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Activities Report 2010-2011

Health and Environmental Sciences Institute

TM

©2011 ILSI Health and Environmental Sciences Institute All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying,recorded, or otherwise, without the prior written permission of ILSI Health andEnvironmental Sciences Institute (HESI).

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2010 - 2011 Activities Report ILSI Health and Environmental Sciences Institute The Global Branch of ILSI

™

1

Introduction........................................................................................................................................................................................1

HESI Technical Committees Overview......................................................................................................................................2Application of Genomics to Mechanism-Based Risk Assessment............................................................................3Cardiac Safety.................................................................................................................................................................................5Developmental and Reproductive Toxicology (DART)..................................................................................................7Immunotoxicology.......................................................................................................................................................................9Integration of Biomonitoring Exposure Data into the Risk Assessment Process.............................................11Protein Allergenicity..................................................................................................................................................................13 Risk Assessment for the 21st Century (RISK21)................................................................................................................15

HESI Project Committees Overview.........................................................................................................................................17Animal Alternatives in Environmental Risk Assessment.............................................................................................19Biological Significance of DNA Adducts............................................................................................................................21Biomarkers of Nephrotoxicity................................................................................................................................................23Development of Methods for a Tiered Approach to Assess the Bioaccumulation of Chemicals...............25Distinguishing Adverse from Non-Adverse/Adaptive Effects...................................................................................27Imaging for Translational Safety Assessment..................................................................................................................29In Vitro Genetic Toxicity Testing (IVGT)...............................................................................................................................31Mixtures...........................................................................................................................................................................................33

HESI Subcommittees Overview .................................................................................................................................................35Evaluating Causality in Epidemiologic Studies................................................................................................................37

HESI Activities Map..........................................................................................................................................................................39

HESI Science 2011............................................................................................................................................................................40

HESI Project Mechanisms..............................................................................................................................................................41

Contents IntroductIon

Collaborative science to innovate and improve the practice of safety and risk assessment is at the core of the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute’s (HESI) programs. Independently, each HESI committee provides important technical input to a given scientific arena such as developmental toxicity, biomarkers, or alternative animal models. Collectively, these programs represent a significant contribution to the fields of safety and risk assessment and environ-mental science.

This Activities Report provides a project by project overview of HESI programs between April 2010 and April 2011. The Report demonstrates the major areas of focus, key impacts, and anticipated next steps for each activity. The list of participating organizations for each committee demonstrates HESI’s commitment to the ‘tripartite’ approach, which permeates all levels of the organization. Leaders from academia, government, and industry share in the direction of individual scientific programs as well as HESI’s organizational governance.

For those already participating in HESI activities, we thank you for your contributions to the 2010-2011 scientific portfolio. For those not yet engaged, we welcome you to become part of the discussion. More information on all projects is available via the HESI website at www.hesiglobal.org or by contacting HESI staff at [email protected].

HESI tEcHnIcal commIttEES

2

Overview

3 Application of Genomics to Mechanism-Based Risk Assessment

5 Cardiac Safety

7 Developmental and Reproductive Toxicology

9 Immunotoxicology

11 Integration of Biomonitoring Exposure Data into the Risk Assessment Process

13 Protein Allergenicity

15 Risk Assessment for the 21st Century

Technical committees are one mechanism by which HESI pools financial and intellectual resources to support credible, unbiased scientific activities that simultaneously address short-term problems and long-range fundamental questions of science. Technical committees conduct and publish research and generate scientific dialogue by sponsoring symposia and workshops around the globe.

The HESI Board of Trustees approves the establishment of a technical committee when a sufficient number of academic, government, and industrial participants share common interest in an aspect of toxicology, health, environmental safety, or other important matters of mutual concern. They operate under three-year charters, which are renewable contingent on a satisfactory review under the HESI Stewardship Program.

The organization’s technical committees address: (1) Application of Genomics to Mechanism-Based Risk Assessment, (2) Cardiac Safety, (3) Developmental and Reproductive Toxicology, (4) Immunotoxicology, (5) Integration of Biomonitoring Exposure Data into the Risk Assessment Process, (6) Protein Allergenicity, and (7) Risk Assessment for the 21st Century.

43

Chair:Dr. Jiri AubrechtPfizer Inc.

Vice-Chair:Dr. Richard PaulesNational Institute of Environmental Health Sciences

HESI Manager: Dr. Raegan B. O’Lone

2010-2011 Activities and Accomplishments

This scientific program is committed to:• Advancing the scientific basis for the development and

application of genomic methodologies, and• Facilitating public discussion and information dissemination

on the use of genomics as a tool to characterize mechanism of action, and facilitate safety assessment of drugs and chemicals.

Areas of scientific focus• Evaluation of methods for assessing microRNAs in toxico-

logical studies;• Sources of variation in in vivo toxicogenomics studies;• Exploration of application of mouse models of the human

population to toxicological assessments; and• Qualification of a genomic approach to provide context to

positive results in chromosome damage assays.

Why get involved?• Help improve the existing risk assessment paradigm

by being a part of the qualification effort for a genomic biomarker approach.

• Generate data via the microRNA project to provide new perspective on best practices for microRNA assessments for toxicological studies.

• Develop new insights into sources of variation in

generated and analyzed; manuscripts are in prepara-tion describing the findings which will provide insight into design of toxicogenomics studies.

What is the Committee’s focus for May 2011 - April 2012 • Preparation of several manuscripts describing the

findings from a six-week rodent study with doxorubi-cin. This study was conducted by the Committee to provide perspective on study design strategies for toxicogenomics studies.

• A collaborative microRNA study, designed to assess sources of variability in microRNA measurements in toxicological studies, and to inform best practices toward standardization of methods.

• Analysis of pooled control and reference toxicant rodent data toward identification of sources of variation in toxicogenomics studies.

• Execution of a collaborative project seeking to explore the use of a genetically diverse panel of mice (the Mouse Model of the Human Population) as a tool for detecting and understanding the mechanisms that underlie drug-induced toxicity.

• Initiation of the experimental program toward generating data to be considered in a genomics biomarker qualification context.

Recent publicationsPettit S, Des Etages SA, Mylecraine L, Snyder R, Fostel J, Dunn RT, Haymes K, Duval M, Stevens J, Afshari C, and Vickers A. Current and Future Applications of Toxicogenomics: Results Summary of a Survey from the HESI Genomics State of the Science Subcommittee. Environmental Health Perspectives 2010;118(7), 992-997.

toxicogenomics studies as well as standards for data reporting formats through The Baseline Animal and Reference Toxicogenomics Data Exchange project.

• Achieve more with less by pooling expertise and resources to explore applications of toxicogenomics data.

• Collaborate on other important issues via existing projects (Cardiac Safety Technical Committee, Biomarkers of Nephrotoxicity Project Committee, and Adverse-Adaptive Project Committee).

Key accomplishments:• Genotoxicity Work Group – completed compound selection

and study design pertaining to an experimental program to provide context to positive findings in chromosome damage assays, which will progress in conjunction with a submission of the data toward a biomarker qualification of the genomic approach with the US Food and Drug Administration (USFDA).

• Use of microRNAs for Toxicological Applications – a work-shop was held in October 2010, helping to inform the scope of a project now in planning phases. A work group has been formed that is near completion of a study design; the experimental work is anticipated to begin mid-2011.

• Doxorubicin Study – the gene expression data has been

Abbott LaboratoriesActelion Pharmaceuticals Ltd.Allergan Inc.Amgen Inc.Astellas Pharma Inc.AstraZeneca PharmaceuticalsBayer HealthCare

PharmaceuticalsBoehringer Ingelheim GmbHBundesinstitut fuer

Arzneimittel und Medizinprodukte

Daiichi Sankyo Co. Ltd.Eli Lilly and Company European Medicines AgencyGeorgetown University Institute de Recherches

Internationales SERVIERJohnson & Johnson

PharmaceuticalsMaastricht University

Merck & Co. Inc.Michigan State UniversityNovartis PharmaceuticalsPfizer Inc.sanofi-aventisSumitomo Chemical Co. Ltd.SyngentaTakeda Pharmaceutical

Company LimitedUnilever PLCUniversity of MinnesotaUS ArmyUS Department of

AgricultureUS Environmental Protection

Agency US Food and Drug

AdministrationUS National Institute of

Environmental Health Sciences

HESI Technical Committees

applIcatIon of GEnomIcS to mEcHanISm-BaSEd rISk aSSESSmEnt applIcatIon of GEnomIcS to mEcHanISm-BaSEd rISk aSSESSmEnt paGE 2

2010 - 2011 Participating organizations:

For more information, contact the committee manager Dr. Raegan B. O’Lone, [email protected]

mailto:rolone%40hesiglobal.org?subject=Fact%20Sheet%20inquiry

65

HESI Technical Committee


Committee LeadersDr. Brian Berridge GlaxoSmithKline

Dr. John Koerner US Food and Drug Administration

Dr. R. Dustan Sarazan Data Sciences International

Dr. Eric Schultze Eli Lilly and Company

Dr. Jean-Pierrre Valentin AstraZeneca

HESI Manager: Syril D. Pettit, MEM


This scientific program is committed to:• Identifying and evaluating improved approaches for

translation of preclinical cardiovascular data to predict clinical outcomes, and

• Fostering technical collaborations and exchanges between nonclinical and clinical scientists involved in cardiovascular safety assessment of drugs and chemicals.

Areas of scientific focus• Assessing the predictivity of nonclinical measures of

arrhythmia (HERG, APD, in vivo QT) for clinical outcomes (TQT) for datasets submitted to the US Food and Drug Administration (USFDA) as part of New Drug Applications (NDA) or Investigational New Drug (IND) reports;

• Characterization of available markers and assays for assessing hemostasis in preclinical animal models;

• Identifying best practices for the integration of both nonclinical functional and structural measures of cardiovas-cular effects; and

• Development and implementation of novel experimental studies that integrate a range of different endpoints and measures to generate a holistic assessment of potential cardiovascular effects.

leading experts and foundational experimental studies has established the Committee at the forefront of cardiovascular safety evaluation in the areas of arrhythmia (TdP), integrative safety evaluation, and cardiac biomarker characterization (particularly cardiac troponin). The Committee’s presence at international scientific workshops and its strong technical publica-tion record is evidence of the program’s significance in the field.

