Endocrine Disruption: What Does the Future Hold for Safety Assessment?

Transcription

1 RSA Conference 2017 Endocrine Disruption: What Does the Future Hold for Safety Assessment? 31 January 1 February 2017 Venue: Cranage Hall, Cheshire, UK Sponsored by:

2 RSA Conference 2017 Endocrine Disruption: What Does the Future Hold for Safety Assessment? January 31st February 1st 2017 Cranage Hall, Cheshire, UK Endocrine disruption (ED) is a hot topic on all agendas with draft EU criteria for EDs published in Both human and environmental safety assessment of agrochemicals, pharmaceuticals, chemicals and biocides require consideration of endocrine disrupting properties. The US and Europe regulate for such properties in different ways with risk based approaches in the US and hazard in the EU. To understand the mechanism(s) of action for ED, adverse outcome pathways can be very helpful and, with application of category approaches, animal testing may be minimized. This conference will explore the regulatory implications of ED assessment across the various areas of chemical use in different regions and how to make best use of the available tools for optimizing or avoiding unnecessary testing. In Memory of Charlotte Croudace An inspiration to RSA

3 Summary Timetable Day 1 (31st January 2017) Arrive 13:00 for coffee Day 2 (1 st February 2017) Start 09:00 Opening Remarks 13:45 by RSA Session 1 Regulatory implications of endocrine disruption (14:00-15:30) Chair: Dr Steve Fairhurst, UK Health and Safety Executive Prof Alan R Boobis OBE, Imperial College London Regulatory update and implications for human health. Risk vs hazard assessment. Prof Peter Matthiessen, Consultant Ecotoxicologist Environmental Hazard and Risk Assessment Approaches: Pellston Workshop output on ED assessment. Dr Christian Strupp, Adama Regulatory Context and Impact on (Agro)Chemicals. Panel discussion Break for coffee (15:30-16:15) Session 2 Assessing endocrine disruption for human health (16:15-17:45) Chair: Prof Ian Kimber OBE, University of Manchester Dr Richard Green, Dow AgroSciences Assessment and Application of Adverse Outcome Pathways Relevant to the Endocrine System. Dr Jenny Odum, RSA Use of the OECD Conceptual Framework in testing for and reviewing endocrine effects. Dr Malgorzata Nepelska, Unilever, UK AOP for PPARactivation in utero leading to impaired fertility in males. Implications for human health? Panel discussion Session 3 - Assessing endocrine disruption in the environment (09:00-10:30) Chair: Prof Peter Matthiessen, Consultant Ecotoxicologist Richard Murray-Smith, RSA Environmental risk assessment and endocrine disruption. Dr Lennart Weltje, BASF SE Masculinisation in wild fish and the possible involvement of azoles a reality check. Dr James Wheeler, Dow AgroSciences Ecotoxicology endocrine testing: current and future perspectives. Panel discussion Break for coffee (10:30-11:15) Session 4 Reducing animal testing for endocrine disruption (11:15-12:15) Chair: Prof Martin Wilks, Swiss Centre for Applied Human Toxicology, University of Basel Dr Stewart Owen, AstraZeneca Minimizing the use of fish in tests using MoA strategies. Prof Mark Cronin, Liverpool John Moores University Use of AOPs to reduce in vivo testing. Panel discussion Final discussion session with invited panellists (12:15-12:45) Chair: Prof Martin Wilks, Swiss Centre for Applied Human Toxicology, University of Basel 13:00 Close of the conference followed by lunch 19:00 Drinks reception followed by Conference Dinner. After Dinner Speaker: Prof Lewis Smith 2

4 Full Programme Day 1 (31st January 2017) Arrive 13:00 for coffee Opening Remarks 13:45 by RSA Session 1 Regulatory implications of endocrine disruption (14: ) Chair: Dr Steve Fairhurst, UK Health and Safety Executive Prof Alan R Boobis OBE, Imperial College London Regulatory update and implications for human health. Risk vs hazard assessment. Definition of an EDC What is the endocrine system Distinguishing between adverse and non-adverse effects Implications of move to non-animal test methods Critical importance of dose-response in addressing many of these issues Prof Peter Matthiessen, Consultant Ecotoxicologist Environmental Hazard and Risk Assessment Approaches: Pellston Workshop output on ED assessment. Hazard or risk assessment for environmental EDs? Case studies of 6 chemicals How environmental hazard and risk assessment of EDs should be carried out Dr Christian Strupp, Adama Regulatory Context and Impact on (Agro)Chemicals. The context: Science or conviction? Global regulatory approaches Do we have an issue and are we testing correctly? What we already have for agrochemicals Global trade Panel discussion Break for coffee (15:30-16:15) 3

