Fundamental Neuropathology for Pathologists and Toxicologists

Principles and Techniques

Brad Bolon, Mark Butt, Brad Bolon, Mark Butt

• Publisher: Wiley
• Year: 2011
• Print ISBN:
  9780470227336
• eBook ISBN:
  9781118002230
• Edition: 1
• Topic: Physical Sciences
• Subtopic: Industrial & Technical Chemistry

This book offers pathologists, toxicologists, other medical professionals, and students an introduction to the discipline and techniques of neuropathology – including chemical and environmental, biological, medical, and regulatory details important for performing an analysis of toxicant-induced neurodiseases. In addition to a section on fundamentals, the book provides detailed coverage of current practices (bioassays, molecular analysis, and nervous system pathology) and practical aspects (data interpretation, regulatory considerations, and tips for preparing reports).

Part 1

Fundamentals of Neurobiology

Chapter 1

Fundamental Neuropathology for Pathologists and Toxicologists: An Introduction

Brad Bolon

GEMpath, Inc., Longmont, Colorado

Doyle G. Graham

Duke–NUS Graduate Medical School, Singapore

The Importance of Neurotoxicological Research

Neurotoxicology is the study of the undesirable consequences that develop in the central nervous system (CNS) or peripheral nervous system (PNS) or both after an organism is exposed to a neurotoxic agent during development or adulthood. Such agents may be exogenous materials such as chemicals contaminating the external habitat (e.g., agrochemicals, pesticides, solvents) or introduced purposely into the internal environment (i.e., drugs); metals; or peptides/proteins (e.g., microbial toxins, biopharmaceuticals). Alternatively, neurotoxic agents may be produced endogenously (e.g., ammonia, unconjugated bilirubin) during the course of certain diseases. Thus, the nervous system is likely to experience constant exposure to a range of neurotoxic agents, although in many instances the level of exposure will be insignificant.

The potential scope of toxicant-induced neuropathology is immense. Each year in the United States, industries manufacture about 85,000 chemicals and register another 2000 to 3000 new compounds.¹ Approximately 3 to 5% of chemicals (between 2500 and 5000 entities) are estimated to be neurotoxic to some degree.² This estimate has serious implications for human, animal, and environmental health, because up to two-thirds of high-production-volume chemicals (those made yearly in quantities exceeding 1 million pounds) have never been tested sufficiently for neurotoxic potential.³ The recognition that neurological dysfunction is a major occupational hazard for adults^{4, 5} and a common congenital occurrence in children⁶ has engendered a wide-ranging global effort to identify and eliminate possible sources of neural damage—principally, sources of neurotoxicant exposure.

Neurotoxicity can present as aberrations in neural structure (i.e., toxicological neuropathology) or function (including altered behavior, biochemistry, cognition, or impulse conduction), or both.^7–11 All structural changes and any persistent functional deficits associated with xenobiotic exposure are judged to be neurotoxic because such effects cannot be countered by the meager regenerative capabilities of the CNS.¹² Reversible functional deficits linked to a recognized neurotoxicological mechanism (e.g., outright neurodegeneration or exaggerated neuropharmacological activity) or that might jeopardize occupational health (for adults) or scholastic performance (especially for children) are also considered to be neurotoxic manifestations. The current “best practice” in conducting risk assessments for potential neurotoxicants is to integrate all available structural and functional evidence in reaching a verdict.^{9, 13, 14} Nevertheless, the permanence of toxicant-induced structural changes in the CNS typically leads regulators to place more emphasis on morphological data rather than on behavioral or biochemical alterations to determine reference doses for managing neurotoxic risk.¹⁵ Therefore, a comprehensive toxicological neuropathology evaluation is and will remain a critical element of the risk assessment process for novel xenobiotics.¹⁶

The catastrophic outcome of neurotoxic damage to affected persons, and the strain placed on the resources (money, time) of their immediate caretakers and the societal entities that must often fund chronic health care, has led to the expanded use of neurotoxicity endpoints as major criteria for assessing the risks posed by exposure to xenobiotics.¹⁷ This approach is a direct result of two factors. First and foremost, an unfortunate aspect of human history from ancient times through the twentieth century is that the neurotoxic effects of many agents [e.g., ethanol, n-hexane, lead, mercury, polychlorinated biphenyls (PCBs)] have been identified first in humans.¹⁸ Second, exposure to potential neurotoxicants remains a common feature of human existence. Slightly less than a third of all high-volume industrial chemicals can elicit neurotoxic syndromes in the workplace.¹⁹ Similarly, many drugs [antiepileptics (e.g., valproic acid), antineoplastics (e.g., vincristine)] can induce neurotoxic sequelae as an undesirable side effect.^{18, 20, 21} Thus, a primary goal of current neurotoxicological research is to prospectively recognize the neurotoxic potential of novel compounds in laboratory animals rather than to discover it retrospectively after epidemics of neurotoxicity in humans.

