Publications by authors named "Gerald Long"

28 Publications

  • Page 1 of 1

Use of Severity Grades to Characterize Histopathologic Changes.

Toxicol Pathol 2018 04 12;46(3):256-265. Epub 2018 Mar 12.

11 Food and Drug Administration, College Park, Maryland, USA.

The severity grade is an important component of a histopathologic diagnosis in a nonclinical toxicity study that helps distinguish treatment-related effects from background findings and aids in determining adverse dose levels during hazard characterization. Severity grades should be assigned based only on the extent (i.e., amount and complexity) of the morphologic change in the examined tissue section(s) and be clearly defined in the pathology report for critical lesions impacting study interpretation. However, the level of detail provided and criteria by which severity grades are assigned can vary, which can lead to inappropriate comparisons and confusion when evaluating pathology results. To help address this issue, a Working Group of the Society of Toxicologic Pathology's Scientific and Regulatory Policy Committee was formed to provide a "points to consider" article on the assignment and application of pathology severity grades. Overall, the Working Group supports greater transparency and consistency in the reporting of grading scales and provides recommendations to improve selection of diagnoses requiring more detailed severity criteria. This information should enhance the overall understanding by toxicologic pathologists, toxicologists, and regulatory reviewers of pathology findings and thereby improve effective communication in regulatory submissions.
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http://dx.doi.org/10.1177/0192623318761348DOI Listing
April 2018

Comparing the incidence of bone tumors in rats chronically exposed to the selective PTH type 1 receptor agonist abaloparatide or PTH(1-34).

Regul Toxicol Pharmacol 2017 Jun 4;86:356-365. Epub 2017 Apr 4.

Radius Health, Inc., 950 Winter Street, Waltham, MA 02451, USA. Electronic address:

Prolonged treatment with human parathyroid hormone (hPTH) in rats results in development of bone tumors, though this finding has not been supported by clinical experience. The PTH type 1 receptor agonist abaloparatide, selected for its bone anabolic activity, is under clinical development to treat postmenopausal women with osteoporosis. To determine the carcinogenic potential of abaloparatide, Fischer (F344) rats were administered SC daily abaloparatide at doses of 0, 10, 25, and 50 μg/kg or 30 μg/kg hPTH(1-34) as a positive control for up to 2 years. Robust increases in bone density were achieved at all abaloparatide doses and with hPTH(1-34). Comprehensive histopathological analysis reflected a comparable continuum of proliferative changes in bone, mostly osteosarcoma, in both abaloparatide and hPTH(1-34) treated rats. Comparing the effects of abaloparatide and hPTH(1-34) at the 25 and 30 μg/kg respective doses, representing similar exposure multiples to the human therapeutic doses, revealed similar osteosarcoma-associated mortality, tumor incidence, age at first occurrence, and metastatic potential. There were no increases in the incidence of non-bone tumors with abaloparatide compared to vehicle. Thus, near life-long treatment with abaloparatide in rats resulted in dose and time dependent formation of osteosarcomas, with a comparable response to hPTH(1-34) at similar exposure.
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http://dx.doi.org/10.1016/j.yrtph.2017.04.001DOI Listing
June 2017

Chronic Toxicity and Carcinogenicity Studies of the Long-Acting GLP-1 Receptor Agonist Dulaglutide in Rodents.

Endocrinology 2015 Jul 10;156(7):2417-28. Epub 2015 Apr 10.

Department of Toxicology, Pathology, and Drug Disposition (R.A.B., J.A.W., H.W.S., J.L.B., J.A.M., J.L.V.), Eli Lilly and Company, Indianapolis, Indiana 46285; Early Development (S.D.S., T.R., T.P., R.L., R.Q.), Covance Laboratories, Madison, Wisconsin 53704; Department of Veterinary Biosciences (T.J.R.), The Ohio State University, Columbus, Ohio 43210; and Experimental Pathology Laboratories, Inc (G.G.L.), Sterling, Virginia 20166.

The tumorigenic potential of dulaglutide was evaluated in rats and transgenic mice. Rats were injected sc twice weekly for 93 weeks with dulaglutide 0, 0.05, 0.5, 1.5, or 5 mg/kg corresponding to 0, 0.5, 7, 20, and 58 times, respectively, the maximum recommended human dose based on plasma area under the curve. Transgenic mice were dosed sc twice weekly with dulaglutide 0, 0.3, 1, or 3 mg/kg for 26 weeks. Dulaglutide effects were limited to the thyroid C-cells. In rats, diffuse C-cell hyperplasia and adenomas were statistically increased at 0.5 mg/kg or greater (P ≤ .01 at 5 mg/kg), and C-cell carcinomas were numerically increased at 5 mg/kg. Focal C-cell hyperplasia was higher compared with controls in females given 0.5, 1.5, and 5 mg/kg. In transgenic mice, no dulaglutide-related C-cell hyperplasia or neoplasia was observed at any dose; however, minimal cytoplasmic hypertrophy of C cells was observed in all dulaglutide groups. Systemic exposures decreased over time in mice, possibly due to an antidrug antibody response. In a 52-week study designed to quantitate C-cell mass and plasma calcitonin responses, rats received twice-weekly sc injections of dulaglutide 0 or 5 mg/kg. Dulaglutide increased focal C-cell hyperplasia; however, quantitative increases in C-cell mass did not occur. Consistent with the lack of morphometric changes in C-cell mass, dulaglutide did not affect the incidence of diffuse C-cell hyperplasia or basal or calcium-stimulated plasma calcitonin, suggesting that diffuse increases in C-cell mass did not occur during the initial 52 weeks of the rat carcinogenicity study.
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http://dx.doi.org/10.1210/en.2014-1722DOI Listing
July 2015