What is the Committee’s focus for May 2011 - April 2012 • Proarrhythmia: The analysis of the proarrhythmia

concordance data will be completed by year end 2011, and publication as well as follow-up studies on non-concordant compounds are anticipated to proceed in 2012;

• Hemostasis: The project team will complete a manu-script on current practices in nonclinical hemostasis assessment and design, and execute novel experimen-tal studies to assess the utility of one or more hemosta-sis assays to improve safety predictions; and

• Integrated safety evaluation: The project team will generate experimental data and recommendations to improve the predictivity (from animal to human, and from short term to long term exposure) of nonclinical cardiovascular data.

Recent publicationsSarazan RD, Mittelstadt S, Guth B, Koerner J, Zhang J, and Pettit S. Cardiovascular Function in Nonclinical Drug Safety Assessment: Current Issues and Opportunities Perspectives from the Health and Environmental Sciences Institute. Online First at International Journal of Toxicology May 1, 2011.

Pettit S, Berridge B, and Sarazan RD. 2010. A Call for More Integrated Cardiovascular Safety Assessment. Journal of Pharmacology and Toxicological Methods.(61)1-2.

Berridge BR, Pettit S, Walker DB, Jaffe AS, Schultze AE, Herman E, Reagan WJ, Lipshultz SE, Apple FS, York MJ. A translational approach to detecting drug-induced cardiac injury with cardiac troponins: consensus and recommendations from the Cardiac Troponins Biomarker Working Group of the Health and Environmental Sciences Institute. Am Heart Journal 2009; 158(1):21–29. Piccini JP, Whellan DJ, Berridge BR, Finkle JK, Pettit SC, Stockbridge N, Valentin JP, Vargas HM, Krucoff MK; CSRC/

Why get involved?By being a member of the HESI Cardiac Safety Committee, you are part of a coordinated team of experts developing practical approaches for improving the predictivity and translatability of cardiac endpoints from animal models to the clinic. Key accomplishments:• HESI’s academic, government, and industry collaboration to

jointly analyze arrhythmia data held by the USFDA is a first of its kind forum. This valuable partnership allows for both data generators and data reviewers to discuss issues related to concordance, data formatting, decision-making, and reporting. Through creative blinding of the datasets, this valuable data resource has been made available for practical discussion and recommendation development.

• Committee’s technical summits have engaged both nonclinical and clinical cardiovascular scientists to identify issues and develop solutions. The Committee’s diverse membership has provided a much needed forum for discussions between the clinical and nonclinical communi-ties and across disciplines with the cardiovascular assess-ment arena (for example, between safety pharmacologists and pathologists).

• Generation of impactful scientific data. The combination of

Abbott LaboratoriesAmgen Inc.AstraZeneca PharmaceuticalsAstellas Pharma Inc.Auburn UniversityBayer HealthCare

PharmaceuticalsBiogen Idec MA Inc.Bristol-Myers Squibb

CompanyBrown University Medical

SchoolCovanceCornell UniversityData Sciences InternationalDuke UniversityEli Lilly and CompanyEuropean Medicines AgencyGlaxoSmithKline F. Hoffman-La Roche Inc.

Irish Medicines AgencyJohnson & Johnson

PharmaceuticalsKarolinska Institute,

Department of MedicineMerck & Co. Inc.Michigan State UniversityNovartis PharmaceuticalsPfizer Inc.sanofi-aventis Uniformed Services

University of Health Sciences School of Medicine

University of MinnesotaUniversity of MiamiUniversity of WisconsinUS Food and Drug

Administration

cardIac SafEty

For more information, contact the committee manager Ms. Syril D. Pettit, [email protected]

cardIac SafEty paGE 2

HESI Writing Group. Current challenges in the evaluation of cardiac safety during drug development: Translational medicine meets the Critical Path Initiative. Am Heart Journal 2009; 158(3):317–326.

Trepakova ES, Koerner J, Pettit SD, Valentin JD; HESI Pro-Arrhythmia Committee. A HESI consortium approach to assess the human predictive value of non-clinical repolarization assays. J Pharmacol Toxicol Methods 2009;60(1):45–50. Pending publicationsBerridge B, Hoffmann P, Turk J, Sellke F, Gintant G, Hirkaler G, Dreher K, Schultze A, Walker D, Edmunds N, Halpern W, Falls J, Sanders M, Pettit S. Integrated Nonclinical In Vivo Cardiovascular Risk Assessment: Gaps and Opportunities. 2011. Submitted.

Schutlze E, Walker D, Turk J, Tarrant J, Pettit S. Current Practices in Hemostasis Testing in Drug Development: Gaps and Opportunities to Promote Heart Health. Manuscript in progress to be completed by August 2011.


87


ChairDr. Bruce Beyer sanofi-aventis

Co-ChairDr. Jane Stewart AstraZeneca HESI Manager: Dr. James Kim


This scientific program is committed to:• Providing a forum in which scientists from academia,

government, and industry can exchange information;• Initiating activities to advance science related to reproduc-

tive and developmental toxicology; and• Developing consensus on the appropriate use of experimen-

tal toxicity data for human health risk assessment.

Areas of scientific focus• The Value of Juvenile Animal Studies,• Testicular Toxicity,• Consensus List of Developmental Toxicants,• Inhibin B, and• Drugs in Human Semen.

Why get involved?• Collaborate on the use of a second test species in develop-

mental and reproductive toxicology study designs; and• Understand, clarify, and describe strain differences of

Sprague-Dawley and Wistar rats, commonly used in preclinical testing.

Key accomplishments:• Developmental Tox – New Directions. Open workshop held

in April 2009. Series of five manuscripts submitted for

from Beckman Coulter. The Steering Team has also been investigating sample stability at -20°C and 80°C. This assay could be extremely valuable for assessing testicular toxicity biomarkers in both preclinical and clinical trials.

• Drugs in Human Semen. The Drugs in Human Semen project is led by an international group of scientists and regulators to address the potential for female and/or conceptus exposure via transfer from male sexual partners during intercourse. The Steering Team defined several experimental research projects to address data gaps and provide supporting evidence for modeling exposure scenarios. Several of these projects are currently completed, and will be presented at the 2011 Teratology Society Annual Meeting in June.

What is the Committee’s focus for May 2011 - April 2012 • Several workshops are planned: 1) Consensus List of

Developmental Toxicants in May 2011, 2) Testicular Toxicity – in vitro models in May 2011, and 3) in vitro spermatogenic models in the fall of 2011.

• Complete the laboratory research projects for Drugs in Human Semen.

• Complete the inter- and intra-laboratory studies on the inhibin B biomarker of testicular damage. Proceed with Stage II of the project focusing on the correlation of in vivo pathogenesis of testicular toxicity with inhibin B.

• Publish manuscripts for Developmental Tox – New Directions, Testicular Toxicity, and the Value of Juvenile Animal Studies.

Recent publicationsDaston GP, Chapin RE, Scialli AR, Piersma AH, Carney EW, Rogers JM, Friedman JM. A different approach to validating screening assays for developmental toxicity. Birth Defects Res B Dev Reprod Toxicol 2010;89, 526-30.

Beyer BK, Chernoff N, Danielsson BR, Davis-Bruno K, Harrouk W, Hood RD, Janer G, Liminga UW, Kim JH, Rocca M, Rogers J, Scialli AR. (2011) ILSI/HESI maternal toxicity workshop summary: maternal toxicity and its impact on study design and data interpretation. Birth Defects Res B Dev Reprod Toxicol 2011;92, 36-51.

publication that summarizes the presentations and discussions.

• The Value of Juvenile Animal Studies. Open workshop held in May 2010. Special issue of Birth Defects Research Part B to be published in the fall of 2011 devoted to the topic, including papers summarizing the workshop, discussion, and conclusions.

• Testicular Toxicity. A manuscript summarizing a survey of HESI members and their experiences with pre-clinical testicular toxicity will be published in 2011. Based on this survey, DART is organizing two workshops to brainstorm on novel in vitro approaches for assessing and evaluating testicular toxicity.

• Consensus List of Developmental Toxicants. The goal of the Consensus List of Developmental Toxicants project is to develop a list of developmental toxicants for use by assay developers and agencies in validating in vitro assays. The Consensus List of Developmental Toxicants Steering Team published a proposed methodology paper in 2010 that explains the rationale for nominations of chemicals to the list. This methodology, based on exposure factors, was pressure-tested in a May 17-18, 2011, workshop in Washing-ton, DC.

• Inhibin B. The Steering Team for this project has conducted inter- and intra-laboratory studies to evaluate a new assay kit

dEvElopmEntal and rEproductIvE toxIcoloGy (dart) dEvElopmEntal and rEproductIvE toxIcoloGy (dart) paGE 2

2010 - 2011 Participating organizations:Abbott LaboratoriesAmgen Inc.AstraZeneca PharmaceuticalsBayer HealthCare

PharmaceuticalsBelgian Federal Agency for

Medicines and Health Products

Boehringer-Ingelheim Pharmaceuticals Inc.

Bristol-Myers Squibb Company

Brown UniversityCelgene CorporationCharles River LaboratoriesCovanceEli Lilly and CompanyEuropean Medicines AgencyExponentF. Hoffman-La Roche Inc.Georgetown UniversityGlaxoSmithKlineInstituto Nacional da

Farmacia e do Medicamento (INFARMED, Portugal)

Johnson & Johnson Pharmaceuticals

Medical College of Wisconsin

Medical Products Agency (Sweden)

Medicines and Healthcare Products Regulatory Agency (MHRA, U.K.)

Merck & Co. Inc.National Institute for Public

Health and the Environment (RIVM, The Netherlands)

Novartis Pharmaceuticals Corporation

Pfizer Inc.Procter & Gamble Companysanofi-aventisTakeda Pharmaceutical

Company LimitedTetra Tech SciencesThe Dow Chemical CompanyUS Environmental Protection

AgencyUS Food and Drug



University of British ColumbiaUniversity of Lisboa

For more information, contact the committee manager Dr. James Kim, [email protected]


109


ChairDr. Ellen Evans Pfizer, Inc.

