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Toxicologic Pathology

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https://www.readbyqxmd.com/read/28136187/particle-induced-pulmonary-alveolar-proteinosis-and-subsequent-inflammation-and-fibrosis
#1
Ernst M Bomhard
This review analyzes the published data on cases of pulmonary alveolar proteinosis (PAP) in workers inhaling crystalline aluminum, indium, silicon, and titanium particles and possible sequelae, that is, inflammation and fibrosis, and compares these findings with those from animal experiments. In inhalation studies in rodents using crystalline indium and gallium compounds, pronounced PAP followed by inflammation and fibrosis down to very low concentration ranges have been reported. Crystalline aluminum, silicon, and titanium compounds also induced comparable pulmonary changes in animals, though at higher exposure levels...
January 1, 2017: Toxicologic Pathology
https://www.readbyqxmd.com/read/27932582/translational-safety-genetics-leveraging-genetic-variation-for-enhanced-safety-assessment
#2
Priyasma Bhoumik, Alberto Del Rio-Espinola, Florian Hahne, Jonathan Moggs, Olivier Grenet
The emerging field of translational safety genetics is providing new opportunities to enhance drug discovery and development. Genetic variation in therapeutic drug targets, off-target interactors and relevant drug metabolism/disposition pathways can contribute to diverse drug pharmacologic and toxicologic responses between different animal species, strains and geographic origins. Recent advances in the sequencing of rodent, canine, nonhuman primate, and minipig genomes have dramatically improved the ability to select the most appropriate animal species for preclinical drug toxicity studies based on genotypic characterization of drug targets/pathways and drug metabolism and/or disposition, thus avoiding inconclusive or misleading animal studies, consistent with the principles of the 3Rs (replacement, reduction and refinement)...
December 8, 2016: Toxicologic Pathology
https://www.readbyqxmd.com/read/27895265/gut-homeostasis-microbial-dysbiosis-and-opioids
#3
Fuyuan Wang, Sabita Roy
Gut homeostasis plays an important role in maintaining animal and human health. The disruption of gut homeostasis has been shown to be associated with multiple diseases. The mutually beneficial relationship between the gut microbiota and the host has been demonstrated to maintain homeostasis of the mucosal immunity and preserve the integrity of the gut epithelial barrier. Currently, rapid progress in the understanding of the host-microbial interaction has redefined toxicological pathology of opioids and their pharmacokinetics...
November 28, 2016: Toxicologic Pathology
https://www.readbyqxmd.com/read/27895264/sex-differences-in-human-and-animal-toxicology-toxicokinetics
#4
Michael Gochfeld
Sex, the states of being female or male, potentially interacts with all xenobiotic exposures, both inadvertent and deliberate, and influences their toxicokinetics (TK), toxicodynamics, and outcomes. Sex differences occur in behavior, exposure, anatomy, physiology, biochemistry, and genetics, accounting for female-male differences in responses to environmental chemicals, diet, and pharmaceuticals, including adverse drug reactions (ADRs). Often viewed as an annoying confounder, researchers have studied only one sex, adjusted for sex, or ignored it...
November 28, 2016: Toxicologic Pathology
https://www.readbyqxmd.com/read/28178900/influence-of-study-design-variables-on-clinical-pathology-data
#5
Adam Aulbach, Anne Provencher, Niraj Tripathi
A number of factors related to study design have the potential to impact clinical pathology test results during the conduct of nonclinical safety studies. A thorough understanding of these factors is paramount in drawing accurate conclusions from clinical pathology data generated during such studies, particularly when attempting to make the distinction between test article and nontest article-related effects. Study design and conduct variables with potential to impact clinical pathology data discussed in this overview include those related to species and test system, animal age, animal care and husbandry practices, fasting, acclimatization periods, effects of transportation and stressors, route of administration, effects of in-life and surgical procedures, influence of study length, timing of blood collections, impact of vehicle/formulation composition, and some general concepts related to drug class...