5 Session 2 Assessing endocrine disruption for human health (16:15-17:45) Chair: Prof Ian Kimber OBE, University of Manchester Dr Richard Green, Dow AgroSciences Assessment and Application of Adverse Outcome Pathways Relevant to the Endocrine System. Overview of the current state of the science with respect to AOPs relevant to the endocrine system and how they are currently being developed and assessed Suggested key elements to be considered when evaluating the utility of these AOPs for different, defined purposes Consideration of how these AOPs may be used in the future e.g., identification of Endocrine Disruptors for regulatory purposes Dr Jenny Odum, RSA Use of the OECD Conceptual Framework in testing for and reviewing endocrine effects. The OECD Conceptual Framework, Guidance Document 150 and how they may be used Weight of evidence approaches Deciding on whether a substance is an ED Dr Malgorzata Nepelska, Unilever, UK AOP for PPAR activation in utero leading to impaired fertility in males. Implications for human health? AOP development process; rationale for choosing pathway Controversy around the pathway: OECD review outcome Examples of uses within regulatory context Panel discussion Conference Dinner Drinks reception sponsored by IEH Consulting 19:00 Dinner with drinks sponsored by JSC International 20:00 After Dinner Speaker: Prof Lewis Smith. 4

6 Day 2 (1 February 2017) Welcome Back Session 3 - Assessing endocrine disruption in the environment (09:00-10:30) Chair: Prof Peter Matthiessen, Independent Consultant Richard Murray-Smith, RSA Environmental risk assessment and endocrine disruption. What does ED mean for ERA? Why we need to demystify ED Why it s not all about NOEC s What s going to change in future ERA s Dr Lennart Weltje, BASF SE Masculinisation in wild fish and the possible involvement of azoles a reality check. Mechanisms and effects of azoles in the laboratory Field observations on masculinisation in wild fish populations Exploring causality and potential for effects Conclusions and implications for regulation Dr James Wheeler, Dow AgroSciences Ecotoxicology endocrine testing: current and future perspectives. Development of new tests in multiple taxa and species The need for better mechanistic understanding of endocrine and non-endocrine toxicities Weight-of-evidence Panel discussion Break for coffee (10:30-11:15) 5

7 Session 4 - Reducing animal testing for endocrine disruption (11:15-12:15) Chair: Prof Martin Wilks, Swiss Centre for Applied Human Toxicology, University of Basel Dr Stewart Owen, AstraZeneca - Minimizing the use of fish in tests using MoA strategies. Exclusion of other MOAs (e.g. cytotoxicity, mutagenicity,) Elucidation of rodent MOA in vivo: We have been working on science-based approaches to prioritise risks posed to the aquatic environment by legacy human pharmaceuticals. A cascade approach using knowledge of the properties and in silico and vitro screens could minimise testing in fish. We can separate endocrine disrupters from other modes of action based on a sensitivity analysis, and have developed a quantitative Adverse Outcome Pathway (qaop) for glucocorticoids that could have wider application in understanding the risks and guiding the testing strategy. Prof Mark Cronin, Liverpool John Moores University Use of AOPs to reduce in vivo testing. Review of current AOPs for endocrine disruption Contribution of AOPs to design in silico and in vitro assays for endocrine disruption Supporting read-across with in silico and in vitro data Integrating information from non-animal tests in an AOP framework to provide a weight of evidence to reduce in vivo testing Panel discussion Final discussion session with invited panellists (12:15-12:45) Chair Prof Martin Wilks, Swiss Centre for Applied Human Toxicology, University of Basel A panel drawn from the session speakers and chairs will discuss issues identified during the seminar. Close of meeting 13:00 by RSA Lunch sponsored by Envigo 6

8 RSA wish to thank the exhibitors and sponsors, CXR Biosciences, Cyprotex Discovery Ltd, JSC International, IEH Consulting, Scymaris, Envigo and Syngenta for their sponsorship of this event. 7

