@article{radcliffe_leavens_wagner_olabisi_struve_wong_tewksbury_chapman_dorman_2010, title={Pharmacokinetics of radiolabeled tungsten (W-188) in male Sprague-Dawley rats following acute sodium tungstate inhalation}, volume={22}, ISSN={["0895-8378"]}, DOI={10.3109/08958370902913237}, abstractNote={Aerosol cloud formation may occur when certain tungsten munitions strike hard targets, placing military personnel at increased risk of exposure. Although the pharmacokinetics of various forms of tungsten have been studied in animals following intravenous and oral administration, tungsten disposition following inhalation remains incompletely characterized. The objective of this study was to evaluate the pharmacokinetics of inhaled tungstate (WO4) in rats. Male, 16-wk-old, CD rats (n = 7 rats/time point) underwent a single, 90-min, nose-only exposure to an aerosol (mass median aerodynamic diameter [MMAD] 1.50 μm ) containing 256 mg W/m3 as radiolabeled sodium tungstate (Na2188WO4). 188W tissue concentrations were determined at 0, 1, 3, 7, and 21 days postexposure by gamma spectrometry. The thyroid and urine had the highest 188W levels postexposure, and urinary excretion was the primary route of 188W elimination. The pharmacokinetics of tungsten in most tissues was best described with a two-compartment pharmacokinetic model with initial phase half-lives of approximately 4 to 6 h and a longer terminal phase with half-lives of approximately 6 to 67 days. The kidney, adrenal, spleen, femur, lymph nodes, and brain continued to accumulate small amounts of tungsten as reflected by tissue:blood activity ratios that increased throughout the 21-day period. At day 21 all tissues except the thyroid, urine, lung, femur, and spleen had only trace levels of 188W. Data from this study can be used for development and refinement of pharmacokinetic models for tungsten inhalation exposure in environmental and occupational settings.}, number={1}, journal={INHALATION TOXICOLOGY}, author={Radcliffe, Pheona M. and Leavens, Teresa L. and Wagner, Dean J. and Olabisi, Ayodele O. and Struve, Melanie F. and Wong, Brian A. and Tewksbury, Earl and Chapman, Gail D. and Dorman, David C.}, year={2010}, month={Jan}, pages={69–76} }
 @article{radcliffe_olabisi_wagner_leavens_wong_struve_chapman_wilfong_dorman_2009, title={Acute sodium tungstate inhalation is associated with minimal olfactory transport of tungsten (W-188) to the rat brain}, volume={30}, ISSN={["0161-813X"]}, DOI={10.1016/j.neuro.2009.02.004}, abstractNote={Olfactory transport of represents an important mechanism for direct delivery of certain metals to the central nervous system (CNS). The objective of this study was to determine whether inhaled tungsten (W) undergoes olfactory uptake and transport to the rat brain. Male, 16-week-old, Sprague–Dawley rats underwent a single, 90-min, nose-only exposure to a Na2188WO4 aerosol (256 mg W/m3). Rats had the right nostril plugged to prevent nasal deposition of 188W on the occluded side. The left and right sides of the nose and brain, including the olfactory pathway and striatum, were sampled at 0, 1, 3, 7, and 21 days post-exposure. Gamma spectrometry (n = 7 rats/time point) was used to compare the levels of 188W found on the left and right sides of the nose and brain and blood to determine the contribution of olfactory uptake to brain 188W levels. Respiratory and olfactory epithelial samples from the side with the occluded nostril had significantly lower end-of-exposure 188W levels confirming the occlusion procedure. Olfactory bulb, olfactory tract/tubercle, striatum, cerebellum, rest of brain 188W levels paralleled blood 188W concentrations at approximately 2–3% of measured blood levels. Brain 188W concentrations were highest immediately following exposure, and returned to near background concentrations within 3 days. A statistically significant difference in olfactory bulb 188W concentration was seen at 3 days post-exposure. At this time, 188W concentrations in the olfactory bulb from the side ipsilateral to the unoccluded nostril were approximately 4-fold higher than those seen in the contralateral olfactory bulb. Our data suggest that the concentration of 188W in the olfactory bulb remained low throughout the experiment, i.e., approximately 1–3% of the amount of tungsten seen in the olfactory epithelium suggesting that olfactory transport plays a minimal role in delivering tungsten to the rat brain.}, number={3}, journal={NEUROTOXICOLOGY}, author={Radcliffe, Pheona M. and Olabisi, Ayodele O. and Wagner, Dean J. and Leavens, Teresa and Wong, Brian A. and Struve, Melanie F. and Chapman, Gail D. and Wilfong, Erin R. and Dorman, David C.}, year={2009}, month={May}, pages={445–450} }
