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European Toxicology From a National Toxicology Program Perspective

European Toxicology From a National Toxicology Program Perspective Dr. Christopher J. Portier Associate Director, National Toxicology Program Director, Environmental Toxicology Program National Institute of Environmental Health Sciences Department of Health and Human Services

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European Toxicology From a National Toxicology Program Perspective

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  1. European ToxicologyFrom a National Toxicology Program Perspective Dr. Christopher J. Portier Associate Director, National Toxicology Program Director, Environmental Toxicology Program National Institute of Environmental Health Sciences Department of Health and Human Services

  2. Toxicology in the 21st CenturyA Roadmap for the National Toxicology Program Dr. Christopher J. Portier Associate Director, National Toxicology Program Director, Environmental Toxicology Program National Institute of Environmental Health Sciences Department of Health and Human Services

  3. Use of Mechanistic Toxicology Studies in Public Health Decision Making

  4. NTP RoadmapApproaching Toxicology Today • First level screen • High-Throughput • Fairly inexpensive • Lot’s of possible mechanistic links • Second Level Screen • Integrated living organism • Medium throughput • Complex inter-related mechanistic information • Definitive Evaluation • Bioassay of the future

  5. NTP RoadmapThe Bioassay of the Future • Species/strain/genetics • Dose spacing/timing/age of exposure • Use of sub-chronic/pre-chronic/other • Toxicokinetics • Digital pathology and non-invasive methods • Addition of mechanistic endpoints • Presentation and interpretation

  6. NTP Rodent Cancer BioassayStrains & Stocks - Should We Switch? • Held June 16-17, 2005 at NIEHS • Three breakout groups • Mouse Models • Rat Models • Multiple Strain Approach • Presentation and background materials • http://ntp.niehs.nih.gov/ • see “Meetings & Workshops”

  7. Strains & StocksMouse Models • Continued use of the mouse in bioassays is essential • B6C3F1 Mice (NTP) • Do not switch yet • Liabilities not yet critical, but could become so • Major liability • increasing incidence of liver tumors in control males (60%+) • likely associated with increasing body weight. • B6C3F1 mice (NCTR) • lower liver tumor background • If alternative model(s) is sought: • Isogenic strains should be used • F1 hybrids preferable to inbreds • Cautious first steps • implement as a 25x2 study • equal numbers of B6C3F1 and the alternative hybrid.

  8. Strains & StocksRat Models • F344/N Rat (NTP) • Replace it • Liabilities mandate that it should not be used. • Three options: • Re-establish the F344/N strain • Create an F1 Hybrid • Choose an appropriate alternative strain/stock (such as outbred Wistar Han) • Multi-strain studies • Do not recommend reducing study size for current strain • Only approach - add entire new strain • “not practical for a screening bioassay”

  9. Strains & StocksMultiple Strain Approach • Multiple strains • Viable approach for cancer hazard identification • Implement incrementally by adding strains to current bioassay • Choose isogenic strains • inbred and/or F1 hybrid • Choosing strains • Form a fixed pool of strains (e.g., 12 for rats) • Select a subset of strains (e.g., 4) to test for a given agent • Minimal amount of 2-year historical control data for any strain selected • Pooled analysis recommended

  10. Strains & StocksNext Steps • Public input to workshop recommendations • Stakeholder discussions • Evaluation • Cost/Practical issues • Scientific concerns and advantages

  11. NTP RoadmapSecond Level Screens • Shorter-term whole animal assays • C. elegans • Zebra fish • Transgenics and others • Molecular screening assays • Gene chips with large numbers of genes • Proteomic screens • Metabolomic screens • Combined assays • Reproductive/developmental/cancer/cardiotox/other

  12. C. ElegansDevelopmental neurotoxicity • Develop the screen • 200 +/- agents • 75 completed • Reproduction, development, behaviour, movement • Expand the tool to expand endpoints • Subtle changes in individual neurons • Alterations in egg sac function and number • Evaluate mechanism • Knock down every gene for a few chemicals

  13. NTP RoadmapHigh-Throughput Screening • Partner with NIH Molecular Libraries Initiative • Screen 120,000 small molecules • Biological probes to study cellular function • Consortium (9 Centers, 100+ NIH Grants) • Initial NTP Steps • One to two thousand agents • NIH ML targets and obvious toxicity targets • Develop data handling tools • Build a validation data set • Expand as warranted • Broader number of assays • Broader number of agents • Wider number of targeted toxicities • Links to extramural community

