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1.  Surface Characteristics and Bioactivity of a Novel Natural HA/Zircon Nanocomposite Coated on Dental Implants 
BioMed Research International  2014;2014:410627.
The surface characteristics of implant which influence the speed and strength of osseointegration include surface chemistry, crystal structure and crystallinity, roughness, strain hardening, and presence of impurities. The aim of this study was to evaluate the bioactivity and roughness of a novel natural hydroxyapatite/zircon (NHA/zircon) nanobiocomposite, coated on 316L stainless steel (SS) soaked in simulated body fluid (SBF). NHA/zircon nanobiocomposite was fabricated with 0 wt.%, 5 wt.%, 10 wt.%, and 15 wt.% of zircon in NHA using ball mill for 20 minutes. The composite mixture was coated on 316L SS using plasma spray method. The results are estimated using the scanning electron microscopy (SEM) observation to evaluate surface morphology, X-ray diffraction (XRD) to analyze phase composition, and transmission electron microscopy (TEM) technique to evaluate the shape and size of prepared NHA. Surfaces roughness tester was performed to characterize the coated nanocomposite samples. The maximum average Ra (14.54 μm) was found in the NHA 10 wt.% of zircon coating. In addition, crystallinity (Xc) was measured by XRD data, which indicated the minimum value (Xc = 41.1%) for the sample containing 10 wt.% of zircon. Maximum bioactivity occurred in the sample containing 10 wt.% of zircon, which was due to two reasons: first, the maximum roughness and, second, the minimum crystallinity of nanobiocomposite coating.
PMCID: PMC4009196  PMID: 24822204
2.  Diversity in early crustal evolution: 4100 Ma zircons in the Cathaysia Block of southern China 
Scientific Reports  2014;4:5143.
Zircons are crucial to understanding the first 500 Myr of crustal evolution of Earth. Very few zircons of this age (>4050 Ma) have been found other than from a ~300 km diameter domain of the Yilgarn Craton, Western Australia. Here we report SIMS U-Pb and O isotope ratios and trace element analyses for two ~4100 Ma detrital zircons from a Paleozoic quartzite at the Longquan area of the Cathaysia Block. One zircon (207Pb/206Pb age of 4127 ± 4 Ma) shows normal oscillatory zonation and constant oxygen isotope ratios (δ18O = 5.8 to 6.0‰). The other zircon grain has a ~4100 Ma magmatic core surrounded by a ~4070 Ma metamorphic mantle. The magmatic core has elevated δ18O (7.2 ± 0.2‰), high titanium concentration (53 ± 3.4 ppm) and a positive cerium anomaly, yielding anomalously high calculated oxygen fugacity (FMQ + 5) and a high crystallization temperature (910°C). These results are unique among Hadean zircons and suggest a granitoid source generated from dry remelting of partly oxidizing supracrustal sediments altered by surface waters. The ~4100 Ma dry melting and subsequent ~4070 Ma metamorphism provide new evidence for the diversity of the Earth's earliest crust.
PMCID: PMC4042129  PMID: 24888297
3.  Enhanced diffusion of Uranium and Thorium linked to crystal plasticity in zircon 
The effects of crystal-plasticity on the U-Th-Pb system in zircon is studied by quantitative microstructural and microchemical analysis of a large zircon grain collected from pyroxenite of the Lewisian Complex, Scotland. Electron backscatter diffraction (EBSD) mapping reveals a c.18° variation in crystallographic orientation that comprises both a gradual change in orientation and a series of discrete low-angle (<4°) boundaries. These microstructural data are consistent with crystal-plastic deformation of zircon associated with the formation and migration of dislocations. A heterogeneous pattern of dark cathodoluminescence, with the darkest domains coinciding with low-angle boundaries, mimics the deformation microstructure identified by EBSD. Geochemical data collected using the Sensitive High Resolution Ion MicroProbe (SHRIMP) shows a positive correlation between concentrations of the elements U, Th and Pb (ranging from 20–60 ppm, 30–110 ppm, and 14–36 ppm, respectively) and Th/U ratio (1.13 – 1.8) with the deformation microstructure. The highest measured concentrations and Th/U coincide with low-angle boundaries. This enrichment is interpreted to reflect enhanced bulk diffusion of U and Th due to the formation and migration of high-diffusivity dislocations. 207Pb/206Pb ages for individual analyses show no significant variation across the grain, and define a concordant, combined mean age of 2451 ± 14 Ma. This indicates that the grain was deformed shortly after initial crystallization, most probably during retrograde Inverian metamorphism at amphibolite facies conditions. The elevated Th over U and consistent 207Pb/206Pb ages indicates that deformation most likely occurred in the presence of a late-stage magmatic fluid that drove an increase in the Th/U during deformation. The relative enrichment of Th over U implies that Th/U ratio may not always be a robust indicator of crystallization environment. This study provides the first evidence of deformation-related modification of the U-Th system in zircon and has fundamental implications for the application and interpretation of zircon trace element data.