 @article{dorman_struve_wong_gross_parkinson_willson_tan_campbell_teeguarden_clewell_et al._2008, title={Derivation of an inhalation reference concentration based upon olfactory neuronal loss in male rats following subchronic acetaldehyde inhalation}, volume={20}, ISSN={["0895-8378"]}, DOI={10.1080/08958370701864250}, abstractNote={Acetaldehyde inhalation induces neoplastic and nonneoplastic responses in the rodent nasal cavity. This experiment further characterizes the dose-response relationship for nasal pathology, nasal epithelial cell proliferation, and DNA–protein cross-link formation in F-344 rats exposed subchronically to acetaldehyde. Animals underwent whole-body exposure to 0, 50, 150, 500, or 1500 ppm acetaldehyde for 6 h/day, 5 days/wk for up to 65 exposure days. Respiratory tract histopathology was evaluated after 4, 9, 14, 30, and 65 exposure days. Acetaldehyde exposure was not associated with reduced body weight gain or other evidence of systemic toxicity. Histologic evaluation of the nasal cavity showed an increased incidence of olfactory neuronal loss (ONL) following acute to subchronic exposure to ≥ 150 ppm acetaldehyde and increased olfactory epithelial cell proliferation following exposure to 1500 ppm acetaldehyde. The severity of the ONL demonstrated dose-and temporal-dependent behaviors, with minimal effects noted at 150–500 ppm acetaldehyde and moderately severe lesions seen in the highest exposure group, with increased lesion severity and extent as the exposure duration increased. Acetaldehyde exposure was also associated with inflammation, hyperplasia, and squamous metaplasia of the respiratory epithelium. These responses were seen in animals exposed to ≥500 ppm acetaldehyde. Acetaldehyde exposure was not associated with increased DNA–protein cross-link formation in the respiratory or olfactory epithelium. A model of acetaldehyde pharmacokinetics in the nose was used to derive an inhalation reference concentration (RfC) of 0.4 ppm, based on the no-observed-adverse-effect level (NOAEL) of 50 ppm for the nasal pathology seen in this study.}, number={3}, journal={INHALATION TOXICOLOGY}, author={Dorman, David C. and Struve, Melanie F. and Wong, Brian A. and Gross, Elizabeth A. and Parkinson, Carl and Willson, Gabrielle A. and Tan, Yu-Mei and Campbell, Jerry L. and Teeguarden, Justin G. and Clewell, Harvey J., III and et al.}, year={2008}, pages={245–256} }
 @article{wetmore_struve_gao_sharma_allison_roberts_letinski_nicolich_bird_dorman_2008, title={Genotoxicity of intermittent co-exposure to benzene and toluene in male CD-1 mice}, volume={173}, DOI={10.1016/j.cbi.2008.03.012}, abstractNote={Benzene is an important industrial chemical. At certain levels, benzene has been found to produce aplastic anemia, pancytopenia, myeloblastic anemia and genotoxic effects in humans. Metabolism by cytochrome P450 monooxygenases and myeloperoxidase to hydroquinone, phenol, and other metabolites contributes to benzene toxicity. Other xenobiotic substrates for cytochrome P450 can alter benzene metabolism. At high concentrations, toluene has been shown to inhibit benzene metabolism and benzene-induced toxicities. The present study investigated the genotoxicity of exposure to benzene and toluene at lower and intermittent co-exposures. Mice were exposed via whole-body inhalation for 6 h/day for 8 days (over a 15-day time period) to air, 50 ppm benzene, 100 ppm toluene, 50 ppm benzene and 50 ppm toluene, or 50 ppm benzene and 100 ppm toluene. Mice exposed