NICEATMNICEATMNational Toxicology Program Center for National Toxicology Program Center for the Evaluation Of Alternative Methodsthe Evaluation Of Alternative Methods

ICCVAMICCVAMInteragency Coordinating Committee on Interagency Coordinating Committee on the Validation of Alternative Methodsthe Validation of Alternative Methods

Leonard M. Schechtman, Ph.D.Leonard M. Schechtman, Ph.D.Chair, ICCVAMChair, ICCVAMDeputy DirectorDeputy Director

FDA National Center for FDA National Center for Toxicological Research (NCTR)Toxicological Research (NCTR)

Rockville, Maryland, USARockville, Maryland, USA

ICCVAM and the Evaluation of ICCVAM and the Evaluation of Alternative Test Methods: Current Alternative Test Methods: Current

Practices and ActivitiesPractices and Activitieshttp://iccvam.niehs.nih.govhttp://iccvam.niehs.nih.gov

Japanese Society of Alternatives to Animal Experiments (JSAAE)Japanese Society of Alternatives to Animal Experiments (JSAAE)Tokyo, Japan, December 8Tokyo, Japan, December 8--9, 20069, 2006

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Genesis & Evolution of ICCVAMGenesis & Evolution of ICCVAMAd Hoc Ad Hoc

CommitteeCommittee19941994

StandingStandingCommitteeCommittee

19971997

PermanentPermanentCommitteeCommittee

20002000

Composition:Composition:15 Federal 15 Federal AgenciesAgenciesICCVAMICCVAM

AuthorizationAuthorizationActAct

ICCVAMICCVAM11

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(scientific & administrative support)(scientific & administrative support)______________________________________________________________________________________________________________________11IInteragency nteragency CCoordinating oordinating CCommittee on the ommittee on the VValidation of alidation of AAlternative lternative MMethodsethods22NNational Toxicology Program ational Toxicology Program IInteragency nteragency CCenter for the enter for the EEvaluation of valuation of AAlternative lternative TToxicological oxicological MMethodsethods

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ICCVAM Authorization Act of 2000ICCVAM Authorization Act of 2000 (P.L.106(P.L.106--545)545)

……an Act to establish, wherever feasible, an Act to establish, wherever feasible, guidelines, recommendations, and guidelines, recommendations, and regulations that promote the regulatory regulations that promote the regulatory acceptance of new or revised acceptance of new or revised scientifically valid toxicological tests scientifically valid toxicological tests that protect human and animal health that protect human and animal health and the environment while reducing, and the environment while reducing, refining, or replacing animal tests and refining, or replacing animal tests and ensuring human safety and product ensuring human safety and product effectivenesseffectiveness

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Regulatory/ResearchRegulatory/ResearchConsumer Product Safety Consumer Product Safety CommissionCommissionDepartment of AgricultureDepartment of AgricultureDepartment of InteriorDepartment of InteriorDepartment of Department of TransportationTransportationEnvironmental Protection Environmental Protection AgencyAgencyFood and Drug Food and Drug AdministrationAdministrationOccupational Safety and Occupational Safety and Health AdministrationHealth Administration

NonNon--Regulatory/ResearchRegulatory/ResearchAgency for Toxic Substances Agency for Toxic Substances and Disease Registryand Disease RegistryDepartment of DefenseDepartment of DefenseDepartment of EnergyDepartment of EnergyNational Cancer InstituteNational Cancer InstituteNational Institute of National Institute of Environmental Health SciencesEnvironmental Health SciencesNational Institute for National Institute for Occupational Safety and Occupational Safety and HealthHealthNational Library of MedicineNational Library of MedicineNational Institutes of HealthNational Institutes of Health

ICCVAM Member AgenciesICCVAM Member Agencies

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ICCVAMICCVAM’’s Missions Mission**

To facilitate development, validation To facilitate development, validation and regulatory acceptance of new and and regulatory acceptance of new and revised regulatory test methods that revised regulatory test methods that reduce, refine, and replace the use of reduce, refine, and replace the use of animals in testing while maintaining animals in testing while maintaining and promoting scientific quality and and promoting scientific quality and the protection of human health, the protection of human health, animal health, and the environmentanimal health, and the environment

