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PCB and OH-PCB. To evaluate the health effect on the next generation, it is necessary to estimate the contamination level of PCBs and OH-PCBs according to the congeners. 622 ENDOCRINE EFFECTS OF A NOVEL HIV-NNRTI IN SEXUALLY IMMATURE FEMALE CYNOMOLGUS MONKEYS. F. van Velsen 4 , J. Sternberg 1 , B. Niggemann 1 , S. Friderichs-Gromoll 1 , G. Weinbauer 1 , I. Vanwelkenhuysen 2 , L. Grooten 2 , S. Lachau-Durand 4 , S. De Jonghe 2 , L. De Schaepdrijver 2 , T. Coogan 3 , L. Lammens 2 , A. Raoof 4 and W. Coussement 2 . 1 Covance Laboratories GmbH, Muenster, Germany, 2 GPCD, Janssen Pharmaceutica, Beerse, Belgium, 3 PCD, Centocor, Radnor, PA and 4 PCD, Tibotec, Beerse, Belgium. The compound has shown endocrine effects on adrenal glands and ovaries in rats and dogs indicative of adrenal CYP21 inhibition and early onset of ovulation (dogs). Non-human primates share with man a significant adrenal androgenic pathway. Inhibition of CYP21 may exert masculinization in prepubertal individuals as has been described for congenital adrenal hypertrophy due to CYP21 deficiency. The chosen model shares with women an identical physiology in terms of onset of puberty and ovulation. The endocrine effects were further evaluated in 1-2 year old female cynomolgus (Macaca fascicularis) treated for 8 weeks with 0, 200 and 500 mg/kg/day. The results on baseline and ACTH-stimulated hormone levels and standard toxicity parameters indicate that the NNRTI inhibits CYP21 also in the cynomolgus monkey. In addition, the compounds appeares to inhibit 17α-hydroxylase and 17,20 lyase (CYP17), key enzymes for the adrenal androgenic pathway. The enzyme inhibitions appeared to be partial and transient. The inhibition of CYP17 and the partial and transient inhibition of CYP21 alleviate the concern of masculinization of prepubertal children. The absence of any indication of early onset of puberty in the immature cynomolgus monkey model being a more relevant model for man neutralizes the concern due to the results of the dog studies. The lower dose tested in the cynomolgus monkeys was not without adrenal endocrine effects whereas the exposure to the compound was not significantly higher than that in adult patients treated with the clinical efficacious daily dose of 25 mg. Longterm clinical safety studies with higher doses than 25 mg qd have never resulted in any clinically relevant endocrine effect. Therefore, it is concluded that the immature cynomolgus monkey model is oversensitive to the adrenal endocrine effects of the NNRTI. 623 IMPAIRED REPRODUCTION IN ADULT MALE, BUT NOT FEMALE, RATS FOLLOWING JUVENILE TREATMENT WITH THE AROMATASE INHIBITOR, EXEMESTANE. G. Cappon 1 , M. E. Hurtt 1 , R. E. Chapin 1 and L. Burns-Naas 2 . 1 DSRD, Pfizer, Groton, CT and 2 DSRD, Pfizer, LaJolla, CA. Aromatase inhibitors are currently being investigated in combination with growth hormone for the ability to improve final height in children. Exemestane is an irreversible steroidal aromatase inhibitor, structurally related to androstenedione. Because of its mechanism of action, the drug was investigated for the potential to affect mature reproductive systems when administered to immature rats. Male and female rat pups were treated with exemestane (0, 30, 100, 300 mg/kg) once daily from PND 7-50 (male) or 7-41 (female). Maturation of the reproductive system was evaluated by monitoring the onset of vaginal patency or preputial separation. After maturation, treated rats were mated with untreated rats to evaluate the potential impact on reproductive function. After mating (males) or on GD14 (females) rats were euthanized and reproductive organs evaluated microscopically. Exemestane was well-tolerated at all dose levels and there were no effects on age at onset of vaginal patency or preputial separation. There was no drug-related effect on female reproductive function. Treatment of juvenile male rats with exemestane caused an increase in cohabitation time prior to copulation and decreased copulation rates; however, pregnancy rates and litter size was not affected in rats that successfully mated. Decreased weight of the testis (10-15%) and epididymis (20-30%) were noted at al dose levels and the number of Sertoli cells was decreased in all dose groups. These data show that an aromatase inhibitor can reduce Sertoli cell proliferation during maturation and at clinically-relevant concentrations. The sensitive window for this effect is limited to the period of Sertoli cell proliferation, which is completed in rats by around PND 15 and prior to puberty in humans. Treatment beginning at a later time relative to the window for Sertoli cell proliferation or for a longer duration is not expected to have any additional adverse effect since the effect is not degenerative. 