Comprehensive Toxicological Assessments of FDA Selected Nominations to the National Toxicology Program; Selected NTP/NIEHS Nominations of FDA Importance FDA-NIEHS InteragencyAgreement FDA-NIEHS Interagency Agreement

Assistant Secretary for Health DHHS NTP Executive Committee: Heads, DHHS Agencies, EPA, OSHA, NCI Asnt. Sec. Labor NTP Board of Scientific Counselors National Toxicology Program (Dr. Ken Olden) NCTR/FDA NIEHS/NIHNIOSH/CDC Technical Reports Subcommittee Reports on Carcinogens Subcommittee Steering Committee Chemical Evaluation Committee Working Group Report on Carcinogens

FDA’s Mission To Protect and Promote Public Health FADAMA directs FDA to draw on the resources from organizations outside FDA with shared interest to help accomplish FDA’s Mission = LEVERAGING Using intellect, time, money and resources in a manner that Maximizes their value in enhancing FDA’s role of protecting and promoting public health

NCTR’s LEVERAGING EFFORTS “An example of an ongoing successful partnership is the one FDA enjoys with the NIEHS/NTP, which funds research and bioassays on FDA-regulated products, at NCTR.” Jane Henney - 10/04/00 FDA Leveraging Handbook

FDA-NIEHS InterAgency Agreement Signed December 6, 1992 Dr. J.E. Henney, FDA Deputy Commissioner for Operations Dr. K.L. Olden, Director, NIEHS

IAG Concept/Genesis Innovative Applied Toxicology Studies FDA Scientists Involved in Protocol Design Mechanistic/Mode of Action Studies Support Chronic Study Interpretation/Risk Assessments Reports in Timely Manner Utilize NCTR’s Expert Scientific Staff / Unique Facilities

IAG Supports FDA Research High Quality/Science-Based Safety Assessments Support Risk Management Decisions Reduce Uncertainty in Risk Assessments and Risk-Benefit Analysis Measurable - Real Time Regulatory Impact

IAG History (Fiscal Years) IAG Signed IAG Open-Ended Expanded to Include Putative Endocrine Disruptor Chemicals Resources to Develop a FDA-NIEHS Phototoxicity Research and Testing Center Resources Set Aside to Renovate 5A Animal Rooms (pending) Additional FDA High Priority Compounds Including Dietary Supplements AIDS Therapeutic Mixtures

Compounds/Agents Nominated - IAG Chloral Hydrate (CDER) Fumonisin B1 (CFSAN) Malachite Green (CVM) Urethane/Ethanol (CFSAN) Riddelliine (CFSAN/NIEHS) Glycolic & Salicylic Acids (CFSAN) Endocrine Disrupting Chemicals (FDA / NIEHS) Phototoxicology Nominations (CFSAN/NTP) Dietary Supplements (CFSAN/NTP) AIDS Therapeutic Mixtures (NTP/CDER) Thimerosal (CBER)

FDA-NIEHS IAG Chloral Hydrate Fumonisin B 1 Malachite Green Urethane/Ethanol  &  Hydroxy Acids Glycolic Acid Salicylic Acid Retinyl Palmitate Thimerosal Riddelliine Endocrine Disruptors Methoxychlor Genistein Nonylphenol Vinclozolin Ethinyl Estradiol Aloe Vera AIDS Therapeutics FDA Nominations FDA/NIEHS Nominations

FY 1999 NTP Nominations Radio Frequency Radiation Emissions (CDRH) DNA-Based Safety Assessment of Selected Vaccines/Therapeutics (CBER) Cefuroxime and Clarithromycin (CDER) p53 Study with Senna (CDER) p53 & TG:AC Studies with Pilocarpine (OOPD)

FY 2000 FDA Nominations trans-Retinyl Palmitate (PT) [CFSAN] D & C Red No. 27 (PT) [CFSAN] D & C Red No. 28 (PT) [CFSAN] Lemon Oil (PT) [CFSAN] Lime Oil (PT) [CFSAN] Thimerosal (Ethyl Mercury) [CBER]

IAG Chemical/Agent Starts FY 2001 Aloe vera (Dr. Boudreau) Phototoxicology Studies Orally Administered Studies trans-Retinyl Palmitate (Dr. Culp) Phototoxicology Studies AIDS Mixtures (Dr. Beland)

FDA-NIEHS IAG Toxicology Study Selection and Review Committee (TSSRC) FDA Product Center(s) Protocol Review NCTR Protocol Review NCTR Support Group Review NTP/NIEHS Protocol Review IAG Executive Team Funding Approval NIEHS/NTP BSC Technical Report Subcommittee Scientific Oversight - Peer Review