  14. HTS ChemicalsFirst Cut Formaldehyde, Phenobarbital, Phenobarbital Free Acid, Mitomycin C, Cyclophosphamide (anhydrous) , 17-beta-Estradiol, DDT (Dichlorodiphenyltrichloroethane), Benzo[a]pyrene , Thalidomide, Cocaine , Clomiphene citrate , Reserpin, Actinomycin D , "Aspirin , ", L-Ascorbic Acid, Fluorouracil, 2,4-Dinitrophenol, Propylthiouracil, Nitrogen mustard (Mechlorethamine), Urethane, Spironolactone, Codeine phosphate , Penicillamine, Trichlorfon, Lynestrenol, Haloperidol , fe, Prednisone, Estrone, DDD, O,P'- , Dibenz[a,h]anthracene, 2-Acetylaminofluorene , Nicotine, Nicotine, Aminopterin, Isoniazid, Pipobroman, N-Nitrosodiethylamine, N-Nitrosodiethylamine, (Mechlorethamine hydrochloride), 1,4-Butanediol dimethanesulfonate (Busulfan), Methylthiouracil, Carbon tetrachloride, Tributyltin oxide, Parathion, Glycine, L-Alanine, 3-Methylcholanthrene, Diethylstilbestrol [DES], Benz[a]anthracene, Chloramphenicol, Benzyltrimethylammonium chloride, 1,1-Dimethylhydrazine (UDMH), Strychnine, Pentobarbital sodium, Diphenylhydantoin, Meprobamate, 1,2-Propylene glycol, Propylene glycol, beta-Propiolactone, Ethinyl estradiol, Sulfamethazine, Chlordane, Progesterone, Cholesterol, 7,12-Dimethylbenz(a)anthracene, Caffeine, Pyrimethamine, Methyltestosterone, Testosterone cypionate, Testosterone and its esters, Chlordiazepoxide, Promethazine hydrochloride, Theophylline, gamma-Hexachlorocyclohexane, 2,3,4,6-Tetrachlorophenol, Methotrexate, 5-Bromo-2'-deoxyuridine (BRDU), Acetazolamide, Nitrofurazone, Nitrofurazone, N-Nitrosomorpholine, Levodopa, Phenoxybenzamine, p-Aminoazobenzene , 4-Dimethylaminoazobenzene, Ethyl ether, Dimethoate, Tetracycline (internal use), Methimazole, Dieldrin, Niridazole, Amitrole, p-Nitrobenzoic acid, Phenylmercuric acetate, Phenacetin, Ethyl methanesulfonate, Aniline, Thioacetamide, Thiourea, DDVP (Dichlorvos) , Fluoroacetic acid, sodium salt, Dimethylnitrosamine, Carbaryl, Carbaryl, Phenoxybenzamine hydrochloride, Phenacemide, Ethanol, Formic acid, Diethyl sulfate, Demeclocycline hydrochloride, Tetracycline hydrochloride (internal use), Colchicine, Benzoic acid, Methyl methanesulfonate, Methyl methanesulfonate, Uracil mustard , Dicumarol , Cycloheximide , Nitrofurantoin, Furazolidone, 5-(Hydroxymethyl)-2-furfural ((HMF)), Methanol, Acetone, Chloroform, CHLOROFORM , Dimethyl sulfoxide, HEXACHLOROETHANE , n,n-Dimethylformamide, N,N-Dimethylformamide, Norethisterone (Norethindrone) , Norethynodrel, (Triaziquone), N-Methyl-N'-nitro-N-nitrosoguanidine, Hexachlorophene, p-Toluenesulfonamide, n-Butanol, Benzene, Benzene, 1,1,1-Trichloroethane, Medroxyprogesterone acetate , Endrin, Mestranol, Methoxychlor, Methoxychlor [95%], DDD (Dichlorodiphenyldichloroethane) , DDE (Dichlorodiphenyldichloroethylene) , Trypan blue (commercial grade), L-Tryptophan, Melatonin, Melatonin, Bromomethane, Methyl chloride, Methyl iodide, Bromoethane, Bromochloromethane, CHLOROETHANE , Vinyl chloride, Vinyl fluoride, Acetonitrile, Acetaldehyde, Methylene chloride, Formamide, Carbon disulfide, Carbon disulfide, Ethylene oxide fe, Bromoform, 2-Bromopropane, Bromodichloromethane, 1,1-Dichloroethane, 1,1-Dichloroethylene, Acetyl chloride, 1,1-Difluoroethane, Phosgene, Chlorodifluoromethane, Nitromethane, Propyleneimine, Propylene oxide, Cacodylic acid, Bromotrichloromethane, t-Butyl alcohol, 1-Chloro-1,1-difluoroethane, Trichlorofluoromethane, Dichlorodifluoromethane, tert-Butyl hydroperoxide, tert-Butyl Hydroperoxide (70% Solution in Water), Tribromoacetic Acid, Dalapon, sodium salt, Trichloroacetic Acid, 1,1,2-Trichloro-1,2,2-trifluoroethane, dl-Camphor, Fluoxymesterone, Heptachlor, Codeine, Triphenyltin hydroxide , Phenolphthalein, Hexachlorocyclopentadiene, Dicyclopentadiene, Dimethyl sulfate, Tetraethyl lead, Carisoprodol, Merphos oxide, Isophorone, Isoprene, Isobutyl alcohol, Isobutyraldehyde, 2-Chlorobutane, 1,2-Dichloropropane, 2-Butanol, Methyl ethyl ketone , 1,1,2-Trichloroethane, Trichloroethylene, Acrylamide, Acrylamide, Monobromoacetic Acid, Acrylic acid, Monochloroacetic Acid, Methyl chlorocarbonate, 1,1,1-2 Tetrabromoethane, 1,1,2,2-Tetrachloroethane, 1,1,2,2-Tetrachloroethane, 1,1,2,2-Tetrachloroethane, Methacrylamide, Dichloroacetic Acid, Dimethylcarbamoyl chloride, 2-Nitropropane, Oxytetracycline (internal use), Tetrabromobisphenol A, Bisphenol A., 4,4'-Dichlorodiphenylsulfone, p,p'-Dichlorodiphenyl Sulfone, Dapsone, alpha-Pinene, Methyl methacrylate, 1-Amino-2,4-dibromoanthraquinone, Warfarin, D&C Red No. 19 , 1-Amino-2-methylanthraquinone , Pentachloronitrobenzene, Acenaphthene, BROMODICHLOROETHANE , Theobromine, Rotenone, Rotenone, Dienestrol, Anthraquinone, Diethyl phthalate, Ethylphthalyl ethylglycolate, Dibutyl phthalate, Di-n-butyl phthalate, Diquat, Phenanthrene, Phthalic anhydride, Butyl benzyl phthalate, Butylphthalyl butylglycolate, N-Nitrosodiphenylamine, GUTHION , Fluorene, CARBAZOLE , Cinnamyl anthranilate , 1,2,3-TRICHLOROBENZENE , Pyrogallol, Hexachlorobutadiene, Hexabromobenzene, Pentachlorophenol, 2,4,6-Trichlorophenol, o-Nitrotoluene, 2-Chloronitrobenzene, Dinoseb, Pulegone, ortho-Anisidine , o-Phenylphenol, Michler's ketone, Decalin, Naphthalene, Quinoline, o-Nitroanisole, Ethoxyquin, 2-Methylnaphthalene , beta-Chloronaphthalene, 2-Naphthylamine, Coumarin, 3,3'-Dichlorobenzidine, 1,1-Biphenyl, 4-AMINOBIPHENYL , Benzidine, 4-Nitrobiphenyl, Methyleugenol, 2-(2-Methyl-4-chlorophenoxy) propionic acid, 2 (2,4,5-Trichlorophenoxy) propionic acid, 2,4,5-Trichlorophenoxyacetic acid, Oleic acid diethanolamine condensate (1:1), Dihydrosafrole, Safrole, 2-Methyl-4-chlorophenoxyacetic acid, 2,4-Dichlorophenoxyacetic acid, 2,4-Dichlorophenoxyacetic acid (2,4-D), Phenazopyridine,