134 SOT 2011 ANNUAL MEETING 624 MOST BPA-FREE PLASTICS RELEASE CHEMICALS HAVING ESTROGENIC ACTIVITY (EA): BPA-FREE DOES NOT MEAN EA-FREE. G. Bittner 1, 2, 3 , C. Z. Yang 1 , S. Yaniger 2 and D. Klein 2 . 1 CertiChem, Inc., Ausin, TX, 2 PlastiPure, Inc., Austin, TX and 3 University of Texas, Austin, TX. Sponsor: R. Tice. Scientists have recently expressed serious concerns about possible adverse health effects of bisphenol-A (BPA) that has estrogenic activity (EA) that causes many adverse health effects at low (pM-nM) doses, especially in fetal and juvenile mammals. We used a roboticized MCF-7 cell proliferation assay to quantify release of chemicals having EA in saline or ethanol extracts of many types of commercially available plastic materials. To properly detect release of chemicals having EA, we show that plastic products should be extracted with more-polar and less-polar solvents—and exposed to common-use stresses such as microwaving, UV radiation, and/or boiling. If only one extraction solvent is used and no common-use stresses are applied, then most plastic products are mischaracterized as EA-free. In contrast, when extracted with two solvent types and exposed to common use stresses, almost all ( over 90%) commercially available plastic products, including those advertised as BPA-free, release chemicals having EA. As one example, all products tested made from Eastman’s Tritan resins released chemicals having easily detectable EA—often at levels greater than that released by BPA-based polycarbonate bottles. Products that do not release chemicals having EA can be cost-effectively made with currently available technologies by using chemicals with no detectable EA in all steps of the manufacturing process. Such EA-free products are producible at minimal additional cost. It is now realistically possible to eliminate the potential health risk posed by the leaching of chemicals having EA from plastics into food products. Supported by NIH SBIR44ES014806. 625 MANGANESE LEVELS IN CARPET DUST ARE ASSOCIATED WITH PROXIMITY TO AGRICULTURAL USE OF MANEB AND MANCOZEB. R. Gunier 1 , D. R. Smith 2 , A. Bradman 1 and B. Eskenazi 1 . 1 University of California, Berkeley, CA and 2 University of California, Santa Cruz, CA. Rationale: Although manganese (Mn) is an essential nutrient, at high exposure levels Mn is a potent neurotoxicant. The fungicides maneb and mancozeb are ~21% Mn by weight and more than 140,000 kg of these pesticides are applied each year in the Salinas Valley, California. However, it is not clear whether these pesticides contribute to environmental Mn exposure to children. The objective of this study was to evaluate the relationship between Mn levels in carpet dust and residential proximity to reported agricultural uses of maneb and mancozeb. Procedures: We collected carpet dust samples from over 300 residences enrolled in the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) study. Carpet dust samples were sieved to < 150 μm, digested in 7.5 N nitric acid and analyzed using inductively coupled plasma optical emission spectroscopy. The latitude and longitude of each residence was determined using GPS. We used a geographic information system to summarize pesticide use for several distances around each residence (500, 1000, 1500 and 2000 m) and time periods prior to dust collection (7, 30, 90 and 180 days). We calculated Pearson correlation coefficients between Mn levels in carpet dust and the pounds of maneb and mancozeb applied for these combinations of distance and time. Results: We found detectable levels of Mn in all homes with a median concentration of 173 μg/g (range=8.4-414 μg/g; n=75 residences analyzed thus far). The strongest correlation (ρ=0.48) with Mn levels in carpet dust (μg Mn/g dust) was observed for the pounds of maneb and mancozeb applied within 1,500 m of the home during the 30 days prior to sample collection. Mn concentrations were also significantly higher in homes where farmworkers lived than in those without farmworkers (p
