@misc{seppanen_forsberg_tiihonen_laitinen_beal_dorman_2024, title={A Systematic Review and Meta-Analysis of the Efficacy and Safety of Rasagiline or Pramipexole in the Treatment of Early Parkinson's Disease}, volume={2024}, ISSN={["2042-0080"]}, DOI={10.1155/2024/8448584}, abstractNote={Background. Rasagiline or pramipexole monotherapy has been suggested for the management of early Parkinson’s disease (PD). The aim of this research was to systematically review the clinical efficacy and safety of rasagiline or pramipexole in early PD (defined as disease duration ≤5 years and Hoehn and Yahr stage of ≤3). Methods. Randomized controlled trials (RCTs) of rasagiline or pramipexole for early PD published up to September 2021 were retrieved. Outcomes of interest included changes in the Unified Parkinson’s Disease Rating Scale (UPDRS) Parts II and III and the incidence of adverse events. Standardized mean difference (SMD), odds ratio (OR), and 95% confidence interval (CI) were calculated, and heterogeneity was measured with the I2 test. Results. Nine rasagiline and eleven pramipexole RCTs were included. One post hoc analysis of one rasagiline study was included. Five studies for each drug were included in meta-analyses of the UPDRS scores. The rasagiline meta-analysis focused on patients receiving 1 mg/day. Rasagiline and pramipexole significantly improved UPDRS Part II and III scores when compared to placebo. Significant heterogeneity among the studies was present (I2 > 70%). Neither rasagiline nor pramipexole increased the relative risk for any adverse events, serious adverse events, or adverse events leading to withdrawal when compared with placebo. Conclusion. Applying a Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach to summarize the evidence, we found moderate confidence in the body of evidence for the efficacy of rasagiline or pramipexole in early PD, suggesting further well-designed, multicenter comparative RCTs remain needed.}, journal={PARKINSONS DISEASE}, author={Seppanen, Pauli and Forsberg, Markus M. and Tiihonen, Miia and Laitinen, Heikki and Beal, Selena and Dorman, David C.}, year={2024}, month={Jan} }
 @article{goehring_dorman_osterrieder_burgess_dougherty_gross_neinast_pusterla_soboll-hussey_lunn_2024, title={Pharmacologic interventions for the treatment of equine herpesvirus-1 in domesticated horses: A systematic review}, volume={2}, ISSN={["1939-1676"]}, url={https://doi.org/10.1111/jvim.17016}, DOI={10.1111/jvim.17016}, abstractNote={Abstract}, journal={JOURNAL OF VETERINARY INTERNAL MEDICINE}, author={Goehring, Lutz and Dorman, David C. and Osterrieder, Klaus and Burgess, Brandy A. and Dougherty, Kelsie and Gross, Peggy and Neinast, Claire and Pusterla, Nicola and Soboll-Hussey, Gisela and Lunn, David P.}, year={2024}, month={Feb} }
 @article{lunn_burgess_dorman_goehring_gross_osterrieder_pusterla_hussey_2024, title={Updated ACVIM consensus statement on equine herpesvirus-1}, volume={3}, ISSN={["1939-1676"]}, url={https://doi.org/10.1111/jvim.17047}, DOI={10.1111/jvim.17047}, abstractNote={Abstract}, journal={JOURNAL OF VETERINARY INTERNAL MEDICINE}, author={Lunn, David P. and Burgess, Brandy A. and Dorman, David C. and Goehring, Lutz S. and Gross, Peggy and Osterrieder, Klaus and Pusterla, Nicola and Hussey, Gisela Soboll}, year={2024}, month={Mar} }
 @misc{neuvonen_huovinen_dorman_laitinen_sahlman_2023, title={Phthalates and polycystic ovary syndrome - Systematic literature review}, volume={121}, ISSN={["1873-1708"]}, DOI={10.1016/j.reprotox.2023.108473}, abstractNote={Polycystic ovary syndrome (PCOS), one of the most common endocrine disorders in women, may involve both environmental and genetic factors. One potential environmental factor of concern is exposure to phthalates and other endocrine disrupting chemicals many of which have adverse effects on the female reproductive system. The aim of this systematic review was to evaluate possible association between prenatal phthalate exposure and PCOS. Six databases were searched for relevant human studies. Inclusion criteria were female human population diagnosed with PCOS and exposed during any lifestage to any phthalate or phthalate metabolite through oral, dermal, inhalation, or intravenous route. Search results were screened for relevance, and studies that met the inclusion criteria were evaluated for study quality using Joanna Briggs Institute (JBI) critical appraisal tools. The systematic literature search yielded seven articles, six case-control studies and one cohort study. Three studies found a significant positive association, two studies found a significant negative association, and two studies found no association between phthalate exposure and the incidence of PCOS. Even though studies found no consistent pattern on association with phthalates and PCOS, the results of analyzed studies did not exclude possible effects of phthalates on the female reproductive and metabolic system. Some of the factors in study design such as recruiting participants from IVF clinics and young age of participants may have biased the results. Further studies with more careful study design and longer follow-up time are needed to bring more reliable information about the role of phthalates in onset of PCOS.}, journal={REPRODUCTIVE TOXICOLOGY}, author={Neuvonen, Roosa and Huovinen, Marjo and Dorman, David C. and Laitinen, Heikki and Sahlman, Heidi}, year={2023}, month={Oct} }
 @article{soboll-hussey_dorman_burgess_goehring_gross_neinast_osterrieder_pusterla_lunn_2023, title={Relationship between equine herpesvirus-1 viremia and abortion or equine herpesvirus myeloencephalopathy in domesticated horses: A systematic review}, volume={12}, ISSN={["1939-1676"]}, url={https://doi.org/10.1111/jvim.16948}, DOI={10.1111/jvim.16948}, abstractNote={Abstract}, journal={JOURNAL OF VETERINARY INTERNAL MEDICINE}, author={Soboll-Hussey, Gisela and Dorman, David C. and Burgess, Brandy A. and Goehring, Lutz and Gross, Peggy and Neinast, Claire and Osterrieder, Klaus and Pusterla, Nicola and Lunn, David P.}, year={2023}, month={Dec} }
 @misc{dorman_2023, title={The Role of Oxidative Stress in Manganese Neurotoxicity: A Literature Review Focused on Contributions Made by Professor Michael Aschner}, volume={13}, ISSN={["2218-273X"]}, DOI={10.3390/biom13081176}, abstractNote={This literature review focuses on the evidence implicating oxidative stress in the pathogenesis of manganese neurotoxicity. This review is not intended to be a systematic review of the relevant toxicologic literature. Instead, in keeping with the spirit of this special journal issue, this review highlights contributions made by Professor Michael Aschner’s laboratory in this field of study. Over the past two decades, his laboratory has made significant contributions to our scientific understanding of cellular responses that occur both in vitro and in vivo following manganese exposure. These studies have identified molecular targets of manganese toxicity and their respective roles in mitochondrial dysfunction, inflammation, and cytotoxicity. Other studies have focused on the critical role astrocytes play in manganese neurotoxicity. Recent studies from his laboratory have used C. elegans to discover new facets of manganese-induced neurotoxicity. Collectively, his body of work has dramatically advanced the field and presents broader implications beyond metal toxicology.}, number={8}, journal={BIOMOLECULES}, author={Dorman, David C.}, year={2023}, month={Aug} }
 @article{osterrieder_dorman_burgess_goehring_gross_neinast_pusterla_hussey_lunn_2023, title={Vaccination for the prevention of equine herpesvirus-1 disease in domesticated horses: A systematic review and meta-analysis}, volume={11}, ISSN={["1939-1676"]}, url={https://doi.org/10.1111/jvim.16895}, DOI={10.1111/jvim.16895}, abstractNote={Abstract}, journal={JOURNAL OF VETERINARY INTERNAL MEDICINE}, author={Osterrieder, Klaus and Dorman, David C. and Burgess, Brandy A. and Goehring, Lutz S. and Gross, Peggy and Neinast, Claire and Pusterla, Nicola and Hussey, Gisela Soboll and Lunn, David P.}, year={2023}, month={Nov} }
 @article{pusterla_dorman_burgess_goehring_gross_osterrieder_soboll hussey_lunn_2023, title={Viremia and nasal shedding for the diagnosis of equine herpesvirus-1 infection in domesticated horses}, ISSN={["1939-1676"]}, url={https://doi.org/10.1111/jvim.16958}, DOI={10.1111/jvim.16958}, abstractNote={Abstract}, journal={JOURNAL OF VETERINARY INTERNAL MEDICINE}, author={Pusterla, Nicola and Dorman, David C. and Burgess, Brandy A. and Goehring, Lutz and Gross, Margaret and Osterrieder, Klaus and Soboll Hussey, Gisela and Lunn, David P.}, year={2023}, month={Dec} }
 @article{dorman_poppenga_schoenfeld-tacher_2022, title={The Current State of Veterinary Toxicology Education at AAVMC Member Veterinary Schools}, volume={9}, ISSN={["2306-7381"]}, DOI={10.3390/vetsci9120652}, abstractNote={This study assessed the depth, breadth, and perception of toxicology education in curricula at Association of American Veterinary Medical Colleges (AAVMC) member veterinary schools. An online questionnaire was sent twice to all 54 AAVMC members and sent once to a veterinary toxicology list serve. The survey covered areas related to instructor demographics, the depth and extent of toxicology taught, and the respondent’s perceptions of their student’s ability to perform entrustable professional activities (EPA). Results were analyzed using descriptive statistics. Our survey resulted in a 44% response rate. All responding schools included toxicology in their curriculum, and it was a required course in 23 programs. Contact hours in stand-alone veterinary toxicology courses ranged from 14 to 45 h. Most respondents indicated that the current time allotted for toxicology was inadequate, despite indicating that most of their students could perform most EPAs autonomously. One exception related to the ability of students to analyze toxicology data. We found small variations in teaching methods and curriculum content. The results of our study can assist veterinary schools in evaluating their curricula to better prepare new graduates for the management of toxicology issues they may face in their veterinary careers.}, number={12}, journal={VETERINARY SCIENCES}, author={Dorman, David C. C. and Poppenga, Robert H. H. and Schoenfeld-Tacher, Regina M. M.}, year={2022}, month={Dec} }
 @article{habre_dorman_abbatt_bahnfleth_carter_farmer_gawne-mittelstaedt_goldstein_grassian_morrison_et al._2022, title={Why Indoor Chemistry Matters: A National Academies Consensus Report}, volume={56}, ISSN={["1520-5851"]}, DOI={10.1021/acs.est.2c04163}, abstractNote={W spend most of our time indoors, and the indoor environment is the greatest contributor to human chemical exposures. Despite its importance, our understanding of indoor chemicals is more limited than that for the outdoor environment. A recent report of the US National Academies helps answer a 2-fold question: why does indoor chemistry matter, and what is needed to advance our scientific understanding of indoor chemistry? Indoor chemistry is dynamic and complex. Thousands of chemicals are found indoors in air, particles, dust, and surfaces, often at concentrations exceeding those found outdoors. Sources can be primary or secondary, continuous or episodic, and of indoor or outdoor origin (Figure 1). Humans modify indoor chemistry through cooking and the use of personal care products and are a primary source of chemicals in the gas and particle phases. Indoors, chemicals partition between air, airborne particles, dust, water, and surfaces. These surfaces act as primary sources and chemical sinks or reservoirs. Partitioning results in both the removal and release of chemicals from surfaces. Partitioning does not occur instantaneously and may require years to achieve pseudoequilibrium due to the slow rates of molecular transport. Equilibrium conditions change over time and respond to changes in relative humidity, temperature, and other environ-}, number={15}, journal={ENVIRONMENTAL SCIENCE & TECHNOLOGY}, author={Habre, Rima and Dorman, David C. and Abbatt, Jonathan and Bahnfleth, William P. and Carter, Ellison and Farmer, Delphine and Gawne-Mittelstaedt, Gillian and Goldstein, Allen H. and Grassian, Vicki H. and Morrison, Glenn and et al.}, year={2022}, month={Aug}, pages={10560–10563} }
 @article{schoenfeld-tacher_dorman_2021, title={Effect of Delivery Format on Student Outcomes and Perceptions of a Veterinary Medicine Course: Synchronous Versus Asynchronous Learning}, volume={8}, ISSN={["2306-7381"]}, DOI={10.3390/vetsci8020013}, abstractNote={The COVID-19 pandemic prompted instruction at many veterinary schools to switch to an emergency remote teaching format to prevent viral transmission associated with in-person synchronous lectures. This study surveyed student perspectives and academic performance in a pre-planned online second-year veterinary toxicology course given at North Carolina State University in Spring 2020. This course relied on asynchronous narrated presentations for content delivery. This method of delivery predated the pandemic and was used throughout the course. Academic performance and patterns of access to materials in the online course was compared with the access patterns and performance of students given classroom-based synchronous teaching in Spring 2019. Assessments evaluated in this study were identical across courses. Students’ academic performance was unaffected by delivery method. Lack of instructor interaction was an important perceived barrier in the asynchronous course. Asynchronous course materials were uniformly accessed across all days of the week, while supplemental materials for the face-to-face course showed a weekly pattern. Moving from letter grades to pass/fail did not change access frequency to supplemental course materials but led to decreased video usage in the asynchronous course. Results suggest that although some veterinary students perceived the switch in delivery format negatively, the method of delivery did not adversely affect performance in this preclinical course.}, number={2}, journal={VETERINARY SCIENCES}, author={Schoenfeld-Tacher, Regina M. and Dorman, David C.}, year={2021}, month={Feb} }
 @article{dorman_foster_lazarowski_2021, title={Training with Multiple Structurally Related Odorants Fails to Improve Generalization of Ammonium Nitrate Detection in Domesticated Dogs (Canis familiaris)}, volume={11}, ISSN={["2076-2615"]}, DOI={10.3390/ani11010213}, abstractNote={A critical aspect of canine scent detection involves the animal’s ability to respond to odors based on prior odor training. In the current study, dogs (n = 12) were initially trained on an olfactory simple discrimination task using vanillin as the target odorant. Based on their performance on this task, dogs were assigned to experimental groups. Dogs in group 1 and 2 (n = 5 dogs/group; 1 dog/group were removed due to low motivation or high error rates) were trained with either two or six forms of ammonium nitrate (AN), respectively. Dogs were then assessed with a mock explosive with AN and powdered aluminum. Dogs in both groups failed to respond to the novel AN-aluminum odor. Mean success rates were 56 ± 5 and 54 ± 4% for groups 1 and 2, respectively. Overall, and individual dog performance was not statistically higher than chance indicating that dogs did not generalize from AN to a similar AN-based odorant at reliable levels desired for explosive detection dogs. These results suggest the use of authentic explosive materials, without the added complication of including category-learning methods, likely remains a cost-effective and efficient way to train explosive scent detection dogs.}, number={1}, journal={ANIMALS}, author={Dorman, David C. and Foster, Melanie L. and Lazarowski, Lucia}, year={2021}, month={Jan} }
 @misc{alpi_vo_dorman_2019, title={Language Consideration and Methodological Transparency in "Systematic" Reviews of Animal Toxicity Studies}, volume={38}, ISSN={["1092-874X"]}, DOI={10.1177/1091581819827232}, abstractNote={ This study evaluated the use of non-English literature (NEL) in systematic reviews (SRs) or meta-analyses (MAs) of animal-based toxicity or communicable disease (CD) studies. A secondary goal was to assess how grant funding, country of primary authorship, or study quality reporting influenced the use of NEL in these reviews. Inclusion criteria and data extraction forms were based on a pilot evaluation of a 10% random sample of reviews that were identified from a PubMed search (2006 to May 2017). This search yielded 111 animal toxicity and 69 CD reviews. Reviews (33 animal toxicity and 32 CD studies) were included when the authors identified their work as an SR or MA, described a literature search strategy, and provided defined inclusion criteria. Extracted data included PubMed indexing of publication type, author affiliations, and grant funding. Language use was mentioned in the methods in 55% of the toxicity SRs and 69% of CD SRs, of which 44% (n = 8) and 41% (n = 9) were limited to English, respectively. Neither the study type, grant funding, nor first author country of affiliation was associated with an increased consideration of NEL. Study quality reporting was more common in SRs that considered multiple languages. Despite guidelines that encourage the use of NEL in SRs and translation tools, SR/MA authors often fail to report language inclusion or focus on English publications. Librarian involvement in SR can promote awareness of relevant NEL and collaborative and technological strategies to improve their incorporation into the SR process. }, number={2}, journal={INTERNATIONAL JOURNAL OF TOXICOLOGY}, author={Alpi, Kristine M. and Vo, Tram A. and Dorman, David C.}, year={2019}, pages={135–145} }
 @article{dorman_2019, title={Use of Nasal Pathology in the Derivation of Inhalation Toxicity Values for Hydrogen Sulfide}, volume={47}, ISSN={["1533-1601"]}, DOI={10.1177/0192623319878401}, abstractNote={ Nasal pathology can play an important role in the risk assessment process. For example, olfactory neuron loss (ONL) is one of the most sensitive end points seen in subchronic rodent hydrogen sulfide (H2S) studies and has been used by several agencies to derive health-protective toxicity values. Alternative methods that rely on computational fluid dynamics (CFD) models to account for the influence of airflow on H2S-induced ONL have been proposed. The use of CFD models result in toxicity values that are less conservative than those obtained using more traditional methods. These alternative approaches rely on anatomy-based CFD models. Model predictions of H2S delivery (flux) to the olfactory mucosal wall are highly correlated with ONL in rodents. Three major areas of focus for this review include a brief description of nasal anatomy, H2S-induced ONL in rodents, derivation of a chronic inhalation reference concentration for H2S, and the use of CFD models to derive alternative toxicity values for this gas. }, number={8}, journal={TOXICOLOGIC PATHOLOGY}, author={Dorman, David C.}, year={2019}, month={Dec}, pages={1043–1048} }
 @article{mays_dorman_mckendry_hanel_2018, title={A pilot study documenting increased thrombin generation following abrupt withdrawal of heparin therapy in healthy dogs}, volume={28}, ISSN={1479-3261}, url={http://dx.doi.org/10.1111/vec.12778}, DOI={10.1111/vec.12778}, abstractNote={Abstract}, number={6}, journal={Journal of Veterinary Emergency and Critical Care}, publisher={Wiley}, author={Mays, Erin M. and Dorman, David C. and McKendry, Colleen and Hanel, Rita M.}, year={2018}, month={Oct}, pages={518–526} }
 @article{van den berg_cattley_cherrie_dorman_dunnick_gohlke_jinot_käfferlein_kopylev_matsumoto_et al._2018, title={Carcinogenicity of some nitrobenzenes and other industrial chemicals}, volume={19}, ISSN={1470-2045}, url={http://dx.doi.org/10.1016/s1470-2045(18)30823-4}, DOI={10.1016/s1470-2045(18)30823-4}, abstractNote={In October, 2018, 14 experts from six countries met at the International Agency for Research on Cancer (IARC) in Lyon, France, to finalise their evaluation of the carcinogenicity of ortho-phenylenediamine and its dihydrochloride salt, 2-chloronitrobenzene, 4-chloronitrobenzene, 1,4-dichloro-2-nitrobenzene, 2,4-dichloro-1-nitrobenzene, 2-amino-4-chlorophenol, para-nitroanisole, and N,N-dimethylacetamide. These assessments will be published in Volume 123 of the IARC Monographs.1}, number={12}, journal={The Lancet Oncology}, publisher={Elsevier BV}, author={Van den Berg, M and Cattley, R and Cherrie, J W and Dorman, D C and Dunnick, J K and Gohlke, J M and Jinot, J and Käfferlein, H U and Kopylev, L and Matsumoto, M and et al.}, year={2018}, month={Dec}, pages={e681–e682} }