  15. HTS ChemicalsFirst Cut (continued) 4-(2-Methyl-4-chlorophenoxy) butyric acid, 4-(2,4-Dichlorophenoxy)butyric acid, Sulfallate, o-Cresol, o-Chlorotoluene , 1,2-Dichlorobenzene, m-Chloroaniline, o-Toluidine, o-Phenylenediamine and its salts, 2-Chlorophenol, 3,4-Dimethylphenol, p-Chloro-o-toluidine , 2,4-Diaminotoluene, 4-Chloro-o-phenylenediamine , 1,2,4,5-Tetrachlorobenzene, 2,4,5-Trichlorophenol, Styrene oxide, 1,2-Dibromo-3-chloropropane, 1,2-Dibromo-3-chloropropane (DBCP, 1,2,3-Trichloropropane, Methyl acrylate, Ethylene thiourea, 2-Methyltetrahydrofuran, 4,4-Thiobis(6-t-butyl-m-cresol), Dichlorophene, Eugenol, Isoeugenol, o-Aminoazotoluene , Furfural, Benzotrichloride , p-tert Butylcatechol, p-Chlorophenyl methyl sulfone, Cumene, alpha-Methyl styrene, Acetophenone, Nitrobenzene, Pyrazinamide, m-Nitrotoluene, 1,3,5-Trinitrobenzene, 5-Nitro-o-anisidine, m-Dinitrobenzene, Valproate (Valproic acid), p-Nitrotoluene, 4-Chloronitrobenzene, p-Nitroaniline, p-Nitrophenol, p-Dinitrobenzene, 4-Vinylcyclohexene, Ethylbenzene, Styrene, Benzyl chloride, Benzaldehyde, N-Nitrosopiperidine, 4,4'-METHYLENEBIS(2-CHLOROANILINE) , Chlorpropham, p-Bromodiphenyl ether, 4,4'-Methylene bis(N,N'-dimethyl)aniline, Methylene Diphenyl Diisocyanate, 4,4'-Methylenedianiline, 4,4'-Diaminodiphenyl ether, Diglycidyl resorcinol ether (DGRE), 1,3-Diphenylguanidine, Triethanolamine, BIS(2-ETHYLHEXYL)ADIPATE , Azobenzene, Acetaminophen, Anethole, Cinnamaldehyde, 2-Ethylhexanol, p-Divinylbenzene, Caprolactam, 2,4-Dimethylphenol, 1,4-Dibromobenzene, P-XYLENE , 4-Methylphenol, 1,4-Dichlorobenzene, p-Chloroaniline, Quinone, Dimethylsuccinate, 4-Vinylcyclohexene Dioxide, 1,2-Epoxybutane, Epichlorohydrin, Allyl glycidol ether, 1,2-Dibromoethane, 1-Bromopropane, Allyl bromide, 1,3-Butadiene, Acrolein, Allyl chloride, 1,2-Dichloroethane, Acrylonitrile, Ethylenediamine, Allyl Alcohol, Propargyl alcohol, Ethylene glycol, Chloromethyl methyl ether, Propylene glycol monomethyl ether, Vinyl acetate, Methyl Isobutyl Ketone, Maleic anhydride, 3-Methylphenol, m-Phenylenediamine, Resorcinol, Bis(2-chloroisopropyl) ether, Toluene, Chlorobenzene, Cyclohexylamine , Cyclohexanone oxime, Phenol, Thiophenol, 3-Picoline, o-Chloropyridine, 1-Chlorobutane, 2-Methoxyethanol, Diethylamine, Tetrahydrofuran, Furan, Thiophene, 2,5-Hexanedione, Acetonylacetone, N,N'-Methylenebisacrylamide, Ethylene glycol monomethyl ether acetate , n-Hexane, 1,4-Butanediol, Butanal Oxime, 2-Ethoxyethanol, Cyclohexane , Pyridine, Ethylene glycol monoethyl ether acetate ,, Diethanolamine, Bis(chloroethyl)ether, Diethylene glycol, 1-Octene, Adiponitrile, 2-Butoxyethanol, Ethylene glycol monobutyl ether, bis(2-Chloroethoxy)Methane, Triethylene glycol monoethyl ether, Baygon, Scopolamine hydrobromide trihydrate, Azaserine, Chlorendic acid , Endosulfan, Dicofol, Paramethadione, Tris(2-chloroethyl) phosphate, Aldicarb, Tetrafluoroethylene, Dantron (Chrysazin; 1,8-Dihydroxyanthraquinone), Anisindione, Quercetin, 