in the China Jintan Child Cohort Study was measured using Wechsler Intelligence Scale for Children (WISC). A questionnaire containing questions on covariates was completed. Children were categorized into three groups according to their BLLs (=10 ug/dL). Performance IQ, verbal IQ, and full scale IQ were compared among the three groups. Linear regression models were fitted for boys and girls separately, adjusting for parental education, children’s age, and iron intake. Results: Compared with boys with BLL=10ug/dL were 3 points lower on performance IQ. Girls with the highest BLL had a 6 point deficit in performance IQ, and a 3 point reduction in verbal IQ compared to those with the lowest BLL. There were no significant differences between
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The Toxicologist Supplement to Toxi
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The Toxicologist Supplement to Toxi
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1 BIODEGRADABLE MATERIALS FOR TISSU
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that genetic toxicology data are ge
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well-orchestrated lung inflammation
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scribed in the literature. We have
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years ago). We will illustrate how
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involved in the biodegradation proc
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stem cells but rather a treatment i
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additional compound showed agreemen
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82 COMPARISON OF 3H-THYMIDINE INCOR
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irritants. While in practice these
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alleles are especially vulnerable t
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109 CD4+ T CELL INTRINSIC TNF RECEP
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118 TO STUDY THE SIGNAL TRANSDUCTIO
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PAHs, such as dioxins, are prevalen
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containing substituents and/or hydr
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146 COMPUTATIONAL MODELING FOR QT P
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suggest that the combination of too
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164 TRANSLOCATOR PROTEIN (18 KDA) (
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function as a metal binding protein
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laboratory has demonstrated that NR
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known. The aim of this study was to
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from 5 to 28 days in duration) in e
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positive cells, caspase-3 activatio
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creased level in the 46 kDa preproe
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invasiveness at concentrations repr
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thracene (DMBA,50 μg in acetone, a
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247 CO-CARCINOGENESIS OF N, N- DIET
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sponds to the endosomal dsRNA that
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ODD in both WT (maximum 177% of con
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Lastly, using p53siRNA cells, p53 w
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its receptor Mpl to exert its funct
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294 LOW LEVEL OF LEAD CAN INDUCE PH
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lunar surface presented potential h
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lar about cellular export mechanism
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DNA in the kidney medulla, grandula
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5.00 and 7.50 mg/kg/day by oral gav
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events and carcinogenesis. Here we
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tinization of cells of the hair fol
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358 CHARACTERIZATION OF GENOME-WIDE
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RNAi were also performed to identif
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376 A FUNCTIONAL CROSSTALK BETWEEN
Page 87 and 88: UGT1A gene induction, while this re
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Page 95 and 96: ment. Paradoxically, buthionine sul
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Page 99 and 100: 442 GENE EXPRESSION AND MORPHOLOGIC
Page 101 and 102: 451 INHIBITION OF THE MITOCHONDRIAL
Page 103 and 104: 460 SULFORAPHANE PREVENTS ACETAMINO