 @article{royal_dorman_2018, title={Comparing Item Performance on Three- Versus Four-Option Multiple Choice Questions in a Veterinary Toxicology Course}, volume={5}, ISSN={2306-7381}, url={http://dx.doi.org/10.3390/vetsci5020055}, DOI={10.3390/vetsci5020055}, abstractNote={Background: The number of answer options is an important element of multiple-choice questions (MCQs). Many MCQs contain four or more options despite the limited literature suggesting that there is little to no benefit beyond three options. The purpose of this study was to evaluate item performance on 3-option versus 4-option MCQs used in a core curriculum course in veterinary toxicology at a large veterinary medical school in the United States. Methods: A quasi-experimental, crossover design was used in which students in each class were randomly assigned to take one of two versions (A or B) of two major exams. Results: Both the 3-option and 4-option MCQs resulted in similar psychometric properties. Conclusion: The findings of our study support earlier research in other medical disciplines and settings that likewise concluded there was no significant change in the psychometric properties of three option MCQs when compared to the traditional MCQs with four or more options.}, number={2}, journal={Veterinary Sciences}, publisher={MDPI AG}, author={Royal, Kenneth and Dorman, David}, year={2018}, month={Jun}, pages={55} }
 @article{foster_bartnikas_maresca-fichter_mercadante_dash_miller_dorman_2018, title={Neonatal C57BL/6J and parkin mice respond differently following developmental manganese exposure: Result of a high dose pilot study}, volume={64}, ISSN={["1872-9711"]}, DOI={10.1016/j.neuro.2017.10.002}, abstractNote={It has been suggested that childhood exposure to neurotoxicants may increase the risk of Parkinson's disease (PD) or other neurodegenerative disease in adults. Some recessive forms of PD have been linked to loss-of-function mutations in the Park2 gene that encodes for parkin. The purpose of this pilot study was to evaluate whether responses to neonatal manganese (Mn) exposure differ in mice with a Park2 gene defect (parkin mice) when compared with a wildtype strain (C57BL/6J). Neonatal parkin and C57BL/6J littermates were randomly assigned to 0, 11, or 25mg Mn/kg-day dose groups with oral exposures occurring from postnatal day (PND) 1 through PND 28. Motor activity was measured on PND 19-22 and 29-32. Tissue Mn concentrations were measured in liver, femur, olfactory bulb, frontal cortex, and striatum on PND 29. Hepatic and frontal cortex gene expression of Slc11a2, Slc40a1, Slc30a10, Hamp (liver only), and Park2 were also measured on PND 29. Some strain differences were seen. As expected, decreased hepatic and frontal cortex Park2 expression was seen in the parkin mice when compared with C57BL/6J mice. Untreated parkin mice also had higher liver and femur Mn concentrations when compared with the C57BL/6J mice. Exposure to≥11mg Mn/kg-day was associated with increased brain Mn concentrations in all mice, no strain difference was observed. Manganese exposure in C57Bl6, but not parkin mice, was associated with a negative correlation between striatal Mn concentration and motor activity. Manganese exposure was not associated with changes in frontal cortex gene expression. Decreased hepatic Slc30a10, Slc40a1, and Hamp expression were seen in PND 29 C57BL/6J mice given 25mg Mn/kg-day. In contrast, Mn exposure was only associated with decreased Hamp expression in the parkin mice. Our results suggest that the Parkin gene defect did not increase the susceptibility of neonatal mice to adverse health effects associated with high-dose Mn exposure.}, journal={NEUROTOXICOLOGY}, author={Foster, Melanie L. and Bartnikas, Thomas B. and Maresca-Fichter, Hailey C. and Mercadante, Courtney and Dash, Miriam and Miller, Chelsea and Dorman, David C.}, year={2018}, month={Jan}, pages={291–299} }
 @article{foster_rao_francher_traver_dorman_2018, title={Olfactory toxicity in rats following manganese chloride nasal instillation: A pilot study}, volume={64}, ISSN={["1872-9711"]}, DOI={10.1016/j.neuro.2017.09.004}, abstractNote={Following inhalation, manganese travels along the olfactory nerve from the olfactory epithelium (OE) to the olfactory bulb (OB). Occupational exposure to inhaled manganese is associated with changes in olfactory function. This pilot study evaluated two related hypotheses: (a) intranasal manganese administration increases OE and OB manganese concentrations; and (b) intranasal manganese exposure impairs performance of previously trained rats on a go-no-go olfactory discrimination (OD) task. Male Fischer 344 rats were trained to either lever press (“go”) in response to a positive conditioned stimulus (CS+: vanillin) or to do nothing (“no go”) when a negative conditioned stimulus (CS−: amyl acetate) was present. Following odor training, rats were randomly assigned to either a manganese (200 mM MnCl2) or 0.9% saline treatment group (n = 4–5 rats/group). Administration of either saline or manganese was performed on isoflurane-anesthetized rats as 40 μL bilateral intranasal instillations. Rats were retested 48 h later using the vanillin/amyl acetate OD task, then euthanized, followed by collection of the OE and OB. Manganese concentrations in tissue samples were analyzed by ICP-MS. An additional cohort of rats (n = 3–4/group) was instilled similarly with saline or manganese and nasal and OB pathology assessed 48 h later. Manganese-exposed rats had increased manganese levels in both the OE and OB and decreased performance in the OD task when compared with control animals. Histopathological evaluation of the caudal nasal cavity showed moderate, acute to subacute suppurative inflammation of the olfactory epithelium and submucosa of the ethmoid turbinates and mild suppurative exudate in the nasal sinuses in animals given manganese. No histologic changes were evident in the OB. The nasal instillation and OD procedures developed in this study are useful methods to assess manganese – induced olfactory deficits.}, journal={NEUROTOXICOLOGY}, author={Foster, Melanie L. and Rao, Deepa B. and Francher, Taylor and Traver, Samantha and Dorman, David C.}, year={2018}, month={Jan}, pages={284–290} }
 @misc{dorman_chiu_hales_hauser_johnson_mantus_martel_robinson_rooney_rudel_et al._2018, title={Polybrominated diphenyl ether (PBDE) neurotoxicity: a systematic review and meta-analysis of animal evidence}, volume={21}, ISSN={["1521-6950"]}, DOI={10.1080/10937404.2018.1514829}, abstractNote={ABSTRACT A recent systematic review (SR) and meta-analysis of human studies found an association between prenatal serum polybrominated diphenyl ethers (PBDE) concentrations and a decrease in the IQ of children. A SR of experimental developmental animal PBDE-mediated neurotoxicity studies was performed in the present study. Outcomes assessed included measures related to learning, memory, and attention, which parallel the intelligence-related outcomes evaluated in the human studies SR. PubMed, Embase, and Toxline were searched for relevant experimental non-human mammalian studies. Evaluation of risk of bias (RoB) and overall body of evidence followed guidance developed by the National Toxicology Program. Animal studies using varying designs and outcomes were available for BDEs 47, 99, 153, 203, 206, and 209 and the technical mixture DE-71. Study reporting of methods and results was often incomplete leading to concerns regarding RoB. A meta-analysis of 6 Morris water maze studies showed evidence of a significant increase in last trial latency (effect size of 25.8 [CI, 20.3 to 31.2]) in PBDE-exposed animals with low heterogeneity. For most endpoints, there were unexplained inconsistencies across studies and no consistent evidence of a dose-response relationship. There is a “moderate” level of evidence that exposure to BDEs 47, 99, and 209 affects learning. For other PBDEs and other endpoints, the level of evidence was “low” or “very low”. The meta-analysis led to stronger conclusions than that based upon a qualitative review of the evidence. The SR also identified RoB concerns that might be remedied by better study reporting.}, number={4}, journal={JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH-PART B-CRITICAL REVIEWS}, author={Dorman, David C. and Chiu, Weihsueh and Hales, Barbara F. and Hauser, Russ and Johnson, Kamin J. and Mantus, Ellen and Martel, Susan and Robinson, Karen A. and Rooney, Andrew A. and Rudel, Ruthann and et al.}, year={2018}, pages={269–289} }
 @misc{dorman_2018, title={Response to Editor: Regarding Foster et al., Neonatal C57BL/6J and parkin mice respond differently following developmental manganese exposure: Result of a high dose pilot study}, volume={69}, ISSN={["1872-9711"]}, DOI={10.1016/j.neuro.2017.11.004}, abstractNote={Rats poisoned with sarin enter into ahyper-cholinergic crisis characterized by excessive salivation, respiratory distress, tremors, seizures, and death. Through the use of rescue medications and an anticonvulsant, death can be avoided in many animals, with the long-term consequences of poisoning partly ameliorated, especially when countermeasures are made available immediately after exposure. However, when anticonvulsant measures are delayed by as little as 30 min, clinical, neurological, cognitive, and psychiatric abnormalities may persist long after the initial exposure. This study sought to determine if the addition of the NMDA receptor antagonist Ketamine to human standard-of-care countermeasures consisting of two rescue medications (2-PAM and atropine) and an anti-convulsant (Midazolam), would afford protection against persistent neurobiological compromise. Rats were exposed to sarin (105 μg/kg via subcutaneous injection), and treated 1 min later with 2-PAM and Atropine Methyl Nitrate (IM) to minimize mortality. One of four anti-convulsant protocols was then initiated at 50 min postsarin:Midazolam alone (MDZ, a single injection (IM) at 0.66 mg/kg); Ketamine alone (KET, a series of five injections (IM) of Ketamine at 7.5 mg/kg, 90 min apart); Midazolam + low dose Ketamine (MDZ + lowKET, a single injection of Midazolam (IM) at 0.66 mg/kg, plus five sequential doses of ketamine (IM) at 2.5 mg/kg, starting at the time of Midazolam dosing and then 90 min apart); Midazolam + high dose Ketamine (MDZ + highKET, a single injection of Midazolam (IM) at 0.66 mg/kg, plus five sequential injections of 7.5 mg/kg Ketamine (IM), starting at the time of Midazolam dosing and then 90 min apart). Animals were preassigned to groups culled at post-exposure Days 1, 7 or 30, for histopathology. For all surviving animals, EEG activity was monitored through skull electrodes for 24-h beginning immediately after sarin exposure. Surviving animals also underwent 24-h EEG monitoring on Days 6, 13, and/or 29, post-sarin. Memory assessment using the Morris Water Maze was performed on Days 1, 4, 7, 14 and 30. Following sarin exposure, 85% of surviving animals demonstrated status epilepticus within 20 min. Each of the anti-convulsant protocols was sufficient to stop convulsions within 1 h of anti-convulsant administration, but all of the animals still showed signs of electrographic status for an additional 2–12 h, without substantial differentiation between treatment groups. However, for post-sarin hours 13–24, the MDZ + highKET group showed significantly less severe EEG abnormalities than the MDZ and KET groups (Mood’s Median Test, p < 0.005). At one month post-exposure, 90% of animals that had received Midazolam alone still showed evidence of some epileptiform activity. In contrast, 90% of animals that had received Midazolam + high dose Ketamine combination therapy had EEG profiles that were within normal limits. This difference in EEG outcomes was highly significant (Mood’s Median Test, p < 0.001). Likewise, on the water maze, the majority of animals that had received Midazolam combined with either high or low dose Ketamine therapy returned to near baseline levels of mnemonic performance within 2 weeks, whereas the majority of the animals that had received midazolam alone or ketamine alone demonstrated persistent and significant memory impairments even at one month postexposure (Mood’s Median Test, p < 0.005). With respect to neuronal necrosis, animals in the MDZ + highKET group showed significantly less overall damage than animals in other treatment groups (Mood’s Median Test, p < 0.001). Of special note were findings in the hippocampus, where only 12% of animals in the MDZ + highKET group showed evidence of necrosis on H&E staining, whereas 100% of animals in the KET group, 70% of animals in the MDZ group, and 40% of animals in the MDZ + lowKET group showed evidence of hippocampal necrosis. Overall, the data demonstrate that Ketamine augmentation of an atropine, 2PAM, and Midazolam standard-ofcare for sarin exposure provides clinically-relevant additional protection against the negative neurobiological consequences of sarin, even when initiation of the anti-convulsant countermeasures is delayed by 50 min.}, journal={NEUROTOXICOLOGY}, author={Dorman, David C.}, year={2018}, month={Dec}, pages={188–188} }
 @article{kedrowicz_hammond_dorman_2018, title={Student Engagement with Rubrics to Promote Enhanced Written Communication of Health Information}, volume={28}, ISSN={2156-8650}, url={http://dx.doi.org/10.1007/s40670-018-0608-4}, DOI={10.1007/s40670-018-0608-4}, number={4}, journal={Medical Science Educator}, publisher={Springer Nature}, author={Kedrowicz, April A. and Hammond, Sarah and Dorman, David C.}, year={2018}, month={Aug}, pages={591–596} }
 @misc{dorman_chiu_hales_hauser_johnson_mantus_martel_robinson_rooney_rudel_et al._2018, title={Systematic reviews and meta-analyses of human and animal evidence of prenatal diethylhexyl phthalate exposure and changes in male anogenital distance}, volume={21}, ISSN={["1521-6950"]}, DOI={10.1080/10937404.2018.1505354}, abstractNote={ABSTRACT Male reproductive alterations found in animals and humans following in utero phthalate exposure include decreased anogenital distance (AGD) and other reproductive-tract malformations. The aim of this investigation was to conduct systematic reviews of human and animal evidence of the effect of in utero exposure to diethylhexyl phthalate (DEHP) on anogenital distance (AGD) in males. PubMed, Embase, and Toxline were searched for relevant human and experimental animal studies on August 15, 2016. Search results were screened for relevance, and studies that met the inclusion criteria were evaluated for quality and data extracted for analysis. Confidence in the human and animal bodies of evidence was assessed and hazard conclusions reached by integrating evidence streams. The search yielded 6 relevant human studies and 19 animal studies. Meta-analysis of 5 human observational prospective cohort studies showed that increased maternal urinary concentrations of DEHP metabolites were associated with decreased AGD in boys (−4.07 [CI, −6.49 to −1.66] % decrease per log10 rise in DEHP metabolites). Meta-analysis and meta-regression of the 19 experimental animal studies found reduced AGD with DEHP treatment, with a dose-response gradient, and with heterogeneity explained by species and strain. There is a moderate level of evidence from human investigations and a high level of data from animal studies that in utero exposure to DEHP decreases AGD. Based upon the available human and animal evidence, and consideration of mechanistic data, DEHP is presumed to be a reproductive hazard to humans on the basis of effects on AGD.}, number={4}, journal={JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH-PART B-CRITICAL REVIEWS}, author={Dorman, David C. and Chiu, Weihsueh and Hales, Barbara F. and Hauser, Russ and Johnson, Kamin J. and Mantus, Ellen and Martel, Susan and Robinson, Karen A. and Rooney, Andrew A. and Rudel, Ruthann and et al.}, year={2018}, pages={207–226} }
 @article{dorman_foster_olesnevich_bolon_castel_sokolsky-papkov_mariani_2018, title={Toxicity associated with ingestion of a polyacrylic acid hydrogel dog pad}, volume={30}, ISSN={["1943-4936"]}, url={http://dx.doi.org/10.1177/1040638718782583}, DOI={10.1177/1040638718782583}, abstractNote={ Superabsorbent sodium polyacrylate polymeric hydrogels that retain large amounts of liquids are used in disposable diapers, sanitary napkins, and other applications. These polymers are generally considered “nontoxic” with acute oral median lethal doses (LD50) >5 g/kg. Despite this favorable toxicity profile, we identified a novel toxic syndrome in dogs and rats following the ingestion of a commercial dog pad composed primarily of a polyacrylic acid hydrogel. Inappropriate mentation, cerebellar ataxia, vomiting, and intention tremors were observed within 24 h after the ingestion of up to 15.7 g/kg of the hydrogel by an adult, castrated male Australian Shepherd mix. These observations prompted an experimental study in rats to further characterize the toxicity of the hydrogel. Adult, female Sprague Dawley rats ( n = 9) were assessed before and after hydrogel ingestion (2.6–19.2 g/kg over 4 h) using a functional observation battery and spontaneous motor activity. Clinical signs consistent with neurotoxicity emerged in rats as early as 2 h after the end of hydrogel exposure, including decreased activity in an open field, hunched posture, gait changes, reduced reaction to handling, decreased muscle tone, and abnormal surface righting. Hydrogel-exposed rats also had reduced motor activity when compared with pre-exposure baseline data. Rats that ingested the hydrogel did not develop nervous system lesions. These findings support the conclusion that some pet pad hydrogel products can induce acute neurotoxicity in animals under high-dose exposure conditions. }, number={5}, journal={JOURNAL OF VETERINARY DIAGNOSTIC INVESTIGATION}, author={Dorman, David C. and Foster, Melanie L. and Olesnevich, Brooke and Bolon, Brad and Castel, Aude and Sokolsky-Papkov, Marina and Mariani, Christopher L.}, year={2018}, month={Sep}, pages={708–714} }
 @article{hamm_sullivan_clippinger_strickland_bell_bhhatarai_blaauboer_casey_dorman_forsby_et al._2017, title={Alternative approaches for identifying acute systemic toxicity: Moving from research to regulatory testing}, volume={41}, ISSN={0887-2333}, url={http://dx.doi.org/10.1016/j.tiv.2017.01.004}, DOI={10.1016/j.tiv.2017.01.004}, abstractNote={Acute systemic toxicity testing provides the basis for hazard labeling and risk management of chemicals. A number of international efforts have been directed at identifying non-animal alternatives for in vivo acute systemic toxicity tests. A September 2015 workshop, Alternative Approaches for Identifying Acute Systemic Toxicity: Moving from Research to Regulatory Testing, reviewed the state-of-the-science of non-animal alternatives for this testing and explored ways to facilitate implementation of alternatives. Workshop attendees included representatives from international regulatory agencies, academia, nongovernmental organizations, and industry. Resources identified as necessary for meaningful progress in implementing alternatives included compiling and making available high-quality reference data, training on use and interpretation of in vitro and in silico approaches, and global harmonization of testing requirements. Attendees particularly noted the need to characterize variability in reference data to evaluate new approaches. They also noted the importance of understanding the mechanisms of acute toxicity, which could be facilitated by the development of adverse outcome pathways. Workshop breakout groups explored different approaches to reducing or replacing animal use for acute toxicity testing, with each group crafting a roadmap and strategy to accomplish near-term progress. The workshop steering committee has organized efforts to implement the recommendations of the workshop participants.}, journal={Toxicology in Vitro}, publisher={Elsevier BV}, author={Hamm, Jon and Sullivan, Kristie and Clippinger, Amy J. and Strickland, Judy and Bell, Shannon and Bhhatarai, Barun and Blaauboer, Bas and Casey, Warren and Dorman, David and Forsby, Anna and et al.}, year={2017}, month={Jun}, pages={245–259} }
 @article{dorman_foster_fernhoff_hess_2017, title={Canine scent detection of canine cancer: a feasibility study}, volume={Volume 8}, ISSN={2230-2034}, url={http://dx.doi.org/10.2147/vmrr.s148594}, DOI={10.2147/vmrr.s148594}, abstractNote={The scent detection prowess of dogs has prompted interest in their ability to detect cancer. The purpose of this study was to determine whether dogs could use olfactory cues to discriminate urine samples collected from dogs that did or did not have urinary tract transitional cell carcinoma (TCC), at a rate greater than chance. Dogs with previous scent training (n=4) were initially trained to distinguish between a single control and a single TCC-positive urine sample. All dogs acquired this task (mean =15±7.9 sessions; 20 trials/session). The next training phase used four additional control urine samples (n=5) while maintaining the one original TCC-positive urine sample. All dogs quickly acquired this task (mean =5.3±1.5 sessions). The last training phase used multiple control (n=4) and TCC-positive (n=6) urine samples to pro-mote categorical training by the dogs. Only one dog was able to correctly distinguish multiple combinations of TCC-positive and control urine samples suggesting that it mastered categorical learning. The final study phase evaluated whether this dog would generalize this behavior to novel urine samples. However, during double-blind tests using two novel TCC-positive and six novel TCC-negative urine samples, this dog did not indicate canine TCC-positive cancer samples more frequently than expected by chance. Our study illustrates the need to consider canine olfactory memory and the use of double-blind methods to avoid erroneous conclusions regarding the ability of dogs to alert on specimens from canine cancer patients. Our results also suggest that sample storage, confounding odors, and other factors need to be considered in the design of future studies that evaluate the detection of canine cancers by scent detection dogs.}, journal={Veterinary Medicine: Research and Reports}, publisher={Dove Medical Press Ltd.}, author={Dorman, David and Foster, Melanie and Fernhoff, Katherine and Hess, Paul}, year={2017}, month={Oct}, pages={69–76} }