Vice-ChairDr. Hervé Lebrec Amgen HESI Manager: Dr. Raegan B. O’Lone


This scientific program is committed to:• Identifying and addressing scientific issues related to the

development and application of immunotoxicology to public health and human health risk assessment;

• Promoting the understanding and appropriate use of immunotoxicologic data to protect human health; and

• Contributing substantively to the scientific decision-making processes relative to the development of guidelines and regulations for immunotoxicologic testing at the local, national, and international levels.

Areas of scientific focus• In vitro predictive and investigational systems: methods and

predictivity;• In vivo nonclinical evaluations: methods, animal species,

strategies;• Testing strategies for environmental chemicals; and• Translational sciences: immunological assessments in clinical

development.

• Canine Immunotoxicity Testing Assessment. Due to the need for increasing the knowledge and awareness of available, reliable dog reagents and assays as well as identifying dog reagents and assays that are missing from the current repertoire, the Committee issued a survey to assess canine immunology and immunotox-icity assessments currently in use among multi-sector scientists. The manuscript describing the survey findings, which will likely help to inform design and conduct of future immunology studies with dogs, has been accepted for publication by the Journal of Immunotoxicology.

• Developmental Immunotoxicity Testing. The Commit-tee held a May 2010 workshop exploring the state of the science with regard to developmental immunotox-icity testing of pharmaceuticals, as well as considering gaps in science and methods and needs for future research. A manuscript describing the state of the science as well as outcomes captured from the May 2010 workshop is in preparation and will be submitted to a peer reviewed journal.

• Nonhuman Primates to Assess Risk for Epstein-Barr Virus (EBV)-Related Lymphomas. The Committee held a workshop on this topic in the fall of 2010. The work-shop considered approaches to assessing the potential risk for the development of EBV-related lymphomas by using assays/endpoints that can be included in standard repeat-dose toxicity studies in NHP. A manuscript describing the workshop outcomes is in preparation and will be submitted to a peer reviewed journal.

What is the Committee’s focus for May 2011 - April 2012 • Exploration of in vitro platforms to predict immunotox-

icity, continuing a Phase 1 cross-laboratory evaluation of an existing methodology.

• Continued collaborative program development in the areas of in vivo immunotoxicity models, cytokine release assays, and drug hypersensitivity reactions.

• Planning toward a fall 2011 workshop on Monitoring T cell Responses in Non-Human Primates for Drug Development.

• Development of a workshop addressing approaches and best practices for assessment of immunotoxicity for environmental chemicals.

• Co-organization of a session on Vaccination in the Context of Immunomodulatory Therapies at the 2011 Federation of Clinical Immunology Societies Annual Meeting; continued exploration of needs in clinical

Why get involved?The Immunotoxicology Technical Committee (ITC) is a unique forum for generating scientific dialogue, fostering research, and developing practical approaches to assessing immunotoxic effects of chemicals and pharmaceutical entities, and understand-ing human risk potential. Key accomplishments:• Non-human Primate (NHP) Control Data Evaluation. The

Committee completed a retrospective inter-laboratory study of T cell-dependent antibody responses (TDAR) and immunophenotyping responses in non-human primates. The TDAR component of this study provided perspective on the impact of study design on TDAR responses in nonhuman primates for potential immunotoxicological/immunophar-macological assessments of pharmaceuticals. The immuno-phenotyping component aimed to characterize normal ranges and variability in commonly tested immune cell subsets, identify factors associated with variability in counts, and may provide guidance for the design and appropriate statistical analysis of immunophenotyping studies in NHPs. This TDAR manuscript has been accepted for publication by the Journal of Immunotoxicology; the immunophenotyping manuscript will be submitted to a peer-reviewed journal shortly.

Abbott LaboratoriesAmgen, Inc.AstraZeneca PharmaceuticalsBASF CorporationBayer AGBoehringer-Ingelheim GmbHBristol-Myers Squibb

CompanyCentre Antipoison-Centre de

Pharmacovigilance Charles River Laboratories Covance E.I. du Pont de Nemours and

CompanyEli Lilly and CompanyGlaxoSmithKline

F. Hoffmann-La Roche Inc.Johnson & Johnson

PharmaceuticalsMedical College of Virginia Merck & Co. Inc. Novartis Pharma AGPfizer Inc.sanofi aventis SyngentaThe Dow ChemicalUniversity of Aachen US Environmental Protection


Administration

ImmunotoxIcoloGy


ImmunotoxIcoloGy paGE 2

immunotoxicology toward further program develop-ment.

Recent publicationsEvans EW, Kawabata TK. Workshop on naturally occurring infections in non-human primates and immunotoxicity implications: Introduction. Journal of Immunotoxicology 2010;Vol. 7, No. 2: 77–78.

Olivier KJ, Price KD, Hutto DL, Lerche NW, Mansfield KG, Simmons JH, Taylor K, Myers LP, Ouyang Y, Evans EW. Naturally occurring infections in non-human primates (NHP) and immunotoxicity implications: Discussion sessions. Journal of Immunotoxicology 2010;Vol. 7, No. 2: 138–146.



1211


Co-ChairDr. Peter Boogaard Shell Health

Co-ChairDr. Steven Robison Procter & Gamble Company

HESI Manager: Dr. Raegan B. O’Lone


This scientific program is committed to:• Delineating the appropriate scientific use(s) of biomonitor-

ing tools and/or biomonitoring data needed to characterize exposure to chemicals, and

• Exploring mechanisms for integrating biomonitoring data and toxicology data into a robust risk assessment process

Areas of scientific focus• Generic Criteria. Aiming to formulate criteria for the use and

interpretation of biomonitoring exposure data by compar-ing biological monitoring methodologies in occupational and environmental settings, and

• Strawman Interpretive Framework. Working to develop a practical method for determining the appropriateness of a biomarker for specific exposures through the use of interpretive criteria.

What is the Committee’s focus for May 2011 - April 2012 The Biomonitoring Committee is working toward comple-tion of the benzene case study for publication in a peer reviewed journal in 2011, after which the Committee will sunset.

Recent publicationsZelenka MP, Barr DB, Nicolich MJ, Lewis RJ, Bird MG, Letinksi DJ, Metcalf SW, O’Lone RB.. A weight of evidence approach for selecting exposure biomarkers for biomonitoring. Biomarkers 2011;16(1):65-73.

Key accomplishments:• Development of a Weight of Evidence Calculator for

assessment of the appropriateness of a biomarker for specific questions of exposure. This framework has been described in a publication and is publicly available for use by the scientific community on the HESI website.

• The Committee earlier developed generic criteria for biomonitoring. The Committee has further explored application of these criteria via a benzene case study that is anticipated for publication later this year.

Agency for Toxic Substances and Disease Registry

BASF CorporationBayer CropScience Centers for Disease Control

National Center for Environmental Health

Emory UniversityExxonMobil Biomedical

Sciences, Inc.Forschungsinstitut für

Arbeitsmedizin der Deutschen Gesetzlichen Unfallversicherung

Mississippi State UniversityProcter & Gamble CompanyShell International B.V.The Dow Chemical CompanyUniversity of LeicesterUS Environmental Protection


Administration

IntEGratIon of BIomonItorInG ExpoSurE data Into tHE rISk aSSESSmEnt procESS


IntEGratIon of BIomonItorInG ExpoSurE data Into tHE rISk aSSESSmEnt procESS paGE 2



1413


ChairDr. Greg Ladics DuPont Company

Vice-ChairDr. Scott McClain Syngenta

HESI Manager: Nancy G. Doerrer, MS


This scientific program is committed to:Advancing the science associated with novel protein allergenicity evaluation, and encouraging the development of reliable and accurate methodologies for characterizing allergenic potential.

Areas of scientific focus• Biochemical parameters associated with allergenic proteins,• Sequence homology/bioinformatics evaluations,• Animal models for predicting human food allergy,• Sera bank development, and• Detection methods to support endogenous allergen

assessments.

Why get involved?• Pool expertise and resources on advancing scientific tools

and methods for safety assessment of novel proteins and genetically modified (GM) crops,

• Contribute to discussions and programs leading to greater awareness and application of reliable and accurate methods for characterizing allergenicity potential,

• Engage in cutting edge biotechnology research, and• Interact directly and frequently with domestic and interna-

tional decision-makers and researchers on biotechnology safety assessment issues.

Nice, France, with EuroPrevall, ILSI Europe, the United Kingdom Food Standards Agency, and the Food Allergy Research and Resource Program (FARRP) to examine global patterns and prevalence of food allergenicity, thresholds (priority setting and criteria), and advance-ments in food allergen risk assessment.

What is the Committee’s focus for May 2011 - April 2012 • The PATC has initiated research in the following areas to

be completed during 2012: ¾ Two-Dimensional Differential Gel Electrophoresis

(2D-DIGE) phase 2 validation: analysis of rice proteins with different cultivars (in collaboration with the Japan National Institute of Health Sciences, Tokyo),

¾ Comparison of 2D assay with Automated Quantitative Analysis (AQUA) Mass Spectrometry (MS) approach (with the Donald Danforth Plant Science Center, St. Louis, Missouri),

¾ Absolute quantitation of seed allergens from three varieties of soy from eight geographical locations (with the University of Missouri, St. Louis), and

¾ Development of a mouse intestinal stem cell model to evaluate potential allergenicity of proteins (with Utrecht University of Applied Sciences, Utrecht, The Netherlands).

• The PATC, in conjunction with IFBiC, will host symposia around the globe on research and advancements in safety assessment of novel proteins and GM crops:

¾ Ottawa, Canada (for Canadian decision-makers); ¾ Paris, France (for two Organisation for Economic

Co-operation and Development [OECD] committees); and

¾ China (for Asian government, academic, and industry researchers, decision-makers, and companies).

• In April 2012, the PATC will host a symposium in Prague on sensitizing properties of proteins.

Recent publicationsDoerrer, N., Ladics, G., McClain, S., Herouet-Guicheney, C., Poulsen, L., Privalle, L., Stagg, N. Evaluating biological variation in non-transgenic crops: executive summary from the ILSI Health and Environmental Sciences Institute workshop, November 16-17, 2009, Paris, France. Regul Toxicol Pharmacol. 2010;58, S2-S7.

