Rwanda Country Programme Evaluation National Roundtable Workshop
WORKSHOP PROGRAMME - Ecetoc
Transcript of WORKSHOP PROGRAMME - Ecetoc
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WORKSHOP PROGRAMME
Applying ‘Omics Technologies in Chemicals Risk
Assessment
10‐12 October, 2016
NH Eurobuilding Hotel, Madrid, Spain
Organised by
European Centre for
Ecotoxicology and Toxicology
of Chemicals
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Objectives:
1. With representatives from European Commission; the OECD; US‐EPA; US‐FDA ‐ share and
update frameworks developed by ECETOC multi‐expert teams on how to aquire, analyse
and apply ‘omics data. Ensue fitness for purpose.
2. Generate consensus of opinion on the steps needed to achieve best practices for applying
‘omics technologies in chemicals risk assessment.
Topics covered (Room Documents distributed prior to the workshop):
Establishing GLP‐like Context for Collecting, Storing and Curating ‘Omics Data
Best Practices for Analysisng ‘Omics Data
Best Practices for WoE Approaches for Integrating ‘Omics Data
Best Practices for Establishing Pathways to Connect Results of ‘Omic Data to Phenotype
Context:
’Omics technologies hold the promise of generating detailed information faster, more accurately
and easier than ever before. These emerging technologies could help:
Reduce animal testing, with the ultimate goal of replacing animal testing altogether
Increase the number of chemicals that can be accurately and efficiently tested in a given
time
Identify new and emerging risks through toxicological screening and reliable biomarkers
Yet current methodological and analytical uncertainties limit the application of ‘omics technologies.
Best practice for acquiring, analysing and applying ‘omics data is needed so that information from
‘omics can be reliably verified and confidently integrated into regulatory risk assessment.
Organizing Committee
Jim Bridges, University of Surrey, UK
Tim Gant, CRCE, UK
Madeleine Laffont, ECETOC
Mark Pemberton, Systox UK
Alan Poole, ECETOC
Weida Tong, NCTR/FDA USA
Ben van Ravenzwaay, BASF
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PROGRAMME
10 October Day 1 (Bruselas room)
12.00‐12.30 Registration (Praga room)
12.30‐13.15 Buffet lunch (Praga room)
13.15‐13.25 Welcome. Objectives of Workshop (Bruselas room)
Alan Poole, ECETOC
Opening Session:
Regulatory‐Science Needs, Challenges, Opportunities
13.25‐14.15 Moderated Panel Discussion / Key Note Speeches:
Regulatory Perspective: needs, challenges, opportunities
Moderator: Alan Poole, ECETOC
Panelists:
Eeva Leinala, OECD
Matt Martin, US‐EPA
Aldert Piersma, RIVM – NL
Tewes Tralau, BfR‐Ge
Andrew Worth, JRC
14.15‐14.30 “Reproducibility” of ‘Omics Data
Leming Shi, Fudan University, Shanghai
Work Stream 1:
Establishing GLP‐like context for Collecting, Storing and Curating Data
Chair: Ben van Ravenzwaay, ECETOC Scientific Committee
14.30‐14.40 Introduction to this Session
Ben van Ravenzwaay, ECETOC Scientific Committee
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14.40‐15.05 ECETOC’s concept for quality assurance of new technology data
considering GLP requirements
Hans‐Martin Kauffmann, BASF Germany
15.05‐15.25 Current Status: Application of GLP (like) data collection in practice
Ben van Ravenzwaay, BASF Germany
Amber Goetz, Syngenta
David Rouquie, BayerCropScience
15.25‐15.30 Details for Breakout Sessions
Madeleine Laffont, ECETOC
15.30‐16.30 Breakouts / Round Table Discussions
Chairs/Rapporteurs:
Beatriz Silva / Kamin Johnson (Bruselas room)
Ben van Ravenzwaay / Madeleine Laffont (Londres room)
John Greally / Ursula Sauer (Paris room)
David Rouquie / Lena Esteves (Viena room)
Brainstorm session on GLP framework:
1. What do you consider as raw data in the context of ‘omics technologies?
2. How can uncontrolled manipulation of data be prevented?
3. Are there (validated) software systems with audit trails for omics technologies available?
4. Do you have experience with the conduct of omics technologies under GLP or in a GLP‐
like manner (or under an ISO‐based quality system)?
5. Which items do you consider as major obstacles for a GLP‐(like) conduct of omics
studies?
6. Do you have ideas how obstacles might be overcome?
16.30‐17.00 Coffee Break
17.00‐18.00 Collection & Feedback from Breakout Session
Moderator: Madeleine Laffont, ECETOC
18.00‐18.15 Wrap up and close
Ben van Ravenzwaay, ECETOC Scientific Committee
18.30‐20.00 Networking Dinner Reception (Florencia room)
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PROGRAMME
11 October Day 2 (Bruselas room)
09.00‐09.10 Welcome. Details of the Day
Madeleine Laffont, ECETOC
Work Stream 2:
Best Practices for WoE Approaches for Integrating ‘Omics Data
Chair: Alan Poole, ECETOC
09.10‐09.20 Introduction to this Session
Alan Poole, ECETOC
09.20‐09.30 Introducing ECETOCs ‘strawman’ framework for discussion
Mark Pemberton, ECETOC Scientific Committee
09.30‐09.40 Quantified Weight of Evidence
Jim Bridges, Surrey University, UK
09.40‐10.00 WoE approaches, a case study
Amber Goetz, Syngenta
10.00‐10.05 Brief details for breakout session planning
Madeleine Laffont, ECETOC
10.05‐11.00 Breakouts / Round Table Discussions
Chairs / Rapporteurs:
Kerstin Schmidt / Roland Buesen (Bruselas room)
Lize Deferme / Madeleine Laffont (Londres room)
Aldert Piersma / Ursula Sauer (Paris room)
Carole Yauk / Lena Esteves (Viena room)
Feedback on Best Practices for WoE Approaches for Integrating ‘Omics Data:
1. What are the drivers for producing such a framework?
2. What are the strengths and weaknesses of the proposal as opposed to currently
available alternatives?