Time for a change: what dominance durations reveal about adaptation effects in the perception of a bi-stable reversible figure.

Atten Percept Psychophys 2015 Apr;77(3):867-82

Department of Psychology, Villanova University, 800 Lancaster Avenue, Villanova, PA, 19085, USA,

The effect of adaptation on the perception of a reversible figure was examined in the context of the so-called "reverse-bias effect" in which prolonged exposure to an unambiguous version of a bi-stable ambiguous stimulus serves to bias an observer to report the alternative version of the subsequently viewed ambiguous stimulus. Exposure to the unambiguous stimulus presumably selectively adapts and weakens the neural structures underlying that particular interpretation of the ambiguous figure. We extended previous research by examining the dominance durations for the two alternatives of the reversible figure (i.e., how long each alternative was perceived when it was dominant) in addition to the measures of response rate and choice preference used by other researchers. We replicated earlier findings with the previously used measures. Interestingly, adaptation with an unambiguous version of the ambiguous stimulus produced an asymmetrical effect on the dominance durations of the subsequently presented ambiguous stimulus, relative to a no-adaptation control. The dominance durations were lengthened for the perceptual organization that was the opposite of the adaptation stimulus while they were relatively unaffected for the perceptual organization that was the same as the adaptation stimulus. Our findings are consistent with the argument that adaptation effects play an important role in perceptual bistability. The asymmetrical dominance-duration findings further suggest that adaptation operates in a perceptual system in which the alternative perceptual representations of an ambiguous figure reciprocally inhibit one another via cross-inhibitory processes, consistent with views developed in other forms of bistable perception (e.g., binocular rivalry).
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http://dx.doi.org/10.3758/s13414-014-0809-xDOI Listing
April 2015

Nonproliferative and proliferative lesions of the rat and mouse female reproductive system.

J Toxicol Pathol 2014 ;27(3-4 Suppl):1S-107S

National Institute of Health Sciences, Tokyo, Japan.

The INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) Project (www.toxpath.org/inhand.asp) is a joint initiative of the Societies of Toxicological Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP) and North America (STP) to develop an internationally accepted nomenclature for proliferative and nonproliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature for classifying microscopic lesions observed in the female reproductive tract of laboratory rats and mice, with color photomicrographs illustrating examples of some lesions. The standardized nomenclature presented in this document is also available electronically on the internet (http://www.goreni.org/). Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous and aging lesions as well as lesions induced by exposure to test materials. There is also a section on normal cyclical changes observed in the ovary, uterus, cervix and vagina to compare normal physiological changes with pathological lesions. A widely accepted and utilized international harmonization of nomenclature for female reproductive tract lesions in laboratory animals will decrease confusion among regulatory and scientific research organizations in different countries and provide a common language to increase and enrich international exchanges of information among toxicologists and pathologists.
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http://dx.doi.org/10.1293/tox.27.1SDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4253081PMC
December 2014

Comparison of select analytes in aerosol from e-cigarettes with smoke from conventional cigarettes and with ambient air.

Regul Toxicol Pharmacol 2014 Dec 24;70(3):704-10. Epub 2014 Oct 24.

Lorillard Tobacco Company, PO Box 21688, Greensboro, NC, USA.

Leading commercial electronic cigarettes were tested to determine bulk composition. The e-cigarettes and conventional cigarettes were evaluated using machine-puffing to compare nicotine delivery and relative yields of chemical constituents. The e-liquids tested were found to contain humectants, glycerin and/or propylene glycol, (⩾75% content); water (<20%); nicotine (approximately 2%); and flavor (<10%). The aerosol collected mass (ACM) of the e-cigarette samples was similar in composition to the e-liquids. Aerosol nicotine for the e-cigarette samples was 85% lower than nicotine yield for the conventional cigarettes. Analysis of the smoke from conventional cigarettes showed that the mainstream cigarette smoke delivered approximately 1500times more harmful and potentially harmful constituents (HPHCs) tested when compared to e-cigarette aerosol or to puffing room air. The deliveries of HPHCs tested for these e-cigarette products were similar to the study air blanks rather than to deliveries from conventional cigarettes; no significant contribution of cigarette smoke HPHCs from any of the compound classes tested was found for the e-cigarettes. Thus, the results of this study support previous researchers' discussion of e-cigarette products' potential for reduced exposure compared to cigarette smoke.
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http://dx.doi.org/10.1016/j.yrtph.2014.10.010DOI Listing
December 2014

Comparison of select analytes in exhaled aerosol from e-cigarettes with exhaled smoke from a conventional cigarette and exhaled breaths.

