scholarly journals International Regulatory Guiding Documents and Best Practice Recommendations on Peripheral Nervous System (PNS) Histopathologic Evaluation in Good Laboratory Practice (GLP)-Compliant Animal Toxicity Studies

2019 ◽  
Vol 48 (1) ◽  
pp. 78-86 ◽  
Author(s):  
Brad Bolon ◽  
Alys Bradley ◽  
Mark T. Butt ◽  
Karl Jensen ◽  
Deepa B. Rao
Keyword(s):  
Nervous System ◽  
Peripheral Nervous System ◽  
Best Practice ◽  
European Medicines Agency ◽  
Practice Recommendations ◽  
Toxicity Studies ◽  
Technical Requirements ◽  
Starting Point ◽  
Regulatory Guidelines ◽  
Animal Toxicity

Assessment of the peripheral nervous system (PNS) tissues during animal toxicity studies generally is included within guiding documents issued by regulatory agencies of individual nations (eg, US Environmental Protection Agency, US Food and Drug Administration) and multinational federations (eg, European Medicines Agency) as well as international cooperative efforts (eg, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, Organisation for Economic Co-operation and Development). The present list of major regulatory guiding documents categorizes recommendations from around the world for sampling and processing PNS tissues (nerves and ganglia) for general animal toxicity studies (ie, where neurotoxicity is not expected) and specialized neurotoxicity studies (ie, where neurotoxicity is anticipated or known to occur). In general, regulatory guidelines call for collection of one or more sensorimotor nerves (usually the sciatic trunk and its branches), though details vary among agencies. Regulatory guiding documents represent a “starting point,” after which additional PNS samples and/or special methods may be implemented at the applicant’s discretion. Best practice recommendations for PNS sampling and processing in animal toxicity studies endorsed by multiple global societies of toxicologic pathology encompass and expand on existing regulatory guidelines.

scholarly journals STP Position Paper: Recommended Best Practices for Sampling, Processing, and Analysis of the Peripheral Nervous System (Nerves and Somatic and Autonomic Ganglia) during Nonclinical Toxicity Studies

2018 ◽  
Vol 46 (4) ◽  
pp. 372-402 ◽  
Author(s):  
Brad Bolon ◽  
Georg Krinke ◽  
Mark T. Butt ◽  
Deepa B. Rao ◽  
Ingrid D. Pardo ◽  
...  
Keyword(s):  
Nervous System ◽  
Peripheral Nervous System ◽  
Cross Sections ◽  
Best Practice ◽  
Sympathetic Ganglia ◽  
Spinal Nerve ◽  
Toxicity Screening ◽  
Toxicity Studies ◽  
General Toxicity ◽  
Perfusion Fixation

Peripheral nervous system (PNS) toxicity is surveyed inconsistently in nonclinical general toxicity studies. These Society of Toxicologic Pathology “best practice” recommendations are designed to ensure consistent, efficient, and effective sampling, processing, and evaluation of PNS tissues for four different situations encountered during nonclinical general toxicity (screening) and dedicated neurotoxicity studies. For toxicity studies where neurotoxicity is unknown or not anticipated (situation 1), PNS evaluation may be limited to one sensorimotor spinal nerve. If somatic PNS neurotoxicity is suspected (situation 2), analysis minimally should include three spinal nerves, multiple dorsal root ganglia, and a trigeminal ganglion. If autonomic PNS neuropathy is suspected (situation 3), parasympathetic and sympathetic ganglia should be assessed. For dedicated neurotoxicity studies where a neurotoxic effect is expected (situation 4), PNS sampling follows the strategy for situations 2 and/or 3, as dictated by functional or other compound/target-specific data. For all situations, bilateral sampling with unilateral processing is acceptable. For situations 1–3, PNS is processed conventionally (immersion in buffered formalin, paraffin embedding, and hematoxylin and eosin staining). For situation 4 (and situations 2 and 3 if resources and timing permit), perfusion fixation with methanol-free fixative is recommended. Where PNS neurotoxicity is suspected or likely, at least one (situations 2 and 3) or two (situation 4) nerve cross sections should be postfixed with glutaraldehyde and osmium before hard plastic resin embedding; soft plastic embedding is not a suitable substitute for hard plastic. Special methods may be used if warranted to further characterize PNS findings. Initial PNS analysis should be informed, not masked (“blinded”). Institutions may adapt these recommendations to fit their specific programmatic requirements but may need to explain in project documentation the rationale for their chosen PNS sampling, processing, and evaluation strategy.

