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Building a Database of Developmental Neurotoxicants: Evidence from Human and Animal Studies
W. Mundy1, S. Padilla1, T. Shafer1, M. Gilbert1, J. Breier1,2, J. Cowden1, K. Crofton1, D. Herr1, K. Jensen1, K. Raffaele3, N. Radio4, and K. Schumacher5. 1Neurotoxicology Div. U.S. EPA, RTP, NC 27711; 2Curriculum in Toxicology, Univ. of N.C. at Chapel Hill, Chapel Hill, NC, 27514; 3 NCEA/ORD, U.S. EPA, Washington, DC, 20460; 4Cellumen, Inc., Pittsburgh, PA. 15238; 5U.S. EPA, Region 7, Kansas City, KS, 66101.
Chemicals with Substantial Evidence of
Evidence: Criteria for Assessment and Endpoints Developmental Neurotoxicity (n≈100)
EPA’s program for the screening and prioritization of chemicals for developmental neurotoxicity makes it essential to assemble a list of chemicals -no in vitro studies were included.
that are toxic to the developing mammalian nervous system. Listed chemicals will We included only studies with the pure chemical (or reasonably so).
2-Ethoxyethyl Acetate
Diazepam
Naltrexone
Acibenzolar-S -methyl
Cytosine Arabinoside
Nicotine
be used to evaluate the sensitivity, reliability, and predictive power of alternative Acrylamide
Methoxyethanol, 2-
developmental neurotoxicity assays. To establish this list, a literature review was -no human studies were included wherein there was exposure to more than one Aldicarb
Deltamethrin
Methylazoxymethanol
conducted for over 400 compounds that have been suggested to be Allethrin
Diazinon
Methylmercury
Aluminum (cl or lactate)
Dieldrin
developmental neurotoxicants, neurotoxicants, or developmental toxicants. We included only studies where the exposure took place during pregnancy or Amino-nicotinamide(6-)
Diethylstilbestrol
Paraquat
Compounds were assigned one of three groups based on the strength of the Aminopterin
Diphenylhydantoin
Parathion (ethyl)
Amphetamine(d -)
Epidermal Growth Factor
evidence for developmental neurotoxicity: We included only studies in which the administered dose was below 5 grams/kg.
PCBs (generic)
(1) no evidence: either there were no reports that met our criteria for evidence, or
Where knowledge was available, we considered only studies where the Aspartame
Ethylene thiourea
Penicillamine
Azacytidine(5-)
Flourouracil(5-)
Permethrin
there were reports which showed no developmental neurotoxicity; administered dose would not be lethal to the offspring.
Fluazinam
Phenylacetate
(2) minimal evidence: one report only or multiple reports from only one laboratory;
We did not include any case reports.
Fluoride
Phenylalanine (d,l)
In studies where the chemical was administered during gestation, to the extent Bioallethrin
Griseofulvin
Phthalate, di-(2-ethylhexyl)
possible, we looked for a litter-based statistical design.
Bis(tri-n-butyltin)oxide
Haloperiodol
Propylthiouracil
(3) substantial evidence: reports from more than one laboratory.
If only acute pharmacological effects were reported (either during dosing or shortly
Bisphenol A
Halothane
Retinoids/vit.A/isotretinoin
The chemicals in the latter group will be especially useful for vetting protocols that Bromodeoxyuridine(5-)
Heptachlor
Salicylate
thereafter), we did not include that study.
Butylated Hydroxy Anisol
Hexachlorobenzene
Tebuconazole
have been proposed as screens for developmental neurotoxicity.