 @article{gruen_dorman_lascelles_2017, title={Caregiver placebo effect in analgesic clinical trials for cats with naturally occurring degenerative joint disease-associated pain}, volume={180}, ISSN={0042-4900 2042-7670}, url={http://dx.doi.org/10.1136/vr.104168}, DOI={10.1136/vr.104168}, abstractNote={A literature review identified six placebo‐controlled studies of analgesics in client‐owned cats with degenerative joint disease‐associated pain. Five studies with 96 cats had available data. Caregiver responses on a clinical metrology instrument, Client‐Specific Outcome Measure (CSOM), were compared to measured activity. Cats were categorised as ‘successes’ or ‘failures’ based on change in CSOM score and activity counts from baseline. Effect sizes based on CSOM score were calculated; factors that were associated with success/failure were analysed using logistic regression. Effect sizes ranged from 0.97 to 1.93. The caregiver placebo effect was high, with 54–74 per cent of placebo‐treated cats classified as CSOM successes compared with 10–63 per cent of cats classified as successes based on objectively measured activity. 36 per cent of CSOM successes were also activity successes, while 19 per cent of CSOM failures were activity successes. No significant effects of cat age, weight, baseline activity, radiographic score, orthopaedic pain score or study type on CSOM success in the placebo groups were found. The caregiver placebo effect across these clinical trials was remarkably high, making demonstration of efficacy for an analgesic above a placebo difficult. Further work is needed to determine whether a potential placebo‐by‐proxy effect could benefit cats in clinical settings.}, number={19}, journal={Veterinary Record}, publisher={BMJ}, author={Gruen, M. E. and Dorman, D. C. and Lascelles, B. D. X.}, year={2017}, month={Mar}, pages={473–473} }
 @article{fish_foster_gruen_sherman_dorman_2017, title={Effect of wearing a Telemetry jacket on behavioral and physiologic parameters of dogs in the open-field test}, volume={56}, number={4}, journal={Journal of the American Association for Laboratory Animal Science}, author={Fish, R. E. and Foster, M. L. and Gruen, M. E. and Sherman, B. L. and Dorman, D. C.}, year={2017}, pages={382–389} }
 @article{dorman_beasley_mcclellan_2017, title={Fifty years of contributions by the American Board of Veterinary Toxicology}, volume={251}, ISSN={["1943-569X"]}, DOI={10.2460/javma.251.3.268}, number={3}, journal={JAVMA-JOURNAL OF THE AMERICAN VETERINARY MEDICAL ASSOCIATION}, author={Dorman, David C. and Beasley, Val R. and McClellan, Roger O.}, year={2017}, month={Aug}, pages={268–270} }
 @article{foster_bartnikas_maresca-fichter_mercadante_dash_miller_dorman_2017, title={Interactions of manganese with iron, zinc, and copper in neonatal C57BL/6J and parkin mice following developmental oral manganese exposure}, volume={15}, ISSN={2352-3409}, url={http://dx.doi.org/10.1016/j.dib.2017.10.050}, DOI={10.1016/j.dib.2017.10.050}, abstractNote={High dose manganese (Mn) exposure can result in changes in tissue concentrations of other essential metals due to Mn-induced alterations in metal absorption and competition for metal transporters and regulatory proteins. We evaluated responses in mice with a Parkin gene defect (parkin mice) and a wildtype strain (C57BL/6J) following neonatal Mn exposure. Neonatal parkin and C57BL/6J littermates were randomly assigned to 0, 11, or 25 mg Mn/kg-day dose groups with oral exposures occurring from postnatal day (PND) 1 through PND 28. We report liver, femur, olfactory bulb, striatum, and frontal cortex iron, copper, and zinc concentrations and changes in hepatic gene expression of different metal transporters in PND 29 parkin and C57BL/6J mice. A companion manuscript (Foster et al., 2017) [1] describes the primary study findings. This data provides insights into strain differences in the way Mn interacts with other trace metals in mice.}, journal={Data in Brief}, publisher={Elsevier BV}, author={Foster, Melanie L. and Bartnikas, Thomas B. and Maresca-Fichter, Hailey C. and Mercadante, Courtney and Dash, Miriam and Miller, Chelsea and Dorman, David C.}, year={2017}, month={Dec}, pages={908–915} }
 @article{dorman_2017, title={Manganese Neurodegeneration}, ISBN={["978-0-12-812764-3"]}, DOI={10.1016/bs.ant.2017.07.007}, abstractNote={Manganese neurotoxicity is an important public health concern associated with high-dose exposure to this metal. Increased brain manganese concentrations occur when manganese intake exceeds its elimination resulting in a movement disorder known as manganism. Manganism most commonly occurs in people following high-dose manganese inhalation. The target for manganese neurotoxicity is predominantly the basal ganglia, which influence motor control. There is also growing concern that lower manganese exposures may contribute to more subtle neurological effects in people or serve as a risk factor for the development of other neurodegenerative diseases. This chapter briefly discusses the essentiality of manganese, exposure sources, manganese pharmacokinetics, neurologic effects seen with manganism, and the scientific evidence for more subtle neurological effects seen following lower dose manganese exposure.}, journal={ENVIRONMENTAL FACTORS IN NEURODEGENERATIVE DISEASES}, author={Dorman, David C.}, year={2017}, pages={157–183} }
 @article{dorman_2017, title={Metal imaging in the brain}, journal={Biometals in Neurodegenerative Diseases: Mechanisms and Therapeutics}, author={Dorman, D. C.}, year={2017}, pages={349–362} }
 @article{mattison_milton_krewski_levy_dorman_aggett_roels_andersen_karyakina_shilnikova_et al._2017, title={Severity scoring of manganese health effects for categorical regression}, volume={58}, ISSN={["1872-9711"]}, DOI={10.1016/j.neuro.2016.09.001}, abstractNote={Characterizing the U-shaped exposure response relationship for manganese (Mn) is necessary for estimating the risk of adverse health from Mn toxicity due to excess or deficiency. Categorical regression has emerged as a powerful tool for exposure-response analysis because of its ability to synthesize relevant information across multiple studies and species into a single integrated analysis of all relevant data. This paper documents the development of a database on Mn toxicity designed to support the application of categorical regression techniques. Specifically, we describe (i) the conduct of a systematic search of the literature on Mn toxicity to gather data appropriate for dose-response assessment; (ii) the establishment of inclusion/exclusion criteria for data to be included in the categorical regression modeling database; (iii) the development of a categorical severity scoring matrix for Mn health effects to permit the inclusion of diverse health outcomes in a single categorical regression analysis using the severity score as the outcome variable; and (iv) the convening of an international expert panel to both review the severity scoring matrix and assign severity scores to health outcomes observed in studies (including case reports, epidemiological investigations, and in vivo experimental studies) selected for inclusion in the categorical regression database. Exposure information including route, concentration, duration, health endpoint(s), and characteristics of the exposed population was abstracted from included studies and stored in a computerized manganese database (MnDB), providing a comprehensive repository of exposure-response information with the ability to support categorical regression modeling of oral exposure data.}, journal={NEUROTOXICOLOGY}, author={Mattison, Donald R. and Milton, Brittany and Krewski, Daniel and Levy, Len and Dorman, David C. and Aggett, Peter J. and Roels, Harry A. and Andersen, Melvin E. and Karyakina, Nataliya A. and Shilnikova, Natalia and et al.}, year={2017}, month={Jan}, pages={203–216} }
 @article{dorman_kedrowicz_2017, title={Survey of Diplomates of the American Board of Veterinary Toxicology Regarding Perceptions of the Value of This Certification}, volume={36}, ISSN={["1092-874X"]}, DOI={10.1177/1091581817726775}, abstractNote={An anonymous, online questionnaire was sent to active diplomates of the American Board of Veterinary Toxicology (DABVTs; n = 95) to determine the attitudes of veterinary toxicologists toward their ABVT certification and the adequacy of the training programs in this discipline. We gathered information related to demographics, educational and work history, and other specialty board membership. Ten questions sought the respondent’s opinion related to the economic value of the specialty, whether workforce shortages for DABVT exist, and whether DABVTs should complete a residency or graduate program. Fifty-one (54%) DABVTs responded. Their mean age was 58 and most (88%) held a graduate degree. When respondents were asked to rate their level of agreement (strongly disagree = 1; strongly agree = 5), most (73%) agreed or strongly agreed (median = 4) that there was a shortage of DABVTs. Fourteen (27%) participants strongly disagreed that the ABVT certification was required for their position, while 15 (29%) strongly agreed with this statement (median = 3). Most respondents agreed that the ABVT certification has been critical to their career (median = 4), in addition to a financial benefit to being a DABVT (median = 4). Most (67%) participants strongly or somewhat disagreed that current training programs are adequate to meet the shortage of DABVT (median = 2). Our findings indicate there is concern about the number of DABVTs and the adequacy of training programs to meet this perceived need. These findings improve our understanding of current attitudes of DABVTs toward their specialty.}, number={5}, journal={INTERNATIONAL JOURNAL OF TOXICOLOGY}, author={Dorman, David C. and Kedrowicz, April A.}, year={2017}, pages={380–385} }
 @article{kedrowicz_hammond_dorman_2017, title={Teaching Tip: Improving Students' Email Communication through an Integrated Writing Assignment in a Third-Year Toxicology Course}, volume={44}, ISSN={0748-321X 1943-7218}, url={http://dx.doi.org/10.3138/jvme.0816-124r2}, DOI={10.3138/jvme.0816-124r2}, abstractNote={ Client communication is important for success in veterinary practice, with written communication being an important means for veterinarian–client information sharing. Effective communication is adapted to clients' needs and wants, and presents information in a clear, understandable manner while accounting for varying degrees of client health literacy. This teaching tip describes the use of a mock electronic mail assignment as one way to integrate writing into a required veterinary toxicology course. As part of this project, we provide baseline data relating to students' written communication that will guide further development of writing modules in other curricula. Two independent raters analyzed students' writing using a coding scheme designed to assess adherence to the guidelines for effective written health communication. Results showed that the majority of students performed satisfactorily or required some development with respect to recommended guidelines for effective written health communication to facilitate client understanding. These findings suggest that additional instruction and practice should emphasize the importance of incorporating examples, metaphors, analogies, and pictures to create texts that are comprehensible and memorable to clients. Recommendations are provided for effective integration of writing assignments into the veterinary medicine curriculum. }, number={2}, journal={Journal of Veterinary Medical Education}, publisher={University of Toronto Press Inc. (UTPress)}, author={Kedrowicz, April A. and Hammond, Sarah and Dorman, David C.}, year={2017}, month={May}, pages={280–289} }
 @article{mclaughlin_marks_dorman_motsinger-reif_hanel_2017, title={Thromboelastographic monitoring of the effect of unfractionated heparin in healthy dogs}, volume={27}, ISSN={["1476-4431"]}, DOI={10.1111/vec.12526}, abstractNote={Abstract}, number={1}, journal={JOURNAL OF VETERINARY EMERGENCY AND CRITICAL CARE}, author={McLaughlin, Christopher M. and Marks, Steven L. and Dorman, David C. and Motsinger-Reif, Alison and Hanel, Rita M.}, year={2017}, pages={71–81} }
 @article{hanel_palmer_baker_brenner_crowe_dorman_gicking_gilger_otto_robertson_et al._2016, title={Best practice recommendations for prehospital veterinary care of dogs and cats}, volume={26}, ISSN={1479-3261}, url={http://dx.doi.org/10.1111/vec.12455}, DOI={10.1111/vec.12455}, abstractNote={Abstract}, number={2}, journal={Journal of Veterinary Emergency and Critical Care}, publisher={Wiley}, author={Hanel, Rita M. and Palmer, Lee and Baker, Janice and Brenner, Jo-Anne and Crowe, Dennis T. Tim and Dorman, David and Gicking, John C. and Gilger, Brian and Otto, Cynthia M. and Robertson, Sheilah A. and et al.}, year={2016}, month={Mar}, pages={166–233} }
 @article{worth_wismer_dorman_2016, title={Diphenhydramine exposure in dogs: 621 cases (2008-2013)}, volume={249}, DOI={10.2460/javma.249.1.77}, abstractNote={Abstract}, number={1}, journal={Journal of the American Veterinary Medical Association}, author={Worth, A. C. and Wismer, T. A. and Dorman, D. C.}, year={2016}, pages={77–82} }
 @article{pettiglio_herrera_foster_dorman_bartnikas_2016, title={Liver metal levels and expression of genes related to iron homeostasis in rhesus monkeys after inhalational manganese exposure}, volume={6}, ISSN={2352-3409}, url={http://dx.doi.org/10.1016/j.dib.2016.01.055}, DOI={10.1016/j.dib.2016.01.055}, abstractNote={Here we present data on liver metal levels and expression of genes related to iron homeostasis in rhesus monkeys after inhalational manganese exposure. Archived liver samples from rhesus monkeys exposed to 0 (n=6), 0.06 (n=6), 0.3 (n=4) and 1.5 (n=4) mg/m3 manganese inhalation for 65 days were obtained from a published study (“Tissue manganese concentrations in young male rhesus monkeys following subchronic manganese sulfate inhalation” [1]). Samples were analyzed by spectroscopy, immunoblotting and quantitative PCR to assess metal levels and gene expression. Liver manganese and iron levels were linearly correlated although only the intermediate manganese exposure level (0.3 mg Mn/m3) led to a statistically significant increase in liver iron levels.}, journal={Data in Brief}, publisher={Elsevier BV}, author={Pettiglio, Michael A. and Herrera, Carolina and Foster, Melanie L. and Dorman, David C. and Bartnikas, Thomas B.}, year={2016}, month={Mar}, pages={989–997} }
 @article{mercadante_herrera_pettiglio_foster_johnson_dorman_bartnikas_2016, title={The effect of high dose oral manganese exposure on copper, iron and zinc levels in rats}, volume={29}, ISSN={["1572-8773"]}, DOI={10.1007/s10534-016-9924-6}, abstractNote={Manganese is an essential dietary nutrient and trace element with important roles in mammalian development, metabolism, and antioxidant defense. In healthy individuals, gastrointestinal absorption and hepatobiliary excretion are tightly regulated to maintain systemic manganese concentrations at physiologic levels. Interactions of manganese with other essential metals following high dose ingestion are incompletely understood. We previously reported that gavage manganese exposure in rats resulted in higher tissue manganese concentrations when compared with equivalent dietary or drinking water manganese exposures. In this study, we performed follow-up evaluations to determine whether oral manganese exposure perturbs iron, copper, or zinc tissue concentrations. Rats were exposed to a control diet with 10 ppm manganese or dietary, drinking water, or gavage exposure to approximately 11.1 mg manganese/kg body weight/day for 7 or 61 exposure days. While manganese exposure affected levels of all metals, particularly in the frontal cortex and liver, copper levels were most prominently affected. This result suggests an under-appreciated effect of manganese exposure on copper homeostasis which may contribute to our understanding of the pathophysiology of manganese toxicity.}, number={3}, journal={BIOMETALS}, author={Mercadante, Courtney J. and Herrera, Carolina and Pettiglio, Michael A. and Foster, Melanie L. and Johnson, Laura C. and Dorman, David C. and Bartnikas, Thomas B.}, year={2016}, month={Jun}, pages={417–422} }
 @article{lazarowski_dorman_2015, title={A comparison of pet and purpose-bred research dog (Canis familiaris) performance on human-guided object-choice tasks}, volume={110}, ISSN={["1872-8308"]}, DOI={10.1016/j.beproc.2014.09.021}, abstractNote={Several studies have shown that domestic dogs respond to human social cues such as pointing. Some experiments have shown that pet dogs outperformed wolves in following a momentary distal point. These findings have lent support to the hypothesis that domestication is responsible for domestic dogs' ability to utilize human gestures. Other studies demonstrating comparable performance in human-socialized wolves suggest this skill depends on experience with relevant human stimuli. However, domestic dogs lacking thorough exposure to humans are underrepresented in the comparative literature. The goal of this study was to evaluate pet and kennel-reared research domestic dogs on their ability to follow two types of point in an object-choice task. This study used young adult, intact male research dogs (n=11) and a comparison group of pet dogs living in human homes (n=9). We found that while pet dogs followed the momentary distal point above chance levels, research dogs did not. Both groups followed the simpler dynamic proximal point; however, pet dogs outperformed research dogs on this task. Our results indicate that ontogenetic experiences may influence a domestic dog's ability to use human gestures, highlighting the importance of testing different sub-populations of domestic dogs.}, journal={BEHAVIOURAL PROCESSES}, author={Lazarowski, Lucia and Dorman, David C.}, year={2015}, month={Jan}, pages={60–67} }
 @article{sherman_gruen_case_foster_fish_lazarowski_depuy_dorman_2015, title={A test for the evaluation of emotional reactivity in Labrador retrievers used for explosives detection}, volume={10}, ISSN={["1878-7517"]}, DOI={10.1016/j.jveb.2014.12.007}, abstractNote={The United States Marine Corps (USMC) uses Labrador retrievers as improvised explosive device detection dogs (IDDs). Of critical importance is the selection of dogs that are emotionally suited for this highly specialized application. The goal of our study was to develop an emotional reactivity test (ERT) as a screening tool for the selection of IDDs. The ERT included a series of subtasks that expose each dog sequentially to visual, auditory, and experiential stimuli with an associated grading scale used by trained observers to rate individual dog responses. In this study, 16 Labrador retrievers that met initial selection criteria as candidate IDDs were assessed using the ERT, measurement of plasma and salivary cortisol concentrations (pre- and post-ERT), and an independent open-field test of anxiety in response to sound stimuli. Based on the sum of its responses, each dog was assigned an aggregate ERT score. Aggregate ERT scores from independent trained observers were highly concordant [Shrout-Fleiss's intraclass correlation (2,1) = 0.96] suggesting excellent inter-rater reliability. The aggregate ERT scores were also negatively correlated with the dogs' scores on the open-field anxiety test (Spearman rank correlation, n = 16, r = −0.57, P = 0.0214). In addition, there were significant increases in salivary (Wilcoxon signed rank, n = 16, S = 38.5, P = 0.0458) and plasma (Wilcoxon signed rank, n = 16, S = 68, P < 0.0001) cortisol levels after the ERT, compared with baseline, suggesting that exposure to the ERT test elements produced a physiological stress response. We conclude that the ERT is a useful pre-training screening test that can be used to identify dogs with a low threshold of emotional reactivity for rejection, and dogs with a high threshold of emotional reactivity for entry into the IDD training program.}, number={2}, journal={JOURNAL OF VETERINARY BEHAVIOR-CLINICAL APPLICATIONS AND RESEARCH}, author={Sherman, Barbara L. and Gruen, Margaret E. and Case, Beth C. and Foster, Melanie L. and Fish, Richard E. and Lazarowski, Lucia and DePuy, Venita and Dorman, David C.}, year={2015}, pages={94–102} }
