NCTR 1996-97 Research Plans

U.S. Department of Health and Human Services

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Cooperating Organization: Environmental Protection Agency - Office of Toxic Substances
Project Number	Principal/ Co-Principal Investigator(s)	Status/ Res. Area/ GOAL	Title	Objective
E0663807	Laborde Dial Hansen Harmon Holson Jones Leakey Sheehan Webb	Active/ R&D Tox/ CNPT	Biologically-Based Dose Response Models for Developmental Toxicity: Effect of Dexamethasone (DEX) During Mid- & Late Gestation on CD Rat Dams & on Fetal Amniotic Fluid, Liver Glycogen Concentration and Enzyme Activity	1. To determine the effect of DEX exposure at two gestational periods (GD 9-14 or GD 14-19) on content and volume of amniotic fluid, and biochemistry of liver. 2. To determine the effect of late DEX exposure (GD 14-19) on maternal urine and blood chemistry. 3. To correlate DEX effects on amniotic fluid and on liver function with the stunting, clefting and wavy ribs produced in rat fetuses by this drug. 4. To assess the degree to which DEX-induced anorexia contributes to any of the above effects
E0667800	Fu Dooley Kadlubar	Active/ Bio Tox/ PRED	Neonatal Mouse Bioassay of Eight Complex Mixtures and Three Positive Control Samples	1. To use neonatal male B6C3F1 mice to determine the tumorigenic activity of eight complex mixtures samples (i.e., smoky coal, aluminum smelter emissions, ambient air, cigarette smoke, coke oven emissions, diesel exhaust, polyethylene incineration and roofing tar), three positive control samples (i.e., benzo(a)pyrene, 6-nitrochrysene, and 4-aminobiphenyl) and their carrier (DMSO). 2. To remove target tissues from treated animals and send to EPA for carcinogen-DNA adduct quantitation and characterization. 3. To prepare appropriate synthetic standards for carcinogen-DNA adduct detection.

Cooperating Organization: National Institute on Aging
Project Number	Principal/ Co-Principal Investigator(s)	Status/ Res. Area/ GOAL	Title	Objective
E0049400	Turturro Hart	Active/ Cal Res/ CNPT	Caloric Restriction in Fischer 344 Rats	Breed and age Fischer 344 calorically restricted rats.

E0050100 thru E0050805	Turturro	Active/ Cal Res/ CNPT	NIA-IAG Caloric Restriction and Aging	Breed and age calorically restricted rodents.
E0050900	Turturro Gaylor Hart Sheldon	Active/ Cal Res/ CNPT	F-344 Rat Fed Ralston-Purina Masoro Mod. Diet	Selected diet for caloric restriction.
P00304	Turturro	Active/ Cal Res/ AGNT	NIA IAG Administrative Overhead	General administration of PCR IAG.

Cooperating Organization: National Institute of Drug Abuse
Project Number	Principal/ Co-Principal Investigator(s)	Status/ Res. Area/ GOAL	Title	Objective
E0663306	Paule Binienda	Active/ Neuro Tox/ AGNT	ADDEND: Preliminary Studies for Determining the Effects of Chronic Cocaine Exposure during Pregnancy on the Behavior of Offspring in Monkeys	Increase the number of offspring in the total gestational exposure (TGE) group to ten. Requesting that 10 nonpregnant animals be maintained under chronic cocaine treatment while they are in the breeding program until at least 10 viable offspring are available. Requesting another 7 animals for inclusion in control group to bring the total to 10.