2-Aminoanthraquinone , Di(2-Ethylhexyl phthalate), Di-n-octyl phthalate, Hexachlorobenzene, 2,4,6-Trinitrotoluene , Benzophenone, Tetralin, 3,4-Dihydrocoumarin, 3,3'-Dimethoxybenzidine (o-Dianisidine), 3,3-Dimethylbenzidine, Anthracene, o-Benzyl-p-chlorophenol, DICHLOROPROP , Lauric acid diethanolamine con(1/1), Lauric acid diethanolamine condensate (1:1), Isosafrole, Dimethyl terephthalate, p-Cresidine , Catechol, 1,2,4-Trichlorobenzene, 2,4-Dichlorophenol, Dichlorphenamide, 2,4-Dinitrotoluene, Triethylamine, Benzethonium chloride, N,N-Dimethylaniline, Malathion, Hexahydro-1,3,5-trinitro-1,3,5-triazine, Simazine, Diphenylamine, Propham, Phenyl glycidyl ether, 1,2-Diphenylhydrazine, Ethylene glycol monophenyl ether, p-Chlorophenyl methyl sulfide, Hydroquinone, Maleic hydrazide, B-Myrcene, Crotonaldehyde, 1,4-Dioxane, Isoamyl acetate, Thiodiglycolic Acid, Dimethylamine, Chlorodibromomethane, Prednisolone sodium phosphate, Primaclone, Aminoglutethimide, Diphenolic acid, Griseofulvin, Tris(2,3-dibromopropyl)phosphate, Nitrogen mustard N-oxide, Methacrylonitrile, Chloroprene, 1-Chloro-2-propanol, Hydroxyurea, Tetrachloroethylene, all-trans-Retinyl acetate, Trimethadione, Potassium dimethyldithiocarbamate, Sodium dimethyldithiocarbamate, Sennoside B, Pyrene, Dimethyl phthalate, Di-n-propyl phthalate, Dipentyl phthalate, 2-Hydroxy-4-methoxybenzophenone, 4,6-Dinitro-o-cyclohexyl phenol, o-Phenylphenate, sodium, DIBENZOFURAN , DIBENZOTHIOPHENE , Captan, Folpet, Chloramben, o-Anisidine hydrochloride , 1-Naphthylamine, Cupferron, Diazoaminobenzene, Phenazopyridine hydrochloride, Di-n-propyl isocinchomeronate (MGK Repellent 326) , Thiram, Metham sodium , Disodium cyanodithioimidocarbonate, Nitrilotriacetic acid, Propazine, 4,4'-Thiodianiline, amino]-2-oxazolidinone, Benzyl acetate, Aramite, Pentamidine isethionate, Estragole, Ethyl acrylate, Monoethanolamine, Bidrin, Ethyl acetate , Thiouracil, Aniline hydrochloride , Nabam, n-Heptane, 2,4-Hexadienal, Triethylene glycol monobutyl ether, Sodium cyanide, CHLORDECONE , Vinblastine sulfate salt, Butabarbital sodium , Endothall, 1,2-Dihydro-2,2,4-trimethylquinoline (monomer), Cytarabine, Sodium diethyldithiocarbamate , 8-Hydroxyquinoline, 8-Hydroxyquinoline, Melphalan, Merphos, Potassium cyanide, Ethyleneimine, Halothane, 2-Aminofluorene , Thioguanine, Bischloroethyl nitrosourea (BCNU) (Carmustine), p-Nitrosodiphenylamine, 1,2-Dichloroethylene (cis), 1,2-Dichloroethylene (trans), Dibenzo[a,h]pyrene , Benzo[g,h,i]perylene, Dibenzo[a,i]pyrene , Dibenzo[a,e]pyrene , Indeno[1,2,3-cd]pyrene, 7H-Dibenzo[c,g]carbazole , Benzo[j]fluoranthene , Benzo[b]fluoranthene, Fluoranthene, Benzo[k]fluoranthene, Acenaphthylene, Chrysene, Dibenz[a,h]acridine , Benzofuran, Cyclohexene oxide, Methyl parathion, PHORATE , Disulfoton, Carbamazepine, Methylphenidate Hydrochloride, 8-Methoxypsoralen, L-Ephedrine, Treosulfan, Naled, Lead acetate, Oxydemeton methyl fe,, Hydrazine/Hydrazine sulfate, THIOCYANATE , Chloral hydrate,