Houston NL, Lee D-G, Stevenson SE, Ladics GS, Bannon GA, McClain S, Privalle L, Stagg N, Herouet-Guicheney C, MacIntosh SC, Thelen JJ. Quantitation of soybean allergens

Key accomplishments:• Proteomics method development: Collaboration with an

academic laboratory in the United States to develop a quantitative approach to measuring the content of specific protein allergens in soybean. The objective of this research, the first phase of which was published in 2010, is to assess and establish a baseline for endogenous allergen variation of novel soy proteins.

• Publication of workshop proceedings on evaluating biologic variation in non-transgenic crops. A special issue of Regula-tory Toxicology and Pharmacology was devoted to the research presented and discussed at the November 2009 PATC workshop in Paris, France, on the utility of “-omics” technologies for assessing variability in plant gene, protein, and metabolite expression.

• Biotechnology outreach to the North American Free Trade Agreement (NAFTA) region: On September 16, 2010, in cooperation with the ILSI International Food Biotechnology Committee (IFBiC), the PATC hosted a symposium in Washington, DC, for decision-makers from Canada, Mexico, and the United States to discuss biotechnology priorities and challenges.

• International outreach on food allergen risk assessment: On October 20-22, 2010, the PATC co-sponsored a symposium in

BASF Plant ScienceBayer CropScienceDow Chemical CompanyDuPont CompanyMonsanto CompanyNational University Hospital,

Copenhagen

SyngentaUS Environmental Protection


Administration

protEIn allErGEnIcIty

For more information, contact the committee manager Ms. Nancy G. Doerrer, [email protected]

protEIn allErGEnIcIty paGE 2

using tandem mass spectrometry. J Proteome Res. 2011;10:763-773. [PATC-sponsored research]

Lee D-G, Houston NL, Stevenson SE, Ladics GS, McClain S, Privalle L, Thelen JJ. Mass spectrometry analysis of soybean seed proteins: optimization of gel-free quantitative workflow. Anal Methods 2010;2: 1577-1583. [PATC-sponsored research]



1615


Committee LeadersProf. Alan R. Boobis Imperial College London

Dr. Timothy P. Pastoor Syngenta

HESI Manager: Dr. Michelle R. Embry


This scientific program is committed to:• Initiating and stimulating a proactive and constructive

dialog amongst experts from industry, academia, the government, and other stakeholders to identify key advancements in risk assessment.

• Designing better methods to bring applicable, accurate, and resource appropriate approaches to the evolving world of human health risk assessment.

• Creating a science-based approach for improving human health risk assessments, and developing a viable mechanism for transitioning to novel approaches, as available and when appropriate.

• Developing an integrated evaluation framework that targets the acquisition and interpretation of essential data to improve the efficiency of human health risk assessment for a large number and broad array of chemicals.

Areas of scientific focus• Dose-Response: Build on the existing mode of action and

Key Events Dose Response Framework (KEDRF) to quantita-tively incorporate dose-response information;

• In vitro to in vivo extrapolation: Utilize Physiologically based pharmacokinetic and pharmacodynamic modeling to predict responses based on dose-dependent mode of action and exposure assessment;

Key accomplishments:• Strong project engagement: Balanced, global,

tripartite project teams formed with regular monthly teleconferences and periodic face-to-face meetings (as necessary).

• Identification of key needs: Over the past year, the established teams have developed their mission and objectives, and are actively working on key projects.

• Workshop on “RISK21: Realizing the Future of Risk Assessment”: A workshop of the project participants, and day-long public session to hear commentary from those not yet directly involved with the program was held in January 2011. Over 80 RISK21 participants and approximately 40 visitors were in attendance at the meeting, which provided a unique opportunity for the participants to evaluate the project and offer sugges-tions on how the project should proceed.

• Presentations at international meetings: Representa-tives of the RISK21 project have given seven separate presentations on the project at various meetings and venues, including the Toxicology Forum, Human Toxicology Project Consortium, ILSI Annual Meetings, National Press Club, and Alliance for Risk Assessment.

What is the Committee’s focus for May 2011 - April 2012 • Development of an integrated framework that will tie

the various components of RISK21 (dose-response, exposure science, and cumulative risk) together.

• Continued sub-team and steering team meetings via monthly teleconferences and periodic face-to-face meetings to advance project goals and objectives. These meetings will also involve coordination amongst sub-teams via identified liaisons.

• Active engagement of additional scientists from other sectors and geographic regions.

• Development of publications and presentations at key scientific meetings, such as the Society of Toxicology, European Societies of Toxicology (EUROTOX), Japanese Society of Toxicology, and The Toxicology Forum.

• Implementation of a comprehensive communications plan for the project.

• Exposure Science: Propose approaches for using new technologies to improve characterization of real-world exposures, and provide the data-driven, evidence base for 21st Century exposure measurement, modeling, and risk assessment;

• Cumulative Risk: Define and develop critical elements of a transparent, consistent, pragmatic, scientific approach for assessing health risks of combined exposures to multiple chemicals in the context of other stressors; and

• Integrated Evaluation Strategies: Develop an integrated evaluation framework that actively incorporates new technologies for chemical products and contaminants that is more accurate, and utilizes less resources than the current paradigm.

Why get involved?The RISK21 Project is envisioned as a sea change in the way we conduct toxicology and exposure science for the purpose of human health risk assessment, and reflects both the challenges of developing better toxicity testing paradigms in the 21st century as well as the clear need to apply our advancing knowledge to understand and manage potential risks to human health.

Applied Pharmacology & Toxicology, Inc.

Auburn UniversityBASF CorporationBayer CropScienceBfR, GermanyChemical Regulation

Directorate, UKCraig Barrow ConsultingCXR BiosciencesDow Corning CorporationE.I. du Pont de Nemours and

CompanyEmory UniversityETH, ZurichEuropean Commission/JRC/

ECVAMExxonMobil Biomedical

Sciences, Inc.George Washington

UniversityGradient CorporationHamner Institutes of Health

SciencesHealth CanadaHumane Society of the

United StatesILSI Research FoundationImperial College LondonIndiana University School of

MedicineJohns Hopkins University/

CAATMedical College of WisconsinMichigan State UniversityMonsanto CompanyNational Institutes of Health

(US)Pacific Northwest National

LaboratoryProcter & Gamble CompanyRadboud University

Nijmegen, The Netherlands

National Institute for Public Health and the Environment (RIVM, The Netherlands)

Rutgers UniversitySwiss Federal Office of Public

HealthSyngentaTed Simon ToxicologyThe Coca-Cola CompanyThe Dow Chemical

Company/Dow AgroSciences

US Consumer Product Safety Commission

US Department of Agriculture

US Environmental Protection Agency

US Food and Drug Administration

University of Aarhus, Denmark

University of Basel, Switzerland

University of California, Los Angeles

University of FloridaUniversity of Guelph, CanadaUniversity of KansasUniversity of London, UKUniversity of MichiganUniversity of Milan, ItalyUniversity of Nebraska

Medical CenterUniversity of Ottawa, CanadaUniversity of Texas HoustonUniversity of Toronto, CanadaUniversity of Washington

Medical CenterUtrecht University, The

NetherlandsVirginia Commonwealth

University

rISk aSSESSmEnt for tHE 21St cEntury (rISk21)

For more information, contact the committee manager Dr. Michelle R. Embry, [email protected]

rISk aSSESSmEnt for tHE 21St cEntury (rISk21) paGE 2



18

HESI projEct commIttEES Overview

19 Animal Alternatives in Environmental Risk Assessment

21 Biological Significance of DNA Adducts

23 Biomarkers of Nephrotoxicity

25 Development of Methods for a Tiered Approach to Assess the Bioaccumulation of Chemicals

27 Distinguishing Adverse from Non-Adverse/Adaptive Effects

29 Imaging for Translational Safety Assessment

31 Relevance and Follow-Up of Positive Results in In Vitro Genetic Toxicology Testing

33 Mixtures

17

Like the technical committees, HESI’s project committees pool intellectual and financial resources to support scientific research, sponsor symposia or workshops, and conduct other technical activities. A project committee generally has a specific task or activity—such as development of a database, organization of a workshop, or preparation of a white paper—with a fixed and specific duration (usually shorter than that of a technical committee).

Project committees operate under two-year charters. These charters are renewable contingent on a satisfactory review under the HESI Stewardship Program.

HESI’s project committees address: (1) Animal Alternatives in Environmental Risk Assessment, (2) Biological Significance of DNA Adducts, (3) Biomarkers of Nephrotoxicity, (4) Development of Methods for a Tiered Approach to Assess the Bioaccumulation of Chemicals, (5) Distinguishing Adverse from Non-Adverse/Adaptive Effects, (6) Imaging for Translational Safety Assessment, (7) Relevance and Follow-Up of Positive Results in In Vitro Genetic Toxicology Testing, and (8) Mixtures.

TM

2019

HESI Project Committee

Committee LeadersDr. Scott E. Belanger Procter & Gamble Company

Dr. Marc LéonardL’Oréal Corporation



This scientific program is committed to:• Ensuring the development of a sound technical basis for

alternative test methods as a means to reduce, refine, or replace standard ecotoxicity test procedures around the globe.

• Providing a forum to coordinate the debates and best emerging practices of the alternatives and animal model development sciences to meet various regulatory needs.

Areas of scientific focus• Alternatives to in vivo chronic ecotoxicity tests• Alternatives to in vivo tests for endocrine disrupting

chemicals• Alternative methodologies for effluent assessment

Why get involved?Through your membership on the HESI Animal Alternatives in Environmental Risk Assessment Project Committee, you are part of an international team of leading scientists and regulators working towards the effective development of alternative methodologies. Key accomplishments:• International workshop on the “Development of alternatives

to chronic ecotoxicity tests: predicting early-life stage and

two years.• Preparation of publications. The Committee is working

to complete three publications on their recent work for submission in late-2011.

What is the Committee’s focus for May 2011 - April 2012 • Completion of publications stemming from the June

2010 workshop• Formation of a project steering team that will develop

detailed project plans in the following key areas: ¾ Investigation of toxicologically relevant adverse

outcome pathways (AOPs): Identifying, describing, and annotating known toxicologically relevant AOPs in fish and amphibians, with an emphasis on chronic pathways.