3. How can the proposal be improved?
4. Identify opportunities for its implementation/development and any perceived obstacles
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11.00‐11.30 Coffee Break
11.30‐12.15 Collection & Feedback from Breakout Session
Moderator: Madeleine Laffont, ECETOC
12.15‐12.30 Wrap up of Work stream 2:
Summary/Next Steps
Alan Poole, ECETOC Secretary General
12.30‐13.30 Buffet Lunch (Praga room)
13.30‐13.45 Welcome Back, Introduction to next Session
Alan Poole, ECETOC
Work Stream 3:
Best Practices for Establishing Pathways to Connect Results of ‘Omics Data to Phenotype
Chair: Alan Poole, ECETOC
13.45‐14.10 Lessons learned from HESI Framework for Establishing Fitness of
Purpose of Non‐animal Methods for Chemical Risk Assessment
Beatriz Silva, Lisbon University
14.10‐14.30 Case Study on Using ‘Omics in Risk Assessment
Kamin Johnson, DOW USA
14.30‐14.50 Epigenetics: Normality in toxicologically relevant species
Richard Meehan, University of Ediburgh, Scotland
14:50‐15.00 Brief details for breakout session planning
Madeleine Laffont, ECETOC
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15.00‐16.00 Breakouts / Round Table Discussions
Connecting Results of ‘Omics Data to Phenotype:
Chairs / Rapporteurs
George Daston/Paul Foster (Bruselas room) Jorg Hackermüller / Madeleine Laffont (Londres room) Bruno Hubesch / Ursula Sauer (Paris room) Danyel Jennen / Lena Esteves (Viena room) Questions for Brainstormers: Answer as many as you can in the time available. 1. How do we move away from using arbitrary fold‐changes in expression to a measure
that takes appropriate account of differences in the dynamic range of expression of
different genes?
2. How do we distinguish between trivial and meaningful changes in expression?
(qualitative and quantitative – which gene, which cell type, which lifestage, what
magnitude, what time‐scale; in vitro or in vivo?)
3. Are changes in the expression of a single gene meaningful? Or should this be in a
pathway? How should a pathway be defined (IPA Is not very specific in identifying
pathways ‐ problem of shared genes in different pathways)
4. Can we define genes/pathways where there is generally a good linkage to phenotypic
changes and ones where the linkage is not very good (changes in mRNA levels often not
accompanied by changes in protein and/or function)?
5. Can expression changes be used as a basis for establishing safe levels of exposure? If so,
how should the dose‐response relationship be assessed (how to obtain a POD)?
6. Can we map omics changes to AOPs and if so how will this information be used?
16.00‐16.30 Coffee Break
16.30‐17.15 Collection & Feedback from Breakout Session
Moderator: Madeleine Laffont, ECETOC
17.15‐17.30 Wrap Up, Close, details for tomorrow
Alan Poole, ECETOC
20.00 Dinner ‐ El Asador de la Esquina del Barnabeu
Santiago Bernabéu Stadium, Entry through gate 46,
Avenida de Concha Espina, 1 ‐ 28036 Madrid
(see walking distance map, in last page of programme)
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PROGRAMME
12 October Day 3 (Bruselas room)
08.30‐08.45 Welcome. Details of morning and introduction to the Session
Alan Poole, ECETOC
Work Stream 4:
Towards Establishing Criteria and Best Practices for Analysing ‘Omics Data
Chair: Weida Tong, NCTR/FDA USA
08.45‐09.10 Introducing ECETOC’s Draft Framework
Tim Gant, Public Health England, CRCE UK
09.10‐09.35 Results and Learnings, Next Steps
Weida Tong, NCTR/FDA USA
09.35‐10.00 Data Analysis/Normalisation/Integration techniques: a metabolomics case study
Tim Ebbels, Imperial College, UK
10.00‐11.00 Breakouts / Round Table Discussions
Chairs / Rapporteurs:
Kerstin Schmidt / Tim Ebbels (Bruselas room)
Amber Goetz / Madeleine Laffont (Londres room)
Tim Gant / Ursula Sauer (Paris room)
Hervé Seitz / Lena Esteves (Viena room)
Feedback on the framework of best practices for analysing omics data:
1. Is the goal to draw up a framework, as such, too simplistic because ‘omics data are
just too complex to be amenable to such an approach?
2. Is the Transcriptomics Analysis Framework (TAF) proposed herein too simplistic
bearing in mind that it merely strives to set a baseline for comparison?
3. Will the regulatory toxicology community accept this approach so that it is likely to
endure?
4. Is there a better way forward?
5. Identify opportunities for its further development / uptake by the industrial scientific
and regulatory community and any perceived obstacles?
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11.00‐11.30 Coffee Break
11.30‐12.00 Collection & Feedback from Breakout Session
Moderator: Madeleine Laffont, ECETOC
12.00‐12.15 Wrap up of this Session
Weida Tong, NCTR/FDA USA
12.15‐12.30 Wrap up, close the workshop
Alan Poole, ECETOC
12.30‐13.30 Buffet Lunch (Praga room)
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11th October Dinner: 20.00 ‐ Walking distance map
NH Collection Hotel to El Asador de la Esquina del Barnabeu Restaurant
Santiago Bernabéu Stadium, Entry through gate 46,
Avenida de Concha Espina, 1 ‐ 28036 Madrid
(10 minutes – 850 meters)
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Applying ‘Omics Technologies in Chemicals Risk Assessment
10‐12 October, 2016 Madrid
PARTICIPANTS
First name Name Affiliation E‐mail
Jim Bridges University of Surrey, UK(Video presentation)
Roland Buesen BASF SE [email protected]
Lyle Burgoon US Army, Env. Lab(dialing‐in)
Brian Chorley US EPA [email protected]
Beatriz da Silva Lima University of Lisbon, Portugal [email protected]
George Daston P&G, US [email protected]
Lize Deferme ExxonMobil, Belgium [email protected]
Timothy Ebbels Imperial College London, UK [email protected]
Lena Esteves G. Verde Communications/ ECETOC [email protected]
Paul Foster NIEHS, US [email protected]
Tim Gant PHE, CRCE, UK [email protected]
Amber Goetz Syngenta, US [email protected]
John Greally Albert Einstein College of Medicine, Yeshiva University, US
Laura Gribaldo European Commission ‐ JRC [email protected]
Jörg Hackermüller UFZ, Germany [email protected]
Jan Hengstler IfADo, Germany [email protected]
Bruno Hubesch Cefic‐LRI Programme [email protected]
Danyel Jennen Maastricht UniversityNetherlands
Kamin Johnson The Dow Chemical Company, US [email protected]
Jun Kanno Japan Organization of Occupational Health and Safety
Hans‐Martin Kauffmann BASF, Germany hans‐[email protected]