Page 105 and 106: drophilic/lipophilic balance. Other
Page 107 and 108: pharmacokinetic and toxicological p
Page 109 and 110: 489 USE OF ‘OMICS DATA TO IMPROVE
Page 111 and 112: 498 APPLICATION OF AGE-SPECIFIC ADJ
Page 113 and 114: 507 A DOSE VOLUME TOLERABILITY STUD
Page 115 and 116: involved the use of an acute inflam
Page 117 and 118: sorption in the gastrointestinal (G
Page 119 and 120: (ABC) transporters actively transpo
Page 121 and 122: 545 BEHAVIORAL EFFECTS OF REPIN IN
Page 123 and 124: a blood pressure phenotype that res
Page 125 and 126: and inhalation exposure system that
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Page 129 and 130: position, on vascular reactivity an
Page 131 and 132: therefore more accurate and reprodu
Page 133 and 134: commercial chrysotile product that
Page 135 and 136: elative to their controls. ST-depre
Page 137: ats. The majority of the studies fo
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Page 143 and 144: 645 EVALUATION OF THE IN VITRO EPIS
Page 145 and 146: 654 TCDD ADSORBED ONTO NATURAL AND
Page 147 and 148: tion revealed no test article-relat
Page 149 and 150: 671 INFLAMMATION AND TISSUE DAMAGE
Page 151 and 152: model, ethanol was found to inhibit
Page 153 and 154: 689 ENHANCED SUPPRESSIVE FUNCTION O
Page 155 and 156: NAC + LPS yielded different levels
Page 157 and 158: 707 LIFE-STAGE PBPK MODELS FOR MULT
Page 159 and 160: downstream of the apical endpoint o
Page 161 and 162: 726 UPDATED ALUMINUM PHARMACOKINETI
Page 163 and 164: global parameter sensitivity analys
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Page 167 and 168: 754 PLASMA, URINE, AND TISSUE CONCE
Page 169 and 170: cently characterized transporter OA
Page 171 and 172: exposure system was developed from
Page 173 and 174: lood cell mass and decrease in urin
Page 175 and 176: practical alternatives to MC in non
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Page 181 and 182: yet is induced in most bladder and
Page 183 and 184: 830 RISK ASSESSMENT OF THE SPILL: C
Page 185 and 186: knowledgebase creation. Results are
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for integrating epidemiology and an
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motor activity, including age of th
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y partial purification of urine (fr
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pacity for self-renewal and may dif
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sue. The depth of our analysis led
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910 IMPLEMENTING CALIFORNIA’S GRE
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concentrations in six tissues and b
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934 THE FDA’S LIVER TOXICITY KNOW
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943 GENOME-WIDE DNA METHYLATION DIF
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membrane localization and subsequen
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trols, respectively. Subtoxic and t
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survival using both smoking regimes
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as non-, weak, moderate, or strong
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988 NNK-INDUCED CYTOKINE ALTERATION
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group (one-way ANOVA, p90 % viabili
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ered as an organ involved in xenobi
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Transport of CPZ across the Caco-2
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estrous cycle and sexual behavior d
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mRNA expression levels. Collectivel
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1043 THE EFFECTS OF ENDOCRINE DISRU
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1052 MONO-2-ETHYLHEXYL PHTHALATE IN
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Results: MC was variable within and
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UtSMCs. Phosphorylation of FoxO1 wa
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nonpregnant and pregnant diabetic m
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1089 PFOA-INDUCED LIVER EFFECTS IN
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events in the liver. AZD9056 was ev
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The peppermint oil caused a concent
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OA did not affect food consumption.
