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National Toxicology Program (NTP)National Toxicology Program (NTP)

Mission: Mission: - coordinate DHHS toxicology research and testing- coordinate DHHS toxicology research and testing- strengthen the science base in toxicology- strengthen the science base in toxicology- provide data for assessments of risks to human health- provide data for assessments of risks to human health- develop and validate new and/or alternative tests for toxicity and - develop and validate new and/or alternative tests for toxicity and carcinogenicitycarcinogenicity

Resources:Resources:- in-house research- in-house research- contracted research and testing- contracted research and testing- coordination of extramural research supported by government and non-- coordination of extramural research supported by government and non-government fundinggovernment funding

Purpose:Purpose:- to provide descriptive pathobiology resulting from chemical exposure- to provide descriptive pathobiology resulting from chemical exposure- to better understand basic biological mechanisms and their response(s) - to better understand basic biological mechanisms and their response(s)

to chemical insultto chemical insult- to provide proper prospective regarding chemical use and human exposure- to provide proper prospective regarding chemical use and human exposure

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NTP OrganizationNTP OrganizationAssistant Secretary for HealthAssistant Secretary for Health

Executive CommitteeExecutive Committee(CPSC, EPA, FDA, NCI,(CPSC, EPA, FDA, NCI,NIEHS, NIOSH, OSHA)NIEHS, NIOSH, OSHA)

Center for Center for Disease ControlDisease Control

NIOSHNIOSH

National ToxicologyNational ToxicologyProgramProgram

National InstitutesNational Institutesof Healthof Health

NIEHSNIEHS(Environmental(Environmental

Toxicology Program)Toxicology Program)

Board of ScientificBoard of ScientificCounselorsCounselors

Food and DrugFood and DrugAdministrationAdministration

NCTRNCTR

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NTP Board of Scientific Counselors ReviewNTP Board of Scientific Counselors Review(Public Meeting)(Public Meeting)

NTP Executive Committee Review SelectionNTP Executive Committee Review Selection

NTP Designs and Initiates StudiesNTP Designs and Initiates StudiesBased on Resources and PrioritiesBased on Resources and Priorities

Public ReviewPublic Review

Federal Agency ReviewFederal Agency Review

National Toxicology Program Nomination National Toxicology Program Nomination ProcessProcess

Federal and State AgenciesFederal and State Agencies PublicPublic

Other OrganizationsOther Organizations

International OrganizationsInternational Organizations

LaborLabor

IndustryIndustryAcademiaAcademia

NIEHS/NTPNIEHS/NTP

Office of NominationsOffice of Nominations

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Toxicological Evaluation ProcessToxicological Evaluation ProcessNational Toxicology ProgramNational Toxicology Program

ChemicalChemicalNominationNomination

Literature Review

Chemical Selection

Study Selection andProtocol Design

14-Day and 13-WeekToxicity Studies(Toxicity Report)

2-Year Studies of ChronicToxicity and Carcinogenicity

Peer Review(Technical Report)

Health & Safety Info.Analytical ChemistryGenetic Toxicology

Chemical DispositionImmunotoxicology

TeratologyReproduction

Neurobehavior

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Classes of Chemicals StudiedClasses of Chemicals Studied

Agricultural ChemicalsConsumer ProductsCosmetics and Cosmetic AdditivesEnvironmental Contaminants FibersFlame RetardantsMetals Monomers used in the Plastics IndustryNatural ProductsPharmaceuticalsSolvents Synthetic Intermediates

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Chemicals Studied by the NTPChemicals Studied by the NTP

Congress mandates that industry test new chemicals and other agents for Congress mandates that industry test new chemicals and other agents for adverse health and environmental effect prior to marketing.adverse health and environmental effect prior to marketing.

NTP studies:NTP studies:- chemicals found in the environment not closely associated with commercial operations

- biological or physical agents that might not be tested without Federal involvement

- commercial agents first marketed prior to current testing requirements- orphan drugs or chemicals that might not be developed without Federal involvement

- mixtures of chemicals for which evaluations can not be required of industry- chemicals for which testing will enhance our knowledge of structure/activity relationships

- chemicals involved in emergencies that require immediate government evaluation

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Classes or Types of Chemicals not Generally Classes or Types of Chemicals not Generally Recommended for NTP StudyRecommended for NTP Study

Chemicals that have been subjects of previous adequate studiesChemicals that have been subjects of previous adequate studies

Highly reactive chemicalsHighly reactive chemicals

Insoluble chemicals Insoluble chemicals

Chemicals that are highly toxic by a known mechanism Chemicals that are highly toxic by a known mechanism

Simple alkanes and their respective alcohols and acids Simple alkanes and their respective alcohols and acids

Esters that will be hydrolyzed to non-toxic alcohols and acidsEsters that will be hydrolyzed to non-toxic alcohols and acids

Chemicals produced in very low volumesChemicals produced in very low volumes

Chemicals used exclusively in closed systems Chemicals used exclusively in closed systems

Biochemicals that normally exist in biological systemsBiochemicals that normally exist in biological systems

Complex mixturesComplex mixtures

Pure elements or simple compounds with no structural alerts Pure elements or simple compounds with no structural alerts

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NCI/NTP Studies & Results To DateNCI/NTP Studies & Results To Date

# Chemicals Tested As:# Chemicals Tested As:

PositivePositive 241241NegativeNegative 146146EquivocalEquivocal 64 64

CarcinogensCarcinogens 451451

PositivePositive 54 54NegativeNegative 15 15InconclusiveInconclusive 2 2

TeratogensTeratogens 71 71

PositivePositive 650 650NegativeNegative 11731173MixedMixed 67 67

Mutagens (Ames Test)Mutagens (Ames Test) 18901890

PositivePositive 40 40NegativeNegative 50 50

ReproductiveReproductive 90 90

Metabolism andMetabolism and 209209 DispositionDisposition

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Testing and Methods Development Testing and Methods Development