to 50 ppm benzene exhibited an increased frequency (2.4-fold) of micronucleated polychromatic erythrocytes (PCE) and increased levels of urinary metabolites (t,t-muconic acid, hydroquinone, and s-phenylmercapturic acid) vs. air-exposed controls. Benzene co-exposure with 100 ppm toluene resulted in similar urinary metabolite levels but a 3.7-fold increase in frequency of micronucleated PCE. Benzene co-exposure with 50 ppm toluene resulted in a similar elevation of micronuclei frequency as with 100 ppm toluene which did not differ significantly from 50 ppm benzene exposure alone. Both co-exposures – 50 ppm benzene with 50 or 100 ppm toluene – resulted in significantly elevated CYP2E1 activities that did not occur following benzene or toluene exposure alone. Whole blood glutathione (GSH) levels were similarly decreased following exposure to 50 ppm benzene and/or 100 ppm toluene, while co-exposure to 50 ppm benzene and 100 ppm toluene significantly decreased GSSG levels and increased the GSH/GSSG ratio. The higher frequency of micronucleated PCE following benzene and toluene co-exposure when compared with mice exposed to benzene or toluene alone suggests that, at the doses used in this study, toluene can enhance benzene-induced clastogenic or aneugenic bone marrow injury. These findings exemplify the importance of studying the effects of binary chemical interactions in animals exposed to lower exposure concentrations of benzene and toluene on benzene metabolism and clastogenicity. The relevance of these data on interactions for humans exposed at low benzene concentrations can be best assessed only when the mechanism of interaction is understood at a quantitative level and incorporated within a biologically based modeling framework.}, number={3}, journal={Chemico-biological Interactions}, author={Wetmore, B. A. and Struve, M. F. and Gao, P. and Sharma, S. and Allison, N. and Roberts, K. C. and Letinski, D. J. and Nicolich, M. J. and Bird, M. G. and Dorman, D. C.}, year={2008}, pages={166–178} }
 @article{dorman_struve_norris_higgins_2008, title={Metabolomic analyses of body fluids after subchronic manganese inhalation in rhesus monkeys}, volume={106}, ISSN={["1096-6080"]}, DOI={10.1093/toxsci/kfn159}, abstractNote={Neurotoxicity is linked with high-dose manganese inhalation. There are few biomarkers that correlate with manganese exposure. Blood manganese concentrations depend upon the magnitude and duration of the manganese exposure and inconsistently reflect manganese exposure concentrations. The objective of this study was to search for novel biomarkers of manganese exposure in the urine and blood obtained from rhesus monkeys following subchronic manganese sulfate (MnSO(4)) inhalation. Liquid chromatography-mass spectrometry was used to identify putative biomarkers. Juvenile rhesus monkeys were exposed 5 days/week to airborne MnSO(4) at 0, 0.06, 0.3, or 1.5 mg Mn/m(3) for 65 exposure days or 1.5 mg Mn/m(3) for 15 or 33 days. Monkeys exposed to MnSO(4) at >or= 0.06 mg Mn/m(3) developed increased brain manganese concentrations. A total of 1097 parent peaks were identified in whole blood and 2462 peaks in urine. Principal component analysis was performed on a subset of 113 peaks that were found to be significantly changed following subchronic manganese exposure. Using the Nearest Centroid analysis, the subset of 113 significantly perturbed components predicted globus pallidus manganese concentrations with 72.9% accuracy for all subchronically exposed monkeys. Using the five confirmed components, the prediction rate for high brain manganese levels remained > 70%. Three of the five identified components, guanosine, disaccharides, and phenylpyruvate, were significantly correlated with brain manganese levels. In all, 27 metabolites with statistically significant expression differences were structurally confirmed by MS-MS methods. Biochemical changes identified in manganese-exposed monkeys included endpoints relate to oxidative stress (e.g., oxidized glutathione) and neurotransmission (aminobutyrate, glutamine, phenylalanine).}, number={1}, journal={TOXICOLOGICAL SCIENCES}, author={Dorman, David C. and Struve, Melanie F. and Norris, Amy and Higgins, Alan J.}, year={2008}, month={Nov}, pages={46–54} }