Cooperating Organization: National Institute of Environmental Health Sciences
Project Number	Principal/ Co-Principal Investigator(s)	Status/ Res. Area/ GOAL	Title	Objective
E0250001 E0250011	Schmued Sandberg Appel Blann Bo Lyn-Cook Paule Schmued Slikker	Active/ Neuro Tox/ METH	Preliminary Assessment of a Method for Screening the Potential Neurotoxic Effects of Anti-HIV Therapeutics Using Autoradiographic Measurement of Cellular Metabolic Markers (CBER)(CDER)	To examine, validate and compare the utility of a number of biological markers (2'3'-d-dideoxycytidine (ddC), 2,3'-d-dideoxyinosine (ddI), isoniazid) of neurotoxic insults using in vivo and in vitro autoradiographic methods.
E0250101	Patterson Binienda Slikker Sandberg Lipe Gillam	Active/ Neuro Tox/ AGNT	Placental Transfer and Fetal Distribution of the Human Immunodeficiency Virus (HIV) Therapeutics: 3'-azido-2',3-dideoxythymidine (AZT), 2'3'-dideoxylinosine (ddI), and 2',3'-didehydro-2'3'-dideoxythymidine (d4T) (CDER)	To determine the placental and fetal distribution of AZT, ddI and d4T, and their phosphorylated metabolites in the later-term rhesus monkey.
E0250201	Patterson Paule Sandberg Schmued Sheevers Slikker Zielinski	Active/ Neuro Tox/ PRED	Neurotoxicological and Behavioral Assessment of the Human Immunodeficiency Virus (HIV) Suppressors 2',3'-dideoxycytidine (ddC) and Thalidomide in Rhesus Monkeys (CDER)	To assess the neurotoxicity and neurobehavioral effects of chronic treatment with the anti-HIV agents 2',3'-dideoxycytidine (ddC) and thalidomide in rhesus monkeys.
E0672504	Schmued Ferguson Morse Paule Slikker	Complete/ Neuro Tox/ PRED	Use of Rodent Operant Test Battery (OTB) and Other Tests to Assess Neurobehavioral Toxicity of ddC (CDER)	To assess the effects of the anti-HIV therapeutic ddc treatment on rodent operant and other behaviors and to compare the results obtained with those of a similar study conducted in monkeys using the NCTR OTB (E0672500).

E0672570E0672571E0672527 E0672537	Sandberg Lyn-Cook Binienda Blann Bo Nickols Paule Schrader Slikker Taylor	Complete/ Neuro Tox & Nutri Tox/ PRED & CNPT	Neurotoxicity Assessment of Anti-Human Immunodeficiency Virus (HIV) Therapeutics in Nonhuman Primates: Comparison of ddI to Isoniazid	To determine if ddI exerts any molecular changes, such as, mutations, activation of oncogenes and epigenetic effect on the DNA in pancreatic tissue or pancreatic acinar cells. Pathological changes observed in these tissues will be correlated with molecular changes noted.