________________________________________________________**Adopted by ICCVAM February 2004Adopted by ICCVAM February 2004

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ICCVAMICCVAM’’s Vision*s Vision*To be recognized as a leading authority on test method To be recognized as a leading authority on test method development and validation both within the federal development and validation both within the federal government and internationallygovernment and internationallyTo play a leading role in:To play a leading role in:

Promoting high quality sciencePromoting high quality science as the basis of national & as the basis of national & international regulatory policyinternational regulatory policySetting and harmonizing international standards for scientific Setting and harmonizing international standards for scientific validationvalidation of test methodsof test methodsPromoting and facilitating the development Promoting and facilitating the development of priority alternative of priority alternative test methodstest methodsIdentifying key alternative test methods and strategies and Identifying key alternative test methods and strategies and facilitating their validation and acceptancefacilitating their validation and acceptanceFostering humane and ethical approaches Fostering humane and ethical approaches to testing that replace, to testing that replace, reduce, and refine the use of animalsreduce, and refine the use of animalsPromoting awareness and adoptionPromoting awareness and adoption of scientifically validated test of scientifically validated test methods by regulatory agencies both nationally & internationallymethods by regulatory agencies both nationally & internationally

To develop the internal and collaborative capacity to To develop the internal and collaborative capacity to carry out its Mission and Visioncarry out its Mission and Vision________________________________________________________**Adopted by ICCVAM February 2004Adopted by ICCVAM February 2004

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Purposes of ICCVAM Purposes of ICCVAM (Public Law 106(Public Law 106--545)545)

Ensure that new/revised/alternative test methods Ensure that new/revised/alternative test methods are scientifically validated to meet agency needsare scientifically validated to meet agency needs, , andand

are more predictive of human health and ecological are more predictive of human health and ecological effects than current methodseffects than current methodscontribute to improved public health contribute to improved public health

Increase efficiency and effectiveness of agency Increase efficiency and effectiveness of agency test method reviewtest method review

Eliminate unnecessary duplicative efforts and share Eliminate unnecessary duplicative efforts and share experiences between regulatory agenciesexperiences between regulatory agenciesOptimize use of scientific expertise outside the Optimize use of scientific expertise outside the governmentgovernment

Reduce, refine, or replace the use of animalsReduce, refine, or replace the use of animalsin testing, where scientifically feasiblein testing, where scientifically feasible

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ICCVAM DutiesICCVAM Duties (Public Law 106(Public Law 106--545)545)

Consider nominations/submissions from agencies and the publicConsider nominations/submissions from agencies and the public for for review and evaluation of validated test methodsreview and evaluation of validated test methodsReview and evaluate new, revised, and alternative test methods Review and evaluate new, revised, and alternative test methods that that may be acceptable for specific regulatory usesmay be acceptable for specific regulatory usesCoordinate technical reviewsCoordinate technical reviews of proposed new or revised or of proposed new or revised or alternative test methods of interagency interestalternative test methods of interagency interestSubmit test recommendations to US Federal agenciesSubmit test recommendations to US Federal agencies, solicit agency , solicit agency responses (due within 180 days), and make these publicly availabresponses (due within 180 days), and make these publicly availableleFacilitate and/or provide guidanceFacilitate and/or provide guidance on:on:

test method test method developmentdevelopmentvalidation criteria, validation studies, validation processesvalidation criteria, validation studies, validation processesacceptanceacceptance of scientifically validated test methodsof scientifically validated test methodsimplementationimplementation of ICCVAMof ICCVAM--recommended validated methodsrecommended validated methods

e.g. by conducting training workshops for regulators and ende.g. by conducting training workshops for regulators and end--users to promote understanding and useusers to promote understanding and use

awarenessawareness of accepted test methods by Federal agencies and of accepted test methods by Federal agencies and other stakeholdersother stakeholdersinteragency and international interagency and international harmonizationharmonization of test methodsof test methods