Nervous System Sampling for General Toxicity and Neurotoxicity Studies in the Laboratory Minipig With Emphasis on the Göttingen Minipig

2021 ◽  
Vol 49 (6) ◽  
pp. 1140-1163
Author(s):  
Ingrid D. Pardo ◽  
Rosa A. Manno ◽  
Raffaella Capobianco ◽  
Aaron M. Sargeant ◽  
James P. Morrison ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Nervous System ◽  
Best Practice ◽  
Target Organ ◽  
Tier 2 ◽  
Practice Recommendations ◽  
Göttingen Minipig ◽  
Toxicity Studies ◽  
General Toxicity ◽  
Tier 1

The use of minipigs as an alternative nonclinical species has increased in the last 20 years. The Society of Toxicologic Pathology (STP) has produced generic “best practice” recommendations for nervous system sampling in nonrodents during general toxicity studies ( Toxicol Pathol 41[7]: 1028–1048, 2013), but their adaptation to the minipig has not been attempted. Here, we describe 2 trimming schemes suitable for evaluating the unique neuroanatomic features of the minipig brain in nonclinical toxicity studies. The first scheme is intended for general toxicity studies (Tier 1) to screen agents with unknown or no anticipated neurotoxic potential; this approach using 7 coronal hemisections accords with the published STP “best practice” recommendations. The second trimming scheme for neurotoxicity studies (Tier 2) uses 14 coronal hemisections and 2 full coronal sections to investigate toxicants where the nervous system is a suspected or known target organ. Collection of spinal cord, ganglia (somatic and autonomic), and nerves from minipigs during nonclinical studies should follow published STP “best practice” recommendations for sampling the central (CNS, Toxicol Pathol 41[7]: 1028–1048, 2013) and peripheral (PNS, Toxicol Pathol 46[4]: 372–402, 2018) nervous systems.

Nervous System Sampling for General Toxicity and Neurotoxicity Studies in Rabbits

2020 ◽  
Vol 48 (7) ◽  
pp. 810-826 ◽  
Author(s):  
Ingrid D. Pardo ◽  
Deepa B. Rao ◽  
James P. Morrison ◽  
Colleen Huddleston ◽  
Alys E. Bradley ◽  
...  
Keyword(s):  
Nervous System ◽  
Best Practice ◽  
Rabbit Brain ◽  
Tier 2 ◽  
Practice Recommendations ◽  
Toxicity Studies ◽  
General Toxicity ◽  
Intact Brain ◽  
The Central Nervous System ◽  
Multiple Species

Although manuscripts for multiple species recommending nervous system sampling for histopathology evaluation in safety assessment have been published in the past 15 years, none have addressed the laboratory rabbit. Here, we describe 2 trimming schemes for evaluating the rabbit brain in nonclinical toxicity studies. In both schemes, the intact brain is cut in the coronal plane to permit bilateral assessment. The first scheme is recommended for general toxicity studies (tier 1) in screening agents where there is no anticipated neurotoxic potential; this 6-section approach is consistent with the Society of Toxicologic Pathology (STP) “best practice” recommendations for brain sampling in nonrodents ( Toxicol Pathol 41: 1028-1048, 20131). The second trimming scheme is intended for dedicated neurotoxicity studies (tier 2) to characterize known or suspected neurotoxicants where the nervous system is a key target organ. This tier 2 strategy relies on coronal trimming of the whole brain into 3-mm-thick slices and then evaluating 12 sections. Collection of spinal cord, ganglia, and nerve specimens for rabbits during nonclinical studies should follow published STP “best practice” recommendations for sampling the central nervous system1 and peripheral nervous system ( Toxicol Pathol 46: 372-402, 20182).

scholarly journals Atlas of Normal Microanatomy, Procedural and Processing Artifacts, Common Background Findings, and Neurotoxic Lesions in the Peripheral Nervous System of Laboratory Animals

2019 ◽  
Vol 48 (1) ◽  
pp. 105-131 ◽  
Author(s):  
Ingrid D. Pardo ◽  
Klaus Weber ◽  
Sarah Cramer ◽  
Georg J. Krinke ◽  
Mark T. Butt ◽  
...  
Keyword(s):  
Nervous System ◽  
Peripheral Nervous System ◽  
Animal Species ◽  
Laboratory Animals ◽  
Toxicity Studies ◽  
Study Materials ◽  
Microscopic Features ◽  
Plastic Resin ◽  
Perfusion Fixation ◽  
Neurotoxic Lesions