February 2017: Toxicologic Pathology
https://www.readbyqxmd.com/read/28178899/recognizing-and-reducing-analytical-errors-and-sources-of-variation-in-clinical-pathology-data-in-safety-assessment-studies
#6
A E Schultze, A R Irizarry
Veterinary clinical pathologists are well positioned via education and training to assist in investigations of unexpected results or increased variation in clinical pathology data. Errors in testing and unexpected variability in clinical pathology data are sometimes referred to as "laboratory errors." These alterations may occur in the preanalytical, analytical, or postanalytical phases of studies. Most of the errors or variability in clinical pathology data occur in the preanalytical or postanalytical phases...
February 2017: Toxicologic Pathology
https://www.readbyqxmd.com/read/28178898/deciphering-sources-of-variability-in-clinical-pathology-it-s-not-just-about-the-numbers
#7
Nancy E Everds
Preanalytical variables can have significant impacts on clinical pathology parameters evaluated during the conduct of a nonclinical safety or toxicity study. These preanalytical variables can be controlled by careful attention to factors such as animal dietary status (diet composition, fasted, and fed state), restraint and anesthesia, intercurrent procedures, timing of clinical pathology collections, and proficiency of animal technicians. The impact of preanalytical variables on test results can be significant enough to result in difficult interpretations and/or regulatory questions or can obfuscate the effects of a test article...
February 2017: Toxicologic Pathology
https://www.readbyqxmd.com/read/28178897/contemporary-and-emerging-applications-in-clinical-pathology
#8
Adam D Aulbach, Holly Jordan, Jacqueline Tarrant
No abstract text is available yet for this article.
February 2017: Toxicologic Pathology
https://www.readbyqxmd.com/read/28056663/principles-for-assessing-adversity-in-toxicologic-clinical-pathology
#9
Lila Ramaiah, Lindsay Tomlinson, Niraj K Tripathi, Laura C Cregar, Allison Vitsky, Barbara von Beust, Valerie G Barlow, William J Reagan, Daniela Ennulat
There is limited direction in the literature or regulatory guidance on determination of adversity for clinical pathology (CP) biomarkers in preclinical safety studies. Toxicologic clinical pathologists representing the American Society for Veterinary Clinical Pathology-Regulatory Affairs Committee and Society of Toxicologic Pathology-Clinical Pathology Interest Group identified principles, overall approach, and unique considerations for assessing adversity in CP data interpretation to provide a consensus opinion...
February 2017: Toxicologic Pathology
https://www.readbyqxmd.com/read/28013573/evaluation-of-mir-216a-and-mir-217-as-potential-biomarkers-of-acute-exocrine-pancreatic-toxicity-in-rats
#10
Jianying Wang, Wenhu Huang, Stephane Thibault, Thomas P Brown, Walter Bobrowski, Hovhannes J Gukasyan, Winston Evering, Wenyue Hu, Annette John-Baptiste, Allison Vitsky
Detecting and monitoring exocrine pancreatic damage during nonclinical and clinical testing is challenging because classical biomarkers amylase and lipase have limited sensitivity and specificity. Novel biomarkers for drug-induced pancreatic injury are needed to improve safety assessment and reduce late-stage attrition rates. In a series of studies, miR-216a and miR-217 were evaluated as potential biomarkers of acute exocrine pancreatic toxicity in rats. Our results revealed that miR-216a and miR-217 were almost exclusively expressed in rat pancreas and that circulating miR-216a and miR-217 were significantly increased in rats following administration of established exocrine pancreatic toxicants caerulein (CL) and 1-cyano-2-hydroxy-3-butene (CHB) as well as in rats administered a proprietary molecule known to primarily affect the exocrine pancreas...
February 2017: Toxicologic Pathology
https://www.readbyqxmd.com/read/28007014/evaluation-of-pepsinogen-i-as-a-biomarker-of-drug-induced-gastric-mucosal-injury-in-cynomolgus-monkeys
#11
Daniela Ennulat, Karen M Lynch, Carie L Kimbrough, Rosanna C Mirabile, Sabine Rehm
Gastric mucosal injury is frequently observed in nonclinical studies of nonhuman primates. Because microscopic evaluation of stomach is generally a terminal procedure, our objective was to determine whether serum pepsinogen I (PG I) could serve as a noninvasive biomarker for detection of gastric mucosal injury in monkey. Serum PG I was measured using a commercial human immunoassay in cynomolgus monkeys ( n = 166) prior to dosing and/or terminally in 11 studies of up to 1 month duration. Mean ( SD) PG I values (ug/L) for monkeys with ( n = 59) and without ( n = 100) gastric mucosal degeneration were 101 (215) and 28 (12...