Cooperating Organization: National Toxicology Program
Project Number	Principal/ Co-Principal Investigator(s)	Status/ Res. Area/ GOAL	Title	Objective
E0210001	Fu Casciano Heinze Kadlubar Von Tungeln Contrera	Active/ Bio Tox/ AGNT	Metabolism and DNA Binding of Chloral Hydrate (CDER)	1. Characterize and quantify the metabolites of chloral hydrate 2. Determine the mechanism of metabolic activation of chloral hydrate 3. Prepare synthetically carcinogen modified DNA adduct(s) of chloral hydrate and its metabolites 4. Determine the principal metabolizing responsible for metabolic activation 5. Study mutagenicity, metabolism and DNA adduct formation of chloral hydrate and its metabolites
E0210101	Beland Contrera Dooley	Active/ Bio Tox/ AGNT	Fourteen-day, Repeat-dose, Range-finding Study of Chloral Hydrate in Male and Female B6C3F1 Mice (CDER)	To determine the doses of chloral hydrate to be used in a chronic study.
E0210201	Beland Contrera Dooley	Active/ Bio Tox/ AGNT	Fourteen-Day, Repeat-Dose, Metabolism Study of Chloral Hydrate in Male and Female B6C3F1 Mice (CDER)	To establish the plasma levels of chloral hydrate and its metabolites in B6C3F1 mice.
E0210301 E0210311	Beland Contrera Dooley	Active/ Bio Tox/ AGNT	Fourteen-Day, Repeat-Dose, Range-Finding Study of Chloral Hydrate in Male and Female Fischer 344 (F344) Rats (CDER)	To determine the doses of chloral hydrate to be used in a chronic study.
E0210401 E0210411	Beland Contrera Dooley	Active/ Bio Tox/ AGNT	Fourteen-Day, Repeat-Dose, Metabolism Study of Chloral Hydrate in Male and Female Fischer 344 (F344) Rats (CDER)	To establish the plasma levels of chloral hydrate and its metabolites in Fischer 344 Rats.
E0210601	Howard Dooley Lorentzen Voss	Active/ Bio Tox/ AGNT	Chronic Tumor Study of Fumonisin B1 in Male and Female B6C3F1 Mice (CFSAN)	To determine the tumorigenicity of fumonisin B1 in male and female B6C3F1 mice following chronic dietary exposure.
E0210801	Howard Dooley Lorentzen Voss	Active/ Bio Tox/ AGNT	Chronic Tumor Study of Fumonisin B1 in Male and Female F344 Rats (CFSAN)	To determine the tumorigenicity of fumonisin B1 in male and female F344 rats following chronic dietary exposure.
E0211001 E0211011 E0211012 E0211013	Laborde Bucci Collins Flynn Hansen Howard Shackleford Terry	Active/ R&D Tox, Bio Tox & Path/ AGNT	Developmental Toxicity Study of Fumonisin B1 in Rabbits (CFSAN)	To determine the effect of Fumonisin B1 on rabbit development by administering the compound during organogenesis.
E0211101 E0211111 E0211121 E0211131 E0211141	Howard Binienda Casciano Couch Martinez Melchior Shaddock Slikker Sutherland Tolleson	Active/ Bio Tox/ AGNT	The Role of Fumonisin B1 in Fusarium sp. Tumorigenicity in Rats (CVM)	Determine the effect of fumonisin B1 on signal transduction pathways in cultured human esophageal epithelial tissues. Determine if DNA damage occurs in vivo in F344 rats when fed in the diet cultures of Fusarium graminearum, Fusarium subglutinans, Fusarium moniliforme or a combination of the three fungi, using 32P-postlabeling technique. Determine the pharmacokinetics of fumonisin B1 in B6C3F1 mice and F344 rats under conditions similar to those used in the chronic bioassay, and in non-human primates.
E0211201	Howard Dooley	Active/ Bio Tox/ AGNT	Tumor Promotion by Fumonisin B1 in Male F344 Rats (CFSAN)	Determine if fumonisin B1 is a tumor promoter, using a classical initiation/promoter design [administration of fumonisin B1 one week after three weeks administration of methylbenzylnitrosamine]. Determine if co-administration of fumonisin B1 with initiator methylbenzylnitrosamine results in an altered tumor yield.
E0211301 E0211311 E0211321	Howard Dooley Lorentzen Voss	Active/ Bio Tox/ AGNT	Sub-chronic (28-day) Study of Fumonisin B1 in Male and Female B6C3F1 Mice (CFSAN)	To determine the toxicity of fumonisin B1 in male and female B6C3F1 mice following a 28-day dietary exposure.