  16. HTS ChemicalsFirst Cut (continued) Nitrogen mustard N-oxide hydrochloride, All-trans retinoic acid developmental , Lasiocarpine, Ochratoxin A, Chlorambucil , Aldrin, Secobarbital sodium, Diethyl-p-nitrophenyl phosphate, Monocrotaline, Testosterone enanthate, alpha-Hexachlorocyclohexane, beta-Hexachlorocyclohexane, delta-Hexachlorocyclohexane, Azacitidine, Diuron, Linuron, DIAZINON , Diazomethane, Perfluoro-1,3-dimethylcyclohexane, Pentafluoroethane, Sodium Cholate, Diazoxide , Procarbazine hydrochloride , Sodium thioglycolate, Nickel acetate, Ergotamine tartrate, Nalidixic acid, Triamterene, 2,3-Butanedione, Oxymetholone, Phenprocoumon, Chlordiazepoxide hydrochloride , Diazepam, Metronidazole, Genistein, Azathioprine, Curcumin, Turmeric oleo resin, Cyanogen, Linolenic acid, Carbonyl sulfide, d-Camphor, Chenodiol, 1,4,5-Trihydroxynaphthalene, ultraviolet A therapy, 4',7-Dihydroxyisoflavone, Auramine, N,N-Bis(2-chloroethyl)-2-naphthylamine (Chlornapazine), Resveratrol, 4-Aminopyridine, Mustard Gas, Potassium silver cyanide, Silver cyanide, Cyanogen bromide, Chlorine cyanide, t-Butylchloride, Tetranitromethane, Chlorobenzilate, Trimethyl phosphate, Echinomycin, Dimethylvinylchloride, Canthaxanthin, Emodin (bulk), Luminol, o-Dinitrobenzene, Merphalan, acetamide, 2-Chloroacetophenone, Sesamol, 4,6-DINITRO-O-CRESOL , Ethionamide, Trioctanoin, Trioctanoin (Tricaprylin), 1,3-Dicyclohexylcarbodiimide, 1,2-Dichloroethylene (cis,trans), cis,trans-1,2-Dichloroethylene, 1,2-Dimethylhydrazine, 2,2,4-Trimethylpentane, 1,3-Dichlorobenzene, Norbixin (cis/trans mixture), Isobutyl nitrite, Barium cyanide, 1,3-Dichloropropene, Bis(chloromethyl)ether, Copper cyanide , alpha-Thujone, Acetohydroxamic acid , Lithium carbonate, 2-imidazolidinone, Glycidol, Methyl isothiocyanate, Nitroguanidine, Zinc cyanide, Ethion, 3-Chloro-2-methylpropene , 1,1-Dichloropropene, Silver acetate, Thallium acetate, Doxycycline (internal use), Chlorotrianisene, C.I. Basic Red 9 monohydrochloride , 2,6-Dimethylphenol, Bromoacetonitrile, Methylazoxymethanol, 2-HEXANONE , Allyl Acetate, Calcium cyanide, Methylazoxymethanol acetate, Vinyl bromide, Tribromochloromethane, Dibromodichloromethane, Megestrol acetate, Methyl carbamate, 1,1,2-Trichloropropane, Dibromonitromethane, Salicylazosulfapyridine, 2,3-Dibromopropionic Acid, 5-Nitroacenaphthene, Acetamide, Bisacodyl, Oxazepam, Oxazepam, Oxazepam , 2,6-DINITROTOLUENE , Myristicin, 2-Nitrofluorene, technical Hexachlorocyclohexane, Pentachlorobenzene, 3,3'-Dichlorobenzidine dihydrochloride, N,N'-Diacetylbenzidine, 2,4-Diaminoanisole, N-Nitroso-N-methylurethane, 1,2,4-Tribromobenzene, 2,3-Dichloropropanol, N-Acetyl-m-Aminophenol, N-Nitrosodi-N-propylamine, Methyl isocyanate, Methoxyacetic acid, Ethoxyacetic acid, Dimethyl Adipate, CARBON MONOXIDE , Selenourea, 1,1,1,2-Tetrachloroethane, Diphenylhydantoin (Phenytoin), sodium salt, Ammonium acetate, Dibromoacetic Acid, o-Toluidine hydrochloride, Clofibrate, 2-methyl-2-ethoxypropane, Altretamine, Amantadine hydrochloride , Procarbazine, Hexamethylphosphoramide , N-Nitroso-N-methylurea, TRIBUTYLTIN , Diisopropylcarbodiimide, Diethylene glycol dinitrate, 2-Methylimidazole, Tetrachlorocyclopentadiene, Indole-3-carbinol, Propanil, 2-Amino-5-(5-nitro-2-furyl)-1,3,4-thiadiazole, Sulfamethoxazole, Phosmet, Trimethoprim, Mercuric chloride, N-Nitroso-N-ethylurea, S-Ethyl dipropylthiocarbamate, 1,4-Dichloro-2-butene, Glycidaldehyde, CARBOPHENOTHION , DDT, O,P'- , n-(1,3-Dimethylbutyl)-n`-phenyl-p-phenylenediamine, Panfuran S, Levonorgestrel implants fe, 1,1,1,2-Tetrafluoroethane, Trichlormethine (Trimustine hydrochloride), 1,6-Hexamethylene diisocyanate, 4-Methylimidazole, 2,6-Toluenediamine, Ametryn, 4,4'-Methylene bis(2-methylaniline), C.I. Solvent Yellow 14 , Lorazepam, Temazepam, N-Methylpyrrolidone, 2,6-Xylidine (2,6-Dimethylaniline), Terbutryn, Lithium citrate, N-Nitroso-di-n-butylamine, N-Hydroxymethyl acrylamide, N-Methylolacrylamide, Isopropyl methanesulfonate, 1,3-Dichloro-2-butene, N-Nitrosopyrrolidine, 2-Cyclohexen-1-one, p-Chlorophenyl methyl sulfoxide, 2,3,5,6-TETRACHLOROPHENOL , Fonofos, Methidathion, Diphenamid, ENDOSULFAN, ALPHA , Tetrachlorovinphos, Heptachlor epoxide, ENDOSULFAN SULFATE , Chromium (III) acetate, Glyphosate, Methadone hydrochloride, N-Nitrosodiethanolamine, 1,3-Propane sultone, Cycloate, Aflatoxin-B1, Decabromodiphenyl ether, Flurazepam hydrochloride, Nickelocene, DICHLOROETHANE , Sodium xylenesulfonate, Gallium arsenide, Cadmium telluride, Cobalt [II] oxide , Antimony trioxide, Molybdenum trioxide, Nickel oxide, Thorium dioxide, Thallic oxide, Tungsten trioxide, Vanadium Pentoxide, Vanadium pentoxide, Zinc phosphide, Cresol (m-/p- mixture), Divinylbenzene, Divinylbenzene [80%], Arsenic trioxide, Xylenes, Tricresyl phosphate, Asbestos, CHROMIUM(VI) OXIDE , Lead subacetate, Polychlorinated biphenyls , Annatto Extract Acid Proof, Neomycin sulfate (internal use), Humic acid, sodium salt, Diisopropyl methylphosphonate, Diepoxybutane , Carbofuran, Trifluralin , Alar, Prometon, 1,2-Diethylhydrazine , Chlorcyclizine hydrochloride , Ethyl vinyl ketone, Methyl tert-butyl ether, Aldicarb sulfoxide, Aldicarb sulfone, Aldicarb sulfone, Tetrahydroaminoacridine Monohydrate, Bromoxynil, Bromoxynil octanoate, Benzyl violet 4B , 1,2,3,4-Butanetetracarboxylic acid [BTCA], 2,3,7,8-Tetrachlorodibenzodioxin, (TCDD), 2,3,7,8-Tetrachlorodibenzo-p-dioxin [TCDD], Pentachloroanisole, Isopropyl methyl phosphonic acid, Nitrofen (technical grade), Dacthal, Benefin, Chlorothalonil, Paraquat, Atrazine, Atrazine, Dicamba, Picloram, Propachlor, Vernam, Nitrapyrin, Direct Black 38 (technical grade), t-Butylhydroquinone, tert-Butylhydroquinone, Butylate, p,p'-Dibromodiphenyl ether, Oxytetracycline hydrochloride (internal use), Pimozide , fe, Vincristine sulfate, Vincristine sulfate salt,

