University Gold Coast Campus, Australia. With contributions by Heather Chapman and Anita Poulsen

This authoritative handbook covers all aspects of immunosenescence, with contributions from experts in the research and clinical areas. It examines methods and models for studying immunosenescence; genetics; mechanisms including receptors and signal transduction; clinical relevance in disease states including infections, autoimmunity, cancer, metabolic syndrome, neurodegenerative diseases, frailty and osteoporosis; and much more.

Clinical Case Studies for the Family Nurse Practitioner is a key resource for advanced practice nurses and graduate students seeking to test their skills in assessing, diagnosing, and managing cases in family and primary care. Composed of more than 70 cases ranging from common to unique, the book compiles years of experience from experts in the field. It is organized chronologically, presenting cases from neonatal to geriatric care in a standard approach built on the SOAP format. This includes differential diagnosis and a series of critical thinking questions ideal for self-assessment or classroom use.