Authors:
Gerald A Long

Int J Environ Res Public Health 2014 Oct 27;11(11):11177-91. Epub 2014 Oct 27.

Lorillard Tobacco Company, P.O. Box 21688, Greensboro, NC 27420, USA.

Exhaled aerosols were collected following the use of two leading U.S. commercial electronic cigarettes (e-cigarettes) and a conventional cigarette by human subjects and analyzed for phenolics, carbonyls, water, glycerin and nicotine using a vacuum-assisted filter pad capture system. Exhaled breath blanks were determined for each subject prior to each product use and aerosol collection session. Distribution and mass balance of exhaled e-cigarette aerosol composition was greater than 99.9% water and glycerin, and a small amount (<0.06%) of nicotine. Total phenolic content in exhaled e-cigarette aerosol was not distinguishable from exhaled breath blanks, while total phenolics in exhaled cigarette smoke were significantly greater than in exhaled e-cigarette aerosol and exhaled breaths, averaging 66 µg/session (range 36 to 117 µg/session). The total carbonyls in exhaled e-cigarette aerosols were also not distinguishable from exhaled breaths or room air blanks. Total carbonyls in exhaled cigarette smoke was significantly greater than in exhaled e-cigarette aerosols, exhaled breath and room air blanks, averaging 242 µg/session (range 136 to 352 µg/session). These results indicate that exhaled e-cigarette aerosol does not increase bystander exposure for phenolics and carbonyls above the levels observed in exhaled breaths of air.
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http://dx.doi.org/10.3390/ijerph111111177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4245607PMC
October 2014

Regulatory forum opinion piece: thresholds in toxicologic pathology.

Toxicol Pathol 2012 Oct 14;40(7):1079-81. Epub 2012 May 14.

Experimental Pathology Laboratories, Indianapolis, Indianna, USA.

The definition of diagnostic thresholds is an important aspect of identification and recording of histopathologic lesions in toxicology studies. Although the primary goal of the pathology examination is to identify and interpret lesions associated with the administration of the test article, the toxicologic pathologist will encounter many changes in the tissues that are variations in tissue morphology, tissue artifacts, and spontaneous background findings. The pathologist must establish appropriate thresholds to produce a comprehensive record of the findings so that potentially treatment-related lesions may be identified. However, the findings should not be so detailed as to create overly complex data with the appearance of differences when none exist. Care must be taken to be consistent in the identification and recording of background lesions, since they are important for historical control data, which is often used as a reference when interpreting findings in current studies. Insufficient or inconsistent recording of findings may result in a deficiency in the historical control data for the identification and interpretation of a finding in the future.
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http://dx.doi.org/10.1177/0192623312443322DOI Listing
October 2012

Dissecting perceptual processes with a new tri-stable reversible figure.

Perception 2012 ;41(10):1163-85

Department of Psychology, Villanova University, Villanova, PA 19085, USA.

Five experiments are presented that examine observers' reports with a new tri-stable reversible figure using two measures of observers' experience with the figure: observers' initial percept upon figure presentation in the test period and the total number of reversals reported in the test period. Experiment 1 demonstrates the equiprobability of the three alternatives for the figure. Experiment 2 demonstrates the powerful effect of fixation location on observers' reported organization of the tri-stable figure. Experiment 3 demonstrates clear priming effects following brief presentation of particular components of the tri-stable figure. Experiment 4 demonstrates clear adaptation effects following prolonged presentation of the same components of the figure used in experiment 3 as well as the transient nature of this adaptation. Experiment 5 demonstrates observers' ability to "hold" each of the three percepts regardless of fixation location. The special sensitivity of the tri-stable figure to these manipulations even with naive subjects and small sample sizes is discussed, and the interplay of both bottom-up and top-down processes on figural reversal is emphasized.
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http://dx.doi.org/10.1068/p7313DOI Listing
April 2013

Hematopoietic proliferative lesions in the spleen of rasH2 transgenic mice treated with MNU.

Toxicol Pathol 2010 Dec 30;38(7):1026-36. Epub 2010 Sep 30.

Eli Lilly and Company, Indianapolis, Indiana 46140, USA.