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ICCVAM GuidelinesICCVAM Guidelines

ICCVAM guidelines provide a ICCVAM guidelines provide a framework framework and guidance and guidance forfor

satisfying validation and regulatory satisfying validation and regulatory acceptance criteria acceptance criteria building a technical dossier to demonstrate building a technical dossier to demonstrate validation of a test methodvalidation of a test methodnavigating the regulatory processes for navigating the regulatory processes for regulatory acceptance and implementationregulatory acceptance and implementation

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ICCVAM Guideline:ICCVAM Guideline: Validation and Regulatory Validation and Regulatory Acceptance of Toxicological Test MethodsAcceptance of Toxicological Test Methods

Report of the Report of the ad hocad hoc Interagency Interagency Coordinating Committee on the Coordinating Committee on the Validation of Alternative Methods Validation of Alternative Methods [ICCVAM] (March 1997)[ICCVAM] (March 1997)Provides information on:Provides information on:

Method validation processMethod validation processRegulatory acceptance processesRegulatory acceptance processesCriteria for validation of a test Criteria for validation of a test method method Criteria for regulatory Criteria for regulatory acceptanceacceptanceImplementation of a validated Implementation of a validated test methodtest methodAvailable onAvailable on--line atline athttp://iccvam.niehs.nih.gov/http://iccvam.niehs.nih.gov/docs/docs.htm#generaldocs/docs.htm#generalFor use in conjunction with For use in conjunction with ICCVAM Guidelines for ICCVAM Guidelines for Nomination and Submission Nomination and Submission of New, Revised, and Alternative of New, Revised, and Alternative Test Methods (2003)Test Methods (2003)

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Provides guidance for test method Provides guidance for test method nominations and submissions and nominations and submissions and respective processes (September 2003) respective processes (September 2003) Details ICCVAM prioritization criteria Details ICCVAM prioritization criteria and validation and regulatory and validation and regulatory acceptance criteria and processesacceptance criteria and processesPProvides basis for decisions on rovides basis for decisions on standardized protocols and validation standardized protocols and validation study designsstudy designsDescribes data and information needed Describes data and information needed to assess a test methodto assess a test method’’s current s current validation status, at any stage of validation status, at any stage of development/completiondevelopment/completionConveys the concept of Performance Conveys the concept of Performance Standards for proposed test methodsStandards for proposed test methodsIncludes a framework for organizing Includes a framework for organizing information supporting the validity of a information supporting the validity of a test method, i.e. format for the test method, i.e. format for the Background Review Document (BRD)Background Review Document (BRD)Available onAvailable on--line at line at http://iccvam.niehs.nih.gov/docs/http://iccvam.niehs.nih.gov/docs/guidelines/subguide.htmguidelines/subguide.htm

ICCVAM Guidelines for Nomination and Submission ICCVAM Guidelines for Nomination and Submission of New, Revised, and Alternative Test Methodsof New, Revised, and Alternative Test Methods

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Background Review Documents (Background Review Documents (BRDsBRDs))

A technical dossier containing a A technical dossier containing a comprehensive review of all available data comprehensive review of all available data and information on a given test methodand information on a given test methodOrganized according to standardized test Organized according to standardized test method submission guidelinesmethod submission guidelines**Provides data and information needed to Provides data and information needed to assess a test methodassess a test method’’s current validation s current validation status and regulatory acceptabilitystatus and regulatory acceptability

______________________________________________________________________________________________________________________________________________________

**ICCVAM Guidelines for the Nomination and Submission of New, ICCVAM Guidelines for the Nomination and Submission of New, Revised, and Alternative Toxicological Methods; NIEHS, 2003; Revised, and Alternative Toxicological Methods; NIEHS, 2003; http://iccvam.niehs.nih.gov/docs/guidelines/subguide.pdfhttp://iccvam.niehs.nih.gov/docs/guidelines/subguide.pdf

