European Toxicology From a National Toxicology Program Perspective

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
• Lots 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. Elegans Developmental 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 (Dichlorodiphenyltrichloroe
thane), Benzoapyrene , 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'-
, Dibenza,hanthracene, 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, Benzaanthracene,
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)ant
hracene, Caffeine, Pyrimethamine,
Methyltestosterone, Testosterone cypionate,
Testosterone and its esters, Chlordiazepoxide,
Promethazine hydrochloride, Theophylline,
gamma-Hexachlorocyclohexane, 2,3,4,6-Tetrachloroph
enol, 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-Dimethylformamid
e, 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, Chlorodifluoromethan
e, 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-triflu
oroethane, 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-Tetrachloroethan
e, 1,1,2,2-Tetrachloroethane, 1,1,2,2-Tetrachloroe
thane, Methacrylamide, Dichloroacetic Acid,
Dimethylcarbamoyl chloride, 2-Nitropropane,
Oxytetracycline (internal use),
Tetrabromobisphenol A, Bisphenol A.,
4,4'-Dichlorodiphenylsulfone, p,p'-Dichlorodipheny
l Sulfone, Dapsone, alpha-Pinene, Methyl
methacrylate, 1-Amino-2,4-dibromoanthraquinone,
Warfarin, DC Red No. 19 , 1-Amino-2-methylanthraq
uinone , 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 (11), 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-Tetrachlorob
enzene, 2,4,5-Trichlorophenol, Styrene oxide,
1,2-Dibromo-3-chloropropane, 1,2-Dibromo-3-chlorop
ropane (DBCP, 1,2,3-Trichloropropane, Methyl
acrylate, Ethylene thiourea, 2-Methyltetrahydrofur
an, 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 (11), 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-dibromopro
pyl)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-methoxy
benzophenone, 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-oxazolidin
one, 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 diethyldithiocarbama
te , 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), Dibenzoa,hpyrene , Benzog,h,iperylene
, Dibenzoa,ipyrene , Dibenzoa,epyrene ,
Indeno1,2,3-cdpyrene, 7H-Dibenzoc,gcarbazole
, Benzojfluoranthene , Benzobfluoranthene,
Fluoranthene, Benzokfluoranthene,
Acenaphthylene, Chrysene, Dibenza,hacridine ,
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-Hexachlorocycloh
exane, 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-CRESO
L , 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, Tetrachlorocyclopent
adiene, 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, DC 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-te
trazocine, 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-Naphtho1,2-dtriazol-2-YL)-3-phenylcoumarin
, Nickel carbonate, Asulam, Flunisolide , fe, DC
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)phthala
te MEHP, Glyoxal trimeric dihydrate,
N-Nitrosomethylvinylamine, Isotretinoin,
CIS-CHLORDANE , TRANS-CHLORDANE , Flurbiprofen ,
fe , DC 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-ethylcarb
azole hydrochloride, Mercaptopurine,
Chlordimeform, Dihydroergotamine mesylate,
Methylene bis(thiocyanate), 5-(Hydroxymethyl)-2-fu
roic 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
(gt 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, DC 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-Nitrosonornicotin
e, 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, DC 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-bindole, ", 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'-deoxythymidi
ne (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'-Hexach
lorobiphenyl, Diflubenzuron, Imazalil,
1,2-Dibromo-2,4-dicyanobutane, 1,2,3,4,6,7,8-HEPTA
CHLORODIBENZO-P-DIOXIN , PENTACHLORODIBENZO-P-DIOX
IN , 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)propionitr
ile, 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, DIBROMOCHLOROPROPAN
E , 1,2-a3',2'-dimidazole), 1,2-
a3',2'-dimidazole), Prochloraz, POLYBROMINATED
BIPHENYLS , Methyl soyate, 9H-pyrido2,3-bindole)
, 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-Hexachlo
rodibenzofuran, Bromodichloroacetic Acid, AROCLOR
1240 , Fomesafen, Fenoxycarb, Rifabutin, Comfrey,
BENZOPYRENE , Sethoxydim, Apollo, Ally,
Leuprolide acetate , fe, Lovastatin, 4,5-f
quinoline), Assure, Paclobutrazol,
4,5-fquinoline), Glufosinate-ammonium,
Trichlorocyclopentadiene, 3-Chloro-4-(dichlorometh
yl)-5-hydroxy-2(5H)-furanone, (MX),
5-hydroxy-2(5H)-furanone), 4,5-fquinoxaline),
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),
phenylimidazol4,5-bpyridine),
3,7-Dinitrofluoranthene, C12approximately 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
21st Century Toxicology NTP Leading
the Way

• 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