PMCID: PMC1769485  PMID: 17181855
4.  An Open System for Intravascular Ultrasound Imaging 
Visualization of the blood vessels can provide valuable morphological information for diagnosis and therapy strategies for cardiovascular disease. Intravascular ultrasound (IVUS) is able to delineate internal structures of vessel wall with fine spatial resolution. However, the developed IVUS is insufficient to identify the fibrous cap thickness and tissue composition of atherosclerotic lesions. Novel imaging strategies have been proposed, such as increasing the center frequency of ultrasound or using a modulated excitation technique to improve the accuracy of diagnosis. Dual-mode tomography combining IVUS with optical tomography has also been developed to determine tissue morphology and characteristics. The implementation of these new imaging methods requires an open system that allows users to customize the system for various studies. This paper presents the development of an IVUS system that has open structures to support various imaging strategies. The system design is based on electronic components and printed circuit board, and provides reconfigurable hardware implementation, programmable image processing algorithms, flexible imaging control, and raw RF data acquisition. In addition, the proposed IVUS system utilized a miniaturized ultrasound transducer constructed using PMN-PT single crystal for better piezoelectric constant and electromechanical coupling coefficient than traditional lead zirconate titanate (PZT) ceramics. Testing results showed that the IVUS system could offer a minimum detectable signal of 25 μV, allowing a 51 dB dynamic range at 47 dB gain, with a frequency range from 20 to 80 MHz. Finally, phantom imaging, in vitro IVUS vessel imaging, and multimodality imaging with photoacoustics were conducted to demonstrate the performance of the open system.
PMCID: PMC3760234  PMID: 23143570
5.  Targeted vertical cross-sectional imaging with handheld near-infrared dual axes confocal fluorescence endomicroscope 
Biomedical Optics Express  2013;4(2):322-330.
We demonstrate vertical cross-sectional (XZ-plane) images of near-infrared (NIR) fluorescence with a handheld dual axes confocal endomicroscope that reveals specific binding of a Cy5.5-labeled peptide to pre-malignant colonic mucosa. This view is perpendicular to the tissue surface, and is similar to that used by pathologists. The scan head is 10 mm in outer diameter (OD), and integrates a one dimensional (1-D) microelectromechanical systems (MEMS) X-axis scanner and a bulky lead zirconate titanate (PZT) based Z-axis actuator. The microscope images in a raster-scanning pattern with a ±6 degrees (mechanical) scan angle at ~3 kHz in the X-axis (fast) and up to 10 Hz (0–400 μm) in the Z-axis (slow). Vertical cross-sectional fluorescence images are collected with a transverse and axial resolution of 4 and 5 μm, respectively, over a field-of-view of 800 μm (width) × 400 μm (depth). NIR vertical cross-sectional fluorescence images of fresh mouse colonic mucosa demonstrate histology-like imaging performance with this miniature instrument.
PMCID: PMC3567718  PMID: 23412564
(170.1790) Confocal microscopy; (170.3880) Medical and biological imaging; (170.4580) Optical diagnostics for medicine; (170.5810) Scanning microscopy
6.  Fabrication and Performance of Endoscopic Ultrasound Radial Arrays Based on PMN-PT Single Crystal/Epoxy 1-3 Composite 
In this paper, 0.7Pb(Mg1/3Nb2/3)O3-0.3PbTiO3 (PMN-PT) single crystal/epoxy 1–3 composite was used as the active material of the endoscopic ultrasonic radial array transducer, because this composite exhibited ultrahigh electromechanical coupling coefficient (kt = 0.81%), very low mechanical quality factor (Qm = 11) and relatively low acoustic impedance (Zt = 12 MRayls). A 6.91 MHz PMN-PT/epoxy 1–3 composite radial array transducer with 64 elements was tested in a pulse-echo response measurement. The −6-dB bandwidth of the composite array transducer was 102%, which was ~30% larger than that of traditional lead zirconate titanate array transducer. The two-way insertion loss was found to be −32.3 dB. The obtained results show that this broadband array transducer is promising for acquiring high-resolution endoscopic ultrasonic images in many clinical applications.
PMCID: PMC3056406  PMID: 21342833
7.  Ferroelectric translational antiphase boundaries in nonpolar materials 
Nature Communications  2014;5:3031.