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Performance StandardsPerformance Standards (PS) (PS) for Validated and Accepted Test Methodsfor Validated and Accepted Test Methods

Provide the Provide the basis forbasis for evaluating the acceptability of evaluating the acceptability of proposed test methods that are mechanistically and proposed test methods that are mechanistically and functionally similar to an adequately validated functionally similar to an adequately validated andandaccepted reference test method accepted reference test method

Provides a means for Provides a means for ““meme--tootoo”” (analogous) test (analogous) test methods seeking validation subsequent to the methods seeking validation subsequent to the validated validated ““pioneerpioneer”” test method which they mimic to test method which they mimic to satisfy established standards and to demonstrate satisfy established standards and to demonstrate their comparabilitytheir comparability

Communicate the basis on which new proprietary (e.g. Communicate the basis on which new proprietary (e.g. copyrighted, trademarked, registered) and copyrighted, trademarked, registered) and nonproprietary test methods have been determined to nonproprietary test methods have been determined to have sufficient accuracy and reliability for a specific have sufficient accuracy and reliability for a specific testing purposetesting purposeRegulatory authorities can use or refer to the PS when Regulatory authorities can use or refer to the PS when they communicate acceptance of a new test methodthey communicate acceptance of a new test method

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Criteria for Prioritization Criteria for Prioritization (1)(1)

1.1. The The extentextent to which the proposed method is: to which the proposed method is: Applicable to regulatory testing needsApplicable to regulatory testing needsApplicable to multiple agencies/programApplicable to multiple agencies/program

2.2. The The extent of expected use extent of expected use or application and or application and impactimpact on human, animal, or ecological healthon human, animal, or ecological health

3.3. The potential for the method, compared to The potential for the method, compared to current methods, to be current methods, to be responsive to the 3Rsresponsive to the 3Rs::

RefineRefine animal use (i.e., decrease or eliminate animal use (i.e., decrease or eliminate pain and distress) pain and distress) ReduceReduce animal use animal use ReplaceReplace animal useanimal use

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4.4. The The completeness of the submission completeness of the submission with with regard to ICCVAM test method submission regard to ICCVAM test method submission guidelinesguidelines

5.5. The potential for the method to provide The potential for the method to provide improved prediction improved prediction of an adverse health or of an adverse health or environmental effect, compared to current environmental effect, compared to current methodsmethods

6.6. The extent to which the test method provides The extent to which the test method provides other advantagesother advantages, such as reduced cost and , such as reduced cost and time to perform, compared to current methods time to perform, compared to current methods

Criteria for Prioritization Criteria for Prioritization (2)(2)

ICCVAMNICEATM16

The The processprocess by which the by which the reliabilityreliability andandrelevance relevance of a test method are of a test method are established for a established for a specific purposespecific purpose

Reliability:Reliability: A measure of the extent to which A measure of the extent to which a test can be performed reproducibly within a test can be performed reproducibly within and among laboratories over timeand among laboratories over timeRelevance:Relevance: The extent to which a test The extent to which a test method will correctly predict or measure the method will correctly predict or measure the biological effect of interestbiological effect of interest

A determination of the A determination of the usefulnessusefulness and and limitationslimitations of a test method for a of a test method for a specific purposespecific purpose

Test Method ValidationTest Method Validation

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RegulatoryRegulatoryAcceptanceAcceptance

Test Method Acceptance CriteriaTest Method Acceptance Criteria

Fits into the regulatory testing structureFits into the regulatory testing structure

Adequately predicts the toxic endpoint of interestAdequately predicts the toxic endpoint of interest

Generates data useful for risk assessmentGenerates data useful for risk assessment

Adequate data available for specified usesAdequate data available for specified uses

Robust & transferableRobust & transferable

Time & costTime & cost--effectiveeffective

3Rs3Rsadequatelyadequatelyconsideredconsidered

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ICCVAM Working GroupsICCVAM Working Groups

