National Toxicology Program (NTP)

3. National Toxicology Program (NTP) Mission: - coordinate DHHS toxicology research and testing - strengthen the science base in toxicology - provide data for assessments of risks to human health - develop and validate new and/or alternative tests for toxicity and carcinogenicity Resources: - in-house research - contracted research and testing - coordination of extramural research supported by government and non-government funding Purpose: - to provide descriptive pathobiology resulting from chemical exposure - to better understand basic biological mechanisms and their response(s) to chemical insult - to provide proper prospective regarding chemical use and human exposure

4. NTP OrganizationAssistant Secretary for Health • Executive Committee • (CPSC, EPA, FDA, NCI, • NIEHS, NIOSH, OSHA) • Center for • Disease Control • NIOSH National Toxicology Program National Institutes of Health NIEHS (Environmental Toxicology Program) Board of Scientific Counselors Food and Drug Administration NCTR

5. National Toxicology Program Nomination Process Public International Organizations Federal and State Agencies Labor Other Organizations NIEHS/NTP Office of Nominations Industry Academia Federal Agency Review Public Review NTP Board of Scientific Counselors Review (Public Meeting) NTP Executive Committee Review Selection NTP Designs and Initiates Studies Based on Resources and Priorities

6. Toxicological Evaluation ProcessNational Toxicology Program • Chemical • Nomination Literature Review Chemical Selection Health & Safety Info. Analytical Chemistry Genetic Toxicology Study Selection and Protocol Design 14-Day and 13-Week Toxicity Studies (Toxicity Report) Chemical Disposition Immunotoxicology Teratology Reproduction Neurobehavior 2-Year Studies of Chronic Toxicity and Carcinogenicity Peer Review (Technical Report)

7. Classes of Chemicals Studied Agricultural Chemicals Consumer Products Cosmetics and Cosmetic Additives Environmental Contaminants Fibers Flame Retardants Metals Monomers used in the Plastics Industry Natural Products Pharmaceuticals Solvents Synthetic Intermediates

8. Chemicals Studied by the NTP • Congress mandates that industry test new chemicals and other agents for adverse health and environmental effect prior to marketing. • 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

9. Classes or Types of Chemicals not Generally Recommended for NTP Study • Chemicals that have been subjects of previous adequate studies • Highly reactive chemicals • Insoluble chemicals • Chemicals that are highly toxic by a known mechanism • Simple alkanes and their respective alcohols and acids • Esters that will be hydrolyzed to non-toxic alcohols and acids • Chemicals produced in very low volumes • Chemicals used exclusively in closed systems • Biochemicals that normally exist in biological systems • Complex mixtures • Pure elements or simple compounds with no structural alerts

10. NCI/NTP Studies & Results To Date • # Chemicals Tested As: Mutagens (Ames Test) 1890 • Carcinogens 451 • Positive 650 • Negative 1173 • Mixed 67 • Positive 241 • Negative 146 • Equivocal 64 • Reproductive 90 • Teratogens 71 • Positive 40 • Negative 50 • Positive 54 • Negative 15 • Inconclusive 2 • Metabolism and 209 • Disposition

11. Testing and Methods Development • NTP emphasis is on a comprehensive approach to characterize the fate and toxicity of chemicals • 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

12. Toxicity/Carcinogenicity Tests • Test 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

13. Prechronic and Chronic Testing • Methods: Species/Strain • Duration of Studies - Fischer 344 rat - Prechronic = 90 days - B6C3F1 mouse - Chronic = 2 years • Number of animals used/Dose • Doses - 10 animals of each sex and - MTD species in prechronic studies - Fractions of MTD - 50 animals/sex/species at each dose in chronic studies • Route of Administration (intended to simulate likely human exposure) - Oral = feed, water, or gavage - Inhalation - Dermal

14. “Batting Average” (How Good are Animal Tests) • For Predicting: Acute Toxicity Very Good Chronic Toxicity Good Carcinogenicity Moderate to Good Mutagenicity Variable • Notes: 1. Animal tests may not result in responses proportional to those seen in humans • 2. Sensitivity may vary with sex and species • 3. Target organ toxicity observed may or may not predict target organs for humans

15. NTP Initiatives Carcinogenesis Toxicity, chronic and prechronic Teratology Reproduction Genetic Toxicity Immunotoxicity Neurobehavioral Teratology Chemical Disposition Tumor Promotion Models Reproductive assays In vitro/short-term teratology tests Genetic toxicity assays NMR Tumor Imaging Transgenic animal assays Alternative Test Systems Chemical Specific Toxicities Target organ responses Toxicokinetics and Risk Assessment Mechanisms of metabolism and toxicity • • Testing • • Methods Development • and Validation • • Applied Research

16. Chemicals in Commerce • Estimated approximately 70 to 75,000 chemicals currently in commerce • Approximately 90% of these chemicals predate TSCA and consist of: • - 20 to 30% discrete organic chemicals • - 10 to 20% inorganic chemicals • - 20 to 30% complex reaction mixtures • - 20 to 30% polymers • Chemicals reported to EPA under Inventory Update Rule = aprox. 8200 Includes: • - undefined mixtures • - biochemicals • - some redundancies • - some, but not all • - naturally occurring chemicals • - drugs and excipients • - cosmetic ingredients • - food additives

17. Chemicals Remaining to be Tested • Estimated unique chemicals reported to EPA = 5,000 • Estimated other chemicals produced and not reported to EPA = 2,500 to 3,000 • Unique chemicals studied in 2 year rodent assays = approximately 1300* • Chance that an untested chemical would be a human carcinogen = 5-10%** • Estimated human carcinogens remaining in production = 400 to 800 • Naturally occurring carcinogens = ? • * Gold, L.S. and Zeiger. E. Eds. Handbook of Carcinogenic Potency and Genotoxicity Databases. • Boca Raton, FL: CRC Press, 1997 in press. • ** Fung et al. The carcinogensis bioassay in perspective: Application in identifying human cancer hazards. • Environmental Health Perspectives 103, 680-3, 1995.