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Everds N.E.,Amgen Inc. | Snyder P.W.,Purdue University | Bailey K.L.,Oklahoma State University | Bolon B.,Ohio State University | And 4 more authors.
Toxicologic Pathology | Year: 2013

Stress often occurs during toxicity studies. The perception of sensory stimuli as stressful primarily results in catecholamine release and activation of the hypothalamic-pituitary-adrenal (HPA) axis to increase serum glucocorticoid concentrations. Downstream effects of these neuroendocrine signals may include decreased total body weights or body weight gain; food consumption and activity; altered organ weights (e.g., thymus, spleen, adrenal); lymphocyte depletion in thymus and spleen; altered circulating leukocyte counts (e.g., increased neutrophils with decreased lymphocytes and eosinophils); and altered reproductive functions. Typically, only some of these findings occur in a given study. Stress responses should be interpreted as secondary (indirect) rather than primary (direct) test article-related findings. Determining whether effects are the result of stress requires a weight-of-evidence approach. The evaluation and interpretation of routinely collected data (standard in-life, clinical pathology, and anatomic pathology endpoints) are appropriate and generally sufficient to assess whether or not changes are secondary to stress. The impact of possible stress-induced effects on data interpretation can partially be mitigated by toxicity study designs that use appropriate control groups (e.g., cohorts treated with vehicle and subjected to the same procedures as those dosed with test article), housing that minimizes isolation and offers environmental enrichment, and experimental procedures that minimize stress and sampling and analytical bias.This article is a comprehensive overview of the biological aspects of the stress response, beginning with a Summary (Section 1) and an Introduction (Section 2) that describes the historical and conventional methods used to characterize acute and chronic stress responses. These sections are followed by reviews of the primary systems and parameters that regulate and/or are influenced by stress, with an emphasis on parameters evaluated in toxicity studies: In-life Procedures (Section 3), Nervous System (Section 4), Endocrine System (Section 5), Reproductive System (Section 6), Clinical Pathology (Section 7), and Immune System (Section 8). The paper concludes (Section 9) with a brief discussion on Minimizing Stress-Related Effects (9.1.), and a final section explaining why Parameters routinely measured are appropriate for assessing the role of stress in toxicology studies (9.2.). © 2013 by The Author(s).

Smith G.,Huntingdon Life science
Bioanalysis | Year: 2011

The measurement of parent drug in biological samples is an integral part of the drug-development process from discovery support through to late phase clinical development. At some point during this process it may also be necessary to measure metabolites of the drug. The regulatory guidelines on metabolite safety testing outline metabolite exposure data that is required to support drug registration. There are also a number of publications that describe strategies for validating bioanalytical methods used to quantify metabolites based on the development status of the drug. Despite current regulatory and scientific thinking on this subject, there still seems to be a consensus in parts of the industry that drug metabolites should be measured whenever possible, provided that it is technically feasible to do so, rather than basing this decision on the development requirements of the drug. One consequence of this strategy is that often several metabolites are quantified when supporting early development studies (e.g., regulatory toxicology studies) using bioanalytical methods that have been fully validated to measure all the metabolites. This approach may be regarded as a questionable use of resources at a time when a more targeted approach to drug-development is probably a better option.

Clewell R.A.,Hamner Institutes for Health Sciences | Thomas A.,Hamner Institutes for Health Sciences | Willson G.,Experimental Pathology Laboratories Inc. | Creasy D.M.,Huntingdon Life science | Andersen M.E.,Hamner Institutes for Health Sciences
Reproductive Toxicology | Year: 2013

Male rat sexual development was evaluated after dietary administration of 0, 760, 3800, 11,400. ppm diisononyl phthalate (DiNP) and 7600. ppm dibutyl phthalate (DBP) from gestation day (GD) 12 to postnatal day (PND) 14. Maternal weight was reduced on GD 20, PND 2 and 14 at 11,400. ppm DiNP. Pup weight was reduced on PND 2 and 14 at 11,400 and 3800. ppm DiNP. DBP induced multinucleated germ cells (MNGs) and Leydig cell aggregates (LCAs) in PND 2 testes. 7600. ppm DBP reduced anogenital distance (AGD) on PND 2 and 14, and increased nipple retention and reproductive tract malformations on PND 49. DiNP induced MNGs (3800. ppm) and LCAs (11,400. ppm) on PND 2, and reduced AGD (11,400. ppm) on PND 14. DiNP did not alter AGD, nipple retention or reproductive tract malformations on PND 49. Global endpoint analysis showed no evidence of a rat " phthalate syndrome" on PND 49 with DiNP administration. © 2012 Elsevier Inc.

Pereira M.E.,Histo Scientific Research Laboratories | MacRi N.P.,Huntingdon Life science | Creasy D.M.,Huntingdon Life science
Toxicologic Pathology | Year: 2011

The rabbit is occasionally used for inhalation and intranasal safety assessment studies, but there are no detailed descriptions of the anatomy or histology of the rabbit nose. To address this deficit, the nasal cavities of thirty-two control adult rabbits were sectioned and examined to provide mapping of the main epithelial types and histological structures present within the cavity and turbinates. Four levels of the nasal cavity were prepared and examined using anatomic landmarks. Level I was sectioned immediately posterior to the incisors, Level II at the first palatal ridge, Level III immediately anterior to the first upper premolar teeth, and Level IV immediately anterior to the first upper molar. Level I was lined predominantly by squamous epithelium with small amounts of thick transitional epithelium, and examination is recommended only for studies involving test article administration via instillation. Level II was lined primarily with transitional and respiratory epithelia, whereas Levels III and IV were lined with respiratory and olfactory epithelia and often contained nasal-associated lymphoid tissue. The vomeronasal organs were evident only in Level II. The similarities and differences of these features are compared with those of other common laboratory species (rat, mouse, dog, and cynomolgus monkey) and man. © 2011 by The Author(s).

Chapin R.E.,Pfizer | Creasy D.M.,Huntingdon Life science
Toxicologic Pathology | Year: 2012

When test article-related testicular toxicity or Leydig cell tumors are identified in nonclinical studies, the measurement of circulating hormones such as luteinizing hormone, follicle-stimulating hormone, inhibin, testosterone, or prolactin is often considered in order to aid mechanistic investigations or to identify potential biomarkers in man. Although some hormone levels are relatively constant, others are subject to wide variability owing to pulsatility of secretion, diurnal rhythms, and stress. To avoid being misled, it is important that this variation is factored into any study design that includes hormone measurements. Since all these possibilities start from the pathologist's reading of the tissue sections, we begin with a review of the morphologic changes that are tied to underlying alterations in hormones. We then provide the reader with basic information and representative hormone data, including coefficients of variation, for the major male reproductive hormones in the three main nonclinical species (rats, dogs, and cynomolgus monkeys). Power and probability tables for rats and dogs allow estimates of the number of animals or samples needed to provide a given likelihood of detecting a hormonal change of a given size. More importantly, we highlight the variability of this process and the real value in readers developing this information at their own site. © 2012 by The Author(s).

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