¾ Critical examination of in vitro assays to detect EDCs and development of a standard chemical reference list: A list of reference chemicals will be identified by the group. The ultimate aim is to evaluate the most promising EDC assays using this list of chemicals, which may involve the development of a future research project.

¾ Evaluation of alternative strategies to assess effluent toxicity to fish: A small research project was initiated mid-2011. The aim is to develop a basic understanding of the relationship between existing alternative methods, such as the Fish Embryo Test (FET), and common sub-chronic methods such as the seven-day larval growth and survival assay.

Pending publications:Volz D, Belanger S, Embry M, Padilla S, Sanderson H, Schirmer K, Scholz S, Villeneuve D. Adverse outcome pathways during early fish development: A framework for identifying and implementing alternative chemical prioritization strategies. Toxicological Sciences. Accepted.

Norberg-King T, Belanger SE, Embry MR, Halder M. Freshwater Fish Sublethal Tests: A review of sublethal fish toxicity tests for the past 60 years. In preparation.

Oris JT, Belanger SE, Bailer AJ. Statistical Characteristics of the OECD 210 Fish Early Life Stage Chronic Toxicity Test. In preparation.

Scholz S, Renner P, Busquet F, Léonard M, Ortego L, Embry M. Critical Evaluation of Animal Alternative Tests for the Identification of Endocrine Active Substances (EAS). In preparation.

endocrine-mediated toxicity in aquatic vertebrate species.” A June 2010 workshop was attended by over 50 scientists representing industry, academia, government, and non-governmental organizations (NGOs) from North America, Europe, and Japan.

• Critical data review. In partnership with funding from L’Oréal, a literature review on alternatives to in vivo tests for endocrine disruptors (EDCs) in fish and amphibians was completed. This review focused on identifying and obtaining key literature relating to the detection andtesting of EDCs in fish and amphibian systems, developing a methodology database, and providing an analysis of the pros and cons of each assay.

• Involvement in Organisation for Economic Co-operation and Development (OECD) Fish Embryo Toxicity (FET) Test Validation. A representative of the HESI committee serves as a scientific observer and advisor to the OECD FET Validation Management group.

• Outreach at international meetings. Nine separate presenta-tions were given at The Society of Environmental Toxicology and Chemistry (SETAC) North America, SETAC Europe, and Society of Toxicology meetings.

• Successful re-charter by the HESI Program Strategy and Stewardship Committee (PSSC). In December 2010, the Committee was reviewed and unanimously re-chartered for

AstraZeneca ABBayer AGDow Corning CorporationDuke University (USA)Eawag (Switzerland)Environment Canada

(Canada)European Commission Joint

Research Centre IHCP / ECVAM (Italy)

ExxonMobil Biomedical Sciences, Inc

Federal Environment Agency (UBA, Germany)

Fraunhofer Institute for Molecular Biology and Applied Ecology (Germany)

Helmholtz Centre for Environmental Research (Germany)

Humane Society International (Belgium)

INERIS (France)L’Oréal CorporationLiverpool John Moores

University (LJMU) (UK)Museum National d’Histoire

Naturelle, Paris (France)National Center for the

Replacement, Refinement, and Reduction of Animals in Research (NC3Rs, UK)

National Institute for Basic Biology (Japan)

National Institute for Environmental Studies (Japan)

National Institute of Public Health (Slovenia)

National Oceanic and Atmospheric Administration (USA)

NIVA (Norway)Organisation for Economic

Cooperation and Development (OECD, France)

Procter & Gamble Companysanofi-aventisSC Johnson & Son Inc.Shell Chemicals, Ltd.SyngentaUK Environment Agency (UK)UK Home Office (UK)Université de Rennes (France)University of Aarhus

(Denmark)University of Bern

(Switzerland)University of Florida (USA)University of Guelph

(Canada)University of Heidelberg

(Germany)University of Liverpool (UK)University of Miami, Ohio

(USA)University of South Carolina

(USA)US Environmental Protection

Agency


anImal altErnatIvES In EnvIronmEntal rISk aSSESSmEnt paGE 2

anImal altErnatIvES In EnvIronmEntal rISk aSSESSmEnt


photo: Dr. Scott E. Belanger, Procter & Gamble Company


2221


ChairDr. Lynn Pottenger The Dow Chemical Company

Co-ChairDr. Robert Mauthe Pfizer, Inc.

HESI Manager: Dr. James Kim


This scientific program is committed to:• Bringing basic science to issues around the biological

significance of low levels of DNA adducts, and derive a scientific consensus on this topic;

• Providing a unique public forum for sharing experience, knowledge, and applications of risk management methods to this topic as well as the implications for risk assessment; and

• Producing a consensus-based, science-driven framework for the application of DNA adduct data to the cancer risk assessment process.

Areas of scientific focus• Organizational framework for evaluating DNA adduct data

for use in risk assessment,• Reviewing DNA adduct technologies and methodologies,

and• Application of DNA adduct data from case studies to

illustrate the use of DNA adduct data in risk assessment.

recognition by the SOT Risk Assessment Specialty Section.

What is the Committee’s focus for May 2011 - April 2012 • Symposia organized by the Committee will be held at

the 2011 conferences of both the Environmental Mutagen Society (October 2011) and the European Environmental Mutagen Society (July 2011).

• The Committee has developed three case studies (vinyl chloride, aflatoxin B1, and tamoxifen) to illustrate the organizational framework developed by the Commit-tee. This will be published in 2011.

Recent publicationsPottenger LH, Carmichael N, Banton MI, Boogaard PJ, Kim JH, Kirkland D, Phillips RD, van Benthem J, Williams GM, Castrovinci A. ECETOC workshop on the biological significance of DNA adducts: Summary of follow-up from an Expert Panel Meeting. Mutat Res, 2009;678, 152-7.

Jarabek AM, Pottenger LH, Andrews LS, Casciano D, Embry MR, Kim JH, Preston RJ, Reddy MV, Schoeny R, Shuker D, Skare J, Swenberg J, Williams GM, Zeiger E. Creating context for the use of DNA adduct data in cancer risk assessment: I. Data organization. Crit Rev Toxicol 2009;39, 659-78.

Himmelstein MW, Boogaard PJ, Cadet J, Farmer PB, Kim JH, Martin EA, Persaud R, Shuker DE. Creating context for the use of DNA adduct data in cancer risk assessment: II. Overview of methods of identification and quantitation of DNA damage. Crit Rev Toxicol 2009;39, 679-94.

Why get involved?• Engage in public and transparent discussions on DNA

adducts as biomarkers of exposure versus biomarkers of effect, and

• Address the biological significance of DNA adducts.

Key accomplishments:• Creating context for the use of DNA adduct data in risk

assessment. The Committee published two articles that describe the organizational framework for evaluating DNA adduct data and its use in risk assessment, and the technolo-gies available for assessing and quantifying DNA damage.

• Workshops on the biological significance of DNA adducts. Open workshops have been held at the Environmental Mutagen Society and the European Environmental Mutagen Society to provide a forum for academic, government, and industry scientists to discuss the use of DNA adduct data in risk assessment.

• Case studies to illustrate the organizational framework to evaluate DNA adduct data. The Committee prepared poster presentations of the case study work for the Society of Toxicology (SOT) (March 2011) and the European Societies of Toxicology (EUROTOX) Congress (August 2011). The March poster presentation was awarded “best presentation”

AstraZeneca ABE.I. du Pont de Nemours and

CompanyErrol Zeiger ConsultingExxonMobil Biomedical

Sciences Inc.L’Oréal CorporationNew York Medical CollegeOpen University (United

Kingdom)Pfizer Inc.Procter & Gamble Company

Shell Chemicals Ltd.The Dow Chemical CompanyUniversity of Leicester

(United Kingdom)University of North CarolinaUS Environmental Protection





BIoloGIcal SIGnIfIcancE of dna adductS paGE 2

BIoloGIcal SIGnIfIcancE of dna adductS



2423


Co-Chair Dr. Magali Guffroy Pfizer, Inc.

Co-Chair Dr. Jean-Charles Gautier sanofi-aventis



This scientific program is committed to:• Advancing the scientific basis for the development and

application of biomarkers of nephrotoxicity,• Developing systematic approaches based on newly available

technologies for the identification and evaluation of biomarkers that bridge from the pre-clinical to clinical stages of drug development, and

• Providing a scientific forum for building consensus regarding how to apply biomarkers of toxicity in risk assessment.

Areas of scientific focus• Characterization of urinary protein site-specific markers of

renal toxicity via novel experimental work,• Exploration of micro-RNAs to serve as markers of renal injury,• Qualification of injury biomarkers via regulatory qualification

processes, and• Defining best practices in the experimental practice of

urinary biomarker collection and analysis.

Why get involved?• Pool financial and human resources to identify and charac-

terize novel renal protein biomarkers,• Generate data on renal associated micro-RNAs with the goal

to gain novel insights into the utility of these markers for safety evaluation and decision-making, and

What is the Committee’s focus for May 2011 - April 2012 • Jointly design novel experimental studies to character-

ize the presence and type of circulating microRNAs associated with exposure to renal toxicants to be conducted and data analyzed.

• Analysis of pooled input from Committee members on best practices in urinary and serum biomarker collection methods to be conducted. Results to be pub-lished.

• Additional publications on the gender-specificity and reversibility of RPA-1, GST-α and GST-µ, and clusterin to be completed and submitted to peer-reviewed press and submission of these data to USFDA/EMA as part of the biomarker qualification program.

• Committee will collaborate with other committees/consortia with related interest and focus (e.g., HESI Genomics Committee, Predictive Safety Testing Consortium renal project, etc.).

Recent publicationsGautier J-C, Riefke B, Walter J, Kurth P, Mylecraine L, Guilpin V, Barlow N, Gury T, Hoffman D, Ennulat D, Schuster K, Harpur E, Pettit S. Evaluation of Novel Biomarkers of Nephrotoxicity in Two Strains of Rat Treated with Cisplatin. Toxicol Pathol. Epub August 17, 2010;38(6):943-56.