9 Speaker and Chair Biographies Dr Steve Fairhurst, Head of REACH, Classification & Labelling and environmental sciences provision, UK Health and Safety Executive, Bootle, Merseyside Steve has worked for the UK Health and Safety Executive (HSE), delivering and managing regulatory toxicology, since the mid-1980s. He is part of the senior management team of HSE s Chemicals Regulation Division (CRD), formed in 2009 to bring together in the UK the regulatory science and the operation of regulatory regimes for UK/EU legislation covering Plant Protection Products (pesticides), biocides and industrial chemicals. In this setting, Steve has senior management responsibility for the delivery of REACH and Classification & Labelling operations. Also, despite having Daphnia-sized credentials, he is the responsible senior manager for HSE s environmental science input to all the above pieces of legislation. Steve has chaired and served on a variety of UK and EU expert committees and groups concerned with chemical hazards and (primarily) occupational health risk considerations. He is also the current chair of the Interdepartmental Group on Health Risks from Chemicals (IGHRC) that operates to harmonise and progress regulatory toxicology across all relevant UK government departments. Since 2010, Steve has led HSE s scientific input into the long-running debate about the most appropriate means of identifying for regulatory purposes chemicals that possess endocrine-disrupting properties, working with a small team in which Susy Brescia has been particularly prominent. We re not finished yet! Prof Alan R Boobis OBE, Imperial College London Alan Boobis is Professor of Biochemical Pharmacology, Imperial College London. His research interests include mechanistic toxicology, risk assessment and food safety. He has published around 240 original research papers. He is a member/chair of several national and international advisory committees and currently chairs the UK Committee on Toxicity. He is chair of the Board of Trustees of the International Life Sciences Institute (ILSI). He has received several awards, including Officer of the British Empire (OBE). Prof Peter Matthiessen, Consultant Ecotoxicologist (independent) Peter Matthiessen has conducted research into the impacts of pollutants on aquatic life since Since the mid-1980s, he has become very involved with studies of endocrine disrupters such as ethynyl estradiol and tributyltin, and he is currently studying the effects of sewage discharges on the ability of fish to make normal corticosteroid responses to stress. He also has a strong advisory role, having just stepped down as a member of the Advisory Committee on Pesticides and joined the EFSA Working Group on Endocrine Disrupting Substances. Most relevantly for this session, Peter is co-chair of the OECD Validation Management Group for Ecotoxicity Tests, and is also a lead author (with Jenny Odum) of OECD guidance document 150 on how to interpret the results of tests with sensitivity to endocrine disrupters. 8

10 Dr Christian Strupp, Adama After completing studies in food chemistry, Christian Strupp moved to Novartis Pharma for thesis and handson work on oxidative stress and genetic knockdown models in toxicology. From there he took a position at RCC/Harlan for several years as a consultant in regulatory toxicology of (agro)chemicals and biocides, also completing the registration program as ERT. He is currently heading the Human Health Team of Adama Agriculture dealing globally with toxicology, metabolism, dietary and non-dietary risk assessment. Prof Ian Kimber OBE, University of Manchester Ian Kimber is currently Professor of Toxicology in the Faculty of Biology, Medicine and Health at the University of Manchester. He also served as Associate Dean for Business Development from He has broad research interests at the interface between toxicology and immunology, with a particular focus on allergy and inflammation. Professor Kimber holds, and has held, a variety of positions on national and international expert and scientific advisory committees. Currently these include the following: Member UK Medicines and Healthcare products Regulatory Agency (MHRA) Devices Expert Advisory Committee, Programme Advisor Food Standards Agency Food Allergy and Intolerance Research Programme, member Scientific Advisory Board National Institute for Biological Standards and Control, member MRC Translational Research Group, and Council member Laboratory Animal Science Association. Professor Kimber was previously: Deputy Chair of the MRC Physiological Medicine and Infection Board ( ), President of the British Toxicology Society ( ), and Chairman of the Board of the UK National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) ( ). Professor Kimber has published over 535 peer-reviewed research papers and review articles, over 100 book chapters, and 6 books. He serves currently on the editorial boards of toxicology, immunology, dermatology and pathology journals. Professor Kimber has received a number of awards and prizes. These include: the SmithKline Beecham Laboratory Animal Welfare Prize (2000) (jointly with David Basketter and Frank Gerberick), the 9th Robert A Scala Award in Toxicology (2001), the Doerenkamp-Zbinden Foundation Prize for Realistic Animal Protection in Biomedical Research (2001), Society of Toxicology Enhancement of Animal Welfare Award (2003) (jointly with Frank Gerberick), and Society of Toxicology Immunotoxicology Career Achievement Award (2005). In 2010 Professor Kimber received the Eurotox Bo Holmstedt Memorial Fellowship Award and Lecture at the International Congress of Toxicology. In 2015 Professor Kimber received the Society of Toxicology Distinguished Toxicology Scholar Award. In 2015 he was awarded the Barnes Prize Lecture by the British Toxicology Society. Professor Kimber was elected to membership of Academia Europaea in In 2011 Professor Kimber was awarded an OBE in the Queen s Birthday Honours list for services to science. Dr Richard Green, Toxicologist and Risk Assessor, Dow AgroSciences Following completion of his PhD at the University of Birmingham, Richard has been working as a toxicologist in the crop protection industry; previously with Syngenta and currently with Dow AgroSciences. His areas of specialism include mechanistic toxicology and endocrine disruption. Currently he is chairing a European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) task force developing guidance on assessment and application of adverse outcome pathways (AOPs) relevant to the endocrine system. 9