The Evolution of Toxicological Neuropathology

People have exhibited an interest in fundamental neuroscience for millennia (Table 1).^{22, 23} Initial neurobiology investigations concentrated on gross anatomical characterization of the CNS and its PNS projections as well as the clinical detection and treatment of diseases affecting the nervous system. Neurohistological evaluations were first undertaken in a piecemeal sense early in the eighteenth century, and more systematic assessments of discrete neural regions were begun in the 1840s. These early studies were organized as descriptive studies of the normal nervous system anatomy. The first neuropathology reports examined neuroanatomical alterations resulting from physical disruption (e.g., Wallerian degeneration in transected axons, first described in 1850) rather than toxicant-mediated neural damage. This emphasis reflected the close alliance between neuropathology and clinical neurology in the European (mainly German) medical schools in which neuropathological research was formalized in the modern era.

Table 1 Selected Historical Landmarks in the Evolution of Toxicological Neuropathology.

Source: Adapted in part from Chudler.²²

Date	Event
ca. 1700 b.c.e.	First written record about the nervous system
ca. 1000 b.c.e.	First written treatise describing surgical treatments for some neurological disorders (Al-Zahrawi, also known as Abulcasis or Albucasis)
ca. 500 b.c.e.	First descriptions of nervous system dissection (cranial and sensory nerves) (Alcmaion of Crotona)
ca. 80	First description linking lead exposure to neurological disease (Dioscorides)
1549	Publication of De Cerebri Morbis, an early book devoted to neurological disease (Jason Pratensis)
1660–1700	First publications dedicated to neuroanatomy: Cerebri Anatome (Thomas Willis, 1664), Neurographia Universalis (Raymond Vieussens, 1684) and The Anatomy of the Brain (Humphrey Ridley, 1695)
1684	First record of a special preservation technique for neural tissue (boiling oil as a hardening agent, by Raymond Vieussens)
1717	First description of the nerve fiber in cross section (Anton van Leeuwenhoek)
1760	Initial demonstration that cerebellar damage affects motor coordination (Arne-Charles Lorry)
1766	Earliest scientific description of the cerebrospinal fluid (Albrecht von Haller)
1810–1825	First functional–structural correlates for many CNS regions are defined
1836	Neuron nucleus and nucleolus first differentiated by microscopy (Gabriel Gustav Valentin)
	Myelinated and unmyelinated axons are discerned (Robert Remak)
1837	Cerebellar neurons and their processes first investigated (Jan Purkinje)
1838	Myelin-forming cells in the peripheral nervous system described (Theodor Schwann)
1842	Spinal cord anatomy first studied in serial sections (Benedikt Stilling)
1844	First illustration provided of the six cerebrocortical layers (Robert Remak)
1850	Initial experimental investigation of axonal degeneration (Augustus Waller)
1859	The term neuroglia is coined (Rudolph Virchow)
1861	Functional localization in the cerebral cortex is described (Paul Broca)
1865	Axons and dendrites are first differentiated (Otto Friedrich Karl Deiters)
1873	First work on the silver nitrate method to enhance neuronal contrast (Camillo Golgi)
1878	Regular interruptions in the peripheral nerve myelin are first appreciated (Louis-Antoine Ranvier)
1884	Granular endoplasmic reticulum is discriminated in neurons (Franz Nissl)
1889	Nerve cells are proposed to be independent functional elements (Santiago Ramón y Cajal)
1891	The lumbar puncture (spinal tap) is developed (Heinrich Quinke)
	Journal of Comparative Neurology is founded
1897	Formaldehyde is employed as a brain fixative (Ferdinand Blum)
1906	First description of Alzheimer's disease (Alois Alzheimer)
	Nobel Prize in Physiology or Medicine awarded to Camillo Golgi and Santiago Ramón y Cajal for their work on neural cytoarchitecture
1921	Microglia described (Pío del Río-Hortega)
1929	Correlation between nerve fiber size and function is identified (Joseph Erlanger and Herbert Spencer Gasser...

Table of contents

• Cover
• Title Page
• Copyright
• Dedication
• Contributors
• Preface
• Acknowledgments
• Introduction
• Part 1: Fundamentals Of Neurobiology
• Part 2: Toxicologic Neuropathology: Methodology
• Part 3: Toxicological Neuropathology: Current Practices
• Part 4: Applied Toxicological Neuropathology
• References
• Index
• Color Plates