• NTP emphasis is on a comprehensive approach NTP emphasis is on a comprehensive approach to to characterize the fate and toxicity of chemicalscharacterize the fate and toxicity of chemicals

• Comprehensive approach involves Comprehensive approach involves - General toxicity studies plus genetic,

reproductive, neuro- and immunotoxicity

- Studies of chronic toxicity and carcinogenicity- Studies to determine the fate and persistence of

chemicals in intact animals- Mechanistic studies

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Toxicity/Carcinogenicity Tests Toxicity/Carcinogenicity Tests

Test effortsTest efforts- Focused on characterizing toxic or carcinogenic

properties of major chemicals and chemical classes

- Toxicity testing is an evolving process which develops and evaluates new methods for toxicity

assessment

- New and improved methods may be incorporated as they are developed and validated

- Less informative methods may be dropped or de-emphasized

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Prechronic and Chronic TestingPrechronic and Chronic Testing

Methods:Methods: Species/StrainSpecies/Strain • Duration of Studies• Duration of Studies

- Fischer 344 rat- Fischer 344 rat - Prechronic = 90 days- Prechronic = 90 days- B6C3F- B6C3F11 mouse mouse - Chronic = 2 years- Chronic = 2 years

Number of animals used/DoseNumber of animals used/Dose • Doses• Doses- 10 animals of each sex and - 10 animals of each sex and - MTD- MTD species in prechronic studies species in prechronic studies - Fractions of - Fractions of

MTDMTD- 50 animals/sex/species at each - 50 animals/sex/species at each dose in chronic studiesdose in chronic studies

Route of Administration (intended to simulate Route of Administration (intended to simulate likely human exposure)likely human exposure)

- Oral = feed, water, or gavage- Oral = feed, water, or gavage- Inhalation - Inhalation - Dermal- Dermal

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““Batting Average” Batting Average” (How Good are Animal Tests)(How Good are Animal Tests)

For Predicting:For Predicting:Acute Toxicity Very GoodChronic Toxicity GoodCarcinogenicity Moderate to GoodMutagenicity Variable

Notes:Notes:1. Animal tests may not result in responses proportional to

those seen in humans 2. Sensitivity may vary with sex and species2. Sensitivity may vary with sex and species 3. Target organ toxicity observed may or may not predict 3. Target organ toxicity observed may or may not predict

target organs for humanstarget organs for humans

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NTP InitiativesNTP Initiatives

• • TestingTesting

• • Methods DevelopmentMethods Development and Validationand Validation

• • Applied ResearchApplied Research

CarcinogenesisToxicity, chronic and prechronicTeratologyReproductionGenetic ToxicityImmunotoxicityNeurobehavioral TeratologyChemical Disposition

Tumor Promotion ModelsReproductive assaysIn vitro/short-term teratology testsGenetic toxicity assaysNMR Tumor ImagingTransgenic animal assaysAlternative Test Systems

Chemical Specific ToxicitiesTarget organ responsesToxicokinetics and Risk AssessmentMechanisms of metabolism and toxicity

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Chemicals in CommerceChemicals in Commerce

Estimated approximately 70 to 75,000 chemicals currently in commerceEstimated approximately 70 to 75,000 chemicals currently in commerce

Approximately 90% of these chemicals predate TSCA and consist of: Approximately 90% of these chemicals predate TSCA and consist of: - 20 to 30% discrete organic chemicals - 20 to 30% discrete organic chemicals - 10 to 20% inorganic chemicals- 10 to 20% inorganic chemicals- 20 to 30% complex reaction mixtures- 20 to 30% complex reaction mixtures- 20 to 30% polymers- 20 to 30% polymers

Chemicals reported to EPA under Inventory Update Rule = aprox. 8200 Chemicals reported to EPA under Inventory Update Rule = aprox. 8200 Includes: Includes:

- undefined mixtures- undefined mixtures- biochemicals- biochemicals- some redundancies- some redundancies- some, but not all- some, but not all

- naturally occurring chemicals - naturally occurring chemicals - drugs and excipients- drugs and excipients- cosmetic ingredients - cosmetic ingredients - food additives- food additives

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Chemicals Remaining to be TestedChemicals Remaining to be Tested

Estimated unique chemicals reported to EPA = 5,000Estimated unique chemicals reported to EPA = 5,000

Estimated other chemicals produced and not reported to EPA = 2,500 to Estimated other chemicals produced and not reported to EPA = 2,500 to

3,0003,000

Unique chemicals studied in 2 year rodent assays = approximately 1300*Unique chemicals studied in 2 year rodent assays = approximately 1300*

Chance that an untested chemical would be a human carcinogen = 5-Chance that an untested chemical would be a human carcinogen = 5-

10%**10%**

Estimated human carcinogens remaining in production = 400 to 800Estimated human carcinogens remaining in production = 400 to 800

Naturally occurring carcinogens = ?Naturally occurring carcinogens = ?

* Gold, L.S. and Zeiger. E. Eds. Handbook of Carcinogenic Potency and Genotoxicity Databases. * Gold, L.S. and Zeiger. E. Eds. Handbook of Carcinogenic Potency and Genotoxicity Databases.

Boca Raton, FL: CRC Press, 1997 in press.Boca Raton, FL: CRC Press, 1997 in press.

** Fung et al. The carcinogensis bioassay in perspective: Application in identifying human cancer hazards.** Fung et al. The carcinogensis bioassay in perspective: Application in identifying human cancer hazards.

Environmental Health Perspectives 103, 680-3, 1995.Environmental Health Perspectives 103, 680-3, 1995.

07_1350slides.ppt