Ferroelectric materials are heavily used in electro-mechanics and electronics. Inside the ferroelectric, domain walls separate regions in which the spontaneous polarization is differently oriented. Properties of ferroelectric domain walls can differ from those of the domains themselves, leading to new exploitable phenomena. Even more exciting is that a non-ferroelectric material may have domain boundaries that are ferroelectric. Many materials possess translational antiphase boundaries. Such boundaries could be interesting entities to carry information if they were ferroelectric. Here we show first that antiphase boundaries in antiferroelectrics may possess ferroelectricity. We then identify these boundaries in the classical antiferroelectric lead zirconate and evidence their polarity by electron microscopy using negative spherical-aberration imaging technique. Ab initio modelling confirms the polar bi-stable nature of the walls. Ferroelectric antiphase boundaries could make high-density non-volatile memory; in comparison with the magnetic domain wall memory, they do not require current for operation and are an order of magnitude thinner.
In ferroelectrics, the domain walls can have different properties than the domains themselves. Here, Wei et al. show that certain domain walls in antiferroelectric materials are ferroelectric, which makes them interesting candidates for new non-volatile memory concepts.
PMCID: PMC3941019  PMID: 24398704
8.  Identifying the Volcanic Eruption Depicted in a Neolithic Painting at Çatalhöyük, Central Anatolia, Turkey 
PLoS ONE  2014;9(1):e84711.
A mural excavated at the Neolithic Çatalhöyük site (Central Anatolia, Turkey) has been interpreted as the oldest known map. Dating to ∼6600 BCE, it putatively depicts an explosive summit eruption of the Hasan Dağı twin-peaks volcano located ∼130 km northeast of Çatalhöyük, and a birds-eye view of a town plan in the foreground. This interpretation, however, has remained controversial not least because independent evidence for a contemporaneous explosive volcanic eruption of Hasan Dağı has been lacking. Here, we document the presence of andesitic pumice veneer on the summit of Hasan Dağı, which we dated using (U-Th)/He zircon geochronology. The (U-Th)/He zircon eruption age of 8.97±0.64 ka (or 6960±640 BCE; uncertainties 2σ) overlaps closely with 14C ages for cultural strata at Çatalhöyük, including level VII containing the “map” mural. A second pumice sample from a surficial deposit near the base of Hasan Dağı records an older explosive eruption at 28.9±1.5 ka. U-Th zircon crystallization ages in both samples range from near-eruption to secular equilibrium (>380 ka). Collectively, our results reveal protracted intrusive activity at Hasan Dağı punctuated by explosive venting, and provide the first radiometric ages for a Holocene explosive eruption which was most likely witnessed by humans in the area. Geologic and geochronologic lines of evidence thus support previous interpretations that residents of Çatalhöyük artistically represented an explosive eruption of Hasan Dağı volcano. The magmatic longevity recorded by quasi-continuous zircon crystallization coupled with new evidence for late-Pleistocene and Holocene explosive eruptions implicates Hasan Dağı as a potential volcanic hazard.
PMCID: PMC3885600  PMID: 24416270
9.  Isotopic evidence for continental ice sheet in mid-latitude region in the supergreenhouse Early Cretaceous 
Scientific Reports  2013;3:2732.
Cretaceous represents one of the hottest greenhouse periods in the Earth's history, but some recent studies suggest that small ice caps might be present in non-polar regions during certain periods in the Early Cretaceous. Here we report extremely negative δ18O values of −18.12‰ to −13.19‰ for early Aptian hydrothermal zircon from an A-type granite at Baerzhe in northeastern China. Given that A-type granite is anhydrous and that magmatic zircon of the Baerzhe granite has δ18O value close to mantle values, the extremely negative δ18O values for hydrothermal zircon are attributed to addition of meteoric water with extremely low δ18O, mostly likely transported by glaciers. Considering the paleoaltitude of the region, continental glaciation is suggested to occur in the early Aptian, indicating much larger temperature fluctuations than previously thought during the supergreenhouse Cretaceous. This may have impact on the evolution of major organism in the Jehol Group during this period.
PMCID: PMC3781392  PMID: 24061068
10.  Single crystal U–Pb zircon age and Sr–Nd isotopic composition of impactites from the Bosumtwi impact structure, Ghana: Comparison with country rocks and Ivory Coast tektites 
Chemical Geology  2010;275(3-4):254-261.