In this study, rasH2-Tg mice treated with N-methyl-N-nitrosurea (MNU) developed exuberant hematoproliferative changes in the spleen that included dysplasia and features of neoplasia. Hematoproliferative change was characterized as exuberant proliferation of hematopoietic cells within the spleen that distorted but did not displace normal splenic morphologic features. The hematopoietic cells were of mixed lineage, but one type, often erythroid, predominated. Cellular atypia was present in all mice with hematoproliferative change, and dysplasia was present in five of eight examined. Hematoproliferative neoplasia was characterized by similar cytologic features but also resulted in displacement/disruption of normal splenic architecture and increased numbers of unidentified blast cells. One case was differentiated toward myeloid proliferation, suggesting granulocytic leukemia. Affected mice had other neoplasms, such as lymphoma and anemia. These proliferative and dysplastic lesions of the spleen in rasH2-Tg mice treated with MNU require additional characterization to definitively differentiate them from the reactive hematopoiesis that can occur in response to inflammatory, neoplastic, or hematopoietic insults in mice.
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http://dx.doi.org/10.1177/0192623310382557DOI Listing
December 2010

Commentary on "Evaluation of possible carcinogenic risk to humans based on liver tumors in rodent assays: the two-year bioassay is no longer necessary".

Authors:
Gerald G Long

Toxicol Pathol 2010 Apr 2;38(3):502-5. Epub 2010 Feb 2.

Eli Lilly and Company, Lilly Research Laboratories, Indianapolis, Indiana, USA.

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http://dx.doi.org/10.1177/0192623309359795DOI Listing
April 2010

Alternative mouse models for carcinogenicity assessment: industry use and issues with pathology interpretation.

Toxicol Pathol 2010 Jan 13;38(1):43-50. Epub 2009 Nov 13.

Lilly Research Laboratories, Indianapolis, Indiana 46225, USA.

The Carcinogenicity Alternative Mouse Models (CAMM) Working Group of the Society of Toxicologic Pathology (STP) surveyed the membership to define current practices and opinions in industry regarding the use of alternative mouse models for carcinogenicity testing. The results of the survey indicated that CAMM are used most often to fulfill a regulatory requirement (e.g., to replace the two-year mouse bioassay) and are being accepted by regulatory agencies. Alternative models are also sometimes used for internal decision making or to address a mechanistic question. The CAMM most commonly used are the p53+/- and rasH2. The rasH2 appears to be the currently accepted model for general carcinogenicity testing. Problems with study interpretation included lack of historic background data, unexpected tumor finding, and tumor identification/characterization of early lesions. Problems with implementation or conduct of the study included extent of the pathology evaluation, numbers of animals, survival, and study duration. Recommendations were developed for, frequency and type of positive control testing, extent of histopathologic examination of test article-treated and positive control animals, current use and future development of diagnostic criteria; increased availability and use of historic data, and use of other genetically modified mice in carcinogenicity testing.
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http://dx.doi.org/10.1177/0192623309354107DOI Listing
January 2010

Panel discussion: alternative mouse models for carcinogenicity assessment.

Toxicol Pathol 2010 Jan 2;38(1):72-5. Epub 2009 Nov 2.

National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.

This article summarizes key points from Dr. Bernard Leblanc's presentation European Perspectives on Alternative Mouse Carcinogenicity Models and a distillation of questions and answers from a panel discussion following presentations on Alternative Mouse Models for Carcinogenicity Assessment at the Society of Toxicologic Pathology's annual symposium on June 23, 2009, in Washington, DC.
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http://dx.doi.org/10.1177/0192623309352091DOI Listing
January 2010

Neoplastic and non-neoplastic changes in F-344 rats treated with Naveglitazar, a gamma-dominant PPAR alpha/gamma agonist.

Toxicol Pathol 2009 Oct 21;37(6):741-53. Epub 2009 Aug 21.

Lilly Research Laboratories, Indianapolis, IN 46225, USA.

The carcinogenic potential of naveglitazar, a gamma-dominant peroxisome proliferator-activated receptor (PPAR) alpha/gamma dual agonist, was evaluated in a two-year study in F344 rats (0, 0.3, 1.0, or 3.0 mg/kg, males; 0, 0.1, 0.3, or 1.0 mg/kg, females). Increased mortality in male rats of the high-dose group was related to cardiac-associated lesions, neoplasms, and undetermined causes. Degeneration and hypertrophy of the myocardium occurred with dose-responsive increased incidence and severity. Neoplasms with increased incidence included sarcomas in male rats and urinary bladder neoplasms in female rats. Most sarcomas in male rats occurred in the adipose tissue of the subcutis and were diagnosed as fibrosarcomas, with fewer liposarcomas and other histologic types. Non-neoplastic changes in adipose tissue included expansion of adipose tissue in multiple sites, alterations in cytoplasmic vesicular pattern in brown and white fat, increases in stroma and mesenchymal cells, and fibrosis. The severity of chronic progressive nephropathy was decreased in a dose-responsive manner in males, and hyperplasia and neoplasia of the mammary gland were decreased in incidence in females. The adverse effects of cardiotoxicity and increased incidence of neoplasms occurred with dose-responsive incidence and/or severity, and a no-effect level for these effects was not achieved in this study.
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http://dx.doi.org/10.1177/0192623309343775DOI Listing
October 2009

Urothelial carcinogenesis in the urinary bladder of rats treated with naveglitazar, a gamma-dominant PPAR alpha/gamma agonist: lack of evidence for urolithiasis as an inciting event.