The ability to differentiate among normal structures, procedural and processing artifacts, spontaneous background changes, and test article–related effects in the peripheral nervous system (PNS) is essential for interpreting microscopic features of ganglia and nerves evaluated in animal species commonly used in toxicity studies evaluating regulated products and chemicals. This atlas provides images of findings that may be encountered in ganglia and nerves of animal species commonly used in product discovery and development. Most atlas images are of tissues from control animals that were processed using routine methods (ie, immersion fixation in neutral-buffered 10% formalin, embedding in paraffin, sectioning at 5 µm, and staining with hematoxylin and eosin) since these preparations are traditionally applied to study materials produced during most animal toxicity studies. A few images are of tissues processed using special procedures (ie, immersion or perfusion fixation using methanol-free 4% formaldehyde, postfixation in glutaraldehyde and osmium, embedding in hard plastic resin, sectioning at 1 µm, and staining with toluidine blue), since these preparations promote better stabilization of lipids and thus optimal resolution of myelin sheaths. Together, this compilation provides a useful resource for discriminating among normal structures, procedure- and processing-related artifacts, incidental background changes, and treatment-induced findings that may be seen in PNS tissues of laboratory animals.

scholarly journals Regulatory Forum Opinion Piece*: Effective Sectioning of Spinal Cord during Regulatory-type Nonclinical Toxicity Studies

2017 ◽  
Vol 45 (5) ◽  
pp. 580-583 ◽  
Author(s):  
Brad Bolon
Keyword(s):  
Spinal Cord ◽  
Nervous System ◽  
White Matter ◽  
Best Practices ◽  
Gray Matter ◽  
Vertical Plane ◽  
Toxicity Studies ◽  
Regulatory Guidelines ◽  
Motor Tracts ◽  
Regulatory Type

Regulatory guidelines for nonclinical neurotoxicity testing require spinal cord evaluation but do not specify a trimming scheme. The Society of Toxicologic Pathology (STP) “best practices” for nervous system sampling during nonclinical general toxicity studies recommend that spinal cord be assessed in both longitudinal/oblique and transverse sections. This article defines possible longitudinal/oblique orientations, describes their benefits and challenges, and provides an expert recommendation regarding suitable trimming planes. Longitudinal parasagittal (LP) sections follow a vertical plane just lateral to the midline, revealing sensory and motor tracts but little gray matter. Longitudinal horizontal sections transect only sensory or motor tracts and variable quantities of gray matter. Oblique vertical (OV) sections angle across the spinal cord from side to side. Oblique transverse (OT) sections slant through from top (dorsal [posterior]) to bottom (ventral [anterior]). Compared to longitudinal planes, oblique orientations demonstrate considerably more gray matter and white matter. Current STP “best practices” explicitly recommend the LP and OV options; the OT orientation also will yield suitable sections while permitting assessment of anatomic symmetry. Selection among the LP, OT, and OV planes should be at the discretion of the study pathologist. The bilaterally symmetrical OT sections likely will be analyzed most easily by nonneuropathologists.

scholarly journals Toxicologic Pathology of the Peripheral Nervous System (PNS): Overview, Challenges, and Current Practices

2018 ◽  
Vol 46 (8) ◽  
pp. 1028-1036 ◽  
Author(s):  
Ingrid D. Pardo ◽  
Deepa B. Rao ◽  
Mark T. Butt ◽  
Bernard S. Jortner ◽  
William M. Valentine ◽  
...  
Keyword(s):  
Nervous System ◽  
Peripheral Nervous System ◽  
Best Practice ◽  
Antiretroviral Drugs ◽  
Industrial Chemicals ◽  
Animal Data ◽  
Environmental Agents ◽  
Safety Studies ◽  
Case Presentations ◽  
Household Chemicals

Peripheral nervous system (PNS) toxicity is a frequent adverse effect encountered in patients treated with certain therapeutics (e.g., antiretroviral drugs, cancer chemotherapeutics), in occupational workers exposed to industrial chemicals (e.g., solvents), or during accidental exposures to household chemicals and/or environmental agents (e.g., pesticides). However, the literature and expertise needed for the effective design, conduct, analysis, and reporting of safety studies to identify and define PNS toxicity are hard to find. This half-day course familiarized participants with basic PNS biology; causes and mechanisms of PNS pathology; classic methods and current best practice recommendations for PNS sampling, preparation, and evaluation; and examples of commonly observed lesions and artifacts. Three concluding case presentations synthesized information from the prior technical lectures by presenting real-world examples of lesions caused by drugs and chemicals to demonstrate how PNS toxicity may be addressed in evaluating product safety during nonclinical studies. Topics emphasized comparative and correlative data among animal species used in toxicity studies and clinical evaluation in humans in order to facilitate the translation of animal data into human risk assessment with respect to PNS toxicologic pathology.