The 1.07 Myr old Bosumtwi impact structure (Ghana), excavated in 2.1–2.2 Gyr old supracrustal rocks of the Birimian Supergroup, was drilled in 2004. Here, we present single crystal U–Pb zircon ages from a suevite and two meta-graywacke samples recovered from the central uplift (drill core LB-08A), which yield an upper Concordia intercept age of ca. 2145 ± 82 Ma, in very good agreement with previous geochronological data for the West African Craton rocks in Ghana. Whole rock Rb–Sr and Sm–Nd isotope data of six suevites (five from inside the crater and one from outside the northern crater rim), three meta-graywacke, and two phyllite samples from core LB-08A are also presented, providing further insights into the timing of the metamorphism and a possibly related isotopic redistribution of the Bosumtwi crater rocks. Our Rb–Sr and Sm–Nd data show also that the suevites are mixtures of meta-greywacke and phyllite (and possibly a very low amount of granite). A comparison of our new isotopic data with literature data for the Ivory Coast tektites allows to better constrain the parent material of the Ivory Coast tektites (i.e., distal impactites), which is thought to consist of a mixture of metasedimentary rocks (and possibly granite), but with a higher proportion of phyllite (and shale) than the suevites (i.e., proximal impactites). When plotted in a Rb/Sr isochron diagram, the sample data points (n = 29, including literature data) scatter along a regression line, whose slope corresponds to an age of 1846 ± 160 Ma, with an initial Sr isotope ratio of 0.703 ± 0.002. However, due to the extensive alteration of some of the investigated samples and the lithological diversity of the source material, this age, which is in close agreement with a possible “metamorphic age” of ∼ 1.8–1.9 Ga tentatively derived from our U–Pb dating of zircons, is difficult to consider as a reliable metamorphic age. It may perhaps reflect a common ancient source whose Rb–Sr isotope systematics has not basically been reset on the whole rock scale during the Bosumtwi impact event, or even reflect another unknown geologic event.
PMCID: PMC2949568  PMID: 21037794
Impactite; U–Pb zircon; Sr–Nd isotopes; Bosumtwi crater; Ghana
11.  Timescales of Quartz Crystallization and the Longevity of the Bishop Giant Magma Body 
PLoS ONE  2012;7(5):e37492.
Supereruptions violently transfer huge amounts (100 s–1000 s km3) of magma to the surface in a matter of days and testify to the existence of giant pools of magma at depth. The longevity of these giant magma bodies is of significant scientific and societal interest. Radiometric data on whole rocks, glasses, feldspar and zircon crystals have been used to suggest that the Bishop Tuff giant magma body, which erupted ∼760,000 years ago and created the Long Valley caldera (California), was long-lived (>100,000 years) and evolved rather slowly. In this work, we present four lines of evidence to constrain the timescales of crystallization of the Bishop magma body: (1) quartz residence times based on diffusional relaxation of Ti profiles, (2) quartz residence times based on the kinetics of faceting of melt inclusions, (3) quartz and feldspar crystallization times derived using quartz+feldspar crystal size distributions, and (4) timescales of cooling and crystallization based on thermodynamic and heat flow modeling. All of our estimates suggest quartz crystallization on timescales of <10,000 years, more typically within 500–3,000 years before eruption. We conclude that large-volume, crystal-poor magma bodies are ephemeral features that, once established, evolve on millennial timescales. We also suggest that zircon crystals, rather than recording the timescales of crystallization of a large pool of crystal-poor magma, record the extended periods of time necessary for maturation of the crust and establishment of these giant magma bodies.
PMCID: PMC3364253  PMID: 22666359
12.  In-Situ U–Pb Dating of Apatite by Hiroshima-SHRIMP: Contributions to Earth and Planetary Science 
Mass Spectrometry  2012;1(2):A0011.
The Sensitive High Resolution Ion MicroProbe (SHRIMP) is the first ion microprobe dedicated to geological isotopic analyses, especially in-situ analyses related to the geochronology of zircon. Such a sophisticated ion probe, which can attain a high sensitivity at a high mass resolution, based on a double focusing high mass-resolution spectrometer, designed by Matsuda (1974), was constructed at the Australian National University. In 1996, such an instrument was installed at Hiroshima University and was the first SHRIMP to be installed in Japan. Since its installation, our focus has been on the in-situ U–Pb dating of the mineral apatite, as well as zircon, which is a more common U-bearing mineral. This provides the possibility for extending the use of in-situ U–Pb dating from determining the age of formation of volcanic, granitic, sedimentary and metamorphic minerals to the direct determination of the diagenetic age of fossils and/or the crystallization age of various meteorites, which can provide new insights into the thermal history on the Earth and/or the Solar System. In this paper, we review the methodology associated with in-situ apatite dating and our contribution to Earth and Planetary Science over the past 16 years.
PMCID: PMC3775829  PMID: 24349912
in-situ analyses; U–Pb dating; SIMS; ion microprobe; chronology
13.  Approaches to developing alternative and predictive toxicology based on PBPK/PD and QSAR modeling. 
Environmental Health Perspectives  1998;106(Suppl 6):1385-1393.