Madeleine Laffont ECETOC, Brussels [email protected]
Eeva Leinala OECD [email protected]
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First name Name Affiliation E‐mail
Matthew Martin EPA, US [email protected]
Patrick McMullen ScitoVation, US [email protected]
Richard Meehan Medical Research Council, UK(dialing‐in)
Mark Pemberton Systox Ltd., UK(Video presentation)
Stefania Perdichizzi ARPA_ER, Italy [email protected]
Aldert Piersma RIVM, Netherlands [email protected]
Alan Poole ECETOC, Brussels [email protected]
David Rouquie Bayer S.A.S. [email protected]
Ursula Sauer Scientific Consultancy ‐ Animal Welfare
Kerstin Schmidt BioMath GmbH, Germany [email protected]
Hervé Seitz CNRS, France [email protected]
Kayo Sumida Sumitomo Chemical Co., Ltd.Japan
[email protected]‐chem.co.jp
Knut Erik Tollefsen Norwegian Institute for Water Research (NIVA)
Weida Tong NCTR/FDA, USA [email protected]
Tewes Tralau BfR, Germany [email protected]
Ben van Ravenzwaay BASF SE, Germany [email protected]
Ralf Weber University of Birmingham, UK [email protected]
Andrew Worth European Commission ‐ JRC [email protected]
Carole Yauk Carleton University, Canada [email protected]
Aldert Piersma RIVM, Netherlands [email protected]
Alan Poole ECETOC, Brussels [email protected]
David Rouquie Bayer S.A.S. [email protected]
Ursula Sauer Scientific Consultancy ‐ Animal Welfare
Kerstin Schmidt BioMath GmbH, Germany [email protected]
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Breakout Sessions Groups
RED GROUP Bruselas room
GREEN GROUPLondres room
BLUE GROUPParis room
BROWN GROUPViena room
Beatriz da Silva Lima (C1)
Ben van Ravenzwaay (C1)
John Greally (C1) David Rouquie (C1)
Kamin Johnson (R1) Madeleine Laffont (R1,2,3,4)
Ursula Sauer (R1,2,3,4) Lena Esteves (R1,2,3,4)
Roland Buesen (R2) Jörg Hackermüller (C3)
Bruno Hubesch (C3) Danyel Jennen (C3)
Brian Chorley
Amber Goetz (C4) Tim Gant (C4) Hervé Seitz (C4)
Stefania Perdichizzi Laura Gribaldo
Patrick McMullen Ralf Weber
Paul Foster (R3) Jun Kanno
Matt Martin Weida Tong
Alan Poole (C2) Eeva Leinala
Aldert Piesema (C2) Tewes Tralau
George Daston (C3) Kayo Sumida
Knut Erik Tollefsen Andrew Worth
Kerstin Schmidt (C4) Lize Deferme (C2)
Hans‐Martin Kauffmann
Jan Hengstler
Tim Ebbels (R4)
Carole Yauk (C2)
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BIOSKETCH
Dr. Alan Poole
Secretary General
ECETOC
Alan Poole earned his Bachelor of Science degree in Biochemistry from the University of Cardiff,
Doctor of Philosophy from University of Surrey and is a Fellow of the Royal College of
Pathologists.
He worked for the UK Medical Research Council studying the modes of action of pulmonary lung
carcinogenesis in particular mesothelioma before moving to Smith Kline and French to lead a
scientific team involved in preclinical development of ethical pharmaceuticals. He was later
employed by Dow Chemical in Switzerland where he worked for over 20 years addressing safety
of industrial chemicals during which time he participated in many industry and governmental
activities.
He has published a book on toxicology as well contributing chapters to several others. He has
published widely in the scientific literature and contributed to various meetings and symposia on
toxicology.
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ABSTRACT
Moderated Panel Discussion / Key Note Speeches:
Regulatory Perspective: needs, challenges, opportunities
Dr. Eeva Leinala
Principal Administrator Hazard Assessment Programme
and Risk Reduction Programme
Organisation for Economic Cooperation and Development
Presentation: OECD Activities On Integrated Approaches to Testing And Assessment
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BIOSKETCH
Dr. Eeva Leinala
Principal Administrator Hazard Assessment Programme
and Risk Reduction Programme
Organisation for Economic Cooperation and Development
Dr. Eeva Leinala is a principal administrator in the Environment Health
and Safety Division of the Organization for Economic Co‐operation and
Development (OECD) where she collaborates with OECD member
countries and stakeholders to advance projects related to risk
assessment and risk reduction of chemicals. She the Principal
Administration for both the Hazard Assessment Programme and the
Risk Reduction Programme. Eeva is leading projects which include
combined exposure assessment, integrated assessment and testing
case studies, predictive approaches such as (Q)SAR, hazard assessment methodologies,
dissemination tools and also risk reduction projects including the Global PFC Group, the Ad‐hoc
Group for the Substitution of Harmful Chemicals and the Issue Team on Sustainable Chemistry.
Prior to the OECD, Dr. Leinala worked in the area of chemical risk assessment at Health Canada for
12 years. Most recently she was the senior manager for the Assessment Methodology Divisions of
the Existing Substances Risk Assessment Bureau focusing on exposure and hazard assessment
methodology development and assessment strategies such as the development of tiered
approaches and grouping of chemicals for assessment under Canada’s Chemicals Management
Plan (CMP). Eeva has also been involved in identifying priorities for assessment (categorization)
from Canada’s Domestic Substances List, the conduct of numerous risk assessments and the
development and implementation of rapid screening under the CMP. She was also involved in
designing various program elements of the different phases of Canada’s Chemicals Management
Plan. Eeva holds a Ph.D. in biochemistry.
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ABSTRACT
Moderated Panel Discussion / Key Note Speeches:
Regulatory Perspective: needs, challenges, opportunities
Matt Martin, PhD
Research Biologist
USEPA's National Center for Computational Toxicology (NCCT)
Presentation: High Throughput Transcriptomics @ USEPA
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BIOSKETCH
Matt Martin, PhD
Research Biologist
USEPA's National Center for Computational Toxicology (NCCT)
Dr. Martin graduated from UNC Chapel Hill focusing on Bioinformatics and Computational Biology
under the direction of Drs. Ivan Rusyn and David Dix.
Dr. Martin is a research biologist within the USEPA's National Center for Computational
Toxicology (NCCT) where he created ToxRefDB (Toxicity Reference Database) and serves as
principal investigator for ToxCast Data Analysis and Predictive Signature Development.