FDA-NIEHS IAG Reviews research concepts and plans Reviews PI designed protocols Recommends protocol modifications (e.g. dose level selection, design changes, additional studies) and protocol implementation Monitors the progress of each study Toxicology Study Selection and Review Committee (TSSRC)

IAG Principle Investigators Chloral Hydrate - Dr. Frederick Beland Fumonisin B1 - Dr. Paul Howard Malachite Green - Dr. Sandra Culp Urethane/Urethane-Ethanol - Dr. Fred Beland Glycolic Acid/Salicylic Acid - Dr. Paul Howard Endocrine Disruptors - Dr. Barry Delclos, Dr. Andy Scallet, Dr. Sherry Ferguson, Dr. Dan Doerge, Dr. Suzanne Morris Riddelliine - Dr.'s Peter Fu & Ming Chou Aloe Vera - Dr. Mary Boudreau Retinyl Palmitate - Dr. Sandra Culp AIDS Therapeutics - Dr. Frederick Beland Thimerosal - Dr. William Slikker

IAG Benefits Enhance Regulatory Decision Process Support Quantitative Risk Assessments New/Innovative Research Approaches Speed Research/Testing Process Utilize NCTR Scientific/Contract Staff FTE/Post-Doc Support Facilities Renovation (Phototoxicology) Equipment Purchase Travel for Scientific Meetings

Funding Source Comparison

FDA-NIEHS Phototoxicology Research and Testing Laboratory & NTP Center for Phototoxicology

IAG (FDA/NIEHS) Overhead to NCTR through FY 2000 Overhead generated from the IAG (FDA/NIEHS) covers the cost of doing business for NIEHS. Resources from "overhead" support facilities maintenance, equipment maintenance, contracts/procurement administration, security, utilities, laundry services, library services, janitorial services, supply management. These indirect costs are determined by usage and vary in rate according to the usage in each area.

IAG (FDA/NIEHS) Post Doc Positions

Animal Room Occupation  53 A and B used for IAG (Endocrine Disruptors, Priority Chemicals A 7 ten-rack rooms (70) 2 seven-rack rooms (14) 4 five-rack rooms (20) B 11 five-rack rooms (55)  53 C and D New born mouse and other Center studies C 10 five-rack rooms (50) 17 two-rack rooms (34) D 4 five-rack rooms (20) 60% of Bldg 53 is used for IAG 100% of Bldg. 5 is used for IAG  Building 5 Phototoxicology 1 Control Room 1 Dose Room (2 Lights) 6 Animal Rooms Building 14 Neurotoxicology & others (No IAG studies)

IAG (FDA/NIEHS) Costs Priority Chemicals Costs are through the life of the project.

IAG (FDA/NIEHS) Costs Endocrine Disrupting Chemicals Costs are through the life of the project.

IAG (FDA/NIEHS) Pathology Resources Pathology hours through August 2000 Project Hours

ADP hours through August 2000 Project Hours IAG (FDA/NIEHS) ADP Resources

IAG (FDA/NIEHS) Animal Care/Diet Prep Resources.Cage weeks reported through August 2000 Cage Weeks

IAG (FDA/NIEHS) Animal Care/Diet Prep Resources by Chemical.Cage weeks reported through August 2000 Cage Weeks

FDA/NIEHS IAG Billed & Estimated Costs through FY 2005 *Some out year projects not yet submitted to Planning for costing are estimated based on similar animal studies. ^=Billed to NIEHS

FDA-NIEHS IAG Innovative applied toxicology studies Involve FDA scientists in protocol design Conduct specific mechanistic/mode of action studies in support of sound science-based safety/risk assessments Reports in a timely manner Utilize NCTR’s unique facilities and expert scientific staff IAG Concept Genesis

FDA-NIEHS IAG FDA Chemical Selection Working Group NTP Interagency Chemical Coordination and Evaluation Committee NTP Executive Committee ò FDA Study director assigned to chemical ò Study director develops research plan ò Study director/PI develops protocol(s) Chemical/Agent Selection, Nomination & Approval

FDA-NIEHS IAG Core Members Core Members NCTR Deputy Director for Research (chair) FDA’s NTP Liaison (vice-chair/Executive Sec) NIEHS Project Officer TSSRC

FDA-NIEHS IAG Ad Hoc Members Ad Hoc Members NCTR Study Director/PI’s FDA & NIEHS scientists Other federal agencies (USDA, NCI, NIOSH) Academia International (Agriculture Canada, U.K.) Industry TSSRC

FDA-NIEHS IAG The FDA-NIEHS IAG has leveraged resources - public funds and scientific expertise - in a most effective and efficient manner which enables both FDA and NTP to better identify chemical/agent hazards, assess safety and human health risk, to the benefit of the American public. Public Health Benefit

IAG Cost Include Labor Government ORISE PAI ROW Bionetics Travel Supplies Equipment Overhead