Identify and Identify and prioritize future prioritize future

test method test method review activities review activities

EvaluateEvaluateadequacy of adequacy of test method test method

submission/BRDsubmission/BRD

Prepare Prepare workshop/expert workshop/expert panel questions panel questions

appropriate for the appropriate for the test methodtest method

Draft test methodDraft test methodrecommendations for recommendations for

consideration by consideration by expert panels and expert panels and then by ICCVAM then by ICCVAM

Identify/recommendIdentify/recommendworkshop or workshop or expert panel expert panel

membersmembers

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ICCVAM Workshops & Peer PanelsICCVAM Workshops & Peer PanelsICCVAM WorkshopsICCVAM Workshops

Evaluate the adequacy of Evaluate the adequacy of current test methodscurrent test methods

Identify toxicity endpoints that Identify toxicity endpoints that need improved test methodsneed improved test methods

Identify promising methods Identify promising methods that should undergo further that should undergo further development and validationdevelopment and validation

Recommend appropriate Recommend appropriate validation studiesvalidation studies

Recommend research & model Recommend research & model development efforts to support development efforts to support improved test methodsimproved test methods

Independent Review PanelsIndependent Review PanelsConduct independent scientific Conduct independent scientific peer review peer review Comprised of national and Comprised of national and international expertsinternational expertsMeetings are Public with the Meetings are Public with the opportunity for public inputopportunity for public inputDevelop scientific consensus Develop scientific consensus on the usefulness and on the usefulness and limitations of test methods limitations of test methods for specific human health or for specific human health or ecological risk assessment ecological risk assessment purposespurposesProduct: Independent Peer Product: Independent Peer Review Report submitted to Review Report submitted to ICCVAMICCVAM

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ICCVAM Validation CriteriaICCVAM Validation Criteria——General ConsiderationsGeneral Considerations

Validation criteria compiled by ICCVAMValidation criteria compiled by ICCVAM—— a toola toolto help guide and facilitate validation efforts for new, to help guide and facilitate validation efforts for new, revised, or alternative test methods and technologiesrevised, or alternative test methods and technologiesProvide Provide guidanceguidance to both test developers and agenciesto both test developers and agenciesFulfillment of these validation criteria will facilitate Fulfillment of these validation criteria will facilitate regulatory acceptanceregulatory acceptance of such methods for of such methods for safety/hazard or risk assessment purposessafety/hazard or risk assessment purposesThe extent to which these validation criteria are met The extent to which these validation criteria are met will vary with the method and its proposed usewill vary with the method and its proposed useThe validation process should The validation process should

be be flexible and adaptableflexible and adaptable given the numbers and types given the numbers and types of test methods being developed for varying purposes of test methods being developed for varying purposes adhere to adhere to sound scientific principlessound scientific principles and include and include accurate documentation/reporting of all supporting data accurate documentation/reporting of all supporting data

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ICCVAM Validation Criteria ICCVAM Validation Criteria (1)(1)

Scientific and regulatory rationaleScientific and regulatory rationale for the test method for the test method + clear statement of its + clear statement of its proposed useproposed useThe The relationship of the test methodrelationship of the test method’’s endpoint(s) to s endpoint(s) to the biologic effect of interestthe biologic effect of interestDetailedDetailed protocolprotocol for the test method must be for the test method must be available and should include a description of:available and should include a description of:

the materials needed the materials needed the parameter(s) measured and how it is measured the parameter(s) measured and how it is measured acceptable test performance criteria acceptable test performance criteria (e.g., positive and negative control responses)(e.g., positive and negative control responses)how data will be analyzed how data will be analyzed the known limitations of the test including a description of the known limitations of the test including a description of the classes of materials that the test can and cannot the classes of materials that the test can and cannot accurately assessaccurately assessa list of the species for which the test results are applicablea list of the species for which the test results are applicable

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ICCVAM Validation Criteria ICCVAM Validation Criteria (2)(2)

Extent of Extent of withinwithin--test variabilitytest variability, and the , and the reproducibility of the test within and among reproducibility of the test within and among laboratorieslaboratories must have been demonstrated must have been demonstrated