  17. HTS ChemicalsFirst Cut (continued) 2,6-Diisopropylphenol, D&C Red No. 8 , Ethyl p-nitrophenyl phenylphosphorothioate, Tributyltin methacrylate, Fluometuron, N-Isopropyl acrylamide, Molinate, Octachloronaphthalene, Triallate, Phosalone, Propargite, 3,3'-Dihydroxybenzidine, Mirex, Captafol, C.I. pigment red 3, Direct blue 15, Malachite Green Oxalate, Oxythioquinox, Dodine, Disperse Blue 1, Terrazole, Direct Blue 6 (technical grade), Oil Orange SS, Octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine, HC Blue 1, 5-Amino-o-cresol, Chlorpyrifos, Diisopropyl sulfate, D4T (2',3'-Didehydro-3'-deoxythymidine), Dideoxydidehydrothymidine, beta-Butyrolactone , Aldrin, 6-Azacytidine, Dibromoacetonitrile, 2,2-Bis(bromomethyl)-1,3-propanediol, 7-(2H-Naphtho[1,2-d]triazol-2-YL)-3-phenylcoumarin, Nickel carbonate, Asulam, Flunisolide , fe, D&C Orange No. 17 , Zinc carbonate hydrate, Pentaerythritol Triacrylate, Phenesterin, Ponceau 3R, thiazole, Tetraethyldithiopyrophosphate, 5-Methylchrysene, Ponceau MX, Nafenopin, Ifosfamide, Streptomycin sulfate, Methacycline hydrochloride, 2',3'-Dideoxyadenosine (ddA), Cladribine, Dacarbazine, Mono(2-ethylhexyl)phthalate [MEHP], Glyoxal trimeric dihydrate, N-Nitrosomethylvinylamine, Isotretinoin, CIS-CHLORDANE , TRANS-CHLORDANE , Flurbiprofen , fe , D&C Red No. 9 , p-a,a,a-Tetrachlorotoluene, Carboxin, 9-cis-Retinoic Acid, Citral, Dimethylaminopropyl chloride HCl, Benzphetamine hydrochloride, 2,2',4,4'-Tetrabromodiphenyl Ether (PBDE 47), 1-Nitropyrene, Vidarabine, 3-Methyl-6-methoxy-2-aminobenzothiazolium chloride, Bromochloroacetic Acid, Cadmium acetate, dihydrate, Terbacil, Berberine chloride dihydrate, d-Limonene, Nickel oxide, Folinic acid, calcium salt, Cyclophosphamide monohydrate, Lead acetate, Lead acetate trihydrate, epsilon-Hexachlorocyclohexane, 3-Amino-9-ethylcarbazole hydrochloride, Mercaptopurine, Chlordimeform, Dihydroergotamine mesylate, Methylene bis(thiocyanate), 5-(Hydroxymethyl)-2-furoic acid, Citrus Red No. 2 , C.I. Acid Red 114 , C.I. pigment red 23, Ammonium nitrate, Norgestrel, Scopolamine hydrobromide trihydrate, Thallium carbonate, Methan-sodium dihydrate, Baythroid, cis-Bixin, Bixin, Methylene blue trihydrate, Estropipate , Prometryn, ENDRIN ALDEHYDE , Thallium(I) sulfate, Lead phosphate, Selenium sulfide, 2',3'-Dideoxycytidine, 2',3'-Dideoxycytidine (ddC), Mercuric chloride, 6-Nitrochrysene, beta-Cyclodextrin, Sodium nitrite, Sodium nitrite, Hydrogen chloride, Phosphoric acid, HYDROGEN FLUORIDE , Ammonia, Sodium Fluoride, BROMINE , CHROMIUM TRIOXIDE , Potassium bromate, Sodium Chlorite, Ammonium sulfamate, Sodium Chlorate, ARSENIC ACID , CALCIUM ARSENATE , Potassium dichromate, Fluorine (soluble fluoride), Selenious acid, Hydrogen sulfide, Aluminum chloride, Aluminum trichloride hexahydrate, Aluminum fluoride, Ammonium arsenate, Manganese (II) sulfate monohydrate, Nickel sulfate hexahydrate, Sodium Dichromate Dihydrate, Sodium dichromate dihydrate (VI), Sodium Bromate, Sodium bromate, Perchlorate and Perchlorate Salts, Thallium chloride, Corn oil, Toxaphene, STROBANE , D & C Yellow II, PYRETHRUM , Turpentine, Oil of pimenta (Allspice), Sesame oil, Senna (powdered), Mancozeb, Demeton, Kava Kava Extract, Menotropins, Polyvinyl alcohol, Iron dextran complex, Methylcellulose, Polyoxyethylenesorbitan monolaurate(Polysorbate 20), Polysorbate 80, Metiram , Chitosan, alpha-Cyclodextrin, Indium trichloride, Cobalt sulfate heptahydrate, Hydrazine sulfate, Boric acid, Sterigmatocystin, Chlorine dioxide, 1,3-DICHLOROPROPENE, CIS- , 1,3-DICHLOROPROPENE, TRANS- , Nitric oxide , Nitrogen dioxide, Thallium nitrate, Cobalt sulfate , Sodium Tungstate Dihydrate, Methamidophos, Barium chloride dihydrate, Direct blue 218, Stanozolol, Resmethrin, Tamoxifen and its salts, N-Nitroso-N-methylethylamine, Monochloramine, Carbendazim, Asbestos, Crocidolite, Asbestos, Chrysotile, CHRYSOTILE ASBESTOS , TRICHLOROBENZENE , Copper indium selenide, Ammonium molybdate, Nickel subsulfide, Thallium selenite, Arsenic Pentoxide, Zineb, AMOSITE ASBESTOS , Asbestos, Amosite, Palygorskite fibers (> 5µm in length), Maneb, Aroclor 1248, Aroclor 1016, AROCLOR , Chlordane, 1-nitrosourea (CCNU) (Lomustine), Cyhexatin, ETHOPROP , N-Nitrososarcosine, Rifampicin, Flutamide, Sodium Selenate, Gallium trichloride, Nickel carbonyl, Titanium dioxide, D&C Red Dye 27, 4,4'-Methylenedianiline dihydrochloride, Quinalphos, Minocycline hydrochloride (internal use), Trilostane, Phenmedipham, Potassium ferricyanide, -1-nitrosourea (Methyl-CCNU), Amoxapine, 3,3’, 4,4’-Tetrachloroazobenzene [TCAB], 3-Hydroxypropylmercapturic acid, Cinnamaldehyde (trans), neat, Chromium picolinate, Nitrate, Nitrite, Talc, Cycasin, Napropamide, Methotrexate sodium, 2,6-Toluenediamine dihydrochloride, Bromate, Trimethylolpropane Triacrylate, Trimethylolpropane triacrylate, cis-Dichlorodiamine platinum, Cisplatin, 5-Methylisopsoralen, Alachlor, Chromium (III), insoluble salts, Direct Brown 95 (technical grade), Ammonium methacrylate, N-Nitrosonornicotine, 12-o-Tetradecanoylphorbol-13-acetate, 12-O-Tetradecanoylphorbol-13-acetate [TPA], methylformylhydrazone), Ethephon, Methomyl, Nickel subsulfide, Sodium Hexafluorosilicate, FLUORIDE ION , Doxycycline monohydrate (internal use), Benomyl, Plicamycin, D&C Red Dye 28, Chromium (VI), Aluminum lactate, Oryzalin, Oxadiazon, Amiodarone hydrochloride , p-Chloroaniline hydrochloride , p-Anisidine hydrochloride, 3,3'-Dimethoxybenzidine dihydrochloride, Methazole, a-Solanine, Daunomycin, Aluminum phosphide, Metribuzin, 2-Ethylhexyl-p-dimethyl-aminobenzoate, Cyanazine, Cytembena, Nifedipine , fe,, Tetrabromobisphenol A-bis(2,3-dibromopropyl ether), Fenamiphos, Indium phosphide, 3,9-Dinitrofluoranthene, Indium trichloride tetrahydrate, Aspartame, Silybin, Methylmercury , Halazepam, Oxamyl, Doxorubicin hydrochloride, Riddelline,

