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Toxicologic Pathology

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https://www.readbyqxmd.com/read/28056663/principles-for-assessing-adversity-in-toxicologic-clinical-pathology
#1
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...
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/27879438/a-comparison-of-rodent-and-nonrodent-laryngeal-and-tracheal-bifurcation-sensitivities-in-inhalation-toxicity-studies-and-their-relevance-for-human-exposure
#5
Vasanthi Mowat, David J Alexander, Andrew M Pilling
In inhalation toxicity studies, drug-induced lesions are frequently reported in the larynx and sometimes at the tracheal bifurcation (carina) in the rat, but less so in the dog or monkey, bringing into question the relevance of these rodent findings for humans. The rat larynx is widely considered to be more sensitive than that of the dog and monkey in its response to inhaled xenobiotics, although we could find no published data to support this. In this review, data from 52 inhalation studies involving rodent and nonrodent species were collated and reviewed...
November 22, 2016: 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
#6
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...
November 22, 2016: Toxicologic Pathology
https://www.readbyqxmd.com/read/27856969/impact-of-age-on-the-male-reproductive-system-from-the-pathologist-s-perspective
#7
Catherine A Picut, Amera K Remick
Age, and in particular young age, can significantly impact the response to toxicants in animals and can greatly influence the interpretation of tissue changes by the toxicologic pathologist. Although this applies to multiple organ systems, the current review focuses on the male reproductive system. When performing microscopic evaluation of male reproductive organs, the toxicologic pathologist must be aware of the dynamic changes in histomorphology, predominantly driven by timed hormonal alterations, at various life stages...
November 16, 2016: Toxicologic Pathology
https://www.readbyqxmd.com/read/27879439/interpreting-and-integrating-clinical-and-anatomic-pathology-results-pulling-it-all-together
#8
Lila Ramaiah, Mary Jane Hinrichs, Elizabeth V Skuba, William O Iverson, Daniela Ennulat
The continuing education course on integrating clinical and anatomical pathology data was designed to communicate the importance of using a weight of evidence approach to interpret safety findings in toxicology studies. This approach is necessary, as neither clinical nor anatomic pathology data can be relied upon in isolation to fully understand the relationship between study findings and the test article. Basic principles for correlating anatomic pathology and clinical pathology findings and for integrating these with other study end points were reviewed...
November 13, 2016: Toxicologic Pathology
https://www.readbyqxmd.com/read/27834287/naphthoquine-induced-central-nervous-system-and-hepatic-vasculocentric-toxicity-in-the-beagle-dog
#9
Jean-Rene Galarneau, Emily K Meseck, Robert L Hall, Wenkui Li, Margaret L Weaver
Naphthoquine phosphate (NP) was considered as a partner drug with a promising antimalarial drug candidate. Here we report unexpected adverse clinical signs and microscopic findings in a canine pilot toxicology study with NP. Male and female dogs were dosed daily by oral gavage with NP at 2, 10, or 50 mg/kg/day for a maximum of 14 days. NP was not tolerated at ≥10 mg/kg/day; several animals were sacrificed in moribund condition and marked neurological clinical signs were noted at 50 mg/kg/day. The main microscopic observation was central nervous system vasculocentric inflammation (mainly lymphocytes and macrophages) in the white and gray matter of various regions of the brain at ≥2 mg/kg/day and at lower incidence in the spinal cord at ≥10 mg/kg/day...
November 9, 2016: Toxicologic Pathology
https://www.readbyqxmd.com/read/27815489/translating-mouse-models-immune-variation-and-efficacy-testing
#10
Rani S Sellers
Mice and humans branched from a common ancestor approximately 80 million years ago. Despite this, mice are routinely utilized as animal models of human disease and in drug development because they are inexpensive, easy to handle, and relatively straightforward to genetically manipulate. While this has led to breakthroughs in the understanding of genotype-phenotype relationships and in the identification of therapeutic targets, translation of beneficial responses to therapeutics from mice to humans has not always been successful...
November 4, 2016: Toxicologic Pathology
https://www.readbyqxmd.com/read/27803290/deciphering-sources-of-variability-in-clinical-pathology-it-s-not-just-about-the-numbers
#11
Niraj K Tripathi, Nancy E Everds, A Eric Schultze, Armando R Irizarry, Robert L Hall, Anne Provencher, Adam Aulbach
The objectives of this session were to explore causes of variability in clinical pathology data due to preanalytical and analytical variables as well as study design and other procedures that occur in toxicity testing studies. The presenters highlighted challenges associated with such variability in differentiating test article-related effects from the effects of experimental procedures and its impact on overall data interpretation. These presentations focused on preanalytical and analytical variables and study design-related factors and their influence on clinical pathology data, and the importance of various factors that influence data interpretation including statistical analysis and reference intervals...