E0211401 E0211411	Howard Dooley Lorentzen Voss	Active/ Bio Tox/ AGNT	Sub-chronic (28-day) Study of Fumonisin B1 in Male and Female F344 Rats (CFSAN)	To determine the toxicity of fumonisin B1 in male and female F344 rats following a 28-day dietary exposure.
E0211511	Slikker Sobotka	Complete/ Neuro Tox/ AGNT	ADDEND: Developmental Neurotoxicological Assessment of Fumonisin (FB1) Toxicosis in Rats (CFSAN)	To assess behavioral and growth effects in postnatal rats after prenatal exposure to purified FB1. Addendum requested in order to replicate findings from E06884.01 and provide data from a higher dose that would show maternal toxicity.
E0211601	Beland Contrera Fullerton Gaylor	Active/ Bio Tox/ AGNT	Tumorigenicity of Chloral Hydrate in B6C3F1 Mice (CDER)	To determine the effect of animal age and duration of exposure upon the tumorigenicity of chloral hydrate in female B6C3F1 mice.
E0211701 X70052	Leakey Turturro Seng Contrera	Active/ Cal Res/ CNPT	Chronic Bioassay of Chloral Hydrate in Male B6C3F1 Mice Using Idealized Body Weight Curves that are Normalized by Modulation of Caloric Intake (CDER)	To determine the chronic toxicity and potential carcinogenicity of chloral hydrate, administered by aqueous gavage, to male B6C3F1 mice; To determine the feasibility of utilizing dietary control (i.e., the manipulation of caloric intake) to control body weight gain so that all mice in each experimental group of the bioassay conform to an ideal weight curve.
E0211801	Culp Mulligan Beland	Active/ Bio Tox/ AGNT	Twenty-eight Day Range finding Study in Mice and Rats Administered Malachite green or Leucomalachite Green in the Diet (CVM)	To determine the doses of malachite green to be used in a two-year feeding bioassay and to compare the biological effects from the administration of malachite green and leucomalachite green.
E0211901 E0211911	Doerge Rushing Churchwell Schmitt	Active/ Chemistry/ METH	Development of Analytical Methods for Determination of Malachite Green	1) Develop analytical methods to assess purity of malachite green (MG) and leuco-malachite green (LMG) that will be used in the NTP animal bioassay; 2) Develop analytical methods to quantify MG and LMG content and determine homogeneity and stability in rodent chow under storage and use condition.
E0212001 P00378	Beland Benson Chan Lorentzen Roberts	Active/ Bio Tox/ AGNT	Effect of Ethanol on the Tumorigenicity of Urethane (Ethyl Carbamate) in B6C3F1 Mice (CFSAN)	To determine the effect of ethanol on the tumorigenicity of urethane (ethyl carbamate) in B6C3F1 mice.
E0212101 P00367	Doerge Syvertson	Active/ Chemistry/ AGNT	Development of Analytical Methods for Determination of Urethane (CFSAN)	Develop analytical methods to assess purity and stability of urethane and ethanol that will be used as test compounds in the NTP rodent bioassay; Develop analytical methods to quantify urethane and ethanol content in aqueous dosing solutions and determine stability under storage and use conditions for the NTP bioassay; Develop analytical procedures to quantify the content of urethane in rodent feed.
E0212201 P00373	Delclos Newbold Weis	In Review/ Bio Tox/ AGNT	Range Finding Study for the Evaluation of the Toxicity of Genistein Administered in the Feed to CD (Sprague-Dawley) Rats	To determine the doses of genistein to be used in a multigeneration bioassay for establishing the effects of this naturally occurring isoflavone on development of reproductive organs, reproduction, cancer of the reproductive organs, and neurological and immunological function.
E0212301 P00372	Delclos Newbold Weis	In Review/ Bio Tox/ AGNT	Range Finding Study for the Evaluation of the Toxicity of Methoxychlor Administered Feed to CD (Sprague-Dawley) Rats	To determine the doses of methoxychlor for use in a multigeneration bioassay for assessing the effects of this pesticide on the development of the reproductive tract, reproduction, cancer of the reproductive organs, and neurological and immunological function.