  18. HTS ChemicalsFirst Cut (continued) Daunomycin HCL, Thiophanate-methyl, Pronamide, Mepiquat chloride, Doxycycline hyclate (internal use), Butylated hydroxyanisole , Bentazon, Clobetasol propionate , 2,4-Decadienal, Nonylphenol, TETRACHLOROPHENOL , Dipropylene glycol, Dipropylene glycol, Adriamycin, hydrochloride, DINITROTOLUENE , DICHLOROBENZENE , TETRACHLOROETHANE , TRICHLOROETHANE , Pentachlorocyclopentadiene, PENTACHLOROBIPHENYL , Gemfibrozil, "A-alpha-C (2-Amino-9H-pyrido, [2,3-b]indole, ", 2,4-/2,6-Toluene diisocyanate mixture, Sodium azide, Triforine, TETRACHLOROBIPHENYL , m-Nitrobenzoic acid, OXYCHLORDANE , Norflurazon, Chromium Picolinate Monohydrate, Thiobencarb, C.I. Direct Blue 218 , 3,3'-Dichloro-4,4'-diaminodiphenyl ether, HEPTACHLOROBIPHENYL , Triazolam, Alprazolam, Atenolol, Pirimiphos-methyl, Teniposide, PENTACHLORODIBENZOFURAN , 3'-Azido-3'-deoxythymidine (AZT), Acephate, Mebendazole, Pentabromodiphenyl Oxide (DE-71) Repackaged, Octabromodiphenyl Ether, Procymidone, Paclitaxel , fe,, Amitraz, ENDOSULFAN, BETA , Diltiazem hydrochloride, Etoposide, Isopropalin, BIS(2-METHOXYETHYL) PHTHALATE , Tebuthiuron, Auranofin, Foscarnet, Acetochlor, HEXACHLORODIBENZO-P-DIOXIN , 2,2',4,4',5,5'-Hexachlorobiphenyl, Diflubenzuron, Imazalil, 1,2-Dibromo-2,4-dicyanobutane, 1,2,3,4,6,7,8-HEPTACHLORODIBENZO-P-DIOXIN , PENTACHLORODIBENZO-P-DIOXIN , Hexabromodiphenyl ether, Iprodione, Quazepam, Ribavirin, Elmiron, AROCLOR 1262 , HEPTACHLORODIBENZO-P-DIOXIN , Sulindac , fe, Trientine hydrochloride, 5-(Hydroxymethyl) furoyl glycine, HEPTACHLORODIBENZOFURAN , 1,2,3,4,6,7,8,9-OCTACHLORODIBENZOFURAN , Fosetyl-al, 2,4-Diaminoanisole sulfate , Dinocap, Danitol, Amikacin sulfate , Tetrabromodiphenyl ether, 1,2,3,7,8-Pentachlorodibenzo-p-dioxin, Pendimethalin, Methoprene, Etodolac , fe , Carboplatin, Chlorocyclopentadiene, TETRACHLORODIBENZO-P-DIOXIN , 1,6-Dinitropyrene, 1,8-Dinitropyrene, Oxyfluorfen, DIBENZOFURANS, CHLORINATED , Bayleton, Difenzoquat, Tribromodiphenyl ether, Tobramycin sulfate, Vinclozolin, Ginseng, Wy-14643, 2,3,7,8-TETRACHLORODIBENZOFURAN , Metolachlor, Hexazinone, Diclofop methyl, Cimetidine, Pydrin, Chlorowax 500C, Propylene glycol monoethyl ether, Cypermethrin, 3'-Amino-3'-deoxythymidine (AMT), HC Yellow 4, Permethrin, Bromacil lithium salt , AROCLOR 1242 , ENDRIN KETONE , Pentostatin, Polygeenan, 2,4-Dimethoxyaniline hydrochloride, Etretinate, Iso-E Super, Chlorozotocin, Tamoxifen, citrate salt, Cefuroxime Free Acid, Carbosulfan, Dimethipin, Acesulfame K, HEXACHLORODIBENZOFURAN , 1,3,4-oxadiazole, PENTACHLOROBUTADIENE , Nitazoxanide, Netilmicin sulfate, Flurprimidol, ALPHA-CHLORDENE , GAMMA-CHLORDENE , BENZOFLUORANTHENE , Propylene glycol mono t-butyl ether, Clorazepate dipotassium , 2,3,4,7,8-Pentachlorodibenzofuran, 3,3',4,4',5-Pentachlorobiphenyl, 4-Nitropyrene, Metalaxyl, Idarubicin hydrochloride, Tridiphane, Misoprostol, Midazolam hydrochloride, Thiodicarb, Fluridone, Ciclosporin (Cyclosporin A; Cyclosporine) , 3-(N-Nitrosomethylamino)propionitrile, Propiconazole, Pentabromodiphenyl