Toxicol Pathol 2008 Feb;36(2):218-31

Lilly Research Laboratories, Greenfield, Indiana 46140, USA. Long_

Naveglitazar, a gamma-dominant peroxisome proliferator-activated receptor (PPAR) alpha/gamma dual agonist, was tested for carcinogenicity in F344 rats in a 2-year study. Changes in urine composition and urothelial morphology were characterized in a companion 18-month investigative study. A significant increase in neoplasms of the bladder occurred only in females of the high-dose group (14/60) in the carcinogenicity study. Trends toward increased cell proliferation in the urothelium were noted in both sexes at all time points evaluated in the 18-month study. Group means for urothelial mitogenesis were increased statistically significantly only in high-dose females at 12 and 18 months. Urothelial hyperplasia occurred in high-dose females at 18 months. Morphologic changes in the urothelium at earlier time points were limited to hypertrophy and decreased immunolabeling of the superficial cells for cytokeratin 20 (a marker of terminal differentiation in urothelial cells) in both males and females. No treatment-related changes in urinary parameters, including urinary sediments, were associated with the occurrence of urothelial proliferation. Urinary pH was unaffected by treatment in both males and females, but expected diurnal changes were demonstrated. Collectively, these data indicate that naveglitazar was associated with hypertrophic and proliferative effects on the urothelium, but a link with changes in urinary parameters was not demonstrated.
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http://dx.doi.org/10.1177/0192623307311757DOI Listing
February 2008

How to keep a reversible figure from reversing: teasing out top-down and bottom-up processes.

Perception 2007 ;36(3):431-45

Office of Graduate Studies, Villanova University, 800 Lancaster Avenue, Villanova, PA 19085, USA.

The nature of processes underlying our perception of reversible figures was examined through two experiments investigating the effects of prior exposure conditions on an observer's report of figural reversal. In experiment 1, observers were adapted over several minutes to an unambiguous version of a rotating Necker cube prior to the presentation of the standard ambiguous figure. Results indicated that adaptation produced an immediate bias to perceive the ambiguous figure in the opposite configuration (ie reverse bias) and to reduce reports of reversal over the test period. The introduction of a brief delay between the adaptation and test periods revealed that this bias is a highly transient effect and is only clearly evident when the adaptation and test figures are matched in size. In experiment 2, observers were primed with an unambiguous figure for a few seconds prior to the presentation of the standard ambiguous figure. In this case, the obtained bias strongly favored the observer's reporting the ambiguous figure to be in the same configuration as the adapting figure (ie positive bias); and neither introducing a delay period nor changing figure size had any effect. We conclude that these experiments reveal the distinct roles of transient, retinally localized neural processes as well as more stable, global processes under specifiable conditions.
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http://dx.doi.org/10.1068/p5630DOI Listing
September 2007

Enduring interest in perceptual ambiguity: alternating views of reversible figures.

Psychol Bull 2004 Sep;130(5):748-68

Department of Psychology, Villanova University, Villanova, PA 19085, USA.

Research favoring the so-called bottom-up and top-down classes of explanations for reversible figures that dominated the literature in last half of the 20th century is reviewed. Two conclusions are offered. First, any single-process model is extremely unlikely to be able to accommodate the wide array of empirical findings, suggesting that the "final" explanation will almost certainly involve a hybrid conceptualization of interacting sensory and cognitive processes. Second, the utility of distinguishing between 2 components of the observer's experience with reversible figures is emphasized. This distinction between the observer's ability to access multiple representations from the single stimulus pattern (ambiguity) and the observer's phenomenal experience of oscillation between those representations (reversibility) permits the literature to be segregated into useful categories of research that expose overlapping but distinctive cortical processes.
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http://dx.doi.org/10.1037/0033-2909.130.5.748DOI Listing
September 2004

Bone neoplasms in F344 rats given teriparatide [rhPTH(1-34)] are dependent on duration of treatment and dose.

Toxicol Pathol 2004 Jul-Aug;32(4):426-38

Lilly Research Laboratories, Greenfield, Indiana, USA.