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1126 PERSISTENT DEVELOPMENTAL ARYLH
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1135 BACH2 BINDING TO Prdm1 AS A ME
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The purpose of this project was to
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one marrow. Since Chk1 is an attrac
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1163 THE MRNA AND MIRNA PROFILE OF
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have now compared the IC50 values b
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1181 ELUCIDATION OF FACTORS DETERMI
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enced by pre-exposure to cigarette
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if abnormal PF was associated with
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weight (P=0.016) and small for gest
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portant cause of death, compared to
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posure groups. However, the differe
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Naphthalene is routinely analyzed i
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1245 SEASONAL CHARACTERIZATION OF H
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1255 URINARY T, T MUCONIC ACID LEVE
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modating a reliable data evaluation
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enzoquinone generate ROS and arylat
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teins (e.g. C3, 4, and 5, APOB, VDB
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1293 TRANSFORMING GROWTH FACTOR BET
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mation was decreased to the same le
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1312 EVALUATION OF THE SENSITIVITY
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luted OFR and CRL. Culture media ex
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urinary TCPy levels, blood and brai
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activity. The dose-response curves
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mice, each with 4 dose groups. One
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exposure to both ATR and DACT has a
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third tetratricopeptide repeats (TP
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7d. 28d after TMT injury there was
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subunits. Each cell type was treate
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1394 COMPARATIVE EFFECTS OF METHYLM
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1403 GENOTOXICITY AND PRE-NEOPLASTI
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vated only in high-dose-treated ani
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1421 DOSE-RESPONSE OF NAPHTHALENE-I
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cisplatin; 1.2-, 1.9- and 2.9-fold
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Day 11 and started to recover on Da
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1448 DEVELOPMENT OF A METHOD FOR QU
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1457 GLOBAL GENE PROFILING REVEALS
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cluding mouse and human macrophage,
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model of lung inflammation and host
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1484 NANOTOXICOLOGY AND NANOHEALTH
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throughput in vitro approach was us
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1502 IMMUNOLOGICAL ASPECTS OF AN AN
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(CIA) and the Streptococcal cell wa
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sitizers were 100% concordant among
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1530 MINIMAL RISK LEVELS FOR STYREN
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ical groups in the field of regulat
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vitro with this potentially insect-
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their performance on toxicological
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need for a better understanding of
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1577 AN IN VITRO MODEL SYSTEM FOR A
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gene expression post-transcriptiona
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1595 GENE EXPRESSION PROFILE OF RAT
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to confirm a hepatotoxic property o
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1613 AN INVESTIGATION OF THE CLEARA
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its nuclear translocation was reduc
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were collected from TK animals at d
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egulated targets were selected for
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U/L after tetracycline. Minocycline
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peri-pubertal FasL-/- mice show a d
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showed similar levels of apoptosis
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1676 TWO BIOMARKERS FOR EVALUATION
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motifs selected. This system was ap
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1693 VOC SERUM LEVELS IN THE GENERA
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1702 DOES THE CLOCK MAKE THE POISON
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those with high nickel content are
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isk assessment. However, unique cha
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model of APAP metabolism and glutat
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logically & morphologically similar
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posure, blood chemistry was analyze
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elated to oxidative stress by measu
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ostasis), but work is needed to tra
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tokine products during carcinogenes
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ways as chemical stressors and, the
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toxicity of nanomaterials relates s
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1815 MEASURING COMPOUND SELECTIVITY
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1825 EFFECTS OF METABOLISM BY INTES
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cyanoacetic acid increased 2-3 fold
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1845 IS THE PROMISCUITY OF THE ARYL
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crorarray analysis. RT-PCR results
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are a family of phase-II biotransfo
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ous labs. As a result of positive s
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down the doses may produce more tox
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spectively. Below 100 mg/l of gemfi
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1900 GENERATION OF PRECISION CUT LI
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iomarkers or observation of lesions
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creased reticulocytes and lymphocyt
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statistically significant interacti
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monize sample preparation and analy
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NPC and sinonasal cancer in neighbo