Endpoints assessed included, but were not limited to:
Butylated hydroxytoluene
Hexachlorophene
Tellurium (salts)
Hydroxyurea
Terbutaline
This presentation has been reviewed by the National Health and Environmental Effects Research Laboratory and approved. Approval Caffeine
Imminodiproprionitrile (IDPN)
Thalidomide
does not signify that the contents reflect the views of the Agency. Carbamazepine
Ketamine
Carbaryl
Carbon monoxide
Triamcinolone
Chlordecone
Tributyltin chloride
Chlordiazepoxide
Trichlorfon
Chlorine dioxide
Medroxyprogesterone
Trichloroethylene
Chlorpromazine
Mepivacaine
Triethyllead
Chlorpyrifos
Methadone
Triethyltin
Methanol
Trimethyltin
Colcemid
Methimazole Trypan blue
Collect lists
Chemicals with Minimal Evidence of
Colchicine
Methylparathion
Urethane
Cypermethrin
Monosodium Glutamate
Valproate
of putative
Dexamethasone
Vincristine
Developmental Neurotoxicity (n≈100)
Diamorphine hydrochloride
Naloxone
DNT chemicals (n≈400)
1,1,1-Trichloroethane
Diaminotoluene (2,5-)
Lidocaine
Abamectin
Dichloromethane (methylene chloride)
Malathion
Acephate
Dichlorvos (DDVP)
Mancozeb
Acetamiprid
Dicrotophos
Maytansine
ActinomycinD
Difluoromethylornithine
Methamidaphos
Amicarbazone (MKH 3586)
Dimethoate
Methyl Ethyl Ketone
DEXAMETHASONE
Astemizole
Atorvastatin
Diphenhydramine
Molinate
Atrazine
Disulfoton
Dexamethasone is synthetic member of the glucocorticoid class of steroid hormones. It is Azinphos methyl
Emamectin
n -Hexane
used to treat inflammation and autoimmune conditions (e.g., rheumatoid arthritis), and to counteract side- BAS 510 (Boscalid)
Endosulphan
Nickel carbonyl
effects of chemotherapy in cancer patients. Synthetic glucocorticoids, including dexamethasone, are also Perchlorate
administered to women at risk for preterm labor to advance fetal maturation and reduce neonatal Bifenthrin
EPTC (S -Ethyl dipropylthiocarbamate)
Phorate (BAS 225 I)
Bismuth Ribromophenate
Ergotamine
Picrotoxin
Numerous studies in animals have shown neurodevelopmental effects of perinatal Brominated veg oil
Ethoxyethanol (2-)
Primidone
dexamethasone treatment in rodents. Doses of 0.2 – 3 mg/kg (which encompasses the therapeutic range Busulfan
Ethylene dibromide
Profenofos
in humans) given to the pregnant dam during gestation or to the offspring postnatally alter neurogenesis Carbofuran
Ethylene oxide
Prothioconazole
and differentiation (Bohn, 1984; Carlos et al., 1992), decrease brain size and brain weight (DeKoskey et Carbon disulfide
Etofenprox
Selenium compounds
al., 1982; Carlos et al., 1992; Ferguson and Holson, 1999), and alter locomotor activity and learning and Chlordane
Fenamiphos
Simvastatin
memory behavior (DeKoskey et al., 1982; Vicedomini et al., 1986; Ferguson et al., 2001; Kreider et al., Chlordimeform
Fenitrothion
Spirodiclofen
2005a). Relatively low doses (0.05 – 0.2 mg/kg) have also been shown to result in long-lasting changes in Chlorfenapyr Fenvalerate
Succamir
neurotransmitter systems and intracellular signaling (Kreider et al., 2005b; Kreider et al., 2006; Slotkin et Each chemical was assigned to one of three categories:
Chlorite, sodium
FK 33-824 (Synthetic enkephalin)
Terbufos
al., 2006). Effects of dexamethasone, including decreased brain weight and hippocampal damage, have 1. No available evidence existed: exclude from
CI-943 (Antipsychotic)
Flufenacet (thiafluamide)
tert-Butylhydroquinone, 2-
also been observed in nonhuman primates (reviewed in Coe and Lubach, 2005).
Clodinafop-propargyl Formaldehyde
Tetrachloethylene
Human developmental neurotoxicity is associated with perinatal exposure to manuscript.
Clothianidin Glufosinate
ammonium
Tetracycline
dexamethasone. Prenatal dexamethasone is routinely administered to mothers at risk for preterm delivery Coumaphos
Glyphosate trimesium
Thiamethoxam
to reduce mortality and the incidence of respiratory distress syndrome and intraventricular hemorage in 2. Minimal evidence existed: put in table in manuscript.
Cyfluthrin
Hexachoroplatinate (Na)
Tribufos (DEF)
premature infants. Postnatal dexamethasone treatment in preterm infants is also used to reduce the risk 3. Substantial evidence existed: write a descriptive
Cyhalothrin
Imidacloprid
Triethylene glycol dimethyl ether
and severity of chronic lung disease. A preponderance of epidemiologic and clinical evidence, however, Cymoxanil
Ivermectin
Trimethadone
indicates that both pre- and post-natal exposure to dexamethasone can result in an increased risk for paragraph for manuscript.
Lasofoxifene
Triphenyl phosphate
cerebral palsy, decreased brain size, and long-term effects on cognition and behavior (reviewed in Baud, Levo-alpha-acetylmethadol
VM-26 (Teniposide)
2004; Purdy, 2004; Purdy and Wiley, 2004; Sloboda et al., 2005).
Dextromoramide
VP-16-213 (Etoposide)
*Registration Eligibility Decision Documents (available online or via Freedom of Information Act)

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