 @article{tickner_dorman_sheton-davenport_2015, title={Answering the Call for Improved Chemical Alternatives Assessments (CAA)}, volume={49}, ISSN={["1520-5851"]}, DOI={10.1021/es505446x}, abstractNote={As knowledge about chemical impacts on health and ecosystems continues to increase, so will pressures to avoid certain chemicals and chemical processes. Identifying and adopting alternatives to chemicals of concern is not straightforward. As such, there are a growing number of efforts by scientists, policymakers and others to improve chemical alternatives assessment (CAA) approaches, processes for identifying, comparing and selecting safer alternatives to chemicals of concern. Two main drivers in these assessments are to identify safer chemical alternatives and avoid situations where a substituted chemical is found to be unsuitable (i.e., “regrettable substitutions”). It is important that entities demanding, selecting, or adopting alternatives to chemicals of concern have adequate processes and a knowledge base to ensure thoughtful consideration of the choices. The foundational elements needed to make more informed chemical substitution choices were recently considered by a U.S. National Research Council (NRC) Committee charged with developing a Framework to Guide the Selection of Chemical Alternatives. A number of key steps may improve CAA as a science-policy discipline, similar to how the NRC “red book” on risk assessment elevated that field: (1) Alternatives assessment should be increasingly embraced and conducted in chemical selection. The goal of alternatives assessment is to inform substitution actions. It is different from a risk assessment or safety assessment, where the goal is to identify a safe level of exposure or characterize the risk associated with a given level of exposure. A number of CAA frameworks exist and while there are significant similarities between them, there are also important differences, including how uncertainties, exposures, and impacts across different life cycle stages are addressed. Gaps and differences in methods will need to be addressed; yet, it is critical that CAA processes be flexible so they can be adapted to varied decision contexts and avoid “paralysis by analysis”. Some may argue that the flexibility in alternatives assessment may not ensure consistency in CAA results across firms or agencies. However, while consistency is a laudable goal, it is rarely achievable, even for existing tools such as risk assessment. Flexibility in the alternatives assessment process provides an opportunity for adaptable evaluation−while ensuring that at least comprehensive thinking and assessment of potential trade-offs occurs. (2) CAAs would benef it f rom research and development ef forts that support the incorporation of novel data streams (e.g., high throughput in vitro assays and in silico approaches). Existing CAA frameworks predominantly rely on traditional toxicology data streams to assess the human health and environmental hazards of chemical use. While useful, this approach does not take advantage of the many developments in toxicity testing that have occurred over the past decade. Given the paucity of data, which can slow down CAAs, it is important that future CAA frameworks incorporate the use of in vitro and other high-throughput assays, toxicity pathway-centric assays, into the assessment process to address gaps in traditional knowledge. Similarly, it is important that emerging developments in toxicity testing be able to support the evaluation, comparison (including hazard categorization) and design of safer chemicals and materials, not simply to obtain more refined risk estimates. As science has advanced in this area, there are immediate opportunities to fill data gaps or screen for potential unexpected consequences using novel approaches. For example, assay results obtained in the nematode, Caenorhabditis elegans, could simultaneously help predict toxicity to people and the soil compartment in ecotoxicity assessments. Zebrafish (Danio rerio) data could, with additional focused research, provide a useful substitute for the longer fish ecotoxicity reproduction studies traditionally conducted with other fish species. Future research efforts are needed to develop principles or tools that support the benchmarking, integration, and hazard categorization of high throughput data on chemical effects, especially}, number={4}, journal={ENVIRONMENTAL SCIENCE & TECHNOLOGY}, author={Tickner, Joel A. and Dorman, David C. and Sheton-Davenport, Marilee}, year={2015}, month={Feb}, pages={1995–1996} }
 @inbook{dorman_2015, title={Extrapyramidal system neurotoxicity}, ISBN={9780444626271}, ISSN={0072-9752}, url={http://dx.doi.org/10.1016/b978-0-444-62627-1.00012-3}, DOI={10.1016/b978-0-444-62627-1.00012-3}, abstractNote={The central nervous system's extrapyramidal system provides involuntary motor control to the muscles of the head, neck, and limbs. Toxicants that affect the extrapyramidal system are generally clinically characterized by impaired motor control, which is usually the result of basal ganglionic dysfunction. A variety of extrapyramidal syndromes are recognized in humans and include Parkinson's disease, secondary parkinsonism, other degenerative diseases of the basal ganglia, and clinical syndromes that result in dystonia, dyskinesia, essential tremor, and other forms of tremor and chorea. This chapter briefly reviews the anatomy of the extrapyramidal system and discusses several naturally occurring and experimental models that target the mammalian (nonhuman) extrapyramidal system. Topics discussed include extrapyramidal syndromes associated with antipsychotic drugs, carbon monoxide, reserpine, cyanide, rotenone, paraquat, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and manganese. In most cases, animals are used as experimental models to improve our understanding of the toxicity and pathogenesis of these agents. Another agent discussed in this chapter, yellowstar thistle poisoning in horses, however, represents an important spontaneous cause of parkinsonism that naturally occurs in animals. The central focus of the chapter is on animal models, especially the concordance between clinical signs, neurochemical changes, and neuropathology between animals and people.}, booktitle={Handbook of Clinical Neurology}, publisher={Elsevier}, author={Dorman, David}, year={2015}, pages={207–223} }
 @article{bazzle_cubeta_marks_dorman_2015, title={Feasibility of flotation concentration of fungal spores as a method to identify toxigenic mushrooms}, volume={6}, journal={Veterinary Medicine: Research and Reports}, author={Bazzle, L.J. and Cubeta, M.A. and Marks, S.L. and Dorman, D.C.}, year={2015}, pages={1–9} }
 @article{lazarowski_foster_gruen_sherman_fish_milgram_dorman_2015, title={Olfactory discrimination and generalization of ammonium nitrate and structurally related odorants in Labrador retrievers}, volume={18}, ISSN={1435-9448 1435-9456}, url={http://dx.doi.org/10.1007/s10071-015-0894-9}, DOI={10.1007/s10071-015-0894-9}, abstractNote={A critical aspect of canine explosive detection involves the animal's ability respond to novel, untrained odors based on prior experience with training odors. In the current study, adult Labrador retrievers (N = 15) were initially trained to discriminate between a rewarded odor (vanillin) and an unrewarded odor (ethanol) by manipulating scented objects with their nose in order to receive a food reward using a canine-adapted discrimination training apparatus. All dogs successfully learned this olfactory discrimination task (≥80 % correct in a mean of 296 trials). Next, dogs were trained on an ammonium nitrate (AN, NH4NO3) olfactory discrimination task [acquired in 60-240 trials, with a mean (±SEM) number of trials to criterion of 120.0 ± 15.6] and then tested for their ability to respond to untrained ammonium- and/or nitrate-containing chemicals as well as variants of AN compounds. Dogs did not respond to sodium nitrate or ammonium sulfate compounds at rates significantly higher than chance (58.8 ± 4.5 and 57.7 ± 3.3 % correct, respectively). Transfer performance to fertilizer-grade AN, AN mixed in Iraqi soil, and AN and flaked aluminum was significantly higher than chance (66.7 ± 3.2, 73.3 ± 4.0, 68.9 ± 4.0 % correct, respectively); however, substantial individual differences were observed. Only 53, 60, and 64 % of dogs had a correct response rate with fertilizer-grade AN, AN and Iraqi soil, and AN and flaked aluminum, respectively, that were greater than chance. Our results suggest that dogs do not readily generalize from AN to similar AN-based odorants at reliable levels desired for explosive detection dogs and that performance varies significantly within Labrador retrievers selected for an explosive detection program.}, number={6}, journal={Animal Cognition}, publisher={Springer Science and Business Media LLC}, author={Lazarowski, Lucia and Foster, Melanie L. and Gruen, Margaret E. and Sherman, Barbara L. and Fish, Richard E. and Milgram, Norton W. and Dorman, David C.}, year={2015}, month={Jul}, pages={1255–1265} }
 @article{dorman_foster_2015, title={Olfactory transport of manganese: Implications for neurotoxicity}, volume={22}, journal={Manganese in health and disease}, author={Dorman, D. C. and Foster, M. L.}, year={2015}, pages={119–132} }
 @article{foster_bartnikas_johnson_herrera_pettiglio_keene_taylor_dorman_2015, title={Pharmacokinetic Evaluation of the Equivalency of Gavage, Dietary, and Drinking Water Exposure to Manganese in F344 Rats}, volume={145}, ISSN={["1096-0929"]}, DOI={10.1093/toxsci/kfv047}, abstractNote={Concerns exist as to whether individuals may be at greater risk for neurotoxicity following increased manganese (Mn) oral intake. The goals of this study were to determine the equivalence of 3 methods of oral exposure and the rate (mg Mn/kg/day) of exposure. Adult male rats were allocated to control diet (10 ppm), high manganese diet (200 ppm), manganese-supplemented drinking water, and manganese gavage treatment groups. Animals in the drinking water and gavage groups were given the 10 ppm manganese diet and supplemented with manganese chloride (MnCl(2)) in drinking water or once-daily gavage to provide a daily manganese intake equivalent to that seen in the high-manganese diet group. No statistically significant difference in body weight gain or terminal body weights was seen. Rats were anesthetized following 7 and 61 exposure days, and samples of bile and blood were collected. Rats were then euthanized and striatum, olfactory bulb, frontal cortex, cerebellum, liver, spleen, and femur samples were collected for chemical analysis. Hematocrit was unaffected by manganese exposure. Liver and bile manganese concentrations were elevated in all treatment groups on day 61 (relative to controls). Increased cerebellum manganese concentrations were seen in animals from the high-manganese diet group (day 61, relative to controls). Increased (relative to all treatment groups) femur, striatum, cerebellum, frontal cortex, and olfactory bulb manganese concentrations were also seen following gavage suggesting that dose rate is an important factor in the pharmacokinetics of oral manganese. These data will be used to refine physiologically based pharmacokinetic models, extending their utility for manganese risk assessment by including multiple dietary exposures.}, number={2}, journal={TOXICOLOGICAL SCIENCES}, author={Foster, Melanie L. and Bartnikas, Thomas B. and Johnson, Laura C. and Herrera, Carolina and Pettiglio, Michael A. and Keene, Athena M. and Taylor, Michael D. and Dorman, David C.}, year={2015}, month={Jun}, pages={244–251} }
 @article{gruen_case_foster_lazarowski_fish_landsberg_depuy_dorman_sherman_2015, title={The use of an open-field model to assess sound-induced fear and anxiety-associated behaviors in Labrador retrievers}, volume={10}, ISSN={["1878-7517"]}, DOI={10.1016/j.jveb.2015.03.007}, abstractNote={Previous studies have shown that the playing of thunderstorm recordings during an open-field task elicits fearful or anxious responses in adult beagles. The goal of our study was to apply this open field test to assess sound-induced behaviors in Labrador retrievers drawn from a pool of candidate improvised explosive devices (IED)-detection dogs. Being robust to fear-inducing sounds and recovering quickly is a critical requirement of these military working dogs. This study presented male and female dogs, with 3 minutes of either ambient noise (Days 1, 3 and 5), recorded thunderstorm (Day 2), or gunfire (Day 4) sounds in an open field arena. Behavioral and physiological responses were assessed and compared to control (ambient noise) periods. An observer blinded to sound treatment analyzed video records of the 9-minute daily test sessions. Additional assessments included measurement of distance traveled (activity), heart rate, body temperature, and salivary cortisol concentrations. Overall, there was a decline in distance traveled and heart rate within each day and over the five-day test period, suggesting that dogs habituated to the open field arena. Behavioral postures and expressions were assessed using a standardized rubric to score behaviors linked to canine fear and anxiety. These fear/anxiety scores were used to evaluate changes in behaviors following exposure to a sound stressor. Compared to control periods, there was an overall increase in fear/anxiety scores during thunderstorm and gunfire sound stimuli treatment periods. Fear/anxiety scores were correlated with distance traveled, and heart rate. Fear/anxiety scores in response to thunderstorm and gunfire were correlated. Dogs showed higher fear/anxiety scores during periods after the sound stimuli compared to control periods. In general, candidate IED-detection Labrador retrievers responded to sound stimuli and recovered quickly, although dogs stratified in their response to sound stimuli. Some dogs were robust to fear/anxiety responses. The results suggest that the open field sound test may be a useful method to evaluate the suitability of dogs for IED-detection training.}, number={4}, journal={JOURNAL OF VETERINARY BEHAVIOR-CLINICAL APPLICATIONS AND RESEARCH}, author={Gruen, Margaret E. and Case, Beth C. and Foster, Melanie L. and Lazarowski, Lucia and Fish, Richard E. and Landsberg, Gary and Depuy, Venita and Dorman, David C. and Sherman, Barbara L.}, year={2015}, pages={338–345} }
 @article{lazarowski_foster_gruen_sherman_case_fish_milgram_dorman_2014, title={Acquisition of a visual discrimination and reversal learning task by Labrador retrievers}, volume={17}, ISSN={["1435-9456"]}, DOI={10.1007/s10071-013-0712-1}, abstractNote={Optimal cognitive ability is likely important for military working dogs (MWD) trained to detect explosives. An assessment of a dog’s ability to rapidly learn discriminations might be useful in the MWD selection process. In this study, visual discrimination and reversal tasks were used to assess cognitive performance in Labrador retrievers selected for an explosives detection program using a modified version of the Toronto General Testing Apparatus (TGTA), a system developed for assessing performance in a battery of neuropsychological tests in canines. The results of the current study revealed that, as previously found with beagles tested using the TGTA, Labrador retrievers (N = 16) readily acquired both tasks and learned the discrimination task significantly faster than the reversal task. The present study confirmed that the modified TGTA system is suitable for cognitive evaluations in Labrador retriever MWDs and can be used to further explore effects of sex, phenotype, age, and other factors in relation to canine cognition and learning, and may provide an additional screening tool for MWD selection.}, number={3}, journal={ANIMAL COGNITION}, author={Lazarowski, Lucia and Foster, Melanie L. and Gruen, Margaret E. and Sherman, Barbara L. and Case, Beth C. and Fish, Richard E. and Milgram, Norton W. and Dorman, David C.}, year={2014}, month={May}, pages={787–792} }
 @article{istvan_marks_murphy_dorman_2014, title={Evaluation of a point-of-care anticoagulant rodenticide test for dogs}, volume={24}, ISSN={1479-3261}, url={http://dx.doi.org/10.1111/vec.12140}, DOI={10.1111/vec.12140}, abstractNote={Abstract}, number={2}, journal={Journal of Veterinary Emergency and Critical Care}, publisher={Wiley}, author={Istvan, Stephanie A. and Marks, Steven L. and Murphy, Lisa A. and Dorman, David C.}, year={2014}, month={Jan}, pages={168–173} }
 @article{lazarowski_dorman_2014, title={Explosives detection by military working dogs: Olfactory generalization from components to mixtures}, volume={151}, ISSN={["1872-9045"]}, DOI={10.1016/j.applanim.2013.11.010}, abstractNote={The training of scent detection dogs using samples of explosives or their chemical precursors is a well-established and documented practice. However an area of canine odor detection that remains under-studied regards a trained dog's perception of an explosive odor when more than one odorant is combined to produce a mixture. The first objective of our study was to determine whether training adult Labrador Retrievers (n = 20) to detect the scent of chemically pure potassium chlorate (PC) was sufficient to produce generalization to PC-based explosive mixtures that contained a novel component. We found that the majority of dogs (87%) trained with pure PC alone did not correctly signal the presence of one or more of four PC-based explosive mixtures. Our second objective was to determine whether training dogs using the separated components found in the PC-based explosives would subsequently enhance detection. Dogs were then trained using a novel static odor delivery device that safely segregated the PC and non-PC components and presented a merged odor to the dog. A statistically significant improvement in percentage of dogs detecting PC-based mixtures after training with the separated components compared to training with PC alone was seen with Mixture 1 (27–100%, P < 0.0001), Mixture 2 (40–81%, P = 0.0229), Mixture 3 (38–94%, P = 0.0004), and Mixture 4 (69–100%, P < 0.005). The results of this study highlight the potential limitations of dogs trained to detect a single odor to then recognize the odor when mixed with other substances. The odor delivery device developed for this study represents an important and effective training option that may reduce the need for using a final PC explosive mixture in canine training.}, journal={APPLIED ANIMAL BEHAVIOUR SCIENCE}, author={Lazarowski, Lucia and Dorman, David C.}, year={2014}, month={Feb}, pages={84–93} }
 @article{taylor_foster_law_centeno_fornero_henderson_trager_stockelman_dorman_2013, title={Assessment of geographical variation in the respiratory toxicity of desert dust particles}, volume={25}, ISSN={["0895-8378"]}, DOI={10.3109/08958378.2013.797524}, abstractNote={Abstract The health consequences of sand particle inhalation are incompletely understood. This project evaluated the respiratory toxicity of sand particles collected at military bases near Fort Irwin USA, in Iraq (Camp Victory, Taji and Talil), and Khost Afghanistan. Our primary focus was on assessing the role of soluble metals in the respiratory toxicity of the sand particles using in vitro and in vivo methods. Replicating rat type II alveolar cell cultures (RLE-6TN) were exposed to sand extracts or vehicle control in serum-free media for ≤24 h. Cytotoxicity was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and assessment of lactate dehydrogenase leakage. The relative in vitro cytotoxicity of the sand extracts was Taji ≈ Talil > Afghanistan > Camp Victory ≈ Fort Irwin. We also assessed extracts of Camp Victory, Afghanistan, and Taji sand for acute and delayed pulmonary toxicity in rats following intratracheal administration. Assessments included biochemical analysis of bronchoalveolar lavage fluid (BALF) and lung histopathology. The in vitro cytotoxicity assay results were partially predictive of in vivo responses. The more cytotoxic Taji sand extract induced an acute irritant response in rats following intratracheal administration. Rats given the less cytotoxic Camp Victory sand extract had minimal biochemical or cytological BALF changes whereas rats given either the Afghanistan or Taji sand extracts demonstrated BALF changes that were suggestive of mild lung inflammation. Unexpectedly, we observed similar lung pathology in all extract-exposed rats. The results of our study can be used to prioritize future particle inhalation studies or guide epidemiological study design.}, number={7}, journal={INHALATION TOXICOLOGY}, author={Taylor, Karen and Foster, Melanie L. and Law, J. McHugh and Centeno, Jose A. and Fornero, Elisa and Henderson, M. Stephen and Trager, Sabrina A. and Stockelman, Michael G. and Dorman, David C.}, year={2013}, month={Jun}, pages={405–416} }