November 1, 2016: Toxicologic Pathology
https://www.readbyqxmd.com/read/28068894/strain-differences-in-a-murine-model-of-air-pollutant-induced-nonatopic-asthma-and-rhinitis
#12
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
#13
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
#14
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
https://www.readbyqxmd.com/read/28068891/immunological-variation-due-to-genetics-of-inflammatory-snps-and-age-and-impact-on-disease-manifestation
#15
Gary R Burleson
The immune system is a critical component in defense against viral, bacterial, parasitic, and fungal diseases. Immunological mechanisms, including immunological mediators, innate immunity, cell-mediated immunity, and humoral-mediated immunity, serve to maintain homeostasis and protect the host from disease. Immunological variation can impact defense mechanisms, however. Two factors in particular that can influence immune function are the single nucleotide polymorphisms (SNPs) and aging. SNPs affecting inflammatory cytokines are an important modifier involved in a number of diseases such as asthma, periodontal disease, atherosclerosis, diabetic retinopathy, psoriasis, and osteoporosis...
January 2017: Toxicologic Pathology
https://www.readbyqxmd.com/read/27879435/identification-of-mhc-haplotypes-associated-with-drug-induced-hypersensitivity-reactions-in-cynomolgus-monkeys
#16
Hong Wu, Jessica Whritenour, Jonathan C Sanford, Christopher Houle, Karissa K Adkins
Drug-induced hypersensitivity reactions can significantly impact drug development and use. Studies to understand risk factors for drug-induced hypersensitivity reactions have identified genetic association with specific human leukocyte antigen (HLA) alleles. Interestingly, drug-induced hypersensitivity reactions can occur in nonhuman primates; however, association between drug-induced hypersensitivity reactions and major histocompatibility complex (MHC) alleles has not been described. In this study, tissue samples were collected from 62 cynomolgus monkeys from preclinical studies in which 9 animals had evidence of drug-induced hypersensitivity reactions...
January 2017: Toxicologic Pathology
https://www.readbyqxmd.com/read/27821709/proceedings-of-the-2016-national-toxicology-program-satellite-symposium
#17
Susan A Elmore, Vivian S Chen, Schantel Hayes-Bouknight, Jessica S Hoane, Kyathanahalli Janardhan, Linda H Kooistra, Thomas Nolte, Kathleen A Szabo, Gabrielle A Willson, Jeffrey C Wolf, David E Malarkey
The 2016 annual National Toxicology Program Satellite Symposium, entitled "Pathology Potpourri" was held in San Diego, CA, at the Society of Toxicologic Pathology's (STP) 35th annual meeting. The goal of this symposium was to present and discuss challenging diagnostic pathology and/or nomenclature issues. This article presents summaries of the speakers' talks, along with select images that were used by the audience for voting and discussion. Some lesions and topics covered during the symposium included malignant glioma and histiocytic sarcoma in the rodent brain; a new statistical method designed for histopathology data evaluation; uterine stromal/glandular polyp in a rat; malignant plasma cell tumor in a mouse brain; Schwann cell proliferative lesions in rat hearts; axillary schwannoma in a cat; necrosis and granulomatous inflammation in a rat brain; adenoma/carcinoma in a rat adrenal gland; hepatocyte maturation defect and liver/spleen hematopoietic defects in an embryonic mouse; distinguishing malignant glioma, malignant mixed glioma, and malignant oligodendroglioma in the rat; comparison of mammary gland whole mounts and histopathology from mice; and discussion of the International Harmonization of Nomenclature and Diagnostic Criteria collaborations...
January 2017: Toxicologic Pathology
https://www.readbyqxmd.com/read/27815490/a-brief-overview-of-the-stp-35th-annual-symposium-on-the-basis-and-relevance-of-variation-in-toxicologic-responses
#18
Armando R Irizarry, Kathryn E Gropp, Darlene Dixon
The title of the 2016 Society of Toxicologic Pathology (STP) Symposium was the "Basis and Relevance of Variation in Toxicologic Responses." Many factors may contribute to variation in toxicologic responses and can confound results, complicate interpretation of data, interfere with reproducibility, and make extrapolation to humans problematic. This brief overview summarizes speaker presentations from each session which describes important factors that may impact the interpretation of nonclinical discovery and developmental toxicity studies...
January 2017: Toxicologic Pathology
https://www.readbyqxmd.com/read/27770107/is-it-adverse-nonadverse-adaptive-or-artifact
#19
Arun R Pandiri, Roy L Kerlin, Peter C Mann, Nancy E Everds, Alok K Sharma, L Peyton Myers, Thomas J Steinbach
One of the principal challenges facing a toxicologic pathologist is to determine and differentiate a true adverse effect from a nonadverse or an adaptive response. Recent publications from the Society of Toxicologic Pathology (STP) and the European STP provide guidance for determining and communicating adversity in nonclinical toxicology studies. In order to provide a forum to inform and engage in a discussion on this important topic, a continuing education (CE) course was held during the 2016 STP Annual meeting in San Diego, CA...
January 2017: Toxicologic Pathology
https://www.readbyqxmd.com/read/27708197/influence-of-study-design-on-developmental-and-reproductive-toxicology-study-outcomes
#20
Paul M D Foster
Regulatory studies of developmental and reproductive toxicity (DART) studies have remained largely unchanged for decades, with exposures occurring at various phases of the reproductive cycle and toxicity evaluations at different ages/times depending on the study purpose. The National Toxicology Program has conducted studies examining the power to detect adverse effects where there is a prenatal exposure, but evaluations occur postnatally. In these studies, examination is required of only 1 male and female pup from each litter beyond weaning...
January 2017: Toxicologic Pathology
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