A long-term study was conducted in female F344 rats to determine the relative importance of dose, treatment duration, and age at initiation of treatment on the incidence of teriparatide [rhPTH[1-34)]-induced bone proliferative lesions. Treatment groups consisted of different combinations of dose (0, 5, or 30 microg/kg/d), treatment duration (6, 20, or 24 months) and age at initiation of treatment (2 or 6 months of age). The primary endpoints were the incidence of bone neoplasms and effects on bone mass and structure as evaluated by quantitative computed tomography and histomorphometery. Significant increases in the incidence of bone tumors (osteoma, osteoblastoma, and osteosarcoma) occurred in rats treated with 30 microg/kg for 20 or 24 months. No neoplasms were found when the 5 microg/kg treatment was initiated at 6 months of age and continued for either 6 or 20 months (up to 70% of life span). This treatment regimen defined a "no-effect" dose for neoplasm formation that nevertheless resulted in substantial increases in bone mass. These results demonstrate that treatment duration and administered dose are the most important factors in the teriparatide-induced bone tumors in rats.
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http://dx.doi.org/10.1080/01926230490462138DOI Listing
February 2005

Recommendations to guide determining cause of death in toxicity studies.

Authors:
Gerald Long

Toxicol Pathol 2004 Mar-Apr;32(2):269-70

Eli Lilly & Co, Greenfield, Indiana 46140, USA.

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http://dx.doi.org/10.1080/01926230490274443DOI Listing
October 2004

The utility of genetically modified mouse assays for identifying human carcinogens: a basic understanding and path forward. The Alternatives to Carcinogenicity Testing Committee ILSI HESI.

Toxicol Sci 2004 Feb 2;77(2):188-94. Epub 2003 Dec 2.

Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA.

The Alternatives to Carcinogenicity Testing Committee of the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute (HESI) conducted a large-scale, multinational collaborative research program to evaluate several genetically modified mouse assays for assessing the human carcinogenic potential of compounds. The data from this testing program have made an important contribution to the general understanding of how these models can be best applied in hazard identification; however, questions still exist regarding methodology and data interpretation. To address these issues, ILSI HESI hosted a February 2003 workshop on the Utility of Transgenic Assays for Risk Assessment. The purpose of this workshop was to reach an understanding of how data from genetically modified mouse models are viewed by different regulatory bodies in the pharmaceutical sector and, based on this understanding, to identify areas in which more experimental work may be needed to increase the utility of data derived from these assays. In the course of discussions, various data gaps related to model selection and protocol issues were identified. Based on the outcome of the workshop, various studies are proposed to provide data to improve the utility of currently available assays for cancer hazard identification and risk assessment purposes.
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http://dx.doi.org/10.1093/toxsci/kfh037DOI Listing
February 2004

Configural biases and reversible figures: evidence of multilevel grouping effects.

Am J Psychol 2002 ;115(4):581-607

Office of Graduate Studies, Villanova University, Vasey Hall, Villanova, PA 19085, USA.

Four experiments sought to identify the processes underlying 2 classes of grouping effects that are readily produced with a hierarchical figure type known as ambiguous triangles. Previous work has shown that aligning small equilateral triangles in particular configurations can both facilitate and interfere with observers' ability to report the pointing direction of the individual triangles. We determined that selectively adapting the observer to low-frequency gratings of the same orientation as the aligned triangles markedly altered the interfering and facilitative effects of the global configuration only when an accuracy measure of performance was used. When a response latency measure was used, no effect of the same adaptation condition was found. Results are discussed in terms of multiple levels of grouping effects in the visual system and the differential sensitivity of these levels to basic neural adaptation.
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April 2003

Apparent mesonephric duct (rete anlage) origin for cysts and proliferative epithelial lesions in the mouse ovary.

Authors:
Gerald G Long

Toxicol Pathol 2002 Sep-Oct;30(5):592-8

Lilly Research Laboratories, A Division of Eli Lilly and Company, Greenfield, Indiana 46256, USA.

Ovaries and adjacent parovarian (mesovarial) tissues of CD-1 mice of various ages were examined to characterize cystic and proliferative epithelial lesions of the ovary and parovarian tissues. Ovaries and adjacent tissues from 6 mice each at approximately 3 and 8 months of age were processed for light microscopy and step-sections (50-micron intervals) of the entire tissue were examined. Tissues were collected from 40 mice each at 16 through 24 months of age and 3 step sections per mouse were examined. Mesonephric duct remnants were found in all mice at 3 and 8 months. Ducts were usually in the mesovarial adipose tissue and near or within the ovarian hilus and were often loosely associated with smooth muscle of the mesovarial ligament. The epithelium of the ducts varied from low cuboidal to columnar, occasional individual cells were ciliated, and small papillary configurations of epithelium were occasionally present. Ducts were dilated (> 1 mm) more often in mice at 8 months compared to 3 months, and some were continuous with cystic spaces within the ovaries. As mice aged (16-24 months), dilation and cystic change in ducts and associated compression of ovarian tissue away from the ovarian hilus became common. The epithelium of dilated ducts was generally flattened, but foci of cuboidal to columnar epithelium and/or occasional ciliated cells were present. Many ducts contained foci of hyperplastic and/or hypertrophic epithelium, and papillary projections of epithelium were occasionally found. Some of the latter lesions were consistent with a diagnosis of papillary cystadenoma. Hyperplasia of associated fibromuscular stroma was limited to a few apparently extraovarian ducts. The results of this study indicate that remnant mesonephric ductular structures are common in and adjacent to the ovaries of CD-1 mice. As mice age, these ducts become dilated and, in some, the epithelium becomes hyperplastic and/or hyperptrophic. These mesonephric duct remnants appear to be a common source of ovarian and parovarian cyts cysts and epithelial neoplasms of the ovary in mice.
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http://dx.doi.org/10.1080/01926230290105785DOI Listing
March 2003

Contrast sensitivity in a dynamic environment: effects of target conditions and visual impairment.