February 2017: Toxicologic Pathology
https://www.readbyqxmd.com/read/27879436/cytological-bone-marrow-cell-differential-counts-and-morphologic-findings-in-healthy-cynomolgus-monkeys-macaca-fascicularis-from-nonclinical-toxicology-studies
#12
Caitlyn M Carter, Laura C Cregar, Adam D Aulbach
Cytological bone marrow evaluation is utilized in nonclinical toxicology studies to characterize hematopoietic effects when the combined interpretation of histologic and complete blood count data does not yield sufficient information. Results from cytological bone marrow examination should be interpreted in the context of variability observed in concurrent control animals with consideration of cytologist experience and historical/published data. Cytological bone marrow differential counts and cellular morphologic findings from 130 (66 male, 64 female) healthy control cynomolgus monkeys from nonclinical toxicology studies were retrospectively analyzed...
February 2017: Toxicologic Pathology
https://www.readbyqxmd.com/read/27729587/practical-considerations-in-clinical-pathology-data-interpretation-and-description
#13
Robert L Hall
Although interpretation and description of clinical pathology test results for any preclinical safety assessment study should employ a consistent standard approach, companies differ regarding that approach and the appearance of the end product. Some rely heavily on statistical analysis, others do not. Some believe reference intervals are important, most do not. Some prefer severity of effects be described by percentage differences from, or multiples of, baseline or control, others prefer only word modifiers...
February 2017: Toxicologic Pathology
https://www.readbyqxmd.com/read/27565173/mek-and-erk-kinase-inhibitors-increase-circulating-ceruloplasmin-and-cause-green-serum-in-rats
#14
Dolores Diaz, Rama Pai, Gary Cain, Nghi La, Donna Dambach, Jacob Schwartz, Jacqueline M Tarrant
Inhibition of the mitogen-activated protein kinase/extracellular signal-regulated (MAPK/ERK) pathway is an attractive therapeutic approach for human cancer therapy. In the course of evaluating structurally distinct small molecule inhibitors that target mitogen-activated protein kinase kinase (MEK) and ERK kinases in this pathway, we observed an unusual, dose-related increase in the incidence of green serum in preclinical safety studies in rats. Having ruled out changes in bilirubin metabolism, we demonstrated a 2- to 3-fold increase in serum ceruloplasmin levels, likely accounting for the observed green color...
February 2017: Toxicologic Pathology
https://www.readbyqxmd.com/read/27543323/assessment-of-cardiac-troponin-i-responses-in-nonhuman-primates-during-restraint-blood-collection-and-dosing-in-preclinical-safety-studies
#15
William J Reagan, Robert Barnes, Peter Harris, Sandy Summers, Sarah Lopes, Makeida Stubbs, David Blackwell, Jill Steidl-Nichols
Limited information has been published on the use of cardiac troponin I (cTnI) as a biomarker of cardiac injury in monkeys. The purpose of these studies was to characterize the cTnI response seen in cynomolgus macaques during routine dosing and blood collection procedures typically used in preclinical safety studies and to better understand the pathogenesis of this response. We measured cTnI using two different methods, the Siemens Immulite cTnI assay and the more sensitive Siemens Troponin I-Ultra assay. We were able to demonstrate that after oral, subcutaneous, or intravenous dosing of common vehicles, as well as serial chair restraint for venipuncture blood collection, that minimal to mild transient increases in cTnI could be detected in monkeys with both assays...