Data describing the level of intraData describing the level of intra-- and interand inter--laboratory laboratory reproducibility and how it varies over timereproducibility and how it varies over timeDegree to which biological variability affectsDegree to which biological variability affects test test reproducibilityreproducibility

Test methodTest method’’s performances performance must have been must have been demonstrated demonstrated usingusing

reference chemicalsreference chemicals orortest agents test agents representativerepresentative of the types of substances to which of the types of substances to which the test method will be appliedthe test method will be appliedshould includeshould include both known positive and known negativeboth known positive and known negative agentsagents

Chemicals or test agents should be Chemicals or test agents should be tested under codetested under codeto exclude biasto exclude bias

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ICCVAM Validation Criteria ICCVAM Validation Criteria (3)(3)

Sufficient data should be provided to permit a Sufficient data should be provided to permit a comparison of the performance of a proposed testcomparison of the performance of a proposed testwith that of the test it is designed to replace with that of the test it is designed to replace

Performance should be evaluated in relation to Performance should be evaluated in relation to existing relevant toxicity testingexisting relevant toxicity testing data and relevant data and relevant toxicity information from the species of concern toxicity information from the species of concern ReferenceReference data from the comparable traditional data from the comparable traditional test method should be available and of acceptabletest method should be available and of acceptablequalityquality

The The limitations of the methodlimitations of the method must be described must be described e.g., e.g., in vitroin vitro or other nonor other non--animal test methods may animal test methods may not replicate all of the metabolic processes relevant not replicate all of the metabolic processes relevant to chemical toxicity that occur to chemical toxicity that occur in vivoin vivo

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ICCVAM Validation Criteria ICCVAM Validation Criteria (4)(4)

Ideally, all data supporting the validity of a test Ideally, all data supporting the validity of a test method should be obtained and reported in accordance method should be obtained and reported in accordance with with Good Laboratory Practices (GLPs)Good Laboratory Practices (GLPs)

Aspects of data collection not performed according to GLPs Aspects of data collection not performed according to GLPs must be fully described, along withmust be fully described, along with their potential impacttheir potential impact

All dataAll data supporting the assessment of the validity of supporting the assessment of the validity of the test method the test method (including raw data)(including raw data) must be available must be available for reviewfor reviewDetailed protocolsDetailed protocols should be readily available and in the should be readily available and in the public domainpublic domainThe method(s) and results should be The method(s) and results should be published published or or submitted for publication in an independent, peersubmitted for publication in an independent, peer--reviewed publicationreviewed publicationThe methodology and results should have been The methodology and results should have been subjected to subjected to independent scientific reviewindependent scientific review

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Regulatory Acceptance CriteriaRegulatory Acceptance Criteria

Closely parallel ICCVAMClosely parallel ICCVAM’’s Validation Criterias Validation CriteriaBoth were developed by regulatory and nonBoth were developed by regulatory and non--regulatory/research agencies working collectivelyregulatory/research agencies working collectivelyBoth are grounded in sound scientific principlesBoth are grounded in sound scientific principlesBoth help guide and facilitate validation efforts for Both help guide and facilitate validation efforts for new, revised, or alternative test methods and new, revised, or alternative test methods and technologies technologies Both seek the endBoth seek the end--goal of regulatory acceptance and goal of regulatory acceptance and implementation for regulatory decisionimplementation for regulatory decision--making making purposespurposesBoth call for adequate consideration given to the 3RsBoth call for adequate consideration given to the 3Rs

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Regulatory AcceptanceRegulatory Acceptance——Additional ConsiderationsAdditional ConsiderationsValidation is a prerequisite for regulatory acceptanceValidation is a prerequisite for regulatory acceptance of a new method (per of a new method (per the ICCVAM Authorization Act, P.L. 106the ICCVAM Authorization Act, P.L. 106--545)545)The The validation process determines the practicalityvalidation process determines the practicality of a method (its reliability of a method (its reliability and relevance) for a particular application inand relevance) for a particular application in a given regulatory programa given regulatory programDegrees of reliability and relevance (extent of validation)Degrees of reliability and relevance (extent of validation) required by a required by a regulatory agency will depend upon use and/or extent of test modregulatory agency will depend upon use and/or extent of test modificationification