Hum Factors 2002 ;44(1):120-32

Office of Graduate Studies, Villanova University, Pennsylvania 19085, USA.

Contrast sensitivity was determined as a function of target velocity (0 degrees - 120 degrees/s) over a variety of viewing conditions. In Experiment 1, measurements of dynamic contrast sensitivity were determined for 24 male and 24 female observers as a function of target velocity for letter stimuli of 2 sizes and 2 durations. Significant main effects were found for target velocity, target size, and target duration, but significant interactions among the variables indicated especially pronounced adverse effects of increasing target velocity for small targets and brief durations. In Experiment 2, the effects of simulated cataracts on dynamic contrast sensitivity were determined for 10 male and 10 female observers. Although the simulated impairment had no effect on traditional acuity scores, dynamic contrast sensitivity was markedly reduced under all conditions but especially with the smaller targets and at higher velocities. Results are discussed in terms of dynamic contrast sensitivity as a useful composite measure of visual functioning that may provide a better overall picture of an individual's visual functioning than does traditional static acuity, dynamic acuity, or contrast sensitivity alone. The measure of dynamic contrast sensitivity may increase understanding of the practical effects of various conditions, such as aging or disease, on the visual system, or it may allow improved prediction of individuals' performance in visually dynamic, situations, such as driving and sports.
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http://dx.doi.org/10.1518/0018720024494784DOI Listing
August 2002

Skeletal changes in rats given daily subcutaneous injections of recombinant human parathyroid hormone (1-34) for 2 years and relevance to human safety.

Toxicol Pathol 2002 May-Jun;30(3):312-21

Lilly Research Laboratories, Greenfield, Indiana 46140, USA.

Fischer 344 rats (60/sex/group) were given daily subcutaneous injections of recombinant human parathyroid hormone (PTH)(1-34) for 2 years at doses of 0, 5, 30, or 75 microg/kg. Treatment caused substantial increases in bone mass consistent with the known pharmacologic effects of once-daily administration. As determined by quantitative computed tomography (QCT) and histomorphometry, bone mass was markedly increased. Substantial new bone formation resulted in a large decrease in marrow space accompanied by altered bone architecture. Bone proliferative lesions were observed in all PTH( 1-34)-treated groups. Osteosarcoma occurred in 3, 21, and 31 male rats and in 4, 12, and 23 female rats in the 5-, 30-, and 75-microg/kg treatment groups, respectively. Focal osteoblast hyperplasia, osteoma, and osteoblastoma were much less frequent. Although the specific cellular or molecular mechanisms responsible for the rat bone tumors have not been fully elucidated, the data suggest that these lesions resulted from the long duration of treatment and the exaggerated pharmacologic response of the rat skeleton to daily treatment with PTH(1-34). Important differences between the rat study and clinical use in adult humans suggest that the increased incidence of bone neoplasia in rats treated for 2 years is likely not predictive of an increased risk of bone cancer in skeletally mature adult humans being given PTH(1-34) for a limited period of time in the treatment of osteoporosis.
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http://dx.doi.org/10.1080/01926230252929882DOI Listing
November 2002

Continuous real-time monitoring of phosphine concentrations in air using electrochemical detectors interfaced by radio telemetry.

Environ Sci Technol 2002 May;36(9):2048-53

Lorillard Tobacco Co., Danville, Virginia 24540, USA.

This work involves the novel use of a radio telemetry-based system that continuously monitors phosphine using two different types of electrochemical detectors (ECD/RT). The ECD/RT units were used to monitor phosphine inside and at varying distances from large tobacco storage warehouses. A master controller unit transferred the data to a personal computer that received and displayed the data. Supervisory control and data acquisition software assimilated the data from each ECD/RT unit, displayed and updated it as new transmissions were received, and stored the data in secure databases. Phosphine concentrations outside five warehouses simultaneously under fumigation and at the facility boundaries were <0.3 parts per million (ppm). Phosphine levels ranged from 0 to 580 ppm inside sealed warehouses. A comparison was made between the data collected at an ECD/RT unit approximately 4 m downwind of a sealed warehouse and a colorimetric tube at the same location. The final phosphine concentration from the colorimetric method was 0.05 ppm and the average over the 20-minute collection period for the ECD/RT was 0.13 ppm. This system allows for continuous, remote monitoring around warehouses under fumigation and superior time resolution allowing timely response to fugitive emissions of phosphine.
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http://dx.doi.org/10.1021/es015774+DOI Listing
May 2002

Qualitative and quantitative analysis of nonneoplastic lesions in toxicology studies.