Harpur E, Ennulat D, Hoffman D, Betton G, Gautier J-C, Riefke B, Bounous D, Schuster K, Beushausen S, Guffroy M, Shaw M, Lock E, Pettit S. Biological Qualification of Biomarkers of Nephrotoxicant-induced Renal Toxicity in Two Strains of Male Rat. Toxicol Pathol. Epub May 18, 2011; doi: 10.1093/toxsci/kfr112.

• Collaborate on identifying ‘best practices’ in urinary and serum biomarker collection to increase the quality and consistency of study data, and thus support more effective use of these data for decision-making.

Key accomplishments:• Qualification of Novel Biomarkers. Novel site specific renal

biomarkers (clusterin and Renal Papillary Antigen-1 [RPA-1]) characterized by the Committee were approved for use in good laboratory practice (GLP) toxicology studies to support renal safety in clinical trials by the European Medicines Agency (EMA) and the US Food and Drug Administration (USFDA). Approvals granted in April and September 2010, respectively as a result of participation in the USFDA/EMA Biomarker Qualification Review process.

• Leadership in Evaluation of MicroRNAs as Renal Biomarkers. Committee has established itself as a leader in the collabora-tive assessment of the potential utility of microRNA measurements to assess renal toxicity. The data generated by the Committee on this endpoint will be a significant contribution to this emerging field.

Astellas PharmaAstraZenecaBayer HealthcareBiogen Idec MA Inc.Bristol-Myers Squibb

CompanyGlaxoSmithKlineJohnson & Johnson

PharmaceuticalsLiverpool John Moores

University

National Institute of Environmental Health Sciences

Newcastle UniversityPfizer Inc.sanofi-aventisUniversity of ArizonaUniversity of Nebraska

Medical CenterUS Food and Drug

Administration


BIomarkErS of nEpHrotoxIcIty paGE 2

BIomarkErS of nEpHrotoxIcIty



2625



Committee LeadersDr. Christina Cowan-Ellsberry Procter & Gamble

Dr. Jean Domoradzki Dow Corning Corporation


This scientific program is committed to:• Developing the tools needed for assessing the potential

bioaccumulation of organic chemicals• Addressing how metrics used to assess bioaccumulation can

be integrated to develop an overall weight of evidence approach for deriving assessment conclusions

• Partnering with other groups involved in research and improvements in bioaccumulation assessment methods

Areas of scientific focus• Developing in vitro assays to predict in vivo fish metabolism • Collecting physical and physiological data to parameterize

models used to extrapolate in vitro biotransformation data to whole fish biotransformation rates and bioconcentration factor estimates

• Examining how laboratory measurements compare to field measurements

• Developing a shortened in vivo BCF test • Creating a new model for chemical transfer efficiency across

the fish gastrointestinal tract Why get involved?Membership on the HESI Bioaccumulation Project Committee gives you the opportunity to work with leading international scientists and regulators to develop novel scientific approaches to improve bioaccumulation assessment. Key accomplishments:• Successful international workshop in February 2011 on

“Moving Bioaccumulation Assessments to the Next Level: Progress Made and Challenges Ahead.”

¾ Attended by 65 scientists and regulators from 14 countries on 4 continents; funded in part by a grant from the USEPA.

¾ Highlighted recent and ongoing research efforts,

Recent publicationsBorgå K, Kidd K, Berglund O, Conder JM, Gobas FAPC, Kucklick J, Malm O, Powell DE, Muir DCG. Trophic Magnification Factors: Impact of Ecology, Ecosystem and Study Design. Integrated Environmental Assessment and Management. Accepted.

Burkhard LP, Cowan-Ellsberry C, Embry MR, Hoke RA, Kidd KA. Introduction to Special Series: Bioaccumulation data from laboratory and field studies: Are they comparable? Integrated Environmental Assessment and Management. Accepted.

Burkhard LP, Arnot JA, Embry MR, Farley KJ, Hoke RA, Kitano M, Leslie HA, Lotufo GR, Parkerton TF, Sappington KG, Tomy GT, Woodburn KB. Comparing Laboratory and Field Measured Bioaccumulation Endpoints. Integrated Environmental Assessment and Management. Accepted. Burkhard LP, Arnot JA, Embry MR, Farley KJ, Hoke RA, Kitano M, Leslie HA, Lotufo GR, Parkerton TF, Sappington KG, Tomy GT. Comparing laboratory and field measured biota-sediment accumulation factors. Integrated Environmental Assessment and Management. Accepted. Conder JM, Gobas FAPC, Borgå K, Muir DCG, Powell DE. Characterizing Bioaccumulative Potential of Chemicals Using Trophic Magnification Factors and Related Measures. Integrated Environmental Assessment and Management. Accepted.

Escher BI, Cowan-Ellsberry CE, Dyer S, Embry MR, Erhardt S, Halder M, Kwon, JH, Johanning K, Oosterwijk MTT, Rutishauser S, Segner H, Nichols J. Protein and lipid binding parameters to extrapolate from the in vitro liver S9 metabolic assay to in vivo rainbow trout (Oncorhynchus mykiss) bioaccumulation potential of hydrophobic organic chemicals. Chemical Research in Toxicology. Accepted.

Petersen LH, Dzialowski E, Huggett DB. The interactive effects of an acute temperature decrease and long-term food deprivation on cardiac and hepatic blood flows in rainbow trout (Oncorhynchus mykiss). Comparative Biochemistry and Physiology. Accepted.

Selck H, Drouillard K, Eisenreich K, Koelmans AA, Palmqvist A, Ruus A, Salvito D, Schultz I, Stewart R, Weisbrod AV, van den Brink NW, van den Heuvel-Greve M. Explaining

identified key gaps in current bioaccumulation knowledge, and discussed obstacles that hinder implementation of recent progress in bioaccumulation science into the regulatory environment.

• Completion of an S9 collaborative study. The project, started in 2007, was aimed at standardizing and validating the in vitro rainbow trout S9 assay to predict in vivo fish metabo-lism of chemicals. Funding was provided by the European Commission, Joint Research Center (JRC/IHCP/ECVAM) and the European Chemical Industry Council (CEFIC). Five laboratories from the United States, Canada, and Australia, and a dedicated team of scientific advisors participated in the project.

• Funding of key scientific research: ¾ Development of a shortened in vivo BCF test using carp

(partnership with University of North Texas, CEFIC-LRI, HESI, and ExxonMobil).

¾ Evaluation of a cryo-preservation methodology for rainbow trout primary hepatocytes. (partnership with University of Bern and DuPont).

¾ Advancement of in vitro methods for estimating uptake of chemicals across the gut (partnership with The Swiss Federal Institute of Aquatic Science and Technology [Eawag]).

• Publication of a special issue of Integrated Environmental Assessment and Management. Stemming from a successful 2009 lab to field workshop, six publications comprising a special issue were accepted for publication.

• Outreach at international meetings. Nine separate presenta-tions on the committee’s work were given at the SETAC North America and Europe meetings.

• Successful re-charter by the HESI Program Strategy and Stewardship Committee (PSSC). In April 2011, the Commit-tee was reviewed and unanimously re-chartered for two years.

What is the Committee’s focus for May 2011 - April 2012 The Committee is working to summarize and prioritize the key areas of research discussed at the 2011 workshop, an integrated approach to bioaccumulation assessment needs to be empha-sized. As a next step, the Committee plans to complete the following in 3 – 4Q 2011:• Finalize a workshop summary and distribute to key partners.• Form a project steering team to lead an effort to increase

connectivity amongst the research areas, initiate communi-cation with the regulatory community, and ultimately, develop a weight of evidence scheme for ‘B’ assessment.

• Work to prioritize areas for research funding in 2011 – 2012 and solicit proposals.

Ajou University (Korea)Akzo NobelAstraZeneca ABCERI (Japan)Dow Corning CorporationE. I. du Pont de Nemours and

CompanyENVIRON Environment CanadaEuropean Commission, Joint

Research Center, Institute for Health and Consumer Protection, European Center for the Validation of Alternative Methods (JRC/IHCP/ECVAM) (Italy)

ExxonMobil Biomedical Sciences, Inc.

Federal University of Rio de Janeiro (Brazil)

Fisheries & Oceans Canada (Canada)

IMARES Wageningen UR (The Netherlands)

InvitrogenL’Oréal CorporationLund University (Sweden)Manhattan CollegeMaxaam AnalyticsMeiji University (Japan)Michigan State UniversityNational Institute for Public

Health and the Environment (RIVM, The Netherlands)

National Institute of Standards & Technology (NIST)

Norwegian Institute for Water Research (NIVA, Norway)

Pacific Northwest National Laboratories (Battelle PNNL)

Pfizer Inc.Procter & Gamble CompanyResearch Institute for

Fragrance Materials (RIFM) Roskilde University (Denmark)

SC Johnson & Sons Inc.Simon Fraser University

(Canada)Swiss Federal Institute of

Aquatic Science and Technology (Eawag) (Switzerland)

The Dow Chemical Company Trent University (Canada)UK Environment Agency (UK)University of Bern

(Switzerland)University of Guelph

(Canada)University of New Brunswick

(Canada)University of North TexasUniversity of Queensland

(Australia)University of Toronto

Scarborough (Canada)University of Windsor

(Canada)US Environmental Protection

AgencyUS Geological SurveyUtrecht University (The

Netherlands)VU University Amsterdam

(The Netherlands)Waterborne Environmental


dEvElopmEnt of mEtHodS for a tIErEd approacH to aSSESS tHE BIoaccumulatIon of cHEmIcalS paGE 2

variability of bioaccumulation measurements between laboratory and field using a modelling approach. Integrated Environmental Assessment and Management. Accepted


dEvElopmEnt of mEtHodS for a tIErEd approacH to aSSESS tHE BIoaccumulatIon of cHEmIcalS


2827


Co-ChairDr. Doug Keller sanofi-aventis

Co-ChairDr. Daland Juberg Dow AgroSciences



This scientific program is committed to:Developing an approach for the evaluation of the continuum of effects observed in toxicological investigations ranging from benign to adverse, and to using this approach to facilitate the integration and utilization of biological information in the safety assessment of chemicals/pharmaceuticals.