 @article{schroeter_kimbell_asgharian_tewksbury_sochaski_foster_dorman_wong_andersen_2013, title={Inhalation dosimetry of hexamethylene diisocyanate vapor in the rat and human respiratory tracts}, volume={25}, ISSN={["1091-7691"]}, DOI={10.3109/08958378.2013.768314}, abstractNote={Hexamethylene diisocyanate (HDI) is a reactive chemical used in the commercial production of polyurethanes. Toxic effects in rodents exposed to HDI vapor primarily occur in the nasal passages, yet some individuals exposed occupationally to concentrations exceeding current regulatory limits may experience temporary reduction in lung function and asthma-like symptoms. Knowledge of interspecies differences in respiratory tract dosimetry of inhaled HDI would improve our understanding of human health risks to this compound. HDI uptake was measured in the upper respiratory tract of anesthetized Fischer-344 rats. Nasal uptake of HDI was >90% in rats at unidirectional flow rates of 150 and 300 ml/min and a target air concentration of 200 ppb. Uptake data was used to calibrate nasal and lung dosimetry models of HDI absorption in rats and humans. Computational fluid dynamics (CFD) models of the nasal passages were used to simulate inspiratory airflow and HDI absorption. Transport of HDI through lung airways was simulated using convection-diffusion based mass transport models. HDI nasal uptake of 90% and 78% was predicted using the rat and human nasal CFD models, respectively. Total respiratory tract uptake was estimated to be 99% in rats and 97% in humans under nasal breathing. Predicted human respiratory uptake decreased to 87% under oral breathing conditions. Absorption rates of inhaled HDI in human lung airways were estimated to be higher than the rat due to lower uptake in head airways. Model predictions demonstrated significant penetration of HDI to human bronchial airways, although absorption rates were sensitive to breathing style.}, number={3}, journal={INHALATION TOXICOLOGY}, author={Schroeter, Jeffry D. and Kimbell, Julia S. and Asgharian, Bahman and Tewksbury, Earl W. and Sochaski, Mark and Foster, Melanie L. and Dorman, David C. and Wong, Brian A. and Andersen, Melvin E.}, year={2013}, month={Feb}, pages={168–177} }
 @article{dorman_alpi_chappell_2013, title={Subject Matter Expert and Public Evaluations of a Veterinary Toxicology Course Brochure-Writing Assignment}, volume={40}, ISSN={["0748-321X"]}, DOI={10.3138/jvme.0912.082r}, abstractNote={ Veterinary schools are increasingly developing students' communication skills, with an emphasis placed on practice conveying medical and scientific knowledge to different audiences. We describe how patient-centered written communication has been integrated into the training of veterinary students using toxicology-related preventive materials. Third-year veterinary students were given an assignment to prepare a client-focused brochure related to veterinary toxicology. Since 2010, 148 students have completed this assignment, with an average score of 93.4%. Use of a grading rubric was instituted in 2011 and resulted in a more rigorous assessment of the brochures by the course instructors. In this study, we evaluated a sample (n=6) selected from 10 brochures volunteered for further public and expert assessment. Each brochure was measured for readability and assessed with a rubric for perceived usefulness and acceptability by 12 veterinary toxicologists and 10 or 11 adult members of the public attending a college of veterinary medicine open house. Veterinary toxicologist review anticipated that the brochures would be useful for most clients, and the public reviewers confirmed this assessment. Evaluation of the brochures using set marking criteria and readability indexes showed that students had successfully targeted the chosen audiences. Feedback showed that the general public rated the sample brochures highly in terms of quality, usefulness, and interest. Completion of this study has resulted in revision of the grading rubric, an increased use of brochure examples, and additional instruction in readability assessment and brochure development, thereby improving the assignment as a learning exercise. }, number={1}, journal={JOURNAL OF VETERINARY MEDICAL EDUCATION}, author={Dorman, David C. and Alpi, Kristine M. and Chappell, Kimberly H.}, year={2013}, pages={19–28} }
 @article{schroeter_dorman_yoon_nong_taylor_andersen_clewell_2012, title={Application of a Multi-Route Physiologically Based Pharmacokinetic Model for Manganese to Evaluate Dose-Dependent Neurological Effects in Monkeys}, volume={129}, ISSN={["1096-0929"]}, DOI={10.1093/toxsci/kfs212}, abstractNote={Manganese (Mn) is an essential element that is neurotoxic under certain exposure conditions. Monkeys and humans exposed to Mn develop similar neurological effects; thus, an improved understanding of the dose-response relationship seen in nonhuman primates could inform the human health risk assessment for this essential metal. A previous analysis of this dose-response relationship in experimental animals (Gwiazda, R., Lucchini, R., and Smith, D., 2007, Adequacy and consistency of animal studies to evaluate the neurotoxicity of chronic low-level manganese exposure in humans, J. Toxicol. Environ. Health Part A 70, 594-605.) relied on estimates of cumulative intake of Mn as the sole measure for comparison across studies with different doses, durations, and exposure routes. In this study, a physiologically based pharmacokinetic model that accurately accounts for the dose dependencies of Mn distribution was used to estimate increases in brain Mn concentrations in monkeys following Mn exposure. Experimental studies evaluated in the analysis included exposures by inhalation, oral, iv, ip, and sc dose routes, and spanned durations ranging from several weeks to over 2 years. This analysis confirms that the dose-response relationship for the neurotoxic effects of Mn in monkeys is independent of exposure route and supports the use of target tissue Mn concentration or cumulative target tissue Mn as the appropriate dose metric for these comparisons. These results also provide strong evidence of a dose-dependent transition in the mode of action for the neurological effects of Mn that needs to be considered in risk assessments for this essential metal.}, number={2}, journal={TOXICOLOGICAL SCIENCES}, author={Schroeter, Jeffry D. and Dorman, David C. and Yoon, Miyoung and Nong, Andy and Taylor, Michael D. and Andersen, Melvin E. and Clewell, Harvey J., III}, year={2012}, month={Oct}, pages={432–446} }
 @article{dorman_mokashi_wagner_olabisi_wong_moss_centeno_guandalini_jackson_dennis_et al._2012, title={Biological responses in rats exposed to cigarette smoke and Middle East sand (dust)}, volume={24}, ISSN={["1091-7691"]}, DOI={10.3109/08958378.2011.647413}, abstractNote={Respiratory symptoms are frequently reported in personnel deployed to the Middle East. This project characterized the respiratory toxicity of inhaled Iraqi sand (IS). Adult rats underwent a 6-wk inhalation to air or mainstream cigarette smoke (MSCS) (3 h/d, 5 d/wk) that included exposure to IS or crystalline silica (1 mg/m3, 19 h/d, 7 d/wk) or air during the last 2 weeks. Assessments included motor activity, whole-body plethysmography, cytological and biochemical analysis of bronchoalveolar lavage fluid, lung metal burden, nasal and lung pathology, and changes in lung protein and gene expression. A number of metals including nickel, manganese, vanadium, and chromium were detected in IS. Elevated lung parenchyma aluminum, silica, barium, manganese, and vanadium concentrations were seen in IS-exposed rats, suggesting that several metals present in IS are bioavailable. Rats exposed to IS only developed mild inflammation in the anterior nose and lung. Silica inhalation was associated with some pulmonary responses that were not seen in IS-exposed rats, such as mild laryngeal and tracheal inflammation, mild tracheal epithelial hyperplasia, and elevated lung silica concentrations. MSCS inhalation with or without co-exposure to either IS or silica resulted in changes consistent with pulmonary inflammation and stress response. Rats exposed to MSCS and silica had more widespread airway lesions when compared with rats exposed to MSCS only. Silica-exposed rats had more robust pulmonary gene expression and proteomic responses than that seen in IS-exposed rat. Our studies show that the respiratory toxicity of IS is qualitatively similar to or less than that seen following short-term silica exposure.}, number={2}, journal={INHALATION TOXICOLOGY}, author={Dorman, David C. and Mokashi, Vishwesh and Wagner, Dean J. and Olabisi, Ayodele O. and Wong, Brian A. and Moss, Owen R. and Centeno, Jose A. and Guandalini, Gustavo and Jackson, David A. and Dennis, William E. and et al.}, year={2012}, month={Jan}, pages={109–124} }
 @article{neurological impacts from inhalation of pollutants and the nose-brain connection_2012, volume={33}, number={4}, journal={NeuroToxicology}, year={2012}, pages={838–841} }
 @article{lucchini_dorman_elder_veronesi_2012, title={Neurological impacts from inhalation of pollutants and the nose–brain connection}, volume={33}, ISSN={0161-813X}, url={http://dx.doi.org/10.1016/j.neuro.2011.12.001}, DOI={10.1016/j.neuro.2011.12.001}, abstractNote={The effects of inhaled particles have focused heavily on the respiratory and cardiovascular systems. Most studies have focused on inhaled metals, whereas less information is available for other particle types regarding the effects on the brain and other extra-pulmonary organs. We review here the key available literature on nanoparticle uptake and transport through the olfactory pathway, the experimental data from animal and in vitro studies, and human epidemiological observations. Nanoparticles (<0.1 μm in one dimension) may easily reach the brain from the respiratory tract via sensory neurons and transport from the distal alveoli into the blood or lymph as free particles or inside phagocytic cells. These mechanisms and subsequent biologic responses may be influenced by the chemical composition of inhaled particles. Animal studies with ambient particulate matter and certain other particles show alterations in neuro-inflammatory markers of oxidative stress and central neurodegeneration. Human observations indicate motor, cognitive, and behavioral changes especially after particulate metal exposure in children. Exposure to co-pollutants and/or underlying disease states could also impact both the biokinetics and effects of airborne particles in the brain. Data are needed from the areas of inhalation, neurology, and metal toxicology in experimental and human studies after inhalation exposure. An increased understanding of the neurotoxicity associated with air pollution exposure is critical to protect susceptible individuals in the workplace and the general population.}, number={4}, journal={NeuroToxicology}, publisher={Elsevier BV}, author={Lucchini, R.G. and Dorman, D.C. and Elder, A. and Veronesi, B.}, year={2012}, month={Aug}, pages={838–841} }
 @article{block_elder_auten_bilbo_chen_chen_cory-slechta_costa_diaz-sanchez_dorman_et al._2012, title={The outdoor air pollution and brain health workshop}, volume={33}, ISSN={0161-813X}, url={http://dx.doi.org/10.1016/j.neuro.2012.08.014}, DOI={10.1016/j.neuro.2012.08.014}, abstractNote={Accumulating evidence suggests that outdoor air pollution may have a significant impact on central nervous system (CNS) health and disease. To address this issue, the National Institute of Environmental Health Sciences/National Institute of Health convened a panel of research scientists that was assigned the task of identifying research gaps and priority goals essential for advancing this growing field and addressing an emerging human health concern. Here, we review recent findings that have established the effects of inhaled air pollutants in the brain, explore the potential mechanisms driving these phenomena, and discuss the recommended research priorities/approaches that were identified by the panel.}, number={5}, journal={NeuroToxicology}, publisher={Elsevier BV}, author={Block, Michelle L. and Elder, Alison and Auten, Richard L. and Bilbo, Staci D. and Chen, Honglei and Chen, Jiu-Chiuan and Cory-Slechta, Deborah A. and Costa, Daniel and Diaz-Sanchez, David and Dorman, David C. and et al.}, year={2012}, month={Oct}, pages={972–984} }
 @misc{the outdoor air pollution and brain health workshop_2012, volume={33}, number={5}, journal={NeuroToxicology}, year={2012}, pages={972–984} }
 @article{schroeter_nong_yoon_taylor_dorman_andersen_clewell_2011, title={Analysis of Manganese Tracer Kinetics and Target Tissue Dosimetry in Monkeys and Humans with Multi-Route Physiologically Based Pharmacokinetic Models}, volume={120}, ISSN={["1096-6080"]}, DOI={10.1093/toxsci/kfq389}, abstractNote={Manganese (Mn) is an essential nutrient with the capacity for toxicity from excessive exposure. Accumulation of Mn in the striatum, globus pallidus, and other midbrain regions is associated with neurotoxicity following high-dose Mn inhalation. Physiologically based pharmacokinetic (PBPK) models for ingested and inhaled Mn in rats and nonhuman primates were previously developed. The models contained saturable Mn tissue-binding capacities, preferential fluxes of Mn in specific tissues, and homeostatic control processes such as inducible biliary excretion of Mn. In this study, a nonhuman primate model was scaled to humans and was further extended to include iv, ip, and sc exposure routes so that past studies regarding radiolabeled carrier-free (54)MnCl(2) tracer kinetics could be evaluated. Simulation results accurately recapitulated the biphasic elimination behavior for all exposure routes. The PBPK models also provided consistent cross-species descriptions of Mn tracer kinetics across multiple exposure routes. These results indicate that PBPK models can accurately simulate the overall kinetic behavior of Mn and predict conditions where exposures will increase free Mn in various tissues throughout the body. Simulations with the human model indicate that globus pallidus Mn concentrations are unaffected by air concentrations < 10 μg/m(3) Mn. The use of this human Mn PBPK model can become a key component of future human health risk assessment of Mn, allowing the consideration of various exposure routes, natural tissue background levels, and homeostatic controls to explore exposure conditions that lead to increased target tissue levels resulting from Mn overexposure.}, number={2}, journal={TOXICOLOGICAL SCIENCES}, author={Schroeter, Jeffry D. and Nong, Andy and Yoon, Miyoung and Taylor, Michael D. and Dorman, David C. and Andersen, Melvin E. and Clewell, Harvey J., III}, year={2011}, month={Apr}, pages={481–498} }
 @article{yoon_schroeter_nong_taylor_dorman_andersen_clewell_2011, title={Physiologically Based Pharmacokinetic Modeling of Fetal and Neonatal Manganese Exposure in Humans: Describing Manganese Homeostasis during Development}, volume={122}, ISSN={["1096-0929"]}, DOI={10.1093/toxsci/kfr141}, abstractNote={Concerns for potential vulnerability to manganese (Mn) neurotoxicity during fetal and neonatal development have been raised due to increased needs for Mn for normal growth, different sources of exposure to Mn, and pharmacokinetic differences between the young and adults. A physiologically based pharmacokinetic (PBPK) model for Mn during human gestation and lactation was developed to predict Mn in fetal and neonatal brain using a parallelogram approach based upon extrapolation across life stages in rats and cross-species extrapolation to humans. Based on the rodent modeling, key physiological processes controlling Mn kinetics during gestation and lactation were incorporated, including alterations in Mn uptake, excretion, tissue-specific distributions, and placental and lactational transfer of Mn. Parameters for Mn kinetics were estimated based on human Mn data for milk, placenta, and fetal/neonatal tissues, along with allometric scaling from the human adult model. The model was evaluated by comparison with published Mn levels in cord blood, milk, and infant blood. Maternal Mn homeostasis during pregnancy and lactation, placenta and milk Mn, and fetal/neonatal tissue Mn were simulated for normal dietary intake and with inhalation exposure to environmental Mn. Model predictions indicate similar or lower internal exposures to Mn in the brains of fetus/neonate compared with the adult at or above typical environmental air Mn concentrations. This PBPK approach can assess expected Mn tissue concentration during early life and compares contributions of different Mn sources, such as breast or cow milk, formula, food, drinking water, and inhalation, with tissue concentration.}, number={2}, journal={TOXICOLOGICAL SCIENCES}, author={Yoon, Miyoung and Schroeter, Jeffry D. and Nong, Andy and Taylor, Michael D. and Dorman, David C. and Andersen, Melvin E. and Clewell, Harvey J., III}, year={2011}, month={Aug}, pages={297–316} }
 @article{andersen_dorman_clewell_taylor_nong_2010, title={Multi-Dose-Route, Multi-Species Pharmacokinetic Models for Manganese and Their Use in Risk Assessment}, volume={73}, ISSN={["1528-7394"]}, DOI={10.1080/15287390903340849}, abstractNote={Manganese (Mn) is an essential element that may be toxic in conditions of overexposure. Nearly 10 years ago, some of the authors of this article published a proposed methodology to perform a tissue-dose-based risk assessment and a detailed list of data needs necessary to perform the assessment. Since that time, a substantial body of Mn pharmacokinetic (PK) data has been generated in rats and nonhuman primates, allowing for the construction of physiologically based pharmacokinetic (PBPK) models for Mn. This study reviews the development of the Mn PBPK models, reassesses the previously identified data needs, and details potential uses of these models in risk assessment of Mn. Based upon numerous animal experiments, pharmacokinetic (PK) models have effectively simulated tissue kinetics of Mn from both inhaled and oral Mn intake. PK models achieve this by incorporating homeostatic control processes, saturable tissue binding capacities, and preferential fluxes in various tissue regions. While minor data gaps still exist, the models captured the main dose-dependent characteristics of Mn disposition in rodents and monkeys and provide a structure to parameterize an equivalent PK description in humans. These models are organized to contribute to a tissue-dose based risk assessment of Mn that simultaneously considers ingestion and inhalation kinetics of Mn along with homeostatic control of Mn.}, number={2-3}, journal={JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH-PART A-CURRENT ISSUES}, author={Andersen, Melvin E. and Dorman, David C. and Clewell, Harvey J., III and Taylor, Michael D. and Nong, Andy}, year={2010}, pages={217–234} }
 @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{yoon_nong_clewell_taylor_dorman_andersen_2009, title={Evaluating Placental Transfer and Tissue Concentrations of Manganese in the Pregnant Rat and Fetuses after Inhalation Exposures with a PBPK Model}, volume={112}, ISSN={["1096-0929"]}, DOI={10.1093/toxsci/kfp198}, abstractNote={A Physiologically Based Pharmaco Kinetic (PBPK) model, based on a published description of manganese (Mn) kinetics in adult rats, has been developed to describe Mn uptake and tissue distribution in the pregnant dam and fetus during dietary and inhalation exposures. This extension incorporated key physiological processes controlling Mn pharmacokinetics during pregnancy and fetal development. After calibration against tissue Mn concentrations observed during late gestation, the model accurately simulated Mn tissue distribution in the dam and fetus following both diet and inhalation exposures to the pregnant rat. Maternal to fetal transfer of Mn through placenta was described using two pathways: a saturable active transport with high affinity and a simple diffusion. The active transport dominates at basal and lower Mn exposure, whereas at higher Mn exposure, the relative contribution of the diffusion pathway increases. To simulate fetal tissue Mn, tissue-binding parameters and preferential influx/efflux rates in fetal brain were adjusted from the adult model based on differential developmental processes and varying tissue demands for Mn in early life. Model simulations were consistent with observed tissue Mn concentrations in fetal tissues, including brain for diet alone and for combined diet and inhalation. Simulations of Mn in placenta and other maternal tissues in late gestation correlated well with measured tissue concentrations. This model, together with our published models for Mn kinetics during lactation and postnatal development, will help to address concerns about Mn neurotoxicity in potentially sensitive human subpopulation, such as infants and children by providing an estimate of Mn exposure in the population of interest.}, number={1}, journal={TOXICOLOGICAL SCIENCES}, author={Yoon, Miyoung and Nong, Andy and Clewell, Harvey J., III and Taylor, Michael D. and Dorman, David C. and Andersen, Melvin E.}, year={2009}, month={Nov}, pages={44–58} }