E0694101	Roberts Benson Howard Newkirk Tolleson	Active/ Bio Tox/ AGNT	Preparation of Antibodies Against the C1-C10 and Tricarballylic C14-C20 Segments of Fumonisin B1: Development for Quantitative and Molecular Biological Techniques	1) Prepare fumonisin B1-protein conjugates for immunization, immunoassay development, and epitope mapping; 2) raise polyclonal anti-fumonisin B1 adduct antisera and characterize titer, affinity, and relevant cross reactivity; 3) evaluate the usefulness of anti-fumonisin B2 antisera to elucidate target organ toxicity and as a tool to isolate or localize macromolecules modified by or binding fumonisin B1; 4) prepare immunoaffinity matrices and evaluate immunoaffinity techniques to enrich/concentrate/purify fumonisin B1 as an aid to the identification and quantification of fumonisin B1 in biological samples including food.
P00293	Beland Contrera	Completed/ Bio Tox/ AGNT	NTP Standard Bioassay (CDER)	This project set up to capture time charges for NTP work or protocol review of NTP-related projects prior to official approval of the project.
P00321	Thompson Holcomb Nestorick	Completed/ Chemistry/ AGNT	NTP Preliminary Investigation on Fumonisin	To provide analytical chemistry support for NTP Fumonisin studies.
P00345	Culp Blankenship Beland	Complete/ Bio Tox/ METH	Development of Methods for Extracting and Analyzing Malachite Green in Rodent Tissues	To develop extraction, HPLC and 32P-postlabeling methods for detecting and analyzing chromatic malachite green, leucomalachite green, malachite green carbinol, and malachite green DNA-adducts in rodents gavaged with malachite green.
P00374	Delclos	Active/ Bio Tox/ AGNT	Preparation of a Comprehensive Research Plan: Synthetic and Naturally Occurring Endocrine Disrupters	Overall research plan for the NTP/NCTR IAG to determine the effects of endocrine disrupting chemicals on fertility and reproductive tract cancers.
X60032	Culp Blankenship	Proposed/ Bio Tox/ AGNT	2-Year Bioassay on Malachite Green	To be developed in FY-97.
X6005101	Delclos Beland Hansen Littlefield Sheehan	Proposed/ Bio Tox/ AGNT	Multi-Generation Studies (Dose Range Finding Study - Compound to be Determined)	To be developed.
X6005102	Delclos	Proposed/ Bio Tox/ AGNT	Multi-Generation Studies (Dose Range Finding Study - Vinclozolin)	To be developed.
X6005103	Delclos	Proposed/ Bio Tox/ AGNT	Multi-Generation Studies (Dose Range Finding Study - Nonylphenol)	To be developed.
X60052	Delclos	Proposed/ Bio Tox/ AGNT	Multi-Generation Studies (OF Generation for Reproductive Assessment - Genistein)	To be developed.
X60053	Delclos	Proposed/ Bio Tox/ AGNT	Multi-Generation Studies (OF Generation for Immuno/Neurotox Assessment - Genistein)	To be developed.
X60054	Delclos	Proposed/ Bio Tox/ AGNT	Multi-Generation NTP Studies (OF Generation for Cancer Assessment - Genistein)	To be developed.
X60055	Delclos	Proposed/ Bio Tox/ AGNT	Multi-Generation Studies (F1 Generation for Reproductive Assessment - Genistein)	To be developed.
X60056	Delclos	Proposed/ Bio Tox/ AGNT	Multi-Generation Studies (F1 Generation for Cancer Assessment - Genistein)	To be developed.
X60057	Delclos	Proposed/ Bio Tox/ AGNT	Multi-Generation Studies (F2 Generation for Reproductive Assessment - Genistein)	To be developed.
X60060	Sheehan Branham Vom Saal Welshons	Proposed/ R&D Tox/ AGNT	Dose Selection Strategy for Estrogenic Endocrine Disruptors - Endocrine Disrupters - Uterine Tissue	To be developed.
X70010	Howard	Proposed/ Bio Tox/ METH	Isolation of Human Genomic Ceramide Synthetase	To be developed.
X70011	Howard	Proposed/ Bio Tox/ METH	DNA Adducts from the Pyrrolizidine Alkaloid Riddelline	To be developed.
X70012	Howard	Proposed/ Bio Tox/ METH	Comparative Toxicity of Fumonisins in Rats	To be developed.

FDA/National Center for Toxicological Research
Web page updated by rla 2003-OCT-07.