Recently, Dr. Martin has taken the lead on developing NCCT’s high‐throughput transcriptomics
program.
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ABSTRACT
Moderated Panel Discussion / Key Note Speeches:
Regulatory Perspective: needs, challenges, opportunities
Prof. Dr. Aldert H. Piersma (Ph.D.)
Centre for Health Protection
National Institute for Public Health and the Environment (RIVM)
Presentation: EST Neural Differentiation/Omics best practice notes
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BIOSKETCH
Prof. Dr. Aldert H. Piersma (Ph.D.)
Centre for Health Protection
National Institute for Public Health and the Environment (RIVM)
2007‐present: Professor of Reproductive and Developmental Toxicology, seconded at the Utrecht
University Faculty of Veterinary Medicine, Institute for Risk Assessment Sciences (IRAS),
Department of Toxicology.
Advisory and educational tasks include: Specialist advisorship with respect to the interpretation of
guideline‐based reproductive toxicity test results for compound registration purposes. Lecturer in
Developmental Biology and Toxicology Courses given at the Utrecht and Wageningen Universities.
Lecturer in the Postacademic Course on Toxicology of the Open University. Served and serves on
Committees and Working Groups of European Union, OECD, and WHO on e.g. Classification and
Labelling, development of Test Guidelines and Technical Guidance Documents, the issue of
Endocrine Disruption and the reproductive toxicicity of antimalarial drugs. Referee for
manuscripts submitted to a.o. Reproductive Toxicology, Toxicology in vitro, Toxicology, Food and
Chemical Toxicology, Pediatric Research.
Current research subjects include Nutrition in Pregnancy and the Prevention of Congenital
Malformations and Adult Disease, Alternatives to Animal Experimentation in Developmental
Toxicology, Developmental Immunotoxicology, Endocrine Disruption, Dose‐Response Analysis
Methodology in relation to Risk Assessment, and the Application of Genomics Technology in
Reproductive Toxicology Testing.
Active role in generating and reviewing Adverse Outcome Pathways and Integrated Approaches to
Testing and Assessment at RIVM and at OECD level. Integrating basic knowledge of
developmental biology into strategies for deriving alternative testing methodologies, including
test batteries and tiered approaches, aiming at innovating chemical and pharmaceutical hazard
and risk assessment based on mechanistic information relevant for man.
Current international expert advisory tasks include the innovation and implementation of EU and
OECD Classification & Labellling for Reproductive Toxicants, the role of validation in novel OECD
test guidelines (OECD GD34), the innovation of testing strategies for the EU existing substances
program (REACH), the definition of novel test guidelines for the neurobehavioural developmenal
study (OECD426) and for the uterotrophic assay, and the role of alternative testing strategies in
the safety evaluation of chemicals (ReProTect, EU‐REACH, OECD).
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ABSTRACT
Moderated Panel Discussion / Key Note Speeches:
Regulatory Perspective: needs, challenges, opportunities
Dr. Tewes Tralau
Head of Unit Coordination and Overall Assessment and
Deputy head of Department, Chemicals and Product Safety
German Federal Institute of Risk Assessment (BfR)
Presentation: Regulatory Toxicology & Omics – Challenges and Perspectives
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BIOSKETCH
Dr. Tewes Tralau
Head of Unit Coordination and Overall Assessment and
Deputy head of Department, Chemicals and Product Safety
German Federal Institute of Risk Assessment (BfR)
Tewes Tralau is a biologist and biochemist specialised on xenobiotic metabolism. Following over a
decade of research in Germany, France, China and the UK he joined the German Federal Institute
of Risk Assessment (BfR) in 2010.
As head of the unit Coordination and Overall Assessment and deputy head of the Department of
Chemicals and Product Safety he oversees the toxicological assessments for consumer products
(i.e., cosmetics, toys and food contact materials) as well as under REACH and CLP.
He is actively involved in the institute’s work for the OECD and the development of assessment
criteria for substances with endocrine activities and heads the institute’s working party on
alternative testing strategies.
Main research interests comprise molecular toxicology and state of the art testing systems with
current projects focusing on molecular sensing and signalling as well as the skin and its
microbiome.
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ABSTRACT
Moderated Panel Discussion / Key Note Speeches:
Regulatory Perspective: needs, challenges, opportunities
Dr. Andrew Worth
Senior Scientific Officer
European Commission ‐ JRC
Presentation: Some perspectives on the regulatory use of 'omics
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BIOSKETCH
Prof. Leming Shi, PhD
Fudan University
Shanghai
Dr. Leming Shi is a professor at the School of Pharmacy and the School of Life Sciences of Fudan
University in Shanghai, China where he established the Center for Pharmacogenomics. Dr. Shi’s
research focuses on pharmacogenomics, bioinformatics, and cheminformatics aiming to realize
personalized medicine by developing biomarkers for early cancer diagnosis and targeted therapy.
As a Principal Investigator at the US Food and Drug Administration (FDA) from 2003 to 2012, Dr.
Shi conceived and led the MicroArray and Sequencing Quality Control (MAQC/SEQC) project
(www.nature.com/nbt/focus/maqc/, www.nature.com/focus/maqc2/, and Nature Biotechnology
2014, in press). Dr. Shi was a co‐founder of Chipscreen Biosciences Ltd. in Shenzhen, China where
he helped develop a chemogenomics‐based drug discovery platform leading to several novel
small‐molecule drug candidates with promising efficacy and safety profiles in anticancer and
antidiabetic clinical trials.
Dr. Shi is a co‐inventor on nine issued patents about novel therapeutic molecules and has
published over 170 peer‐reviewed papers (ten of them appeared in Nature Biotechnology). Dr. Shi
received his Ph.D. in computational chemistry from the Chinese Academy of Sciences in Beijing,
and is a guest faculty at the US FDA and an adjunct professor of medicine at the University of
Arkansas for Medical Sciences.