Systematic toxicity testing, using conventional toxicology methodologies, of single chemicals and chemical mixtures is highly impractical because of the immense numbers of chemicals and chemical mixtures involved and the limited scientific resources. Therefore, the development of unconventional, efficient, and predictive toxicology methods is imperative. Using carcinogenicity as an end point, we present approaches for developing predictive tools for toxicologic evaluation of chemicals and chemical mixtures relevant to environmental contamination. Central to the approaches presented is the integration of physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) and quantitative structure--activity relationship (QSAR) modeling with focused mechanistically based experimental toxicology. In this development, molecular and cellular biomarkers critical to the carcinogenesis process are evaluated quantitatively between different chemicals and/or chemical mixtures. Examples presented include the integration of PBPK/PD and QSAR modeling with a time-course medium-term liver foci assay, molecular biology and cell proliferation studies. Fourier transform infrared spectroscopic analyses of DNA changes, and cancer modeling to assess and attempt to predict the carcinogenicity of the series of 12 chlorobenzene isomers. Also presented is an ongoing effort to develop and apply a similar approach to chemical mixtures using in vitro cell culture (Syrian hamster embryo cell transformation assay and human keratinocytes) methodologies and in vivo studies. The promise and pitfalls of these developments are elaborated. When successfully applied, these approaches may greatly reduce animal usage, personnel, resources, and time required to evaluate the carcinogenicity of chemicals and chemical mixtures.
PMCID: PMC1533423  PMID: 9860897
14.  Proceedings of the 2010 National Toxicology Program Satellite Symposium 
Toxicologic pathology  2010;39(1):240-266.
The 2010 annual National Toxicology Program (NTP) Satellite Symposium, entitled “Pathology Potpourri,” was held in Chicago, Illinois, in advance of the scientific symposium sponsored jointly by the Society of Toxicologic Pathology (STP) and the International Federation of Societies of Toxicologic Pathologists (IFSTP). The goal of the annual NTP Symposium is to present current diagnostic pathology or nomenclature issues to the toxicologic pathology community. This article presents summaries of the speakers' presentations, including diagnostic or nomenclature issues that were presented, along with select images that were used for voting or discussion. Some topics covered during the symposium included a comparison of rat and mouse hepatocholangiocarcinoma, a comparison of cholangiofibrosis and cholangiocarcinoma in rats, a mixed pancreatic neoplasm with acinar and islet cell components, an unusual preputial gland tumor, renal hyaline glomerulopathy in rats and mice, eosinophilic substance in the nasal septum of mice, INHAND nomenclature for proliferative and nonproliferative lesions of the CNS/PNS, retinal gliosis in a rat, fibroadnexal hamartoma in rats, intramural plaque in a mouse, a treatment-related chloracne-like lesion in mice, and an overview of mouse ovarian tumors.
PMCID: PMC3096448  PMID: 21177527
NTP Satellite Symposium; INHAND nomenclature; hepatocholangiocarcinoma; acinar-islet cell; preputial gland; hyaline glomerulopathy; eosinophilic substance; ependymoma; axonal degeneration; retinal gliosis; fibroadnexal hamartoma; intramural plaque; chloracne; ovary; cholangiocarcinoma
15.  Continuing Education Course #1: Non-Invasive Imaging as a Problem-Solving Tool and Translational Biomarker Strategy in Toxicologic Pathology 
Toxicologic pathology  2010;39(1):267-272.
The continuing education course “Non-Invasive Imaging as a Problem-Solving Tool and Translational Biomarker Strategy in Toxicologic Pathology” provided a thorough overview of commonly used imaging modalities and the logistics required for integration of small animal imaging into toxicologic pathology. Non-invasive imaging (NIN) is gaining acceptance as an important modality in toxicologic pathology. This technology allows non-terminal, time-course evaluation of functional and morphologic endpoints and can be used to translate biomarkers between preclinical animal models and human patients. Non-invasive imaging can support drug development as well as basic research in academic or industrial environments. An initial overview of theoretical principles was followed by focused presentations on magnetic resonance imaging (MRI)/magnetic resonance microscopy (MRM), positron emission tomography (PET)/single proton emission computed tomography (SPECT), ultrasonography (US, primarily focused on echocardiography), optical (bioluminescent) imaging, and computed tomography (CT). The choice of imaging modality will depend on the research question and the needed resolution.
PMCID: PMC3519422  PMID: 21147931
Non-invasive imaging; magnetic resonance imaging; computed tomography; ultrasound; positron emission tomography; single proton emission computed tomography; optical imaging
16.  Human exposure assessment and the National Toxicology Program. 
Environmental Health Perspectives  1998;106(10):623-627.