Areas of scientific focus• Develop criteria to facilitate the determination of adverse

from other types of changes (e.g., pharmacologic, adaptive, homeostatic, or non-functional). These criteria may include biologically relevant information such as temporality, genomic and tissue response, and identification of target organ or system.

• Develop an evaluation framework that integrates and prioritizes the information that characterizes an observed/measured change in a biological system.

the proposed framework. • The Adverse vs. Adaptive Project Committee held a

workshop in May 2011 to stimulate discussion on a proposed framework for distinguishing adverse from adaptive, non-functional and pharmacological changes using two case studies with in vitro, whole animal, and human data.

What is the Committee’s focus for May 2011 - April 2012 The workshop discussions will be used to prepare a manuscript for publication in the peer-reviewed literature. Next steps will be determined.

Why get involved?• Provide focus on the challenges of the new research environ-

ment described in the National Research Council’s (NRC’s) vision of toxicity testing in the 21st century.

• Be among the first to engage in discussions about the interpretation of data derived using new technologies.

• Foster and promote a tripartite consensus approach to understanding biological perturbations, toxicity pathways, and apical endpoints in the context of safety assessment.

Key accomplishments:• Working definitions of “adverse” and “adaptive” effects:

Agreement on definitions was critical for the development of an evaluation framework.

• Framework development. The proposed framework addresses the challenges inherent in characterizing biological changes in the context of a continuum of effects (from benign to adverse). This framework, upon further refinement, will facilitate decision-making by providing clarity of information/data considered, their relative importance, and the risk context.

• Case study development. Two case studies, acetaminophen and dimethylarsinate, were used to refine the elements of

AstraZenecaBASF CorporationBayer HealthCare

PharmaceuticalsBrown UniversityCharles River LaboratoriesColorado State UniversityDow AgroSciencesExperimental Pathology

LaboratoriesGlaxoSmithKlineF. Hoffmann-La Roche, Inc.

Monsanto CompanyNational Institute of


sanofi-aventisSyngenta US Environmental Protection


Administration


dIStInGuISHInG advErSE from non-advErSE/adaptIvE EffEctS paGE 2

dIStInGuISHInG advErSE from non-advErSE/adaptIvE EffEctS



3029


Committee LeadersDr. Brian Berridge GlaxoSmithKline

Dr. G. Allan Johnson Duke University



This scientific program is committed to:Integrating imaging approaches into current safety assessment paradigms for drugs and/or hazard assessment approaches for chemicals.

Areas of scientific focusAssessment of the sensitivity and specificity of different imaging modalities (magnetic resonance imaging [MRI], computed tomography [CT], Echo) to identify organ-specific changes in function and/or structure in animal models.

Why get involved?• You are part of a first-of-its-kind initiative to develop and

interpret a robust dataset around the use of imaging for nonclinical safety assessment and environmental hazard identification.

• An opportunity to collaborate with leading researchers in the field of small animal imaging, and learn from their technological resources and expertise.


Key accomplishments:• Formulation of a multi-organization team of experts to

address a significant gap in nonclinical safety evaluation. Despite the frequent use of imaging tools to assess clinical populations, their routine use in animal studies has been hindered by a lack of foundational information about the reproducibility, sensitivity, and regulatory context for the data. This Committee’s work will address this gap.

• Study design development for the first multi-site and multi-sector (industry, academia, and government) study to assess the utility of imaging for preclinical cardiac and neuro safety evaluation.

What is the Committee’s focus for May 2011 - April 2012 • The Committee will be conducting and analyzing multi-site

laboratory studies with a rodent cardiac model to compare the sensitivity and reproducibility of different imaging modalities. Complimentary studies to assess neurotoxicity endpoints are also in design.

• The Committee will be conducting a Continuing Education Course on the use of imaging at the American College of Toxicology Annual Meeting in November 2011.

Astellas Pharma Inc.AstraZeneca Pharmaceuticals

Ltd.Bayer HealthCareBoehringer Ingelheim GmbHBristol-Myers Squibb

CompanyCovanceDuke University Center for In

Vivo MicroscopyGlaxoSmithKline

F. Hoffman-La Roche Inc.National Institutes of HealthPfizer Inc.sanofi-aventis Takeda Pharmaceutical

Company LimitedUS Food and Drug

AdministrationUS Environmental Protection

Agency


ImaGInG for tranSlatIonal SafEty aSSESSmEnt paGE 2

ImaGInG for tranSlatIonal SafEty aSSESSmEnt

photo: Dr. G. Allan Johnson, Duke CIVM


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ChairDr. Véronique Thybaud sanofi-aventis

Vice-ChairDr. Bhaskar Gollapudi The Dow Chemical Company

HESI Manager: Dr. James Kim


This scientific program is committed to:• Improving the scientific basis of the interpretation of results

from in vitro genetic toxicology tests for purposes of more accurate human risk assessment,

• Developing follow-up strategies for determining the relevance of in vitro test results to human health, and

• Providing a framework for integration of in vitro testing results into a risk-based assessment of the effects of chemical exposures on human health.

Areas of scientific focus• Quantitative assessment and dose-response modeling of

genetox data,• Improving Existing Assays,• New Approaches,• Validation of the Pig-a assay, and• Genotoxicity of Nanomaterials.

Why get involved?• Move the field of genetic toxicology from a qualitative

science to quantitative approaches to better understand human health risk, and promote this ‘paradigm-shift’ of how genetox data are considered in risk assessment practices;

• Ensure that future generations of genetic toxicologists will have access to cell lines with well-characterized provenance;

genetox data. Data can be exported into appropriate formats for further statistical analyses and modeling efforts.

What is the Committee’s focus for May 2011 - April 2012 • A workshop on New Approaches is being organized for

2012 to bring in expertise outside of the genetic toxicology discipline to better understand how advances in knowledge and technologies might be applied to the field. It is also hoped that this workshop will provide cross-fertilization of ideas and technologies between genetic toxicologists and other scientific fields.

• The Improving Existing Assays workgroup is in the process of setting up an international network of cell banks that will provide common cell lines used in genetic toxicity testing. The IVGT recognized that many commercially available cell lines may have ‘drifted’ (genomically) over time, and are no longer as useful. The workgroup will also publish recommendations on monitoring genetic drift of cell lines and a guideline on good cell culture practices to prevent drift from occurring in the future. Human and animal S9 will also be compared for metabolic activation of agents that damage DNA.

• Experts in various dose-response models are engaged and will provide analyses of data in the genetox database. These analyses will provide the foundation for appropriate in vitro to in vivo extrapolation, and explore whether non-linear dose-response curves can apply to direct-acting DNA reactive agents.

• The Genetox of Nanomaterials workgroup will complete their publication summarizing the 2010 workshop.

• The IVGT will be hosting a symposium on the Commit-tee’s activities and findings at the Japan Society of Toxicology conference in July 2011.

Recent publicationsGollapudi BB, Thybaud V, Kim JH, Holsapple M. Strategies for the follow-up of positive results in the in vitro genotoxicity assays-An international collaborative initiative. Environ Mol Mutagen 2011;52, 174-6.

Dearfield KL, Thybaud V, Cimino MC, Custer L, Czich A, Harvey JS, Hester S, Kim JH, Kirkland D, Levy DD, Lorge E, Moore MM, Ouedraogo-Arras G, Schuler M, Suter W, Sweder K, Tarlo K, van Benthem J, van Goethem F, Witt KL. Follow-up actions from positive results of in vitro genetic toxicity

and• Work with many international experts in the field of genetic

toxicology. Key accomplishments:• Decision Tree Review. This workgroup comprehensively

evaluated in vitro genetic toxicity assays, and used this information to develop a decision tree schematic for testing of chemicals and pharmaceuticals.

• New and Emerging Technologies. Open workshop held in May 2008 to discuss advances in assays and technologies used to assess genetic toxicity endpoints. From this workshop, the IVGT identified the Pig-a assay as a particu-larly useful in vivo assay that could be ‘bolted’ onto current in vivo testing study designs. IVGT participants have been involved in performing laboratory work and data to support assay validation.

• Genotoxicity of Nanomaterials. Workshop was organized and held in October 2010 at the Environmental Mutagen Society conference. A manuscript is being prepared that summarizes the presentations, the breakout group discus-sions, and the recommendations from the workshop.

• Genetox Database. To support the quantitative analyses of genetox data, the IVGT collaborated with Health Canada to construct a relational database to house dose-response

AstraZeneca ABBayer HealthCare AGBioRelianceBristol-Myers Squibb

CompanyCovanceErrol Zeiger ConsultingFederal Institute for Drugs

and Medical Devices (BfArM, Germany)

GlaxoSmithKlineHealth Canada Institut de Recherches

Internationales SERVIERJohnson & Johnson

PharmaceuticalsKirkland ConsultingLitron LaboratoriesL’Oréal CorporationMitsubishi Tanabe Pharma

CorporationNational Institute of Health

Sciences (Japan)National Institute for Public

Health and the Environment (RIVM, The

Netherlands)New York Medical CollegeNovartis Pharma AGPfizer Inc.Procter & Gamble Companysanofi-aventisSt. George’s Univ. of London

(United Kingdom)Swansea University (United

Kingdom)Takeda Pharmaceutical

Company LimitedThe Coca-Cola CompanyThe Dow Chemical CompanyToxicology Consulting

Services US Department of

AgricultureUS Environmental Protection


Administration

In vItro GEnEtIc toxIcIty tEStInG (IvGt)


In vItro GEnEtIc toxIcIty tEStInG (IvGt) paGE 2

testing. Environ Mol Mutagen 2011;52, 177-204.

Lynch AM, Sasaki JC, Elespuru R, Jacobson-Kram D, Thybaud V, De Boeck,M, Aardema MJ, Aubrecht J, Benz RD, Dertinger SD, Douglas GR, White PA, Escobar PA, Fornace A, Jr. Honma M, Naven RT, Rusling JF, Schiestl RH, Walmsley RM, Yamamura E, van Benthem J, Kim JH. New and emerging technologies for genetic toxicity testing. Environ Mol Mutagen 2011; 52, 205-23.



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Committee LeaderDr. Rosemary ZaleskiExxonMobil Biomdedical Sciences, Inc.