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ABSTRACT
Introduction to session:
Establishing GLP‐like context for Collecting, Storing and Curating Data
Dr. Ben van Ravenzwaay
BASF SE
ECETOC Scientific Committee
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ABSTRACT
Establishing GLP‐like context for Collecting, Storing and Curating Data:
ECETOC’s concept for quality assurance of new technology data
considering GLP requirements
Dr. Hans‐Martin Kauffmann
BASF SE, Ludwigshafen, Germany
New technologies have gained increasing importance to support regulatory non‐clinical GLP
(Good Laboratory Practice) studies and to contribute to the risk assessment of chemical
substances. To increase the likelihood that new technology data are fully accepted in a regulatory
context it is necessary to consider how to perform such studies considering GLP principles1. A GLP
environment comprises a standard operating procedure system, proper pre‐planning and conduct
documentation as well as inspections of independent quality assurance staff. Definition of raw
data (original data records) is required for the different data recording systems/technologies (e.g.
transcriptomics, proteomics, metabolomics) and it is essential to prevent any uncontrolled data
changes. Further requirements include transparent and reproducible data processing steps, as
well as safe data storage and archiving procedures.
Software used for data recording and processing should be validated and data changes should be
traceable (audit trail) or disabled. Particular challenges to fulfill GLP requirements are likely to be
associated with (1) raw data definition, (2) complete reproducibility of final results with respect to
raw data, (3) transparent description of data processing steps, and (4) validation of procedures
and software / audit trail documentation. Nevertheless, even if it would be impossible to fulfill
individual requirements in a fully GLP‐compliant way, an “as GLP‐like as possible” procedure
would help to promote regulatory reliability of new technology data.
1OECD Principles on good laboratory practice (as revised in 1997). Paris: OECD; 1998
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BIOSKETCH
Dr. Hans‐Martin Kauffmann
BASF SE, Ludwigshafen, Germany
Hans‐Martin Kauffmann studied Biochemistry at the University of Tübingen,
Germany, and performed his doctoral thesis at the Institute of Toxicology in
Tübingen in the area of molecular biology/toxicology. Afterwards, he
worked as postdoctoral fellow at the University of Kaiserslautern, Germany,
with responsibility for different projects concerning regulation of drug
transporters of the ATP‐binding cassette family.
Since 2002, he is Certified Toxicologist of the German Society for
Experimental and Clinical Pharmacology and Toxicology (DGPT) and EUROTOX registered
Toxicologist.
He started his professional career in 2001 at Aventis Pharma (now Sanofi) in Frankfurt, Germany,
being study director for general, genetic and analytical GLP toxicology studies. Starting in 2005, he
was project toxicologist for non‐clinical drug safety with monitoring function for GLP studies and
project responsibility from preclinical phase up to Phase III. From 2010, he had test facility
management responsibility and was member of the GLP Compliance Committee.
In 2011, he moved to BASF SE Experimental Toxicology and Ecology in Ludwigshafen, Germany,
acting as head of the GLP Quality Assurance Unit. Moreover, he leads a project team establishing
the quality management system DIN EN ISO/IEC 17020 in this test facility.
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ABSTRACT
Establishing GLP‐like context for Collecting, Storing and Curating Data:
Current Status: Application of GLP (like) data collection in practice
Dr. Ben van Ravenzwaay
BASF Germany
Dr. Amber Goetz
Syngenta Crop Protection LLC, USA
Dr. David Rouquie
Bayer Cropscience, Sophia Antipolis, France
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BIOSKETCH
Dr. Amber Goetz, PhD
Syngenta Crop Protection LLC, USA
Dr. Goetz graduated from North Carolina State University with her Ph.D. in molecular and cellular
toxicology. Amber conducted her graduate research at the Reproductive Toxicology Division
(RTD) and National Center for Computational Toxicology (NCCT) within the U.S. EPA National
Health and Environmental Effects Research Laboratory (NHEERL). Her areas of expertise span
regulatory, human health and safety, toxicology, molecular biology, toxicogenomics, and mode of
action research. She has over nine years of professional experience supporting product safety,
risk assessment, and regulatory policy development. As a staff scientist in the Toxicology and
Health Sciences department of Syngenta, her accountabilities include the design and
interpretation of investigative and guideline toxicity studies that are used for operator and
consumer risk assessments and product registrations. She is responsible for managing several
crop protection active ingredient development projects as well as maintaining regulatory
registrations for several herbicide and fungicide compounds. She participates in initiatives under
the Health and Environmental Sciences Institute (HESI) and engages in various scientific
collaborations in the areas of genomics.
Dr. David Rouquié, PhD
Bayer Cropscience, Sophia Antipolis, France
David received his Ph.D in Biochemistry and Molecular Biology from Montpellier University,
France. Then, he moved to the Max Planck Institute of Cologne, Germany as postdoctoral fellow
where he worked on auxin transport systems using cell biology techniques. In 2000, he joined
RhoBio (Joint Venture between Bayer CropScience & Biogemma) in Evry, France where he was
responsible for genomic projects such as the construction of EST collections, cDNA microarrays,
transcriptome analysis or BAC library screening using the tools of molecular biology, robotic and
informatic. Since 2004, he moved to the research center of Bayer CropScience in Sophia Antipolis,
France where he applies a panel of molecular, cellular and computational tools in in vitro and in
vivo studies to support the early phase compound selection and the mechanistic investigations
necessary for registration of new active ingredients.
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BIOSKETCH
Dr. Madeleine Laffont
Human Health Scientist
ECETOC
Madeleine Laffont is a medical doctor by training (Imperial College,
London) and a consultant events moderator and project management
specialist for environment & health issues by profession (Qatar,
Belgium).
She helps clients define and implement environment/health strategies;
project/crisis management; communication and stakeholder
engagement.
Since May 2014, Madeleine has managed ECETOC’s human health science area as contract agent.
Formerly, Madeleine managed a range of environment and health issues for Cefic (the European
Chemical Industry Council) for several years.
36
ABSTRACT
Best Practices for WoE Approaches for Integrating ‘Omics Data:
Introducing ECETOCs ‘strawman’ framework for discussion
Dr. Mark Pemberton, PhD
Principal Consultant
Systox Limited
Presentation: Quantitative Weight of Evidence
37
BIOSKETCH
Dr. Mark Pemberton, PhD
Principal Consultant
Systox Limited
Mark Pemberton, Ph.D., is a regulatory toxicologist with extensive experience in
methacrylate and cyanide toxicology. Mark has worked for over 30 years as a business
toxicologist and in addition to his work on product risk management has directed trade
association activities and associated regulatory programs across the world. He is a
member of the European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC)
Scientific Committee and has worked on, chaired and stewarded several past and current
task forces on chemicals and regulatory issues.
Before starting his consultancy business in 2011, Mark worked for ICI in Pharmaceutical
research, as a study director and facility manager at the Central Toxicology Laboratory
and latterly as a business toxicologist with responsibility for several of ICI’s businesses.