AdjunctAdjunct (e.g. mechanistic) tests might require more limited validation(e.g. mechanistic) tests might require more limited validationDefinitive Definitive tests would require extensive validationtests would require extensive validation

Validated methods are not automatically acceptedValidated methods are not automatically accepted by regulatory agencies, by regulatory agencies, despite their being validated; theydespite their being validated; they need to fit into the need to fit into the regulatory structureregulatory structureof a given agencyof a given agencyDetermination of whether a test method is considered by an agencDetermination of whether a test method is considered by an agency to be y to be useful for a specific purpose is also a function of an useful for a specific purpose is also a function of an agencyagency’’s regulatory s regulatory mandate(s) and/or the products regulated under its purviewmandate(s) and/or the products regulated under its purviewFlexibilityFlexibility is essential in determining acceptability of methods to ensure is essential in determining acceptability of methods to ensure that that appropriate scientific information is considered in regulatory aappropriate scientific information is considered in regulatory assessmentsssessmentsAcceptance of test methods will be aided ifAcceptance of test methods will be aided if regulatory agencies are involved regulatory agencies are involved throughout all phases of the process: development, throughout all phases of the process: development, prevalidationprevalidation/optimization, /optimization, validation, and acceptance phasesvalidation, and acceptance phasesRegulations, guidelines, guidances or recommendationsRegulations, guidelines, guidances or recommendations regarding newly regarding newly validated and accepted tests or test batteries should be promulgvalidated and accepted tests or test batteries should be promulgatedated

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International ActivitiesInternational ActivitiesReciprocal Observer status on respective ICCVAM and ECVAM Reciprocal Observer status on respective ICCVAM and ECVAM scientific advisory committees (SACATM, ESAC)scientific advisory committees (SACATM, ESAC)ICCVAMICCVAM––ECVAM collaborations to evaluate several alternative ECVAM collaborations to evaluate several alternative in in vitro vitro test methods for assessing dermal irritation, ocular toxicity, test methods for assessing dermal irritation, ocular toxicity, morphological transformation, etc.morphological transformation, etc.Partnered with ECVAM to develop and support final adoption of:Partnered with ECVAM to develop and support final adoption of:

OECD GD No. 34 (OECD GD No. 34 (Guidance Guidance Document Document oon tn the he Validation aValidation and nd International Acceptance International Acceptance oof New f New or Updated Test Methods or Updated Test Methods for for HHazard Assessmentazard Assessment) ) OECD guidance on application of GLPs to OECD guidance on application of GLPs to in vitroin vitro toxicity testingtoxicity testing

Interactions with Japanese Center for the Validation of Interactions with Japanese Center for the Validation of Alternative Methods (JaCVAM): Alternative Methods (JaCVAM):

Supported establishment and inauguration of JaCVAMSupported establishment and inauguration of JaCVAMInvited to participate at November 2006 SACATM meetingInvited to participate at November 2006 SACATM meetingValidation Management Team for Validation Management Team for in vivoin vivo and and in vitro in vitro Comet AssayComet Assay

Phase 1Phase 1—— validate the validate the in vivoin vivo rodent Comet assay as an alternative to rodent Comet assay as an alternative to the the in vivoin vivo rat liver unscheduled DNA synthesis (UDS) assayrat liver unscheduled DNA synthesis (UDS) assayPhase 2Phase 2—— validate the validate the in vitroin vitro rodent Comet assay as an alternative to rodent Comet assay as an alternative to the the in vivoin vivo Comet assay for the detection of Comet assay for the detection of genotoxicgenotoxic test substancestest substances

Next Next World Congress on AlternativesWorld Congress on Alternatives –– Tokyo, Aug 2007Tokyo, Aug 2007

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INDIAINDIA CHINACHINA

KOREAKOREA