The National Institute of Environmental Health Sciences/National Toxicology Program (NIEHS/NTP) is developing a new interagency initiative in exposure assessment. This initiative involves the NIEHS, the Centers for Disease Control and Prevention through its National Center for Environmental Health, the National Institute for Occupational Safety and Health, the EPA, and other participating institutes and agencies of the NTP. This initiative will benefit public health and priority setting in a number of ways. First, as discussed above, it will strengthen the scientific foundation for risk assessments by the development of more credible exposure/response relationships in people by improving cross-species extrapolation, the development of biologically based dose-response models, and the identification of sensitive subpopulations and for "margin of exposure" based estimates of risk. Second, it will provide the kind of information necessary for deciding which chemicals should be studied with the limited resources available for toxicological testing. For example, there are 85,000 chemicals in commerce today, and the NTP can only provide toxicological evaluations on 10-20 per year. Third, we would use the information obtained from the exposure initiative to focus our research on mixtures that are actually present in people's bodies. Fourth, we would obtain information on the kinds and amount of chemicals in children and other potentially sensitive subpopulations. Determinations of whether additional safety factors need to be applied to children must rest, in part, upon comparative exposure analyses between children and adults. Fifth, this initiative, taken together with the environmental genome initiative, will provide the science base essential for meaningful studies on gene/environment interactions, particularly for strengthening the evaluation of epidemiology studies. Sixth, efficacy of public health policies aimed at reducing human exposure to chemical agents could be evaluated in a more meaningful way if body burden data were available over time, including remediation around Superfund sites and efforts to achieve environmental justice. The exposure assessment initiative is needed to address public health needs. It is feasible because of recent advances in analytical technology and molecular biology, and it is an example of how different agencies can work together to better fulfill their respective missions.
PMCID: PMC1533173  PMID: 9755136
17.  Inhalation toxicology of isoprene in F344 rats and B6C3F1 mice following two-week exposures. 
Isoprene (2-methyl-1,3-butadiene) was selected for toxicologic evaluations because of its structural similarity to 1,3-butadiene, a potent rodent carcinogen. Two-week inhalation toxicology studies of isoprene were conducted in F344 rats and B6C3F1 mice at exposure concentrations of 0, 438, 875, 1750, 3500, or 7000 ppm. For rats, there were no chemically related changes in survival, body weight gain, clinical signs, hematologic or clinical chemistry parameters, or gross or microscopic lesions. Exposure of mice to isoprene did not produce mortalities and only caused a decrease in body weight gain for male mice in the 7000 ppm exposure group; however, hematologic changes and microscopic lesions including testicular atrophy, olfactory epithelial degeneration, and forestomach epithelial hyperplasia were observed in isoprene-exposed mice. Similar toxicologic effects have been previously observed in B6C3F1 mice exposed to 1,3-butadiene. A species difference in susceptibility between rats and mice exposed to isoprene was evident in these short-term exposure studies.
PMCID: PMC1567730  PMID: 2401278
18.  Infectious diseases of the upper respiratory tract: implications for toxicology studies. 
The consequences of adventitious infectious agents upon the interpretation of toxicology studies performed in rats and mice are incompletely understood. Several prevalent murine pathogens cause alterations of the respiratory system that can confuse the assessment of chemically induced airway injury. In some instances the pathogenesis of infection with these agents has been relatively well studied in the lower respiratory tract. However, there are few well-controlled studies that have examined the upper respiratory region, which result in interpretive problems for toxicologic pathologists. The conduct and interpretation of both short-term and chronic rodent bioassays can be compromised by both the clinical and subclinical manifestations of infectious diseases. This paper reviews several important infectious diseases of the upper airway of rats and mice and discusses the potential influence of these conditions on the results of toxicology studies.
PMCID: PMC1568352  PMID: 2200664
19.  Application of DNA arrays to toxicology. 
Environmental Health Perspectives  1999;107(8):681-685.
DNA array technology makes it possible to rapidly genotype individuals or quantify the expression of thousands of genes on a single filter or glass slide, and holds enormous potential in toxicologic applications. This potential led to a U.S. Environmental Protection Agency-sponsored workshop titled "Application of Microarrays to Toxicology" on 7-8 January 1999 in Research Triangle Park, North Carolina. In addition to providing state-of-the-art information on the application of DNA or gene microarrays, the workshop catalyzed the formation of several collaborations, committees, and user's groups throughout the Research Triangle Park area and beyond. Potential application of microarrays to toxicologic research and risk assessment include genome-wide expression analyses to identify gene-expression networks and toxicant-specific signatures that can be used to define mode of action, for exposure assessment, and for environmental monitoring. Arrays may also prove useful for monitoring genetic variability and its relationship to toxicant susceptibility in human populations.