Mark was the founder of the European Chemical Industry Council (CEFIC) Methacrylates
Sector Group Methacrylates Toxicology Committee and chaired this between 1992 and
2002.
Mark is the current chairman of the US Methacrylate Producers Association (MPA),
Science Committee and the US Cyanide Council Toxicology Committee, the US Cyanide
Counsel and a member of the US Acylonitrile Association. Mark received a B.Sc. (Honours)
in Biology from Manchester University and a Ph.D. in Toxicology from Bradford University,
UK
38
ABSTRACT
Best Practices for WoE Approaches for Integrating ‘Omics Data:
Quantified Weight of Evidence
Prof. Jim Bridges
Emeritus Professor of Toxicology and Environmental Health,
University of Surrey, Guildford, UK
Presentation: Use of quantitative weight of evidence (QWoE) to utilise ‘omics’ data
39
BIOSKETCH
Prof. Jim Bridges
Emeritus Professor of Toxicology and Environmental Health,
University of Surrey, Guildford, UK
40
ABSTRACT
Best Practices for WoE Approaches for Integrating ‘Omics Data:
WoE approaches, a case study
Dr. Amber Goetz, PhD
Syngenta Crop Protection LLC, USA
Presentation: Mouse Liver Tumor ‐ Mode of Action Use of Toxicogenomics in Weight of Evidence
for Human Relevance Assessment
41
BIOSKETCH
Dr. Amber Goetz, PhD
Syngenta Crop Protection LLC, USA
Dr. Goetz graduated from North Carolina State University with her Ph.D. in molecular and cellular
toxicology. Amber conducted her graduate research at the Reproductive Toxicology Division
(RTD) and National Center for Computational Toxicology (NCCT) within the U.S. EPA National
Health and Environmental Effects Research Laboratory (NHEERL). Her areas of expertise span
regulatory, human health and safety, toxicology, molecular biology, toxicogenomics, and mode of
action research. She has over nine years of professional experience supporting product safety,
risk assessment, and regulatory policy development. As a staff scientist in the Toxicology and
Health Sciences department of Syngenta, her accountabilities include the design and
interpretation of investigative and guideline toxicity studies that are used for operator and
consumer risk assessments and product registrations. She is responsible for managing several
crop protection active ingredient development projects as well as maintaining regulatory
registrations for several herbicide and fungicide compounds. She participates in initiatives under
the Health and Environmental Sciences Institute (HESI) and engages in various scientific
collaborations in the areas of genomics.
42
ABSTRACT
Best Practices for Establishing Pathways to Connect Results of ‘Omics Data to Phenotype:
Lessons learned from HESI Framework for Establishing Fitness of Purpose of
Non‐animal Methods for Chemical Risk Assessment
Prof. Beatriz Silva Lima,PharmD, PhD.
Faculty of Pharmacy
Lisbon University, Portugal
43
BIOSKETCH
Prof. Beatriz Silva Lima,PharmD, PhD.
Faculty of Pharmacy
Lisbon University, Portugal
Beatriz is full Professor of Pharmacology and Regulatory Science
in the Faculty of Pharmacy, Universidade de Lisboa University.
She heads the Department of Pharmacological Sciences and is a
member of the NDA Advisory Board , expert in non‐clinical safety
strategies for chemical, biological & advanced therapies,
mechanistic safety, juvenile animal study design and
interpretation.
Currently she Chairs the Scientific Committee of the Innovative Medicines Initiative (IMI).
Beatriz has been for around twenty years Non‐Clinical and Regulatory Science expert for
Infarmed, Portugal and for the European Medicines Agency where she developed multiple tasks,
eg: member of the Committee of Human Medicines; member of the Committee of Advanced
Therapies; member of the CHMP Scientific Advice Working Party member; Chair of the Safety
Working Party and has been involved in ICH discussions on several non‐clinical guidelines on
behalf of the European Commission.
44
ABSTRACT
Best Practices for Establishing Pathways to Connect Results of ‘Omics Data to Phenotype:
Case Study on Using ‘Omics in Risk Assessment
Dr. Kamin Johnson
Lead Scientist Toxicology and
Environmental Research and Consulting
The Dow Chemical Company
Using omics data to identify toxicity hazard for risk assessment has been a long‐standing goal.
This presentation will briefly highlight the challenges and successes applying transcriptomics for
hazard identification.
A straw‐man proposal will be presented to pivot from employing omics for hazard identification
to using omics to generate a bioactivity‐based point of departure for chemical risk assessment.
45
BIOSKETCH
Dr. Kamin Johnson
Lead Scientist Toxicology and
Environmental Research and Consulting
The Dow Chemical Company
Dr. Kamin Johnson is a Lead Scientist for The Dow Chemical Company’s Toxicology and
Environmental Research and Consulting function. At Dow, he is responsible for the scientific
conduct and interpretation of DART and mode‐of‐action studies and is involved in research
activities developing predictive toxicity methods. Prior to joining Dow, Kamin was a Principal
Investigator at The Hamner Institutes for Health Sciences and the Alfred I. duPont Hospital for
Children.
He has served on National Institutes of Health study sections reviewing reproductive biology and
toxicology grants, was a counselor for the Reproductive and Toxicology Specialty Section of the
Society of Toxicology, and is currently a member of the National Academy of Sciences Committee
on Unraveling Low Dose Toxicity: Case Studies of Systematic Review of Evidence.
His current research interests are in identifying toxicity mechanisms/modes‐of‐action and using
omic data to predict repeat dose toxicity. Kamin received his PhD in molecular biology, cell
biology, and biochemistry from Brown University.
46
ABSTRACT
Best Practices for Establishing Pathways to Connect Results
of ‘Omics Data to Phenotype:
Epigenetics: Normality in toxicologically relevant species
Professor Richard R. Meehan
Group Leader, Chromosome Biology, MRC Human Genetics Unit
Western General Hospital, Edinburgh
Presentation: Establishing Rat liver epigenome ground states
47
BIOSKETCH
Professor Richard R. Meehan
Group Leader, Chromosome Biology, MRC Human Genetics Unit
Western General Hospital, Edinburgh
In 1982 TCD (Dublin) I earned my Genetics degree (III). My PhD at MRC CAPCU (Edinburgh) was
supervised by the superlative duo of ND Hastie & CR Wolf. We mapped and identified
polymorphisms in cytochrome P‐450 genes linking clearance and response to therapeutic drugs. I
was very lucky to do my post‐docs with Adrian Bird at IMP, Vienna and later at Edinburgh
University. We characterised methyl‐CpG binding (MeCP) activities in animals; identifying MeCP2
which is associated with Rett syndrome, a progressive neurologic disorder. In 1995 my lab at
Edinburgh Biochemistry Department used the Xenopus laevis model. Over the years, and against
expectation, we identified non‐catalytic roles for the maintenance methyltransferase, xDnmt1, in
transcriptional silencing and repair. I was also fortunate to collaborate with Lorraine Young and Sir
Ian Wilmut in demonstrating that cloned sheep have altered DNA methylation patterns.