 @article{yoon_nong_clewell_taylor_dorman_andersen_2009, title={Lactational Transfer of Manganese in Rats: Predicting Manganese Tissue Concentration in the Dam and Pups from Inhalation Exposure with a Pharmacokinetic Model}, volume={112}, ISSN={["1096-0929"]}, DOI={10.1093/toxsci/kfp197}, abstractNote={Manganese (Mn) is an essential element. However, excess Mn causes neurotoxicity. Fetuses and neonates have been discussed as potentially sensitive subpopulations for Mn. In the present study, a previously published physiologically based pharmacokinetic model for Mn in adult rats was extended to examine exposure conditions that could lead to increased central nervous system Mn in developing rats. The basic structure had saturable tissue binding, homeostatic control of uptake and excretion, and tissue-specific increases in Mn from inhalation. Modifications made for lactating dam and pups included differential tissue-binding capacities in developing pups, increased absorption of dietary Mn in lactating dam, and more efficient gastrointestinal absorption and lower basal biliary excretion in pups. Enhancement of biliary excretion in pups was also required to accurately simulate tissue Mn during early postnatal inhalation. Overall, these changes were concordant with the biology of Mn and other essential metals during development. The resulting model simulations match a variety of published studies on maternal Mn homeostasis during lactation, milk Mn levels, and changing patterns of neonatal tissue Mn for normal dietary intake and with Mn inhalation. Our successful description of Mn kinetics across these life stages suggests that the present model can help describe the relationship between dose of exposure and target tissue Mn concentrations across different developmental stages and its potential risks and assess whether infants and children should be regarded as susceptible populations for Mn inhalation.}, number={1}, journal={TOXICOLOGICAL SCIENCES}, author={Yoon, Miyoung and Nong, Andy and Clewell, Harvey J., III and Taylor, Michael D. and Dorman, David C. and Andersen, Melvin E.}, year={2009}, month={Nov}, pages={23–43} }
 @article{nong_taylor_clewell_dorman_andersen_2009, title={Manganese Tissue Dosimetry in Rats and Monkeys: Accounting for Dietary and Inhaled Mn with Physiologically based Pharmacokinetic Modeling}, volume={108}, ISSN={["1096-0929"]}, DOI={10.1093/toxsci/kfn264}, abstractNote={Manganese (Mn) is an essential nutrient required for normal tissue growth and function. Following exposures to high concentrations of inhaled Mn, there is preferential accumulation of Mn in certain brain regions such as the striatum and globus pallidus. The goal of this research was to complete a physiologically based pharmacokinetic (PBPK) model for Mn in rats and scale the model to describe Mn tissue accumulation in nonhuman primates exposed to Mn by inhalation and diet. The model structure includes saturable tissue binding with association and dissociation rate constants, asymmetric tissue permeation flux rate constants to specific tissues, and inducible biliary excretion. The rat PBPK model described tissue time-course studies for various dietary Mn intakes and accounted for inhalation studies of both 14-day and 90-day duration. In monkeys, model parameters were first calibrated using steady-state tissue Mn concentrations from rhesus monkeys fed a diet containing 133 ppm Mn. The model was then applied to simulate 65 exposure days of weekly (6 h/day; 5 days/week) inhalation exposures to soluble MnSO(4) at 0.03 to 1.5 mg Mn/m(3). Sensitivity analysis showed that Mn tissue concentrations in the models have dose-dependencies in (1) biliary excretion of free Mn from liver, (2) saturable tissue binding in all tissues, and (3) differential influx/efflux rates for tissues that preferentially accumulate Mn. This multispecies PBPK model is consistent with the available experimental kinetic data, indicating preferential increases in some brain regions with exposures above 0.2 mg/m(3) and fairly rapid return to steady-state levels (within several weeks rather than months) after cessation of exposure. PBPK models that account for preferential Mn tissue accumulation from both oral and inhalation exposures will be essential to support tissue dosimetry-based human risk assessments for Mn.}, number={1}, journal={TOXICOLOGICAL SCIENCES}, author={Nong, Andy and Taylor, Michael D. and Clewell, Harvey J., III and Dorman, David C. and Andersen, Melvin E.}, year={2009}, month={Mar}, pages={22–34} }
 @misc{goldhaber_dorman_gardner_adeshina_2009, title={Provisional Advisory Levels (PALs) for acrylonitrile}, volume={21}, ISSN={["1091-7691"]}, DOI={10.3109/08958370903202804}, abstractNote={Application of Provisional Advisory Level (PAL) protocols was performed for acrylonitrile, as experimental data permitted. Three levels (PAL 1, PAL 2, and PAL 3), distinguished by severity of toxic effects, are developed for 24-hour, 30-day, 90-day, and 2-year durations of potential drinking water and inhalation exposures for the general public. For background on the PAL Program and a description of the methodology used in deriving PALs, the reader is referred to accompanying papers in this Supplement. Human data were limited to inhalation exposures. The animal experimental data set for this chemical was robust for inhalation and oral studies, with the exception of appropriate data for inhalation 30-day, 90-day, and 2-year PAL 3 values. PAL estimates were approved by the Expert Consultation Panel for Provisional Advisory Levels in October 2007. Oral 24-hour PALs for acrylonitrile are PAL 1 = 7 mg/L; PAL 2 = 23 mg/L; and PAL 3 = 88 mg/L. Oral 30-day and 90-day PALs are PAL 1 = 0.35 mg/L; PAL 2 = 7 mg/L; and PAL 3 = 17 mg/L. Oral 2-year PALs are PAL 1 = 0.35 mg/L; PAL 2 = 3.5 mg/L; and PAL 3 = 12 mg/L. Acrylonitrile inhalation PAL values for 24-hour exposure are PAL 1 = 0.17 ppm; PAL 2 = 3.5 ppm; and PAL 3 = 5.1 ppm; the 30-day and 90-day inhalation exposure values are PAL 1 = 0.15 ppm and PAL 2 = 0.60 ppm. The 2-year inhalation values are PAL 1 = 0.014 ppm and PAL 2 = 0.12 ppm. PAL 3 values for 30 days, 90 days, and 2 years are not recommended due to insufficient data.}, journal={INHALATION TOXICOLOGY}, author={Goldhaber, Susan and Dorman, David and Gardner, Donald and Adeshina, Femi}, year={2009}, month={Dec}, pages={17–55} }
 @article{marshall_dorman_gardner_adeshina_2009, title={Provisional Advisory Levels (PALs) for hydrogen sulfide (H2S)}, volume={21}, ISSN={["0895-8378"]}, DOI={10.3109/08958370903202812}, abstractNote={Application of Provisional Advisory Levels (PALs) protocols was performed for hydrogen sulfide (H2S) as experimental data permitted. Three levels (PAL 1, PAL 2, and PAL 3), distinguished by severity of toxic effects, are developed for 24-hour, 30-day, 90-day, and 2-year durations of potential drinking water and inhalation exposures for the general public. For background on the PAL program and a description of the methodology used in deriving PALs, the reader is referred to accompanying papers in this Supplement. The database includes human experimental studies, worker exposure evaluations, as well as case studies on acute and repeated exposure. The database of animal studies is substantial, covering multiple species and addressing acute, repeated, and subchronic exposure scenarios. PAL estimates were approved by the Expert Consultation Panel for Provisional Advisory Levels in November 2006. No reliable data were found on oral exposure, making it impractical to estimate PALs for drinking water. Because H2S exists as a gas, partitioning to air is likely to occur with an environmental release. H2S inhalation PAL values for 24-hour exposure are PAL 1 = 1.2 ppm; PAL 2 = 7.0 ppm; and PAL 3 = 27 ppm; the 30-day and 90-day inhalation exposure values are PAL 1 = 0.85 ppm and PAL 2 = 3.0 ppm. PAL 3 values for 30-day and 90-day exposures are not recommended due to insufficient data. Long-term data were insufficient to estimate 2-year inhalation PALs.}, journal={INHALATION TOXICOLOGY}, author={Marshall, Thomas and Dorman, David and Gardner, Donald and Adeshina, Femi}, year={2009}, month={Dec}, pages={56–72} }
 @article{struve_gaido_hensley_lehmann_ross_sochaski_willson_dorman_2009, title={Reproductive Toxicity and Pharmacokinetics of di-n-butyl Phthalate (DBP) Following Dietary Exposure of Pregnant Rats}, volume={86}, ISSN={["1542-9741"]}, DOI={10.1002/bdrb.20199}, abstractNote={Abstract}, number={4}, journal={BIRTH DEFECTS RESEARCH PART B-DEVELOPMENTAL AND REPRODUCTIVE TOXICOLOGY}, author={Struve, Melanie F. and Gaido, Kevin W. and Hensley, Janan B. and Lehmann, Kim P. and Ross, Susan M. and Sochaski, Mark A. and Willson, Gabrielle A. and Dorman, David C.}, year={2009}, month={Aug}, pages={345–354} }
 @misc{bolon_anthony_butt_dorman_green_little_valentine_weinstock_yan_sills_2008, title={"Current Pathology Techniques" Symposium Review: Advances and Issues in Neuropathology}, volume={36}, ISSN={["1533-1601"]}, DOI={10.1177/0192623308322313}, abstractNote={ Our understanding of the mechanisms that incite neurological diseases has progressed rapidly in recent years, mainly owing to the advent of new research instruments and our increasingly facile ability to assemble large, complex data sets acquired across several disciplines into an integrated representation of neural function at the molecular, cellular, and systemic levels. This mini-review has been designed to communicate the principal technical advances and current issues of importance in neuropathology research today in the context of our traditional neuropathology practices. Specific topics briefly addressed in this paper include correlative biology of the many facets of the nervous system; conventional and novel methods for investigating neural structure and function; theoretical and technical issues associated with investigating neuropathology end points in emerging areas of concern (developmental neurotoxicity, neurodegenerative conditions); and challenges and opportunities that will face pathologists in this field in the foreseeable future. We have organized this information in a manner that we hope will be of interest not only to professionals with a career focus in neuropathology, but also to general pathologists who occasionally face neuropathology questions. }, number={6}, journal={TOXICOLOGIC PATHOLOGY}, author={Bolon, Brad and Anthony, Douglas C. and Butt, Mark and Dorman, David and Green, Michael V. and Little, Peter B. and Valentine, William M. and Weinstock, Daniel and Yan, James and Sills, Robert C.}, year={2008}, month={Oct}, pages={871–889} }
 @article{schroeter_kimbell_gross_willson_dorman_tan_clewell_2008, title={Application of Physiological Computational Fluid Dynamics Models to Predict Interspecies Nasal Dosimetry of Inhaled Acrolein}, volume={20}, ISSN={0895-8378 1091-7691}, url={http://dx.doi.org/10.1080/08958370701864235}, DOI={10.1080/08958370701864235}, abstractNote={Acrolein is a highly soluble and reactive aldehyde and is a potent upper-respiratory-tract irritant. Acrolein-induced nasal lesions in rodents include olfactory epithelial atrophy and inflammation, epithelial hyperplasia, and squamous metaplasia of the respiratory epithelium. Nasal uptake of inhaled acrolein in rats is moderate to high, and depends on inspiratory flow rate, exposure duration, and concentration. In this study, anatomically accurate three-dimensional computational fluid dynamics (CFD) models were used to simulate steady-state inspiratory airflow and to quantitatively predict acrolein tissue dose in rat and human nasal passages. A multilayered epithelial structure was included in the CFD models to incorporate clearance of inhaled acrolein by diffusion, blood flow, and first-order and saturable metabolic pathways. Kinetic parameters for these pathways were initially estimated by fitting a pharmacokinetic model with a similar epithelial structure to time-averaged acrolein nasal extraction data and were then further adjusted using the CFD model. Predicted air:tissue flux from the rat nasal CFD model compared well with the distribution of acrolein-induced nasal lesions from a subchronic acrolein inhalation study. These correlations were used to estimate a tissue dose-based no-observed-adverse-effect level (NOAEL) for inhaled acrolein. A human nasal CFD model was used to extrapolate effects in laboratory animals to human exposure conditions on the basis of localized tissue dose and tissue responses. Assuming that equivalent tissue dose will induce similar effects across species, a NOAEL human equivalent concentration for inhaled acrolein was estimated to be 8 ppb.}, number={3}, journal={Inhalation Toxicology}, publisher={Informa UK Limited}, author={Schroeter, Jeffry D. and Kimbell, Julia S. and Gross, Elizabeth A. and Willson, Gabrielle A. and Dorman, David C. and Tan, Yu-Mei and Clewell, Harvey J., III}, year={2008}, month={Jan}, pages={227–243} }
 @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{erikson_dorman_lash_aschner_2008, title={Duration of airborne-manganese exposure in rhesus monkeys is associated with brain regional changes in biomarkers of neurotoxicity}, volume={29}, ISSN={0161-813X}, url={http://dx.doi.org/10.1016/j.neuro.2007.12.007}, DOI={10.1016/j.neuro.2007.12.007}, abstractNote={Juvenile (20-24-month-old) rhesus monkeys were exposed to airborne-manganese sulfate (MnSO(4)) 1.5 mg Mn/m(3) (6h/day, 5 days/week) for 15 or 33 days, or for 65 days followed by a 45 or 90 days post-exposure recovery period, or air. We assessed biochemical endpoints indicative of oxidative stress and excitotoxicity in the cerebellum, frontal cortex, caudate, globus pallidus, olfactory cortex, and putamen. Glutamine synthetase (GS), glutamate transporters (GLT-1 and GLAST) and tyrosine hydroxylase (TH) protein levels, metallothionein (MT), GLT-1, GLAST, TH and GS mRNA levels, and total glutathione (GSH) levels were determined for all brain regions. Exposure to Mn significantly decreased MT mRNA in the caudate (vs. air-exposed controls). This depression persisted at least 90 days post-exposure. In contrast, putamen MT mRNA levels were unaffected by Mn exposure. GLT-1 and GLAST were relatively unaffected by short term Mn exposure, except in the globus pallidus where exposure for 33 days led to decreased protein levels, which persisted after 45 days of recovery for both proteins and 90 days of recovery in the case of GLAST. Exposure to 1.5 mg Mn/m(3) caused a significant decrease in GSH levels in the caudate and increased GSH levels in the putamen of monkey exposed for 15 and 33 days with both effects persisting at least 90 days post-exposure. Finally, TH protein levels were significantly lowered in the globus pallidus of the monkeys exposed for 33 days but mRNA levels were significantly increased in this same region. Overall, the nonhuman primate brain responds to airborne Mn in a heterogeneous manner and most alterations in these biomarkers of neurotoxicity are reversible upon cessation of Mn exposure.}, number={3}, journal={NeuroToxicology}, publisher={Elsevier BV}, author={Erikson, Keith M. and Dorman, David C. and Lash, Lawrence H. and Aschner, Michael}, year={2008}, month={May}, pages={377–385} }
 @article{roberts_thomas_dorman_2008, title={Gene Expression Changes Following Acute Hydrogen Sulfide (H2S)-induced Nasal Respiratory Epithelial Injury}, volume={36}, ISSN={["1533-1601"]}, DOI={10.1177/0192623308317422}, abstractNote={ Hydrogen sulfide (H2S) is a naturally occurring gas that is also associated with several industries. The potential for widespread human inhalation exposure to this toxic gas is a public health concern. The nasal epithelium is especially susceptible to H2S-induced pathology. Injury to and regeneration of the nasal respiratory mucosa occurred in animals with ongoing H2S exposure, suggesting that the regenerated respiratory epithelium under-goes an adaptive response and becomes resistant to further injury. To better understand this response, ten-week-old male Sprague-Dawley rats were exposed nose-only to either air or 200 ppm H2S for three hours per day for one day or five consecutive days. Nasal respiratory epithelial cells at the site of injury and regeneration were laser capture microdissected, and gene expression profiles were generated at three, six, and twenty-four hours after the initial three-hour exposure and at twenty-four hours after the fifth exposure using the Affymetrix Rat Genome 230 2.0 microarray. Gene ontology enrichment analysis showed that H2S exposure altered gene expression associated with a variety of biological processes, including cell cycle regulation, protein kinase regulation, and cytoskeletal organization and biogenesis. Surprisingly, our results did not show a significant change in cytochrome oxidase gene expression or bioenergetics. }, number={4}, journal={TOXICOLOGIC PATHOLOGY}, author={Roberts, E. S. and Thomas, R. S. and Dorman, D. C.}, year={2008}, month={Jun}, pages={560–567} }
 @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 6h/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{nong_teeguarden_clewell_dorman_andersen_2008, title={Pharmacokinetic Modeling of Manganese in the Rat IV: Assessing Factors that Contribute to Brain Accumulation During Inhalation Exposure}, volume={71}, ISSN={1528-7394 1087-2620}, url={http://dx.doi.org/10.1080/15287390701838697}, DOI={10.1080/15287390701838697}, abstractNote={A recently published physiologically based pharmacokinetic (PBPK) model successfully accounted for steady-state tissue manganese (Mn) concentration seen with normal dietary intakes and for biphasic, whole-body time-course profiles observed with tracer (54Mn) dosing. In this present study, PBPK modeling was used to evaluate Mn kinetics and brain concentrations in rats exposed to Mn both in their diet and by inhalation. Three published studies were used: (1) rats fed on diets ranging from 2 to 100 ppm, (2) rats on 125 ppm in diet and exposed via inhalation at 0.0 to 3.00 mg Mn/m3 each day for 14 d, and (3) rats to 0.1 or 0.5 mg Mn/m3 for 6 h/d, 5 d/wk over a 90-d period. The original model structure with well-mixed and “deep” compartments for each tissue could not describe rapid increases in tissue concentrations and rapid declines seen in high concentration inhalation studies. A second structure was developed that included (1) saturable, high-affinity binding of Mn in all tissues and (2) asymmetric diffusion from blood into brain (i.e., transport into and out of specific brain regions such as the striatum was described with different diffusion constants). This second model was consistent with liver and striatum experimental data. Preferential increases in some brain regions were predicted for exposures above 0.2 mg/m3 and had a rapid (i.e., 1 or 2 wk) return to steady-state levels. Multi-dose-route PBPK models for Mn based on this alternative model structure can be readily scaled to evaluate tissue Mn kinetics in other species and for human populations. Once validated across test animals, these PBPK models will be useful in tissue-dose based risk assessment with manganese.}, number={7}, journal={Journal of Toxicology and Environmental Health, Part A}, publisher={Informa UK Limited}, author={Nong, Andy and Teeguarden, Justin G. and Clewell, Harvey J., III and Dorman, David C. and Andersen, Melvin E.}, year={2008}, month={Feb}, pages={413–426} }
 @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} }
 @article{roberts_soucy_bonner_page_thomas_dorman_2007, title={Basal Gene Expression in Male and Female Sprague-Dawley Rat Nasal Respiratory and Olfactory Epithelium}, volume={19}, ISSN={0895-8378 1091-7691}, url={http://dx.doi.org/10.1080/08958370701513113}, DOI={10.1080/08958370701513113}, abstractNote={The nasal epithelium is an important target site for chemically induced toxicity and carcinogenicity. Experimental studies show that site-specific lesions can arise within the nasal respiratory or olfactory epithelium following the inhalation of certain chemicals. Moreover, gender differences in epithelial response are also reported. To better understand and predict gender differences in response of the nasal epithelium to inhaled xenobiotics, gene expression profiles from naive male and female Sprague-Dawley rats were constructed. Epithelial cells were manually collected from the nasal septum, naso- and maxillo-turbinates, and ethmoid turbinates of nine male and nine female rats. Gene expression analysis was performed using the Affymetrix Rat Genome 430 2.0 microarray. Surprisingly, there were few gender differences in gene expression. Gene ontology enrichment analysis identified several functional categories, including xenobiotic metabolism, cell cycle, apoptosis, and ion channel/transport, with significantly different expression between tissue types. These baseline data will contribute to our understanding of the normal physiology and selectivity of the nasal epithelial cells' response to inhaled environmental toxicants.}, number={11}, journal={Inhalation Toxicology}, publisher={Informa UK Limited}, author={Roberts, Elizabeth S. and Soucy, Nicole V. and Bonner, Anna M. and Page, Todd J. and Thomas, Russell S. and Dorman, David C.}, year={2007}, month={Jan}, pages={941–949} }
 @article{struve_mcmanus_wong_dorman_2007, title={Basal ganglia neurotransmitter concentrations in rhesus monkeys following subchronic manganese sulfate inhalation}, volume={50}, ISSN={0271-3586 1097-0274}, url={http://dx.doi.org/10.1002/ajim.20489}, DOI={10.1002/ajim.20489}, abstractNote={Abstract}, number={10}, journal={American Journal of Industrial Medicine}, publisher={Wiley}, author={Struve, Melanie F. and McManus, Brian E. and Wong, Brian A. and Dorman, David C.}, year={2007}, pages={772–778} }