11 Dr Jenny Odum, Consultant Toxicologist, Regulatory Science Associates Jenny Odum has over 25 years experience as an industrial toxicologist and is currently a Consultant Toxicologist with Regulatory Science Associates. She has a broad range of expertise within toxicological specialities in both regulatory and research arenas and has published widely. She is an expert in the field of endocrine disruption, providing specialist advice on endocrine disruption testing and assessment in the field of human health and written position statements for compound defence. She is a member of a number of OECD expert panels on testing for endocrine disruption and the development of test guidelines. She has also co-authored a number of OECD guidance documents on tests for endocrine disrupters and reproductive toxicology. Dr.Małgorzata Lucyna Nepelska, Risk assessor /Novel approaches, Unilever, UK Dr. Nepelska is a Risk Assessor / Novel approaches at Unilever. Previously employed by the European Commission's Joint Research Centre (JRC) in Ispra/Italy as Scientific Project Officer. She specialized in scientific policy support for mode of action based assessment of endocrine disrupting chemicals with focus on AOP development. Dr. Nepelska is a researcher by nature and biotechnologist by training. She graduated from the Warsaw Agricultural University in the Interfaculty Studies of Biotechnology and obtained her PhD. degree in Physiology and pathophysiology from the University Pierre et Marie Curie in Paris. Currently, she is finalising a Postgraduate Toxicology course at the Vienna Medical University. She had her first hand-on laboratory experience abroad at the University of Natural Resources and Applied Life Sciences in Vienna. Next, at the Austrian Research Centres she performed the experimental part of her master thesis. Both of these experiences gave her applied knowledge of molecular biology, microbiology and immunology. Having obtained her MSc she continued to conduct research in the field of endocrinology/neurobiology. Between 2007 and 2008, she worked at the National Hellenic Research Foundation in Athens. Within this project she examined the neuroprotective properties of natural compounds and their mode of action. The next step in her career was an internship at the International Atomic Energy Agency s Laboratories in Seibersdorf/Austria. In this work she used genomics for the identification of new genetic markers for the susceptibility to pathogens. Her co-supervised PhD study took place in France and included an exchange period at the Karolinska Institutet in Sweden. In this project a pioneer high-throughput functional screening approach was applied for the identification of new bacterial molecules that are involved in the crosstalk with nuclear receptors regulating the key genes in human host physiology. Her work is guided by need to rationalize and help to make connections between ideas. Dr Nepelska`s research interest encompasses: development of alternative approaches in risk assessment with particular focus on AOPs, nuclear receptors and their role in response to xenobiotics and involvement of human microbiota in reaction to harmful compounds. 10