 @article{struve_wong_marshall_kimbell_schroeter_dorman_2008, title={Nasal uptake of inhaled acrolein in rats}, volume={20}, ISSN={["1091-7691"]}, DOI={10.1080/08958370701864219}, abstractNote={An improved understanding of the relationship between inspired concentration of the potent nasal toxicant acrolein and delivered dose is needed to support quantitative risk assessments. The uptake efficiency (UE) of 0.6, 1.8, or 3.6 ppm acrolein was measured in the isolated upper respiratory tract (URT) of anesthetized naive rats under constant-velocity unidirectional inspiratory flow rates of 100 or 300 ml/min for up to 80 min. An additional group of animals was exposed to 0.6 or 1.8 ppm acrolein, 6 h/day, 5 days/wk, for 14 days prior to performing nasal uptake studies (with 1.8 or 3.6 ppm acrolein) at a 100 ml/min airflow rate. Olfactory and respiratory glutathione (GSH) concentrations were also evaluated in naive and acrolein-preexposed rats. Acrolein UE in naive animals was dependent on the concentration of inspired acrolein, airflow rate, and duration of exposure, with increased UE occurring with lower acrolein exposure concentrations. A statistically significant decline in UE occurred during the exposures. Exposure to acrolein vapor resulted in reduced respiratory epithelial GSH concentrations. In acrolein-preexposed animals, URT acrolein UE was also dependent on the acrolein concentration used prior to the uptake exposure, with preexposed rats having higher UE than their naive counterparts. Despite having increased acrolein UE, GSH concentrations in the respiratory epithelium of acrolein preexposed rats were higher at the end of the 80 min acrolein uptake experiment than their in naive rat counterparts, suggesting that an adaptive response in GSH metabolism occurred following acrolein preexposure.}, number={3}, journal={INHALATION TOXICOLOGY}, author={Struve, Melanie F. and Wong, Victoria A. and Marshall, Marianne W. and Kimbell, Julia S. and Schroeter, Jeffry D. and Dorman, David C.}, year={2008}, pages={217–225} }
 @article{dorman_struve_wong_marshall_gross_willson_2008, title={Respiratory tract responses in male rats following subchronic acrolein inhalation}, volume={20}, ISSN={["0895-8378"]}, DOI={10.1080/08958370701864151}, abstractNote={The goal of this study was to characterize the respiratory tract toxicity of acrolein, including nasal and pulmonary effects, in adult male F344 rats. Animals underwent whole-body exposure to 0, 0.02, 0.06, 0.2, 0.6, or 1.8 ppm acrolein for 6 hr/day, five days/week for up to 65 exposure days (13 exposure weeks). Respiratory tract histopathology was evaluated after 4, 14, 30, and 65 exposure days, as well as 60 days after the end of the 13 week exposure. Acrolein exposure was associated with reduced body weight gain. Rats exposed to ≥ 0.06 ppm acrolein had depressed terminal body weights when compared with air-exposed controls. Histologic evaluation of the nasal cavity showed olfactory epithelial inflammation and olfactory neuronal loss (ONL) following exposure to 1.8 ppm acrolein. Moderately severe ONL in the dorsal meatus and ethmoid turbinates occurred within four days while septal involvement developed with ongoing exposure. A rostral-caudal gradient in lesion severity was noted, with the anterior portion of the nasal cavity being more severely affected. Acrolein exposure was associated with inflammation, hyperplasia, and squamous metaplasia of the respiratory epithelium. The lateral wall was amongst the most sensitive locations for these responses and increased respiratory epithelial cell proliferation occurred at this site following 4 to 30 days of exposure to ≥ 0.6 ppm acrolein. The NOAEL for nasal pathology seen in this study was 0.2 ppm acrolein.}, number={3}, journal={INHALATION TOXICOLOGY}, author={Dorman, David C. and Struve, Melanie F. and Wong, Brian A. and Marshall, Marianne W. and Gross, Elizabeth A. and Willson, Gabrielle A.}, year={2008}, pages={205–216} }