Toxicol Pathol 2002 Jan-Feb;30(1):93-6

Experimental Pathology Laboratories, Inc, Research Triangle Park, North Carolina 27709, USA.

A pathology report is written to convey information concerning the pathologic findings in a study. This type of report must be complete, accurate and communicate the relative importance of various findings in a study. The overall quality of the report is determined by three Quality Indicators: thoroughness, accuracy, and consistency. Thoroughness is the identification of every lesion present in a particular organ or tissue, including spontaneous background lesions. Experienced pathologists familiar with background lesions may disregard certain types of lesions or establish a threshold or a severity above which background lesions are diagnosed. Accuracy is the ability to make, and precisely communicate, correct diagnoses. Nomenclature of lesions is a matter of definition and experienced pathologists generally agree as to what terms are to be used. Consistency is the uniform use of a specific term to record a defined lesion and implies that the same diagnostic criteria are being followed for each type of diagnosis. The relative severity of nonneoplastic lesions can be recorded either semiquantitatively or quantitatively. Semiquantitative analysis involves the application of defined severity grades or ranges for specific lesions. Quantitative analysis (counts and measurements) can be performed manually or electronically, utilizing image analysis and stereological techniques to provide numerical values. When both qualitative and quantitative parameters are applied in preparation of a pathology report, the recorded pathology findings can be interpreted and put into perspective. The use of this approach assures a reader that the pathology report meets the highest standards.
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http://dx.doi.org/10.1080/01926230252824761DOI Listing
September 2002

The Trp53 hemizygous mouse in pharmaceutical development: points to consider for pathologists.

Toxicol Pathol 2002 Jan-Feb;30(1):147-56

Pfizer Nagoya Laboratories, Taketoyo, Aichi, Japan.

ILSI-HESI sponsored an international consortium for the evaluation of alternative models, including the TrpS3+/- mouse. for use in short-term carcinogenicity testing of pharmaceuticals. Products of the ILSI evaluation included guidance for protocol design and assay interpretation, spontaneous tumor incidences, diagnostic criteria for common proliferative lesions, and results of assays for pharmaceutical agents that are known human and/or rodent carcinogens and non-carcinogens. Based on the ILSI evaluation, recommended protocol elements for this model include: 26-week study duration, groups > or = 15/sex/dose, a positive control group (benzene or p-cresidine), a negative control group and 3 dose groups, the high dose set at MTD or MFD, routine in-life evaluations, and complete necropsies with microscopic evaluation of tissues. Favored statistical analyses are trend tests or pair-wise comparisons, with no adjustments for survival. For an assay to be valid, positive control groups must demonstrate an effect, and the MTD or MFD must be reached in both sexes. Criteria for a negative response include a valid assay, no statistical increase in common tumors, no biologically significant numerical increase in rare tumors, and no tumor incidence above that of historical controls. Positive responses can consist of statistically significant increases in the incidence of a common tumor or numerical increases in a rare tumor, which may not be statistically significant. In either case, the incidence should be clearly above historical control values. Evidence of a dose response or occurrence of hyperplasia in a tissue with a neoplastic response can support interpreting an assay as positive. The two most common spontaneous tumors (> 1 %) in Trp53+/- mice are malignant thymic lymphomas and subcutaneous sarcomas. Use of implanted electronic transponders can increase the incidence of sarcomas. Important rare spontaneous tumors (incidence < or = 1%) are osteosarcomas and pulmonary adenomas. Many other tumor types have been reported to occur sporadically in Trp53+/- mice. Diagnostic challenges for this model include differentiating lymphoma from atypical thymic hyperplasia and recognizing the variable histopathology of subcutaneous sarcomas. In reported bioassays, Trp53+/- mice responded positively to genotoxic carcinogens, negatively to non-genotoxic rodent carcinogens, and negatively to noncarcinogens, indicating that unlike the 2-year mouse assay, this short-term assay is not overly sensitive. Positive responses often elicited an increase in tumors that occur spontaneously. To successfully use this model, pathologists must understand the biology of the Trp53 tumor suppressor gene and the principles of protocol design and data interpretation for short-term bioassays. They must also know the historical response pattern of Trp53+/- mice to test agents and be able to accurately diagnose tumors in this model. Use of the Trp53+/- mouse presents the pharmaceutical industry with several challenges, one of which is managing the uncertainty created by a lack of precedents for regulatory decisions about some possible outcomes for short-term carcinogenicity assays.
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http://dx.doi.org/10.1080/01926230252824860DOI Listing
September 2002
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