12 Prof Lewis Smith Lewis Smith is now retired but continues to act as a consultant on toxicology and governance issues. From 1971 to 1991, Lewis was responsible for a number of toxicological research projects in ICI and was ultimately Head of the Biochemical Toxicology Department in the Central Toxicology Laboratory (CTL). In 1991, Lewis left ICI to become Professor of Biochemical Toxicology at the University of Leicester and Director of both the Medical Research Council s Institute for Environment and Health and the MRC Toxicology Unit. Lewis has published approximately 100 articles, papers or book chapters on various aspects of the mechanism of toxicity of drugs, pesticides and industrial chemicals. In 1998, he returned as Director of Zeneca s CTL (previously ICI). After Zeneca merged with Astra in 1999, the biotech and agroscience businesses of AstraZeneca and Novartis were hived off and merged to form Syngenta. Lewis held several positions in Syngenta's head office in Basel including head of product development. He retired from Syngenta in Richard Murray-Smith, Consultant in Environmental Risk Assessment, Regulatory Science Associates Richard is a consultant ERA specialist working with Regulatory Science Associates. Richard worked for AstraZeneca (AZ), formerly ICI/Zeneca, for >20 years, initially in mathematical modelling, then as a project manager, environmental risk assessor and as Head of Global Environmental Risk Assessment (ERA) and Compliance. Richard is a technical expert in Environmental Risk Assessment (ERA), specializing in pharmaceuticals and general chemicals. He is fully conversant with the technical ERA requirements under REACH and EMA. He has represented AZ and national and EU pharmaceutical trade associations on many occasions in presenting industry views on developing regulatory ERA policy and guidelines. He has been a member of several ECETOC and OECD taskforces and participated in SETAC Pellston and DIA workshops and seminars on pharmaceuticals in the environment and ERA of pharmaceuticals. Richard has acted as project manager for many clients, helping to define protocols and manage delivery of studies to agreed timelines, including bespoke studies for difficult substances and suspected endocrine disruptors, several of which involved interactions with regulatory agencies to agree the design of studies. Dr. Lennart Weltje, Senior Regulatory Scientist, BASF SE, Crop Protection Ecotoxicology, Germany Lennart Weltje is a senior regulatory ecotoxicologist at BASF Crop Protection in Limburgerhof, Germany. Lennart holds a BSc and MSc in Biology (Utrecht University, The Netherlands) and a PhD in Ecotoxicology and Environmental Chemistry (Delft University, The Netherlands). From 1993 to 1995, he was employed as soil ecotoxicologist at the National Institute for Public Health and the Environment (RIVM, Bilthoven, The Netherlands) working on mixture toxicity. In 2001 he received a 2-year EU Marie-Curie postdoc fellowship to work on endocrine disruption in freshwater invertebrates at the International Graduate School in Zittau, Germany. In 2004 he started working for BASF, conducting aquatic risk assessments for plant protection products and biocides. Other topics he is involved with include endocrine disruption, mixture toxicity, sediment and aquatic invertebrates. Lennart is an active member of the endocrine disruption expert groups of the European Crop Protection Association, ECETOC and the SETAC Advisory Group on Endocrine Disruptor Testing and Risk Assessment and author of about 40 peer-reviewed papers. 11

13 Dr James Wheeler, Dow AgroSciences James is currently a Regulatory Ecotoxicologist working for Dow AgroSciences based in Abingdon, UK. Previous to that he worked, in a similar role, at Syngenta subsequent to completing a PhD at Royal Holloway University of London. He has broad interests based around ecotoxicological testing and environmental risk assessment for plant protection products. In addition to implementing the 3Rs into chemical safety assessment. James is a member of several scientific advisory groups. Currently these include the following: The OECD Endocrine Disruptor Testing and Assessment Task Force, OECD Validation Management Group for ecotoxicology, Ecotoxicology Team member for the National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) and various industry association working groups. He has published over 50 research papers, review articles and book chapters. Professor Martin Wilks, Director of the Swiss Centre for Applied Human Toxicology, University of Basel Martin Wilks has been the founding director of the Swiss Centre for Applied Human Toxicology (SCAHT) since 2009 and Adjunct Professor at the Medical Faculty of the University of Geneva since Supported by the Swiss Confederation and the universities of Basel, Geneva and Lausanne, the SCAHT is dedicated to research, education and regulatory services in human toxicology and health risk assessment. Professor Wilks research and professional interests include clinical toxicology, toxico-epidemiology and risk assessment of chemical exposures. He obtained a doctorate in medicine in 1986 following his medical studies and internship at the Medical School Hannover (Germany). After completing a Ph.D. in toxicology at the University of Surrey (UK) in 1990 he worked as a medical toxicologist in the national health service and the chemical industry in the UK and Switzerland. He is a EUROTOX Registered Toxicologist and Fellow of the Royal College of Physicians of Edinburgh. He is President-elect of the European Association of Poison Control Centres and Clinical Toxicologists (EAPCCT) and Executive Committee member and Chairman of the Education Sub-Committee of EUROTOX, a Board member of the Swiss Society of Toxicology and Chairman of its Registration Committee. Professor Wilks is currently a member of the Committee for the Assessment of Poisonings at the German Federal Institute for Risk Assessment, and the Scientific Advisory Board of the Institutes for Medical NBC Protection, Medical Academy of the German Army. Dr Stewart Owen, AstraZeneca Stewart leads the AstraZeneca research into environmental effects of pharmaceuticals. This presentation will highlight recent progress with academic collaborations that he has developed over 10 years with AstraZeneca. He has 20 years postdoctoral experience and has interests in animal welfare leading the global AstraZeneca approach to 3Rs. 12

14 Prof Mark Cronin, Liverpool John Moores University Mark Cronin is Professor of Predictive Toxicology at Liverpool John Moores University. He has over 25 years expertise in the application of in silico approaches to predict the toxicity and fate of chemicals. Research in recent years has centred on the application of these alternatives for product development and regulatory risk assessment. Current research includes the application of chemical grouping and read-across to assess human health and environmental endpoints, in particular the linking of the Adverse Outcome Pathways (AOPs) to category formation. 13

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