Glucuronyl 3-sulfate occurs exclusively on distal unmyelinated terminals of selected sensory neurons in the peripheral nervous system

1995 ◽  
Vol 53 ◽  
pp. 958-959
Author(s):  
S.S. Spicer ◽  
B.A. Schulte
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Cerebral Cortex ◽  
Peripheral Nervous System ◽  
Sensory Neurons ◽  
Sensory Nerves ◽  
Tissue Antigens ◽  
The Central Nervous System ◽  
The Brain ◽  
Leu 7

Generation of monoclonal antibodies (MAbs) against tissue antigens has yielded several (VC1.1, HNK- 1, L2, 4F4 and anti-leu 7) which recognize the unique sugar epitope, glucuronyl 3-sulfate (Glc A3- SO4). In the central nervous system, these MAbs have demonstrated Glc A3-SO4 at the surface of neurons in the cerebral cortex, the cerebellum, the retina and other widespread regions of the brain.Here we describe the distribution of Glc A3-SO4 in the peripheral nervous system as determined by immunostaining with a MAb (VC 1.1) developed against antigen in the cat visual cortex. Outside the central nervous system, immunoreactivity was observed only in peripheral terminals of selected sensory nerves conducting transduction signals for touch, hearing, balance and taste. On the glassy membrane of the sinus hair in murine nasal skin, just deep to the ringwurt, VC 1.1 delineated an intensely stained, plaque-like area (Fig. 1). This previously unrecognized structure of the nasal vibrissae presumably serves as a tactile end organ and to our knowledge is not demonstrable by means other than its selective immunopositivity with VC1.1 and its appearance as a densely fibrillar area in H&E stained sections.

Questions and Answers

2000 ◽  
Vol 5 (2) ◽  
pp. 3-3
Author(s):  
Christopher R. Brigham ◽  
James B. Talmage
Keyword(s):  
Nervous System ◽  
Peripheral Nervous System ◽  
Spinal Nerve ◽  
Sensory Loss ◽  
Residual Symptoms ◽  
Additional Information ◽  
Questions And Answers ◽  
Motor Nerves ◽  
Symptoms And Signs ◽  
Limited Motion

Abstract Lesions of the peripheral nervous system (PNS), whether due to injury or illness, commonly result in residual symptoms and signs and, hence, permanent impairment. The AMA Guides to the Evaluation of Permanent Impairment (AMA Guides) describes procedures for rating upper extremity neural deficits in Chapter 3, The Musculoskeletal System, section 3.1k; Chapter 4, The Nervous System, section 4.4 provides additional information and an example. The AMA Guides also divides PNS deficits into sensory and motor and includes pain within the former. The impairment estimates take into account typical manifestations such as limited motion, atrophy, and reflex, trophic, and vasomotor deficits. Lesions of the peripheral nervous system may result in diminished sensation (anesthesia or hypesthesia), abnormal sensation (dysesthesia or paresthesia), or increased sensation (hyperesthesia). Lesions of motor nerves can result in weakness or paralysis of the muscles innervated. Spinal nerve deficits are identified by sensory loss or pain in the dermatome or weakness in the myotome supplied. The steps in estimating brachial plexus impairment are similar to those for spinal and peripheral nerves. Evaluators should take care not to rate the same impairment twice, eg, rating weakness resulting from a peripheral nerve injury and the joss of joint motion due to that weakness.

Chronic neonatal mild stress induces long lasting alterations on peripheral nervous system programming in mice

2004 ◽  
Author(s):  
G. Galietta ◽  
A. Capasso ◽  
A. Fortuna ◽  
F. Fabi ◽  
P. Del Basso ◽  
...  
Keyword(s):  
Nervous System ◽  
Peripheral Nervous System ◽  
Mild Stress ◽  
System Programming
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