 @article{sochaski_mcmanus_struve_wallace_dorman_2007, title={Inhibition and recovery of maternal and foetal cholinesterase enzymes following fenitrothion administration in CD rats}, volume={37}, ISSN={0049-8254 1366-5928}, url={http://dx.doi.org/10.1080/00498250600966360}, DOI={10.1080/00498250600966360}, abstractNote={The purpose of this study was to characterize tissue esterase activity and blood fenitrothion concentrations in the rat dam and foetus following in-utero exposure to the organophosphate insecticide fenitrothion. Time-mated, 8-week-old rats were gavaged on gestation day 19 with 0, 5, or 25 mg fenitrothion kg−1. Fenitrothion was absorbed rapidly from the gastrointestinal tract, with peak maternal and foetal blood levels observed 0.5–1.0 h after dosing. Fenitrothion concentrations in maternal and foetal blood were virtually identical and demonstrated a non-linear dose–response relationship. Acetylcholinesterase and carboxylesterase activities in maternal liver and blood and in foetal liver and brain decreased within 30–60 min of fenitrothion exposure. Esterase inhibition occurred at a fenitrothion dose (5 mg kg−1) that has not been previously associated with reproductive toxicity, suggesting that esterase inhibition should be considered as the critical effect in risk assessments for this pesticide.}, number={1}, journal={Xenobiotica}, publisher={Informa UK Limited}, author={Sochaski, M. A. and McManus, B. M. and Struve, M. F. and Wallace, D. G. and Dorman, D. C.}, year={2007}, month={Jan}, pages={19–29} }
 @article{teeguarden_dorman_covington_clewell_andersen_2007, title={Pharmacokinetic Modeling of Manganese. I. Dose Dependencies of Uptake and Elimination}, volume={70}, ISSN={1528-7394 1087-2620}, url={http://dx.doi.org/10.1080/15287390701384601}, DOI={10.1080/15287390701384601}, abstractNote={Homeostatic mechanisms controlling uptake, storage, and elimination of dietary manganese (Mn) afford protection against fluctuations in tissue manganese (Mn) levels. Homeostatic control of inhaled Mn is less well understood, but important in assessing likely risks of Mn inhalation. Two compartmental kinetic models were used to characterize the influence of Mn exposure level and route (oral, inhalation) on uptake, elimination, and transport of Mn. The models were fitted to or used to interpret data from five whole-body Mn elimination studies: one dietary Mn balance study, two biliary elimination studies, and one acute and one chronic. As dietary Mn concentrations increased from low sufficiency (1.5 ppm) to sufficiency (20 ppm), control of Mn uptake shifts from the intestine (principally) to more proportional control by both intestinal tissues and liver. Using a two-compartment distribution model, the increased elimination of 54Mn tracer doses in response to increases in dietary Mn (rats and mice) or inhaled Mn (rats) resulted from elevation in Mn elimination rate constants rather than changes in intercompartmental transfer rate constants between a central compartment and deep compartment. The pharmacokinetic (PK) analysis also indicated differential control of absorption in single gavage oral dose studies versus continuous high oral doses in the feed. The gavage study indicated increased elimination rate constants, and the chronic study showed reduced rate constants for absorption. These dose dependencies in uptake and elimination are necessary inputs for comprehensive PK models guiding human health risk assessments with Mn.}, number={18}, journal={Journal of Toxicology and Environmental Health, Part A}, publisher={Informa UK Limited}, author={Teeguarden, Justin G. and Dorman, David C. and Covington, Tammie R. and Clewell, Harvey J., III and Andersen, Melvin E.}, year={2007}, month={Aug}, pages={1493–1504} }
 @article{teeguarden_dorman_nong_covington_clewell_andersen_2007, title={Pharmacokinetic Modeling of Manganese. II. Hepatic Processing After Ingestion and Inhalation}, volume={70}, ISSN={1528-7394 1087-2620}, url={http://dx.doi.org/10.1080/15287390701384619}, DOI={10.1080/15287390701384619}, abstractNote={Current concerns regarding inhalation exposure to Mn, a component from oxidation of the gasoline antiknock agent MMT, have stimulated interest in developing kinetic tools for describing the inhalation and combined inhalation/oral route kinetics of Mn. Kinetic approaches were integrated kinetic for (1) bulk tissue Mn kinetics and (2) hepato-intestinal control of oral-route Mn uptake into a integrated model structure connecting systemic and oral Mn. Linkages were developed between the hepato-intestinal and systemic tissues in order to evaluate differences in hepatic processing of orally absorbed Mn and systemic Mn. The integrated, unified model described the uptake, net absorption, and elimination of ingested Mn and the elimination kinetics of iv administered (systemic) Mn by treating Mn arriving at the liver from systemic versus portal blood differently. Hepatic extraction of orally absorbed Mn in rats predicted through simulation of the oral uptake data was 19, 54, and 78% at dietary exposures of 1.5, 11.2, and 100 ppm, respectively. In contrast, hepatic extraction of systemic Mn predicted through simulation of elimination kinetics iv tracer Mn was much less, 0.004, 0.005, or 0.009% at dietary levels of 2, 10, and 100 ppm, respectively. These differences in hepatic processing of blood Mn derived from different dose routes need to be accounted for in more complete PK models for Mn that are intended to support human health risk assessments.}, number={18}, journal={Journal of Toxicology and Environmental Health, Part A}, publisher={Informa UK Limited}, author={Teeguarden, Justin G. and Dorman, David C. and Nong, Andy and Covington, Tammie R. and Clewell, Harvey J., III and Andersen, Melvin E.}, year={2007}, month={Aug}, pages={1505–1514} }
 @article{struve_turner_dorman_2007, title={Preliminary investigation of changes in the sexually dimorphic nucleus of the rat medial preoptic area following prenatal exposure to fenitrothion}, volume={27}, ISSN={0260-437X 1099-1263}, url={http://dx.doi.org/10.1002/jat.1267}, DOI={10.1002/jat.1267}, abstractNote={Abstract}, number={6}, journal={Journal of Applied Toxicology}, publisher={Wiley}, author={Struve, Melanie F. and Turner, Katie J. and Dorman, David C.}, year={2007}, pages={631–636} }
 @article{dorman_struve_clewell_andersen_2006, title={Application of pharmacokinetic data to the risk assessment of inhaled manganese}, volume={27}, ISSN={0161-813X}, url={http://dx.doi.org/10.1016/j.neuro.2006.03.003}, DOI={10.1016/j.neuro.2006.03.003}, abstractNote={There is increased interest within the scientific community concerning the neurotoxicity of manganese owing in part to the use of methylcyclopentadienyl manganese tricarbonyl (MMT) as a gasoline fuel additive and an enhanced awareness that this essential metal may play a role in hepatic encephalopathy and other neurologic diseases. Neurotoxicity generally arises over a prolonged period of time and results when manganese intake exceeds its elimination leading to increases in brain manganese concentration. Neurotoxicity can occur following high dose oral, inhalation, or parenteral exposure or when hepatobiliary clearance of this metal is impaired. Studies completed during the past several years have substantially improved our understanding of the health risks posed by inhaled manganese by determining exposure conditions that lead to increased concentrations of manganese within the central nervous system and other target organs. Many of these studies focused on phosphates, sulfates, and oxides of manganese since these are formed and emitted following MMT combustion by an automobile. These studies have evaluated the role of direct nose-to-brain transport of inhaled manganese and have examined differences in manganese toxicokinetics in potentially sensitive subpopulations (e.g., fetuses, neonates, individuals with compromised hepatic function or sub-optimal manganese intake, and the aged). This manuscript reviews the U.S. Environmental Protection Agency's current risk assessment for inhaled manganese, summarizes these contemporary pharmacokinetic studies, and considers how these data could inform future risk assessments of this metal following inhalation.}, number={5}, journal={NeuroToxicology}, publisher={Elsevier BV}, author={Dorman, David C. and Struve, Melanie F. and Clewell, Harvey J., III and Andersen, Melvin E.}, year={2006}, month={Sep}, pages={752–764} }
 @article{roberts_wong_mcmanus_marshall_lancianese_dorman_2006, title={Changes in Intracellular pH Play a Secondary Role in Hydrogen Sulfide-Induced Nasal Cytotoxicity}, volume={18}, ISSN={0895-8378 1091-7691}, url={http://dx.doi.org/10.1080/08958370500434156}, DOI={10.1080/08958370500434156}, abstractNote={Hydrogen sulfide (H2S) is a naturally occurring gas that is also associated with several industries. The potential for widespread human inhalation exposure to this toxic gas is recognized as a public health concern. The nasal epithelium is particularly susceptible to H2S-induced pathology. Cytochrome oxidase inhibition is postulated as one mechanism of H2S toxicity. Another mechanism by which the weak acid H2S could cause nasal injury is intracellular acidification and cytotoxicity. To further understand the mechanism by which H2S damages the nasal epithelium, nasal respiratory and olfactory epithelial cell isolates and explants from naive rats were loaded with the pH-sensitive intracellular chromophore SNARF-1 and exposed to air or 10, 80, 200, or 400 ppm H2S for 90 min. Intracellular pH was measured using flow cytometry or confocal microscopy. Cell lysates were used to quantify total protein and cytochrome oxidase activity. A modest but statistically significant decrease in intracellular pH occurred following exposure of respiratory and olfactory epithelium to 400 ppm H2S. Decreased cytochrome oxidase activity was observed following exposure to >10 ppm H2S in both respiratory and olfactory epithelia. None of the treatments resulted in cytotoxicity. The intracellular acidification of nasal epithelial cells by high-dose H2S exposure and the inhibition of cytochrome oxidase at much lower H2S concentrations suggest that changes in intracellular pH play a secondary role in H2S-induced nasal injury.}, number={3}, journal={Inhalation Toxicology}, publisher={Informa UK Limited}, author={Roberts, E. S. and Wong, V. A. and McManus, B. E. and Marshall, M. W. and Lancianese, S. and Dorman, D. C.}, year={2006}, month={Jan}, pages={159–167} }
 @article{taylor_erikson_dobson_fitsanakis_dorman_aschner_2006, title={Effects of inhaled manganese on biomarkers of oxidative stress in the rat brain}, volume={27}, ISSN={0161-813X}, url={http://dx.doi.org/10.1016/j.neuro.2006.05.006}, DOI={10.1016/j.neuro.2006.05.006}, abstractNote={Manganese (Mn) is a ubiquitous and essential element that can be toxic at high doses. In individuals exposed to high levels of this metal, Mn can accumulate in various brain regions, leading to neurotoxicity. In particular, Mn accumulation in the mid-brain structures, such as the globus pallidus and striatum, can lead to a Parkinson's-like movement disorder known as manganism. While the mechanism of this toxicity is currently unknown, it has been postulated that Mn may be involved in the generation of reactive oxygen species (ROS) through interaction with intracellular molecules, such as superoxide and hydrogen peroxide, produced within mitochondria. Conversely, Mn is a required component of an important antioxidant enzyme, Mn superoxide dismutase (MnSOD), while glutamine synthetase (GS), a Mn-containing astrocyte-specific enzyme, is exquisitely sensitive to oxidative stress. To investigate the possible role of oxidative stress in Mn-induced neurotoxicity, a series of inhalation studies was performed in neonatal and adult male and female rats as well as senescent male rats exposed to various levels of airborne-Mn for periods of time ranging from 14 to 90 days. Oxidative stress was then indirectly assessed by measuring glutathione (GSH), metallothionein (MT), and GS levels in several brain regions. MT and GS mRNA levels and regional brain Mn concentrations were also determined. The collective results of these studies argue against extensive involvement of ROS in Mn neurotoxicity in rats of differing genders and ages. There are, however, instances of changes in individual endpoints consistent with oxidative stress in certain brain tissues.}, number={5}, journal={NeuroToxicology}, publisher={Elsevier BV}, author={Taylor, Michael D. and Erikson, Keith M. and Dobson, Allison W. and Fitsanakis, Vanessa A. and Dorman, David C. and Aschner, Michael}, year={2006}, month={Sep}, pages={788–797} }
 @article{roberts_bonner_everitt_dorman_2006, title={Lethargy and hind limb paralysis in a day-23 timed pregnant rat}, volume={35}, ISSN={0093-7355 1548-4475}, url={http://dx.doi.org/10.1038/laban0206-19}, DOI={10.1038/laban0206-19}, number={2}, journal={Lab Animal}, publisher={Springer Science and Business Media LLC}, author={Roberts, Elizabeth S., DVM, PhD and Bonner, Anna M., BA and Everitt, Jeffrey I., DVM and Dorman, David C., DVM, PhD}, year={2006}, month={Feb}, pages={19–19} }
 @article{kimbell_schroeter_dorman_andersen_2006, title={Life beyond the air phase: adding tissue disposition to models of nasal airway transport}, volume={39}, ISSN={0021-9290}, url={http://dx.doi.org/10.1016/S0021-9290(06)84040-6}, DOI={10.1016/S0021-9290(06)84040-6}, journal={Journal of Biomechanics}, publisher={Elsevier BV}, author={Kimbell, J.S. and Schroeter, J.D. and Dorman, D.C. and Andersen, M.E.}, year={2006}, month={Jan}, pages={S270–S271} }
 @article{dorman_wong_2006, title={Neurotoxicity of inhaled manganese: A reanalysis of human exposure arising from showering}, volume={66}, ISSN={0306-9877}, url={http://dx.doi.org/10.1016/j.mehy.2005.08.001}, DOI={10.1016/j.mehy.2005.08.001}, number={1}, journal={Medical Hypotheses}, publisher={Elsevier BV}, author={Dorman, David C. and Wong, Brian A.}, year={2006}, month={Jan}, pages={199–200} }
 @article{leavens_parkinson_james_house_elswick_dorman_2006, title={Respiration in Sprague-Dawley Rats During Pregnancy}, volume={18}, ISSN={0895-8378 1091-7691}, url={http://dx.doi.org/10.1080/08958370500444361}, DOI={10.1080/08958370500444361}, abstractNote={Minute ventilation and tidal volume increase in humans during pregnancy. Little data exists, however, on the respiration in pregnant rats, despite their widespread use as an animal model. Since respiration will affect the pharmacokinetics of volatile compounds and ultimately the dose to the fetus, we conducted a study to evaluate respiration in rats during pregnancy. Whole-body plethysmography was used to measure the breathing frequency and tidal volume approximately every other day from gestation day (GD) 1 to 21 in 16 timed pregnant and 16 nonpregnant, female, Sprague-Dawley rats. Minute ventilation was calculated as a product of the breathing frequency and tidal volume, and the body weight of each rat was used to determine the scaled ventilation. Multivariate analysis of variance methods for a repeated-measures design were used to analyze the respiratory data. Breathing frequency was not affected by pregnancy; however, tidal volume was somewhat greater in pregnant versus nonpregnant rats. The increase in tidal volume resulted in significantly increased minute ventilation in pregnant rats compared to nonpregnant rats during the latter period of gestation. Due to the increased body weight of the pregnant rats, the scaled ventilation at the end of gestation was significantly lower in pregnant rats compared to nonpregnant rats. This study provides important reference values that can be used in pharmacokinetic models during pregnancy.}, number={4}, journal={Inhalation Toxicology}, publisher={Informa UK Limited}, author={Leavens, Teresa L. and Parkinson, Carl U. and James, R. Arden and House, Dennis and Elswick, Barbara and Dorman, David C.}, year={2006}, month={Jan}, pages={305–312} }
 @article{yokel_lasley_dorman_2006, title={The Speciation of Metals in Mammals Influences Their Toxicokinetics and Toxicodynamics and Therefore Human Health Risk Assessment}, volume={9}, ISSN={1093-7404 1521-6950}, url={http://dx.doi.org/10.1080/15287390500196230}, DOI={10.1080/15287390500196230}, abstractNote={Chemical form (i.e., species) can influence metal toxicokinetics and toxicodynamics and should be considered to improve human health risk assessment. Factors that influence metal speciation (and examples) include: (1) carrier-mediated processes for specific metal species (arsenic, chromium, lead and manganese), (2) valence state (arsenic, chromium, manganese and mercury), (3) particle size (lead and manganese), (4) the nature of metal binding ligands (aluminum, arsenic, chromium, lead, and manganese), (5) whether the metal is an organic versus inorganic species (arsenic, lead, and mercury), and (6) biotransformation of metal species (aluminum, arsenic, chromium, lead, manganese and mercury). The influence of speciation on metal toxicokinetics and toxicodynamics in mammals, and therefore the adverse effects of metals, is reviewed to illustrate how the physicochemical characteristics of metals and their handling in the body (toxicokinetics) can influence toxicity (toxicodynamics). Generalizing from mercury, arsenic, lead, aluminum, chromium, and manganese, it is clear that metal speciation influences mammalian toxicity. Methods used in aquatic toxicology to predict the interaction among metal speciation, uptake, and toxicity are evaluated. A classification system is presented to show that the chemical nature of the metal can predict metal ion toxicokinetics and toxicodynamics. Essential metals, such as iron, are considered. These metals produce low oral toxicity under most exposure conditions but become toxic when biological processes that utilize or transport them are overwhelmed, or bypassed. Risk assessments for essential and nonessential metals should consider toxicokinetic and toxicodynamic factors in setting exposure standards. Because speciation can influence a metal's fate and toxicity, different exposure standards should be established for different metal species. Many examples are provided which consider metal essentiality and toxicity and that illustrate how consideration of metal speciation can improve the risk assessment process. More examples are available at a website established as a repository for summaries of the literature on how the speciation of metals affects their toxicokinetics. This article is based on a workshop entitled “Metal Speciation in Toxicology: Determination and Importance for Risk Assessment” presented at the 42nd Annual Meeting of the Society of Toxicology, March, 2003, Salt Lake City, UT.}, number={1}, journal={Journal of Toxicology and Environmental Health, Part B}, publisher={Informa UK Limited}, author={Yokel, Robert A. and Lasley, Stephen M. and Dorman, David C.}, year={2006}, month={Jan}, pages={63–85} }
 @article{aschner_erikson_dorman_2005, title={Manganese Dosimetry: Species Differences and Implications for Neurotoxicity}, volume={35}, ISSN={1040-8444 1547-6898}, url={http://dx.doi.org/10.1080/10408440590905920}, DOI={10.1080/10408440590905920}, abstractNote={Abstract Manganese (Mn) is an essential mineral that is found at low levels in food, water, and the air. Under certain high-dose exposure conditions, elevations in tissue manganese levels can occur. Excessive manganese accumulation can result in adverse neurological, reproductive, and respiratory effects in both laboratory animals and humans. In humans, manganese-induced neurotoxicity (manganism) is the overriding concern since affected individuals develop a motor dysfunction syndrome that is recognized as a form of parkinsonism. This review primarily focuses on the essentiality and toxicity of manganese and considers contemporary studies evaluating manganese dosimetry and its transport across the blood–brain barrier, and its distribution within the central nervous system (CNS). These studies have dramatically improved our understanding of the health risks posed by manganese by determining exposure conditions that lead to increased concentrations of this metal within the CNS and other target organs. Most individuals are exposed to manganese by the oral and inhalation routes of exposure; however, parenteral injection and other routes of exposure are important. Interactions between manganese and iron and other divalent elements occur and impact the toxicokinetics of manganese, especially following oral exposure. The oxidation state and solubility of manganese also influence the absorption, distribution, metabolism, and elimination of manganese. Manganese disposition is influenced by the route of exposure. Rodent inhalation studies have shown that manganese deposited within the nose can undergo direct transport to the brain along the olfactory nerve. Species differences in manganese toxicokinetics and response are recognized with nonhuman primates replicating CNS effects observed in humans while rodents do not. Potentially susceptible populations, such as fetuses, neonates, individuals with compromised hepatic function, individuals with suboptimal manganese or iron intake, and those with other medical states (e.g., pre-parkinsonian state, aging), may have altered manganese metabolism and could be at greater risk for manganese toxicity.}, number={1}, journal={Critical Reviews in Toxicology}, publisher={Informa UK Limited}, author={Aschner, Michael and Erikson, Keith M. and Dorman, David C.}, year={2005}, month={Jan}, pages={1–32} }