PMCID: PMC1566480  PMID: 10417368
20.  Nonneoplastic nasal lesions in rats and mice. 
Rodents are commonly used for inhalation toxicology studies, but until recently the nasal passages have often been overlooked or only superficially examined. The rodent nose is a complex organ in which toxicant-induced lesions may vary, depending on the test compound. A working knowledge of rodent nasal anatomy and histology is essential for the proper evaluation of these responses. Lack of a systematic approach for examining rodent nasal tissue has led to a paucity of information regarding nonneoplastic lesions in the rodent nose. Therefore, slides from the National Toxicology Program (NTP) and the Chemical Industry Institute of Toxicology (CIIT) were examined, and the literature was reviewed to assemble the spectrum of nonneoplastic rodent nasal pathology. Presented are lesions associated with the various types of epithelia lining the rodent nasal cavity plus lesions involving accessory nasal structures. Even though there are anatomic and physiologic differences between the rodent and human nose, both rats and mice provide valuable animal models for the study of nasal epithelial toxicity, following administration of chemical compounds.
PMCID: PMC1568333  PMID: 2200665
21.  An industrial approach to evaluation of pyrolysis and combustion hazards. 
In addition to the usual toxicology studies necessary for the safe manufacture and use of polymers at room temperature, special studies are needed for polymers which will be used at elevated temperatures. This paper discusses various areas to be investigated and principles for deciding on test materials, tests, and test conditions, polytetrafluoroethylene (PTFE) and fluorinated polyethylene-propylene (PFEP) pyrolysis studies being used as an illustrative case history. Some limitations of animal testing also are mentioned. A toxicological spectrum relating toxicological determinants to PTFE temperature is developed.
PMCID: PMC1475183  PMID: 1175553
22.  Exposure, metabolism, and toxicity of rare earths and related compounds. 
Environmental Health Perspectives  1996;104(Suppl 1):85-95.
For the past three decades, most attention in heavy metal toxicology has been paid to cadmium, mercury, lead, chromium, nickel, vanadium, and tin because these metals widely polluted the environment. However, with the development of new materials in the last decade, the need for toxicological studies on those new materials has been increasing. A group of rare earths (RE) is a good example. Although some RE have been used for superconductors, plastic magnets, and ceramics, few toxicological data are available compared to other heavy metals described above. Because chemical properties of RE are very similar, it is plausible that their binding affinities to biomolecules, metabolism, and toxicity in the living system are also very similar. In this report, we present an overview of the metabolism and health hazards of RE and related compounds, including our recent studies.
PMCID: PMC1469566  PMID: 8722113
23.  Toxic evaluation of organic extracts from airborne particulate matter in Puerto Rico. 
Environmental Health Perspectives  2000;108(7):635-640.
In recent years, several hypotheses have emerged to explain the toxicologic activity of particulate matter. Organic compounds, ultrafine particles, biologic components, and transition metals are some of the constituents that reportedly exert some type of adverse effect on human health. A considerable fraction of the urban particulate matter consists of carbon compounds, which originate mostly from anthropogenic sources. The toxicity of organic fractions from particulate matter have been mainly evaluated by considering their mutagenic activity. This research expands on the toxicologic profile of organic compounds adsorbed to particulate matter, specifically in Puerto Rico, by using the cytotoxic neutral red bioassay (NRB). The NRB uses normal human epidermal keratinocytes or other types of cells to measure the effect on cell viability when exposed to organic compounds associated to the particles in the air. We validated the NRB for particulate matter by using a standard reference material (SRM 1649). We used the NRB to determine toxicologic differences of extracts between an urban industrialized site with anthropogenic activity versus a coastal region with less human activity. The cytotoxicity associated with organic compounds in particulate matter collected at the urban industrialized site was detected in both the particulate matter (3/4) 10 microm in aerodynamic diameter (PM(10)) and particulate matter (3/4) 100 microm in aerodynamic diameter (PM(100)). Greater toxic effects were observed in PM(10) extracts than in PM(100) extracts, but PM(10) toxic effects were not significantly different from those in PM(100). The extracts from the industrialized site were more cytotoxic than the extracts from coastal reference site, although in the summer, extracts from both sites were significantly cytotoxic to normal human epidermal keratinocytes. In addition, the nonpolar extracts of both PM(10) and PM(100) exerted the greatest cytotoxicity, followed by the polar, and, finally, the moderately polar extract. This study demonstrates that extracts from the Guaynabo industrialized site were more toxic than similar extracts obtained from a reference coastal site in Fajardo, Puerto Rico.