Ether (PBDE 99), N-Carboxymethyl-N-nitrosourea , Furmecyclox, Castor oil, ethoxylated (Emulphor EL-620L), Trp-P-1 (Tryptophan-P-1), Acifluorfen, sodium, Sodium phenobarbital, Chlorowax 40, Nonabromodiphenyl ether, 4-(N-Methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), Sodium zomepirac, Chlorsulfuron, Avermectin B1, 4-Hydroxyphenyl retinamide, Silymarin, Goserelin acetate , fe,, Nimodipine, Cyromazine, Flutolanil, Fenoxaprop ethyl, Tralomethrin, Halobetasol propionate, Amdro, DIBROMOCHLOROPROPANE , [1,2-a:3',2'-d]imidazole), [1,2- a:3',2'-d]imidazole), Prochloraz, POLYBROMINATED BIPHENYLS , Methyl soyate, 9H-pyrido[2,3-b]indole), Cyhalothrin/Karate, beta-Cyclodextrin hydrate, Shale-oils, Coconut oil acid diethanolamine Con(2/1), 2,2',4,4',5,5'-Hexabromodiphenyl Ether (PBDE-153), Fluvalinate, 2',3'-Dideoxyinosine (ddI), Haloxyfop-methyl , Fluazifop butyl, Mitoxantrone dihydrochloride, 1,2,3,4,7,8-Hexachlorodibenzofuran, Bromodichloroacetic Acid, AROCLOR 1240 , Fomesafen, Fenoxycarb, Rifabutin, Comfrey, BENZOPYRENE , Sethoxydim, Apollo, Ally, Leuprolide acetate , fe, Lovastatin, [4,5-f] quinoline), Assure, Paclobutrazol, 4,5-f]quinoline), Glufosinate-ammonium, Trichlorocyclopentadiene, 3-Chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone, (MX), 5-hydroxy-2(5H)-furanone), 4,5-f]quinoxaline), Lactofen, Savey, Harmony, Fusarin C, Tebuconazole, Fluticasone propionate, Clarithromycin, purified, Pravastatin sodium, Imazaquin, Pursuit, Triasulfuron, Ganciclovir sodium, Isoxaben, Biphenthrin, Trimetrexate glucuronate, Londax, Azithromycin, Black Cohosh, Blackberry extract, 4-Nonylphenol, branched, NuStar, Nafarelin acetate, AMERICIUM-241 , Systhane, Ginkgo Biloba Extract, Chlorimuron-ethyl, Doxycycline calcium (internal use), Urofollitropin, Merbarone, Hydroxypropyl-alpha-cyclodextrn, 1,2,3,4,6,7-Hexachloronaphthalene (PCN 66), 1,2,3,5,6,7-Hexachloronaphthalene (PCN 67), phenylimidazol[4,5-b]pyridine), 3,7-Dinitrofluoranthene, C12;approximately 60 percent chlorine by weight), Zileuton, Cidofovir, Filgrastim, Arotinoid, Nevirapine, Fullerite, 3TC, Isoxaflutole, Saquinavir Mesylate, Nelfinavir mesylate, Celecoxib, SC-560,

  19. NTP RoadmapData Analysis and Interpretation • Information technology • NTP website changes • New databases, new tools • Methods development • Analysis tools • HTS, MTS • Multiple strain studies • Genomics • Technological advances • imaging • Interaction with public health decision makers • How and when to use new results • Steps as we proceed • Staffing and expansion of skills • Additional NTP staff • Training

  20. Collaborative Participation at All Levels MULTI-TIERED Testing Program MECHANISTIC Linkage in All Tiers SCIENCE-BASED Priority Setting and Interpretation EFFICIENT Utilization of Resources Developing the Best Science to Achieve the Best Decisions Basic Research Public Health Research In Toxicology Testing And Evaluation NTP 21st Century ToxicologyNTP Leading the Way

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