 @article{dorman_mcelveen_marshall_parkinson_arden james_struve_wong_2005, title={Maternal–fetal Distribution of Manganese in the Rat Following Inhalation Exposure to Manganese Sulfate}, volume={26}, ISSN={0161-813X}, url={http://dx.doi.org/10.1016/j.neuro.2004.08.004}, DOI={10.1016/j.neuro.2004.08.004}, abstractNote={Studies examining the pharmacokinetics of manganese during pregnancy have largely focused on the oral route of exposure and have shown that the amount of manganese that crosses the rodent placenta is low. However, limited information exists regarding the distribution of manganese in fetal tissues following inhalation. The objective of this study was to determine manganese body burden in CD rats and fetuses following inhalation of a MnSO4 aerosol during pregnancy. Animals were evaluated following pre-breeding (2 weeks), mating (up to 14 days) and gestational (from gestation day (GD) 0 though 20) exposure to air or MnSO4 (0.05, 0.5, or 1 mg Mn/m3) for 6 h/day, 7 days/week. The following maternal samples were collected for manganese analysis: whole blood, lung, pancreas, liver, brain, femur, and placenta. Fetal tissues were examined on GD 20 and included whole blood, lung, liver, brain, and skull cap. Maternal lung manganese concentrations were increased following exposure to MnSO4 at ≥0.05 mg Mn/m3. Maternal brain and placenta manganese concentrations were increased following exposure of pregnant rats to MnSO4 at ≥0.5 mg Mn/m3. Increased fetal liver manganese concentrations were observed following in utero exposure to MnSO4 at ≥0.5 mg Mn/m3. Manganese concentrations within all other fetal tissues were not different from air-exposed controls. The results of this study demonstrate that the placenta partially sequesters inhaled manganese, thereby limiting exposure to the fetus.}, number={4}, journal={NeuroToxicology}, publisher={Elsevier BV}, author={Dorman, David C. and McElveen, Anna M. and Marshall, Marianne W. and Parkinson, Carl U. and Arden James, R. and Struve, Melanie F. and Wong, Brian A.}, year={2005}, month={Aug}, pages={625–632} }
 @article{slikkerjr_andersen_bogdanffy_bus_cohen_conolly_david_doerrer_dorman_gaylor_2004, title={Dose-dependent transitions in mechanisms of toxicity}, volume={201}, ISSN={0041-008X}, url={http://dx.doi.org/10.1016/j.taap.2004.06.019}, DOI={10.1016/j.taap.2004.06.019}, abstractNote={Scientists and decision makers from all sectors agree that risk assessments should be based on the best available science. Several years ago, the Health and Environmental Sciences Institute (HESI), a global branch of the International Life Sciences Institute (ILSI), identified the need for better scientific understanding of dose-dependent transitions in mechanisms of toxicity as one avenue by which the best and latest science can be integrated into the decision making process. In July 2001, the HESI Project Committee on Dose-Dependent Transitions in Mechanisms of Toxicity established a group of academic, government, and industry scientists to engage in active technical discourse on the issue of dose-dependent transitions in mechanisms of toxicity. Over the next 18 months, case studies were examined. These case studies included acetaminophen, butadiene, ethylene glycol, formaldehyde, manganese, methylene chloride, the peroxisome proliferator-activated receptor, progesterone/hydroxyflutamide, propylene oxide, vinyl acetate, vinyl chloride, vinylidene chloride, and zinc (Slikker, W., Jr., Andersen, M.E., Bogdanffy, M.S., Bus, J.S., Cohen, S.D., Conolly, R.B., David, R.M., Doerrer, N.G., Dorman, D.C., Gaylor, D.W., Hattis, D., Rogers, J.M., Setzer, R.W., Swenberg, J.A., Wallace, K., 2004. Dose-dependent transitions in mechanisms of toxicity: case studies. Toxicol. Appl. Pharmacol. 201(3), 226–294 (this issue)). The HESI Project Committee sponsored two technical workshops in 2003. The first of these workshops took place on February 12–13, 2003, and was co-sponsored by the Agency for Toxic Substances and Disease Registry, the American Chemistry Council, the National Institute of Environmental Health Sciences, the Society of Toxicology, and the U.S. Environmental Protection Agency. Additional support was provided by Health Canada. Invited experts from government, academia, and industry provided scientific perspectives and recommendations at the workshop. The purpose of the workshop was to examine approaches to dose–response analysis, learn from the case study examples, and gather feedback from invited participants on the impact of dose-dependent transitions on the risk assessment process. The second forum consisted of a workshop in March 2003 at the Society of Toxicology Annual Meeting in Salt Lake City, UT. This paper addresses the issues discussed at both workshops, and presents the consensus conclusions drawn by expert participants.}, number={3}, journal={Toxicology and Applied Pharmacology}, publisher={Elsevier BV}, author={Slikkerjr, W and Andersen, M and Bogdanffy, M and Bus, J and Cohen, S and Conolly, R and David, R and Doerrer, N and Dorman, D and Gaylor, D}, year={2004}, month={Dec}, pages={203–225} }
 @article{slikkerjr_andersen_bogdanffy_bus_cohen_conolly_david_doerrer_dorman_gaylor_2004, title={Dose-dependent transitions in mechanisms of toxicity: case studies}, volume={201}, ISSN={0041-008X}, url={http://dx.doi.org/10.1016/j.taap.2004.06.027}, DOI={10.1016/j.taap.2004.06.027}, abstractNote={Experience with dose response and mechanisms of toxicity has shown that multiple mechanisms may exist for a single agent along the continuum of the full dose-response curve. It is highly likely that critical, limiting steps in any given mechanistic pathway may become overwhelmed with increasing exposures, signaling the emergence of new modalities of toxic tissue injury at these higher doses. Therefore, dose-dependent transitions in principal mechanisms of toxicity may occur, and could have significant impact on the interpretation of reference data sets for risk assessment. To illustrate the existence of dose-dependent transitions in mechanisms of toxicity, a group of academic, government, and industry scientists, formed under the leadership of the ILSI Health and Environmental Sciences Institute (HESI), developed a series of case studies. These case studies included acetaminophen, butadiene, ethylene glycol, formaldehyde, manganese, methylene chloride, peroxisome proliferator-activated receptor (PPAR), progesterone/hydroxyflutamide, propylene oxide, vinyl acetate, vinyl chloride, vinylidene chloride, and zinc. The case studies formed the basis for technical discourse at two scientific workshops in 2003.}, number={3}, journal={Toxicology and Applied Pharmacology}, publisher={Elsevier BV}, author={Slikkerjr, W and Andersen, M and Bogdanffy, M and Bus, J and Cohen, S and Conolly, R and David, R and Doerrer, N and Dorman, D and Gaylor, D}, year={2004}, month={Dec}, pages={226–294} }
 @article{pfeifer_roper_dorman_lynam_2004, title={Health and environmental testing of manganese exhaust products from use of methylcyclopentadienyl manganese tricarbonyl in gasoline}, volume={334-335}, ISSN={0048-9697}, url={http://dx.doi.org/10.1016/j.scitotenv.2004.04.043}, DOI={10.1016/j.scitotenv.2004.04.043}, abstractNote={This paper reviews recent research on the environmental effects of methylcyclopentadienyl manganese tricarbonyl (MMT), personal exposures to airborne Mn as a result of MMT use, chemical characterization of the manganese particulates emitted from the tailpipe and progress in developing a (PBPK) model for manganese in rodents. Recent studies show that manganese is emitted as a mixture of compounds with an average valence of about 2.2. The major products are sulfate, phosphate, and smaller amounts of oxides. Because only small amounts of Mn are used in gasoline (<18 mg Mn/gal) and less than 15% of the combusted Mn is emitted, soil along busy roads is not elevated in Mn, even after long-term use of MMT. A very large population-based study of manganese exposures in the general population in Toronto, where MMT has been used continuously for over 20 years, showed that manganese exposures were quite low, the median annual exposure was 0.008 μg Mn/m3. A great amount of toxicological research on Mn has been carried out during the past few years that provides data for use in developing a PBPK model in rodents. These data add greatly to the existing body of knowledge regarding the relationship between Mn exposure and tissue disposition. When complete, the PBPK model will contribute to our better understanding of the essential neurotoxic dynamics of Mn.}, journal={Science of The Total Environment}, publisher={Elsevier BV}, author={Pfeifer, G.D. and Roper, J.M. and Dorman, D. and Lynam, D.R.}, year={2004}, month={Dec}, pages={397–408} }
 @article{erikson_dobson_dorman_aschner_2004, title={Manganese exposure and induced oxidative stress in the rat brain}, volume={334-335}, ISSN={0048-9697}, url={http://dx.doi.org/10.1016/j.scitotenv.2004.04.044}, DOI={10.1016/j.scitotenv.2004.04.044}, abstractNote={Neurotoxicity linked to excessive brain manganese levels can occur as a result of high level Mn exposures and/or metabolic aberrations (liver disease and decreased biliary excretion). Increased brain manganese levels have been reported to induce oxidative stress, as well as alterations in neurotransmitter metabolism with concurrent neurobehavioral and motor deficits. Two putative mechanisms in which manganese can produce oxidative stress in the brain are: (1) via its oxidation of dopamine, and (2) interference with normal mitochondrial respiration. Measurements of antioxidant species (e.g., glutathione and metallothionein), and the abundance of proteins (enzymes) exquisitely sensitive to oxidation (e.g., glutamine synthetase) have been commonly used as biomarkers of oxidative stress, particularly in rat brain tissue. This paper examines the link between manganese neurotoxicity in the rat brain and common pathways to oxidative stress.}, journal={Science of The Total Environment}, publisher={Elsevier BV}, author={Erikson, Keith M. and Dobson, Allison W. and Dorman, David C. and Aschner, Michael}, year={2004}, month={Dec}, pages={409–416} }
 @article{dorman_mcmanus_parkinson_manuel_mcelveen_everitt_2004, title={Nasal Toxicity of Manganese Sulfate and Manganese Phosphate in Young Male Rats Following Subchronic (13-Week) Inhalation Exposure}, volume={16}, ISSN={0895-8378 1091-7691}, url={http://dx.doi.org/10.1080/08958370490439687}, DOI={10.1080/08958370490439687}, abstractNote={Growing evidence suggests that nasal deposition and transport along the olfactory nerve represents a route by which inhaled manganese and certain other metals are delivered to the rodent brain. The toxicological significance of olfactory transport of manganese remains poorly defined. In rats, repeated intranasal instillation of manganese chloride results in injury to the olfactory epithelium and neurotoxicity as evidenced by increased glial fibrillary acidic protein (GFAP) concentrations in olfactory bulb astrocytes. The purpose of the present study was to further characterize the nasal toxicity of manganese sulfate (MnSO4) and manganese phosphate (as hureaulite) in young adult male rats following subchronic (90-day) exposure to air, MnSO4 (0.01, 0.1, and 0.5 mg Mn/m3), or hureaulite (0.1 mg Mn/m3). Nasal pathology, brain GFAP levels, and brain manganese concentrations were assessed immediately following the end of the 90-day exposure and 45 days thereafter. Elevated end-of-exposure olfactory bulb, striatum, and cerebellum manganese concentrations were observed following MnSO4 exposure to ≥0.01, ≥0.1, and 0.5 mg Mn/m3, respectively. Exposure to MnSO4 or hureaulite did not affect olfactory bulb, cerebellar, or striatal GFAP concentrations. Exposure to MnSO4 (0.5 mg Mn/m3) was also associated with reversible inflammation within the nasal respiratory epithelium, while the olfactory epithelium was unaffected by manganese inhalation. These results confirm that high-dose manganese inhalation can result in nasal toxicity (irritation) and increased delivery of manganese to the brain; however, we could not confirm that manganese inhalation would result in altered brain GFAP concentrations.}, number={6-7}, journal={Inhalation Toxicology}, publisher={Informa UK Limited}, author={Dorman, David C. and McManus, Brian E. and Parkinson, Carl U. and Manuel, Chris A. and McElveen, Anna M. and Everitt, Jeffrey I.}, year={2004}, month={Jan}, pages={481–488} }
 @article{dorman_mcmanus_marshall_james_struve_2004, title={Old age and gender influence the pharmacokinetics of inhaled manganese sulfate and manganese phosphate in rats}, volume={197}, ISSN={0041-008X}, url={http://dx.doi.org/10.1016/j.taap.2004.02.010}, DOI={10.1016/j.taap.2004.02.010}, abstractNote={In this study, we examined whether gender or age influences the pharmacokinetics of manganese sulfate (MnSO(4)) or manganese phosphate (as the mineral form hureaulite). Young male and female rats and aged male rats (16 months old) were exposed 6 h day(-1) for 5 days week(-1) to air, MnSO(4) (at 0.01, 0.1, or 0.5 mg Mn m(-3)), or hureaulite (0.1 mg Mn m(-3)). Tissue manganese concentrations were determined in all groups at the end of the 90-day exposure and 45 days later. Tissue manganese concentrations were also determined in young male rats following 32 exposure days and 91 days after the 90-day exposure. Intravenous (54)Mn tracer studies were also performed in all groups immediately after the 90-day inhalation to assess whole-body manganese clearance rates. Gender and age did not affect manganese delivery to the striatum, a known target site for neurotoxicity in humans, but did influence manganese concentrations in other tissues. End-of-exposure olfactory bulb, lung, and blood manganese concentrations were higher in young male rats than in female or aged male rats and may reflect a portal-of-entry effect. Old male rats had higher testis but lower pancreas manganese concentrations when compared with young males. Young male and female rats exposed to MnSO(4) at 0.5 mg Mn m(-3) had increased (54)Mn clearance rates when compared with air-exposed controls, while senescent males did not develop higher (54)Mn clearance rates. Data from this study should prove useful in developing dosimetry models for manganese that consider age or gender as potential sensitivity factors.}, number={2}, journal={Toxicology and Applied Pharmacology}, publisher={Elsevier BV}, author={Dorman, David C and McManus, Brian E and Marshall, Marianne W and James, R.Arden and Struve, Melanie F}, year={2004}, month={Jun}, pages={113–124} }
 @article{dorman_mcmanus_marshall_james_struve_2004, title={Old age and gender influence the pharmacokinetics of inhaled manganese sulfate and manganese phosphate in rats}, volume={197}, ISSN={0041-008X}, url={http://dx.doi.org/10.1016/j.taap.2004.02.010}, DOI={10.1016/S0041-008X(04)00141-3}, abstractNote={In this study, we examined whether gender or age influences the pharmacokinetics of manganese sulfate (MnSO4) or manganese phosphate (as the mineral form hureaulite). Young male and female rats and aged male rats (16 months old) were exposed 6 h day−1 for 5 days week−1 to air, MnSO4 (at 0.01, 0.1, or 0.5 mg Mn m−3), or hureaulite (0.1 mg Mn m−3). Tissue manganese concentrations were determined in all groups at the end of the 90-day exposure and 45 days later. Tissue manganese concentrations were also determined in young male rats following 32 exposure days and 91 days after the 90-day exposure. Intravenous 54Mn tracer studies were also performed in all groups immediately after the 90-day inhalation to assess whole-body manganese clearance rates. Gender and age did not affect manganese delivery to the striatum, a known target site for neurotoxicity in humans, but did influence manganese concentrations in other tissues. End-of-exposure olfactory bulb, lung, and blood manganese concentrations were higher in young male rats than in female or aged male rats and may reflect a portal-of-entry effect. Old male rats had higher testis but lower pancreas manganese concentrations when compared with young males. Young male and female rats exposed to MnSO4 at 0.5 mg Mn m−3 had increased 54Mn clearance rates when compared with air-exposed controls, while senescent males did not develop higher 54Mn clearance rates. Data from this study should prove useful in developing dosimetry models for manganese that consider age or gender as potential sensitivity factors.}, number={2}, journal={Toxicology and Applied Pharmacology}, publisher={Elsevier BV}, author={Dorman, David C and McManus, Brian E and Marshall, Marianne W and James, R.Arden and Struve, Melanie F}, year={2004}, month={Jun}, pages={113–124} }
 @article{dorman_struve_gross_brenneman_2004, title={Respiratory tract toxicity of inhaled hydrogen sulfide in Fischer-344 rats, Sprague–Dawley rats, and B6C3F1 mice following subchronic (90-day) exposure}, volume={198}, ISSN={0041-008X}, url={http://dx.doi.org/10.1016/j.taap.2004.03.010}, DOI={10.1016/j.taap.2004.03.010}, abstractNote={The goal of this study was to characterize the toxicity of hydrogen sulfide (H2S), including nasal and pulmonary effects, in adult male and female Fischer-344 and Sprague-Dawley rats and B6C3F1 mice. Animals underwent whole-body exposure to 0, 10, 30, or 80 ppm H2S for 6 h/day for at least 90 days. Exposure to 80 ppm H2S was associated with reduced feed consumption during either the first exposure week (rats) or throughout the 90-day exposure (mice). Male Fischer-344 rats, female Sprague-Dawley rats, and female B6C3F1 mice exposed to 80 ppm H2S had depressed terminal body weights when compared with air-exposed controls. Subchronic H2S inhalation did not result in toxicologically relevant alterations in hematological indices, serum chemistries, or gross pathology. Histologic evaluation of the nose showed an exposure-related increased incidence of olfactory neuronal loss (ONL) and rhinitis. ONL occurred following exposure to > or =30 ppm H2S in both sexes of all experimental groups, with one exception, male Sprague-Dawley rats demonstrated ONL following exposure to 80 ppm H2S only. A 100% incidence of rhinitis was found in the male and female B6C3F1 mice exposed to 80 ppm H2S. In the lung, exposure to H2S was associated with bronchiolar epithelial hypertrophy and hyperplasia in male and female Sprague-Dawley rats following exposure to > or =30 ppm H2S and in male Fischer-344 rats exposed to 80 ppm H2S. Our results confirm that the rodent nose, and less so the lung, are highly sensitive to H2S-induced toxicity, with 10 ppm representing the NOAEL for ONL following subchronic inhalation.}, number={1}, journal={Toxicology and Applied Pharmacology}, publisher={Elsevier BV}, author={Dorman, David C and Struve, Melanie F and Gross, Elizabeth A and Brenneman, Karrie A}, year={2004}, month={Jul}, pages={29–39} }
 @article{dorman_brenneman_mcelveen_lynch_roberts_wong_2002, title={OLFACTORY TRANSPORT: A DIRECT ROUTE OF DELIVERY OF INHALED MANGANESE PHOSPHATE TO THE RAT BRAIN}, volume={65}, ISSN={1528-7394 1087-2620}, url={http://dx.doi.org/10.1080/00984100290071630}, DOI={10.1080/00984100290071630}, abstractNote={Experiments examining the dosimetry of inhaled manganese generally focus on pulmonary deposition and subsequent delivery of manganese in arterial blood to the brain. Growing evidence suggests that nasal deposition and transport along olfactory neurons represents another route by which inhaled manganese is delivered to certain regions of the rat brain. The purpose of this study was to evaluate the olfactory uptake and direct brain delivery of inhaled manganese phosphate ( 54 MnHPO 4 ). Male, 8-wk-old, CD rats with either both nostrils patent or the right nostril occluded underwent a single, 90-min, nose-only exposure to a 54 MnHPO 4 aerosol (0.39 mg 54 Mn/m 3 ; MMAD 1.68 w m, σ g 1.42). The left and right sides of the nose, olfactory pathway, striatum, cerebellum, and rest of the brain were evaluated immediately after the end of the 54 MnHPO 4 exposure and at 1, 2, 4, 8, and 21 d postexposure with gamma spectrometry and autoradiography. Rats with two patent nostrils had equivalent 54 Mn concentrations on both sides of the nose, olfactory bulb, and striatum, while asymmetrical 54 Mn delivery occurred in rats with one occluded nostril. High levels of 54 Mn activity were observed in the olfactory bulb and tubercle on the same side (i.e., ipsilateral) to the open nostril within 1-2 d following 54 MnHPO 4 exposure, while brain and nose samples on the side ipsilateral to the nostril occlusion had negligible levels of 54 Mn activity. Our results demonstrate that the olfactory route contributes to 54 Mn delivery to the rat olfactory bulb and tubercle. However, this pathway does not significantly contribute to striatal 54 Mn concentrations following a single, short-term inhalation exposure to 54 MnHPO 4 .}, number={20}, journal={Journal of Toxicology and Environmental Health, Part A}, publisher={Informa UK Limited}, author={Dorman, David C. and Brenneman, Karrie A. and McElveen, Anna M. and Lynch, Sean E. and Roberts, Kay C. and Wong, Brian A.}, year={2002}, month={Oct}, pages={1493–1511} }