PMCID: PMC1638202  PMID: 10903617
24.  Proceedings of the 2011 National Toxicology Program Satellite Symposium 
Toxicologic pathology  2011;40(2):321-344.
The 2011 annual National Toxicology Program (NTP) Satellite Symposium, entitled “Pathology Potpourri,” was held in Denver, Colorado in advance of the Society of Toxicologic Pathology’s 30th Annual Meeting. The goal of the NTP Symposium is to present current diagnostic pathology or nomenclature issues to the toxicologic pathology community. This article presents summaries of the speakers’ presentations, including diagnostic or nomenclature issues that were presented, along with select images that were used for audience voting or discussion. Some lesions and topics covered during the symposium include: proliferative lesions from various fish species including ameloblastoma, gas gland hyperplasia, nodular regenerative hepatocellular hyperplasia, and malignant granulosa cell tumor; spontaneous cystic hyperplasia in the stomach of CD1 mice and histiocytic aggregates in the duodenal villous tips of treated mice; an olfactory neuroblastoma in a cynomolgus monkey; various rodent skin lesions, including follicular parakeratotic hyperkeratosis, adnexal degeneration, and epithelial intracytoplasmic accumulations; oligodendroglioma and microgliomas in rats; a diagnostically challenging microcytic, hypochromic, responsive anemia in rats; a review of microcytes and microcytosis; nasal lesions associated with green tea extract and Ginkgo biloba in rats; corneal dystrophy in Dutch belted rabbits; valvulopathy in rats; and lymphoproliferative disease in a cynomolgus monkey.
PMCID: PMC3490626  PMID: 22089839
NTP Satellite Symposium; ameloblastoma; gas gland hyperplasia; stomach cystic hyperplasia; sodium dichromate dihydrate; olfactory neuroblastoma; cynomolgus monkey; adnexal degeneration; parakeratotic hyperkeratosis; oligodendroglioma; microglioma; microcytic hypochromic anemia; microcytosis; spherocytosis; poikilocytosis; green tea; Ginkgo biloba; corneal dystrophy; Dutch belted rabbit valvulitis; valvulopathy; post-transplant lymphoproliferative disease
25.  Proceedings of the 2013 Joint JSTP/NTP Satellite Symposium 
Journal of Toxicologic Pathology  2013;26(2):231-257.
The first joint Japanese Society of Toxicologic Pathology (JSTP) and National Toxicology Program (NTP) Satellite Symposium, entitled “Pathology Potpourri,” was held on January 29th at Okura Frontier Hotel in Tsukuba, Ibaraki, Japan, in advance of the JSTP’s 29th Annual Meeting. The goal of this Symposium was to present current diagnostic pathology or nomenclature issues to the toxicologic pathology community. This article presents summaries of the speakers’ presentations, including diagnostic or nomenclature issues that were presented, select images that were used for audience voting or discussion, and the voting results. Some lesions and topics covered during the symposium include: treatment-related atypical hepatocellular foci of cellular alteration in B6C3F1 mice; purulent ventriculoencephalitis in a young BALB/c mouse; a subcutaneous malignant schwannoma in a RccHan:WIST rat; spontaneous nasal septum hyalinosis/eosinophilic substance in B6C3F1 mice; a rare pancreatic ductal cell adenoma in a young Lewis rat; eosinophilic crystalline pneumonia in a transgenic mouse model; hyaline glomerulopathy in two female ddY mice; treatment-related intrahepatic erythrocytes in B6C3F1 mice; treatment-related subendothelial hepatocytes in B6C3F1 mice; spontaneous thyroid follicular cell vacuolar degeneration in a cynomolgus monkey; congenital hepatic fibrosis in a 1-year-old cat; a spontaneous adenocarcinoma of the middle ear in a young Crl:CD(SD) rat; and finally a series of cases illustrating some differences between cholangiofibrosis and cholangiocarcinoma in Sprague Dawley and F344 rats.
PMCID: PMC3695348  PMID: 23914068
JSTP/NTP Satellite Symposium; atypical foci of cellular alteration; cholangiocarcinoma; cholangiofibrosis; congenital hepatic fibrosis; eosinophilic crystalline pneumonia; eosinophilic substance; epithelioid type of malignant schwannoma; hyaline glomerulopathy; intrahepatocytic erythrocytes; middle ear adenocarcinoma; nasal septum hyalinosis; pancreatic ductal cell adenoma; subendothelial hepatocytes; thyroid follicular cell vacuolar degeneration; ventriculoencephalitis

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