February 2017: Toxicologic Pathology
https://www.readbyqxmd.com/read/27189632/identification-and-evaluation-of-novel-microrna-biomarkers-in-plasma-and-feces-associated-with-drug-induced-intestinal-toxicity
#16
Dalia Y Kalabat, Allison Vitsky, Wesley Scott, Erick Kindt, Kyle Hayes, Annette John-Baptiste, Wenhu Huang, Amy H Yang
Gastrointestinal toxicity is dose limiting with many therapeutic and anticancer agents. Real-time, noninvasive detection of markers of toxicity in biofluids is advantageous. Ongoing research has revealed microRNAs as potential diagnostic and predictive biomarkers for the detection of select organ toxicities. To study the potential utility of microRNA biomarkers of intestinal injury in a preclinical toxicology species, we evaluated 3 rodent models of drug-induced intestinal toxicity, each with a distinct mechanism of toxicity...
February 2017: Toxicologic Pathology
https://www.readbyqxmd.com/read/27102652/serum-natriuretic-peptides-as-differential-biomarkers-allowing-for-the-distinction-between-physiologic-and-pathologic-left-ventricular-hypertrophy
#17
Michael E Dunn, Thomas G Manfredi, Kevin Agostinucci, Steven K Engle, Josh Powe, Nicholas M P King, Luis A Rodriguez, Kathryn E Gropp, Matthew Gallacher, Frederick J Vetter, Vijay More, Prajakta Shimpi, David Serra, Heidi M Colton
Given the proven utility of natriuretic peptides as serum biomarkers of cardiovascular maladaptation and dysfunction in humans and the high cross-species sequence conservation of atrial natriuretic peptides, natriuretic peptides have the potential to serve as translational biomarkers for the identification of cardiotoxic compounds during multiple phases of drug development. This work evaluated and compared the response of N-terminal proatrial natriuretic peptide (NT-proANP) and N-terminal probrain natriuretic peptide (NT-proBNP) in rats during exercise-induced and drug-induced increases in cardiac mass after chronic swimming or daily oral dosing with a peroxisome proliferator-activated receptor γ agonist...
February 2017: Toxicologic Pathology
https://www.readbyqxmd.com/read/28068894/strain-differences-in-a-murine-model-of-air-pollutant-induced-nonatopic-asthma-and-rhinitis
#18
Jack R Harkema, Lucas A Hotchkiss, Nicholas A Vetter, Daven N Jackson-Humbles, Ryan P Lewandowski, James G Wagner
Ozone is an irritating gas found in photochemical smog. Epidemiological associations have been made between the onset of asthma and childhood exposures to increasing levels of ambient ozone (i.e., air pollutant-induced nonatopic asthma). Individuals, however, vary in their susceptibility to this outdoor air pollutant, which may be due, in part, to their genetic makeup. The present study was designed to test the hypothesis that there are murine strain-dependent differences in pulmonary and nasal pathologic responses to repeated ozone exposures...
January 2017: Toxicologic Pathology
https://www.readbyqxmd.com/read/28068893/differences-in-types-and-incidence-of-neoplasms-in-wistar-han-and-sprague-dawley-rats
#19
Klaus Weber
A substantial quantity of data on Sprague-Dawley (SD) and Hannover Wistar rats strains have been published concerning their source, diet, and housing conditions, as well as the incidences of nonneoplastic lesions and neoplasms observed in different laboratories. Differences between the commonly used rat strains provided by different breeders (i.e., CD (SD) vs. Harlan Sprague-Dawley strain or Crl: WI(Han) vs. Wistar Hannover (Han)-derived strain, continued breeding by RCC Ltd., Switzerland, thereafter continued breeding by Harlan) may include, but are not limited to, body weight, incidence, and onset of major nonneoplastic lesions and neoplasms, and these can impact the development of a nonclinical safety program...
January 2017: Toxicologic Pathology
https://www.readbyqxmd.com/read/28068892/cornerstones-of-toxicology
#20
A Wallace Hayes, Darlene Dixon
The 35th Annual Society of Toxicologic Pathology Symposium, held in June 2016 in San Diego, California, focused on "The Basis and Relevance of Variation in Toxicologic Responses." In order to review the basic tenants of toxicology, a "broad brush" interactive talk that gave an overview of the Cornerstones of Toxicology was presented. The presentation focused on the historical milestones and perspectives of toxicology and through many scientific graphs, data, and real-life examples covered the three basic principles of toxicology that can be summarized, as dose matters (as does timing), people differ, and things change (related to metabolism and biotransformation)...
January 2017: Toxicologic Pathology
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