workshop programme - ecetoc

1

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


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


09.00‐09.10 Welcome. Details of the Day


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



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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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


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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?




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


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


09.35‐10.00 Data Analysis/Normalisation/Integration techniques: a metabolomics case study

Tim Ebbels, Imperial College, UK


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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12.00‐12.15 Wrap up of this Session


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)

[email protected]

Roland Buesen BASF SE [email protected]

Lyle Burgoon US Army, Env. Lab(dialing‐in)

[email protected]

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

[email protected]

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

[email protected]

Kamin Johnson The Dow Chemical Company, US [email protected]

Jun Kanno Japan Organization of Occupational Health and Safety

[email protected]

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)

[email protected]

Mark Pemberton Systox Ltd., UK(Video presentation)

[email protected]

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

[email protected]

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)

[email protected]

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

[email protected]

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:


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



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



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



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



Dr. Andrew Worth

Senior Scientific Officer

European Commission ‐ JRC

Presentation: Some perspectives on the regulatory use of 'omics

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BIOSKETCH

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ABSTRACT

“Reproducibility” of ‘Omics Data

Prof. Leming Shi

Fudan University

Shanghai

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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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BIOSKETCH


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


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


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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ABSTRACT

35

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.

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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


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


WoE approaches, a case study



Presentation: Mouse Liver Tumor ‐ Mode of Action Use of Toxicogenomics in Weight of Evidence

for Human Relevance Assessment

41

BIOSKETCH



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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