I joined the MRC HGU, Edinburgh in 2003. Moving into mammalian systems as they provide an
‘omics’ advantage. With Sari Pennings we demonstrated that Kaiso, an MeCP, integrates
epigenetic and Wnt signalling pathways in development and cancer. Our collaborative
Breakthrough Breast Cancer group (D. Harrison director) showed that aberrantly methylated
genes distinguish breast (and other tumour types) tumours of different lineages. I was part of a
consortium (MARCAR) that aims to develop short‐term assays indicative of exposure to non‐
genotoxic carcinogens. We demonstrated that liver 5‐hydroxymethylcytosine profiles undergo
dynamic changes in response to drug exposure. Integrative analysis of these changes identifies
potential mechanisms of drug action and may be predictive of long‐term outcomes
We are interested in utilizing epigenetic profiles as molecular read‐outs of xenobiotic response in
model systems and assessing their applicability to clinical settings.
48
ABSTRACT
Towards Establishing Criteria and Best Practices for Analysing ‘Omics Data:
Analysing Data: Towards developing a framework for transcriptomics and
other Big Data analysis for regulatory application
Prof. Timothy W Gant
Centre for Radiation, Chemical and Environmental Effects, Harwell Science and Innovation Campus, Public Health England, Oxfordshire, UK
Big Data has been part of the landscape of toxicology for nearly two decades and has contributed much to our undertaking of modes and mechanisms of toxicity; but despite the extensive use of ‘Big Data’ and in particular ‘omics data in toxicology research these data sets have yet to be routinely utilised in regulatory toxicity. This is partly because from the first generation of these data sets it was apparent that, even before considering interpretation, large data sets pose challenges. Some of these challenges have been quality control of data generation, normalization, recognition of outliers and univariate statistical analysis. Additionally there are challenges with the associated experimental meta data and last but not least data interpretation. There are biological and experimental variables revealed by these large data sets that may not be seen, or be of consequence, when fewer measurements are taken.
The challenges of adequate meta data associated with the experiment and availability of the data were addressed with the standards set out in MIAME (Minimum information about a microarray experiment) (Brazma A et al Nat Genet. 2001 Dec;29(4):365‐71). For data quality the MAQC consortium has led the way in addressing the issue of quality control in data generation both with microarrays (Nat Biotechnol. 2006 Sep;24(9):1151‐61) and next generation sequencing methods (Nat Biotechnol. 2014 Sep;32(9):903‐14). This consortium has also addressed to some extent best practice in the initial analysis of these data, but not to the point of recommendation of methods.
The adoption of standards for the univariate data analysis has been slower than the adoption of the standards for meta data collection and standardisation of methods for the generation of data. The causes for this are not clear but one possible reason is that there are many different ways of processing the data. Everyone has their favourite and can divide the data in the way that suits their experiment or hypothesis for example by changing the statistical parameters. While this can be acceptable for research where justification for the method used will be subject to peer review and likely replication, it is not acceptable for regulatory use where consistency is paramount.
While certain mathematical and statistical methods for the univariate have achieved a level of greater acceptability, a framework of best practice has not been developed that can be routinely applied to the primary analysis of data to the point of the generation of a gene list for subsequent interpretation. The point of such a framework is not to be prescriptive in the method of data analysis, but to provide a common method that can be used for comparison across data sets, colloquially stated – setting a sea‐level. If this can be achieved then there is a common reference point onto which other analysis methods can be overlaid if desired. This presentation will present the initial thoughts from a group of experts convened by ECETOC to examine the issues of transcriptomics data analysis for regulatory application and the derivation of the first outline framework for setting a sea‐level analysis.
49
BIOSKETCH
Prof. Tim Gant
Head of the Department of Toxicology
Centre for Radiation, Chemicals and Environmental Hazards
Public Health England
Prof. Tim Gant is Head of the Department of Toxicology in the Centre for Radiation, Chemicals and
Environmental Hazards; Public Health England; Honorary Visiting Professor in the faculty of Health
and Medical Science, University of Surrey and honorary Senior Research Fellow, Imperial College
London. BSc at the School of Pharmacy, University of London 1985 and PhD in 1988.
Joined the National Cancer Institute Bethesda Maryland, USA in 1988 and stayed until 1993
leaving for a position in the Medical Research Council Toxicology Unit (MRC‐TU), Leicester, UK.
Tenure achieved with the MRC in 2002. In Sept 2011 left the MRC to join Public Health England
(then the Health Protection Agency).
Served on the External Scientific Advisory Panel of the European Confederation of Chemical
Industries for seven years and chaired for four years.
Current chair of the British Toxicology (BTS) Society Scientific Sub‐Committee and serves on the
BTS Executive Committee. Currently a scientific advisor to European Centre for Ecotoxicology and
Toxicology of Chemicals and current member of the Health and Environmental Sciences Institute
(Washington DC), Emerging Issues Committee.
Served as reviewer for many papers and research programmes with MRC, BBSRC and CRUK.
50
ABSTRACT
Towards Establishing Criteria and Best Practices for Analysing ‘Omics Data:
Towards Reproducible Toxicogenomics for Risk Assessment
Weida Tong
Director, Division of Bioinformatics and Biostatistics
National Center for Toxicological Research (NCTR)
the US Food and Drug Administration (FDA)
Toxicogenomics has enjoyed widespread attention as an alternative means to study the
underlying molecular mechanisms of toxicity and address challenges that are difficult to
overcome by conventional toxicology methods. Rapid progress over the last decades has moved
the toxicogenomics technologies from an exploratory to an applied stage. This maturity is largely
benefit from an increasing amount of toxicogenomics data available in the public domain and the
knowledge gain by analyzing these data. However, the pace at which toxicogenomics was
expected to perform in regulatory decision‐making has been slow. This could be due to lack of
established framework to guide reproducible toxicogenomics analysis in decision‐making. We
conducted analysis of data generated from 4 different types of toxicogenomics study design,
ranging from a simple design involving only technical replicates to a complex design with data
from multi‐generation study.