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showed incidences of lung and nasal
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utylbenzenes, exhibited most simila
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1975 DIFFERENTIAL MODULATION OF CYP
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organic As to MMA(V) and a lower ca
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ole in invasion and metastasis of c
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3T3-L1 cells to low-levels of arsen
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2011 IDENTIFICATION OF A NOVEL VX M
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This work was supported by Cooperat
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2029 EFFICACY OF ENDOTRACHEAL ADMIN
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Diazepam injections and its combina
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2047 ESTERASE ACTIVITIES AND HEMOST
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nanoparticle-induced toxicity progr
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house, were iv infused into rats ov
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een explored. This study investigat
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croscopic analysis revealed that on
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egg yolk collected from turtles inh
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consistency of results in both expe
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2111 CYTOCHROME P450 3A5 GENOTYPE I
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esidues of organophosphates or thei
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manganism. Recent work from our lab
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Aβ1-40 in CSF and hippocampus in P
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2147 CATALASE MANIPULATIONS MODIFY
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ation based on real-world exposure
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NPs. Aggregation of citrate-stabili
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2175 THE ROLE OF SURFACE CHEMISTRY
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seen rapid uptake in biological ima
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effect on uterine weight or vaginal
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dicating widespread exposure. While
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components into the liver parenchym
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2223 ISOLATION AND DETECTION OF RIC
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stored (-20 celsius degree). The co
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2241 DDA, A BIOMARKER FOR ENVIRONME
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2249 INTERACTION BETWEEN DIETARY SE
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2258 PHARMACOKINETICS, EXCRETION BA
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2267 SENSITIVE AND SPECIFIC FLUORES
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2276 METABOLISM AND DISPOSITION OF
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ment of hypertension in companion a
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for the propyl series can be used f
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2304 IN VITRO EXPOSURE AND EVALUATI
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2313 THE SYNERGISTIC EFFECT OF SODI
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genes that play a crucial role in M
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2330 THE ROLE OF TRANSFORMING GROWT
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ined following up to 96 h continuou
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effect doses obtained with the rat
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diated transcriptional response of
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docrine disruptor activities of EDC
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individuals. Week 6 results were qu
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functionality of photosystem II and
Page 519 and 520:
wild mice (Mus musculus) from areas
Page 521 and 522:
2406 TOXICITY AND BIOACCUMULATION O
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Isocitric acid is the acid in the h
Page 525 and 526:
2425 EFFECTS OF FUMONISINS IN ETHAN
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centration(μg/g) were: 5.1-95.3; 2
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2445 AUTOPHAGY IN DEVELOPMENT: A LI
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sures to inhaled Mn in dust. Nevert
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2466 CRITICAL EVALUATION OF ANIMAL
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elationships predict that resting r
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2489 COMPARATIVE TOXICITY OF BIODIE
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2497 TRANSCRIPTIONAL REGULATION OF
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2506 TOXICOLOGICAL CONSIDERATIONS O
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launched with the aim of developing
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forms mRNA expression levels were a
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2534 CUTANEOUS WOUND HEALING IN THE
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wells (0, 1, 5, 10, 25, 50, 100, an
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2553 AN ORGANOTYPIC MICROLIVER PLAT
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serum-free media. At 24 hrs, the gr
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2572 INCREASED ARSENIC BIOACCESSIBI
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nology to develop improved methods.
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tuna, swordfish, or mako shark (3.5
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nificantly reduce circulating thyro
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grouped into 9 observation periods
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histopathological or biochemical ev
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exhibited a hyperactive phenotype,
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the search of effective drugs for e
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2644 COVALENT BINDING OF 14 C 2-MET
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aries targeting all transcription f
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(p 9 weeks) and CSC phenotype acqui
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2673 IMMUNE-MEDIATED VASCULAR INJUR
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for risk identification and charact
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to control toxicant delivery in tob
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Author Index (Continued) The numera
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Keyword Index (Continued) Arsenite
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Keyword Index (Continued) Covalent
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Keyword Index (Continued) flow cyto
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Keyword Index (Continued) innate im
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Keyword Index (Continued) nanoparti
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Keyword Index (Continued) preservat
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Keyword Index (Continued) Thrombocy
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Toxicological Sciences The Official
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