This scientific program is committed to:• Developing a decision-framework to advance and improve

mixtures risk assessment methodology.• Designing methods to prioritize those environmental

chemical mixtures that should be subject to in-depth risk assessment and those that are expected to be of lesser concern.

Areas of scientific focusExamining the potential application of a threshold of toxicologi-cal concern (TTC) approach to mixtures risk assessment as a screening-level, “Tier 0” approach.

Key accomplishments:• Publication of synergy review: Prior to developing the Tier 0

TTC methodology, it was essential to know whether synergistic interactions can occur at low, environmentally relevant exposure levels. A committee-sponsored literature review was initiated and the results of this review were published in Critical Reviews in Toxicology. Due to the relevance of the review findings, there is strong international interest in this publication.

• Development of Tier 0 TTC methodology: TTC Tier 0 methodology to assess a hypothetical mixture of chemicals in surface water was developed by the Committee. This

mental and non-governmental bodies.• Presentations at international meetings: Representa-

tives of the Mixtures Project Committee project have given presentations on the group’s work at European Societies of Toxicology (EUROTOX)/International Congress of Toxicology (ICT) and Toxicology Forum Meetings.

What is the Committee’s focus for May 2011 - April 2012 • Publication of case examples prepared for the February

2011 WHO OECD HESI Workshop.• Presentation of Committee work at several interna-

tional meetings, including the Society of Toxicology, EUROTOX, and the International Toxicology of Mixtures Conference.

• The Committee plans to sunset in Fall 2011.

Recent publicationsBoobis A, Budinsky R, Collie S, Crofton K, Embry M, Felter S, Hertzberg R, Kopp D, Mihlan G, Mumtaz M, Price P, Solomon K, Teuschler L, Yang R, Zaleski R. Critical analysis of literature on low-dose synergy for use in screening chemical mixtures for risk assessment. Critical Reviews in Toxicology 2011;41(5): 369-83.

Boobis A, Budinsky R, Crofton K, Embry M, Felter S, Mihlan G, Mumtaz M, Price P, Solomon K, Zaleski R. Annex B Example case study B: Tier 0 – Substances potentially detectable in surface water. Regulatory Toxicology and Pharmacology 2011. In press.

initial example was included as an example appendix within the World Health Organization/International Programme on Chemical Safety’s (IPCS) Framework for Assessing Risk of Combined Exposures to Multiple Chemicals, published in Regulatory Toxicology and Pharmacology.

• Development of Tier 0 TTC case studies: The Committee developed four case examples illustrating the Tier 0 TTC approach: carbamates, commercial hexane, drinking water contaminants, and pharmaceuticals in drinking water. These examples were presented and discussed at the February 2011 World Health Organization-International Programme on Chemical Safety (WHO-IPCS)/Organisation for Economic Co-operation and Development (OECD)/HESI Workshop, included in the official OECD-led meeting report, and several will be written up for publication.

• WHO OECD ILSI/HESI International Workshop on Risk Assessment of Combined Exposures to Multiple Chemicals: The Committee provided funding and support of this international workshop in February 2011, whose goals were to inform participants about the WHO framework and explore application of the framework through discussion of a number of illustrative case studies. Four case examples were provided by HESI and discussed by ~60 participants representing 14 countries as well as international govern-

Bayer CropScience Centers for Disease Control,

ATSDRDow Corning CorporationEli Lilly and CompanyExxonMobil Biomedical

Sciences, Inc.Imperial College London

Procter & Gamble CompanySyngentaThe Dow Chemical CompanyUS Environmental Protection

AgencyUniversity of Guelph

mIxturES


mIxturES paGE 2



HESI SuBcommIttEES Overview

37 Evaluating Causality in Epidemiologic Studies

Subcommittees are formed as a result of a stakeholder solicitation process (the HESI Emerging Issues Process) followed by prioritization of proposals, voting, and selection of at least one new Subcommittee each year depending on availability of staff resources. In contrast to Technical and Project Committees, which are self-supporting, HESI Subcommittees are fully supported by the organization during their first year, followed by partial support the second year. Subcommittees typically have a finite lifetime of two years or less, but can petition the HESI Board of Trustees for elevation to Project or Technical Committee status. HESI currently supports one Emerging Issues Subcommittee: Evaluating Causality in Epidemiologic Studies.

35 36

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3837

HESI Subcommittee

Committee LeaderDr. Carol Burns The Dow Chemical Company



This scientific program is committed to:Stimulating a dialogue on the methods and issues related to evaluating causality and interpreting evidence from published epidemiology studies.

Areas of scientific focus• Strengthen the value and impact of epidemiologic studies in

quantitative health risk assessments by fostering agreement on what constitutes clear and relevant epidemiologic evidence for causation.

• Address fundamental issues in epidemiology such as prior knowledge, study design, and systematic and random errors.

• Promote a dialogue on interpreting the potential for false positive and negative results in published epidemiology studies.

Why get involved?• Promote better use of human data in risk assessments by

establishing clear, quantitative criteria for evaluating causality in epidemiologic studies.

• Engage in cross-disciplinary discussion about evaluating causality in epidemiologic studies with the epidemiology, toxicology, and medical communities.

Key accomplishments:The Subcommittee on Evaluating Causality in Epidemiologic Studies was initiated in the fall of 2010. Early accomplishments include the development of a strong tripartite Steering Team, a robust Subcommittee, and a work plan for the coming year.

What is the Committee’s focus for May 2011 - April 2012 • The Subcommittee will hold a workshop in 2012 to stimulate

a dialogue on evaluating causality in epidemiologic studies in a risk assessment context by bridging the gap between theory and practice, and engaging multi-disciplinary experts from the epidemiology, medical, and toxicology communi-ties.

• The workshop discussions will be used to prepare a manuscript for publication in the peer-reviewed literature.

EvaluatInG cauSalIty In EpIdEmIoloGIc StudIES EvaluatInG cauSalIty In EpIdEmIoloGIc StudIES paGE 2

2010 - 2011 Participating organizations:Aarhus University Hospital,

DenmarkATSDR National Center for

Environmental HealthBayer CropScienceBristol-Myers Squibb

CompanyDLW Consulting ServicesE.I. du Pont de Nemours and

CompanyExxonMobil Biomedical

Sciences, Inc.GlaxoSmithKlineHarvard School of Public

HealthIndiana UniversityMcGill UniversityMedical Research Council,

University of Leicester, UKMonsanto Company

National Institute of Child Health and Human Development

National Institute of Environmental Health Sciences

Procter & Gamble CompanyShell Oil CompanyThe Dow Chemical CompanyUniversity of Aarhus,

DenmarkUniversity of Guelph, CanadaUniversity of North Carolina

at Chapel HillUS Environmental Protection


Administration



4039

HESI actIvItIES map

Outreach is an essential component of HESI’s programs, affording an opportunity to communicate the science and improve awareness of committee efforts. Outreach in 2010 broadly engaged over 1,000 scientists internationally in discussion of public health and environmental issues via workshops, symposia, and oral and poster presentations. The outreach map captures a breadth of HESI workshops and presentations throughout 2010.

HESI actIvItIES map

HESI Outreach 2010

16 workshops 31 presentations 6 countries

Over 1100 scientists participating

HESI ScIEncE 2011

HESI ScIEntIfIc portfolIo

HESI ‘s scientific programs are conducted by multi-sector committees that organize, support, and execute collaborative laboratory research programs, workshops, conferences, literature reviews, the development and analysis of databases, etc. These committees have substantial participation from academic and government scientists, and disseminate the products of their activities through peer-reviewed journals, monographs, and other print- and web-based publications.

HESI Science 2011

Translational Biology

• Cardiac safety evaluation• Biomarkers of renal toxicity• Developmental and reproductive tox• Immunotoxicology

New Technologies

• Imaging for safety evaluation• Genomics in mechanism-based risk assessment

New Approaches

• BiologicalsignificanceofDNAadducts• Adjuvant/vaccine safety and risk of autoimmunity

Environmental Toxicology

• Animal alternatives in environmental risk assessment

• Methods for a tiered approach to assess bioaccumulation

Assessing Risk

• Risk assessment in the 21st Century (Risk 21) • Relevance of positive results from in vitro

genotoxicity testing• Protein allergenicity• Distinguishing adverse from non-adverse/adaptive

effects• Assessing risks from mixtures• Evaluating causality in epidemiologic studies

41

Health and Environmental Sciences Institute1156 15th Street, N.W.Second FloorWashington, DC 20005USA1.202.659.3306 voice1.202.659.3617 faxwww.hesiglobal.org

HESI projEct mEcHanISmS

propSoSInG a HESI projEct

The adoption of new programs and projects allows HESI to address the most relevant emerging science and serve as a resource for its stakeholders to pursue collaborative scientific evaluation. Three mechanisms for proposing new projects are in place and are described below. More information about each of these project mechanisms can be found at http://www.hesiglobal.org/i4a/pages/index.cfm?pageid=3540.

HESI EmErGInG ISSuES procESS

The Emerging Issues process is HESI’s traditional and longest-standing project adoption process. The mechanism ensures a platform for broad input on new science, and creates an opportunity for all interested parties (public and private) to engage in project development without the hurdle of an initial financial commitment.

HESI rESourcES-at-InItIatIon procESS

The HESI Resources-at-Initiation (RAI) process is a mechanism for responding to well-defined and time-sensitive projects. The RAI process includes requirements for dedicated funding up front by the project submitters, as well as tripartite engagement and relevance to the mission of HESI.

IntEGratIon Into ExIStInG HESI ScIEntIfIc commIttEES

The direct integration of a project into an existing HESI committee is appropriate for single party submitters (one scientist, organization, or company) whose idea is directly relevant to the mission and objectives of the targeted committee. The proposal should augment the current research portfolio of the committee. Proposals should be submitted directly to the HESI staff manager of the committee.

HESI is always seeking opportunities to increase the impact and relevance of its portfolio. If you have suggestions or would like to propose new program areas, please contact Nancy G. Doerrer, MS (HESI Associate Director) at [email protected].

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Documents

Activities Report Health and Environmental 2010-2011 Sciences …hesiglobal.org/wp-content/uploads/sites/11/2015/11/... · 2019-04-20 · Merck & Co. Inc. Michigan State University