Many observations were made, for example, for the complex study design where the source of
variance is not well understood and thus difficult to be incorporated into a sophisticated
statistical model, a simple statistical formula such as Welch t‐test usually yields better
reproducible results of differentially expressed genes (DEGs) for microarray data. Taking lessons‐
learned from this study, the presentation will discuss extensively some key questions in applying
toxicogenomics for risk assessment and where is the challenge lies to address these questions
appropriately. These knowledge will form a scientific basis to develop a framework for assessing
safety of new medical products and conducting risk assessment of industrial chemicals with
toxicogenomics, an effort has been undertaken by the taskforce organized by ECETOC (European
Centre for Ecotoxicology and Toxicology of Chemicals).
51
BIOSKETCH
Dr. Weida Tong
Director, Division of Bioinformatics and Biostatistics
NCTR/FDA
Summary
Research fields: Drug safety, drug repurposing, pharmacogenomics/ toxicogenomics, biomarker
development, and personalized medicine
Most current and active projects:
1. Supervising the FDA‐led community‐wide MicroArray Quality Control (MAQC) consortium to
assess emerging molecular technologies (microarrays, GWAS and NGS), including MAQC‐1,
MAQC‐II and MAQC‐III/SEQC.
2. Development of Liver Toxicity Knowledge Base (LTKB) for study of drug‐induced liver injury
(DILI)
3. Development of the FDA genomic tools, ArrayTrack suite
4. Conducting in silico studies on drug repositioning
Weblink: http://www.fda.gov/ScienceResearch/BioinformaticsTools/
Specialties: Bioinformatics, chemoinformatics, toxicogenomics, personlized medicine, next‐
generation sequencing, toxicology, network pharmacology, molecular modeling and systems
biology.
52
ABSTRACT
Towards Establishing Criteria and Best Practices for Analysing ‘Omics Data
Data Analysis in Metabolomics
Tim Ebbels
Imperial College London
In this short talk, I will briefly introduce metabolomics and the kind of data it generates.
I will summarise the data analysis workflow and discuss differences with transcriptomics data
analysis.
I will present some approaches to improving reproducibility and data quality, as well as
highlighting some current challenges and key bottlenecks in the field.
53
BIOSKETCH
Dr. Tim Ebbels, PhD
Imperial College London
Tim Ebbels obtained his PhD in astrophysics from the University of
Cambridge and in 1998 moved into bioinformatics via postdoctoral
work at Imperial College in the metabolic profiling group of Prof
Jeremy Nicholson.
He was a key post‐doctoral member of the Consortium for
Metabonomic Toxicology (COMET), a large academic‐industry
collaboration which developed expert systems for predicting
adverse effects in pre‐clinical toxicity studies via mathematical
models of metabolic profiles.
In 2003 he joined Prof David Jones’ group at University College London to work on modelling and
visualisation of transcriptomic data. In 2005 he returned to a faculty position at Imperial, within
one of the world’s largest metabolic spectroscopy departments. His group focuses on the
application of bioinformatic, machine learning and chemometric techniques to post‐genomic
data, with a particular emphasis on metabolomics.
He is involved in projects ranging from environmental monitoring, through molecular
epidemiology, to toxicogenomics and high performance computing infrastructures. Much work
focuses on modelling of the analytical technologies used to obtain metabolic profiles, but his
group is also addressing problems of data integration, visualisation and time series analysis.
Tim is a Director of the international Metabolomics Society (serving as Secretary for 2014‐16) and
is a Fellow of the Royal Society of Chemistry.
54
BIOSKETCH
Dr. Ursual G. Sauer
Ursula G. Sauer is a Doctor of Veterinary Medicine. She has been working in the areas of
regulatory toxicology and alternatives to animal testing since 1992. In 2007, she set up her own
business as a freelance scientific consultant and scientific writer. Since then, she has been
engaged in numerous projects related to regulatory toxicology with assignments from industry,
animal welfare organisations, authorities and academia. Her assignments for the European Centre
for the Toxicology and Ecotoxicology of Chemicals (ECETOC) include writing the publications for
the ECETOC Task Force Nanomaterials that has set up and evaluated a Decision‐making
framework for the grouping and testing of nanomaterials (Arts et al., 2014, 2015, 2016) and the
reporting of the outcome of the ECETOC workshop Advancing the use of noncoding RNA in
regulatory toxicology (Aigner et al., 2016). U.G. Sauer is a member of the Editorial Board of ATLA
(Alternatives to Animal Experiments) and a member of the Working Group on Alternative
Methods of the German Society of Toxicology.
References
Aigner A, Buesen R, Gant T, Gooderham N, Greim H, Hackermüller J, Hubesch B, Laffont M,
Marczylo E, Meister G, Petrick JS, Rasoulpour RJ, Sauer UG, Schmidt K, Seitz H, Slack F, Sukata T,
van der Vies SM, Verhaert J, Witwer KW, Poole A. 2016. Advancing the use of noncoding RNA in
regulatory toxicology: Report of an ECETOC workshop. Regul Toxicol Pharmacol pii: S0273‐
2300(16)30266‐5.
Arts JH, Hadi M, Keene AM, Kreiling R, Lyon D, Maier M, Michel K, Petry T, Sauer UG, Warheit D,
Wiench K, Landsiedel R. 2014. A critical appraisal of existing concepts for the grouping of
nanomaterials. Regul Toxicol Pharmacol 70:492‐506.
Arts JH, Hadi M, Irfan MA, Keene AM, Kreiling R, Lyon D, Maier M, Michel K, Petry T, Sauer UG,
Warheit D, Wiench K, Wohlleben W, Landsiedel R. 2015. A decision‐making framework for the
grouping and testing of nanomaterials (DF4nanoGrouping). Regul Toxicol Pharmacol 71(Suppl
2):S1‐S27.
Arts JH, Irfan MA, Keene AM, Kreiling R, Lyon D, Maier M, Michel K, Neubauer N, Petry T, Sauer
UG, Warheit D, Wiench K, Wohlleben W, Landsiedel R. 2016. Case studies putting the decision‐
making framework for the grouping and testing of nanomaterials (DF4nanoGrouping) into
practice. Regul Toxicol Pharmacol 76:234‐61.
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