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Delineating Toxicity Pathways of Peripheral Neuropathy. David Herr, Ph.D. Neurotoxicology Division US EPA RTP, NC McKim Conference on Predictive Toxicology. What is Neurotoxicity?.

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Delineating toxicity pathways of peripheral neuropathy l.jpg

Delineating Toxicity Pathways of Peripheral Neuropathy

David Herr, Ph.D.

Neurotoxicology Division

US EPA

RTP, NC

McKim Conference on Predictive Toxicology


What is neurotoxicity l.jpg
What is Neurotoxicity?

  • Neurotoxicity: “An adverse change in the structure or function of the central and/or peripheral nervous system following exposure to a chemical, physical, or biological agent”1

  • Adverse Effect: “Alterations from baseline or normal conditions that diminish an organism’s ability to survive, reproduce, or adapt to the environment”1

    1Guidelines for Neurotoxicity Risk Assessment

    Federal Register, 63(93):26926-26954, 1998

    http://cfpub.epa.gov/ncea/raf/recordisplay.cfm?deid=12479


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Complexity of Nervous System

  • Peripheral Nervous System (PNS)

    • Peripheral Nerves

    • Neuromuscular Junction

  • Autonomic Nervous System (ANS)

  • Central Nervous System (CNS)

  • Characteristics that increase vulnerability

    • High energy requirements

    • Electrical transmission of action potentials and chemical transmission

    • Long spatial extensions (axons) and large cell volumes

      • Need to transport cellular material


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  • Behavioral

    • Parasthesias

    • Increased reaction time

    • Vibrotactile abnormalities

    • Paralysis

Signs of Peripheral/Central Neuropathies

  • Biochemical

    • Neurofilament accumulations

    • Changes in axonal transport

    • Altered myelin

    • Altered ion gradients

  • Physiological

    • Decreased amplitudes of nerve action potentials

    • Decreased nerve conduction velocity

    • Denervation potentials in muscles

    • Alterations in somatosensory evoked potentials

  • Pathological

    • Neuronal / Axonal degeneration

    • Changes in myelin


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QSAR

NRC 21st Centrury Toxicology Testing Paradigm

Reversibility

Systems Biology: Define normal function and its bounds, where further insult compromises function and leads to toxicity

NRC, 2007


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Patterns of Neurotoxic Injury

  • Neuronopathy: Death of entire neuron

    • Astrocyte proliferation

  • Axonopathy: Axon degenerates

    • Neuronal chromatolysis

    • Nissl substance and nucleus to periphery

  • Myelinopathy: Injury to Schwann or Oligodendrocytes

Adapted From: Anthony et al., Casarett & Doull, 2001


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Types of Toxicity – Neuronopathies

  • Primary “Neuronal” Site of Action

    • Metabolic Inhibitors: 6-Amino-nicotinamide, arsenic

    • Inhibit DNA/Protein Synthesis: cloramphenicol, doxorubicin

    • Protein Binding: thallium, methyl mercury (?)

    • Excitotoxicity: B-N-Methylamino-L-alanine (BMAA)

  • Multiple chemical classes, Modes of action(s)

    • No single event leads to neuronal death

    • Overwhelm repair process = f:(dose, duration, persistence, repair)

    • Can model NMDA receptors, metabolic inhibitors (?),

      propensity for protein binding (?), etc…

    • What is critical event to produce neuropathy?


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Types of Toxicity - Axonopathies

  • Classical Agents:

  • Gamma-Diketones (Hexane,

    2,5-Hexanedione,

    n-butyl ketone)

  • Carbon Disulfide

  • B,B’-Iminodipropionitrile

  • Acrylamide

  • Zinc Pyridinethione

Adapted From: Anthony et al., Casarett & Doull, 2001


Mechanisms of pns toxicity n hexane and cs 2 l.jpg

CS2 reacts with

amino groups

Gamma-Diketone reacts

with amino groups

Mechanisms of PNS Toxicity - n-hexane and CS2

Dithiocarbamate adducts

with lysyl amino groups

Pyrrole Formation

Isothiocyanate adducts

react with protein

nucleophiles

Pyrrole Oxidation

N,S-dialkyldithiocarbamate

esters are slowly

reversible

Thiourea adducts are

irreversible

Covalent Protein X-Linking

Adapted From: Anthony et al., Casarett & Doull, 2001


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Irreversible = OPIDN

Reversible = No OPIDN

Mechanisms of PNS Toxicity - OPIDN

Group A:

Phosphonates = phosphorofluoridates =

phosphonofluoridates = phophorodiaminodofluoridates =

phosphoroamidofluoridates > phosphates >

phosphorotrithioates > phosphorothioates =

phosphonothioates = phosphinofluoridates >

phosphorochloridates

Adapted From: O’Callaghan, 2003

Winthrow et al., 2003

Massicotte, 1998

Chambers and Levi, 1992


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Mechanisms of PNS Toxicity - Axonopathy

  • Primary “Axonal” Site of Action

    • Neurofilament Cross-Linking: 2,5-Hexanedione, 3,4-dimethyl-hexanedione, CH3n-butyl ketone, CS2

      • Distal -> central

    • Altered Axonal Transport: IDPN (anteriorgrade), pyridinethione (retrograde), acrylamide? (nerve terminal)

    • Organophosphate-Induced Delayed Neuropathy: Tri-ortho-cresyl phosphate (TOCP), O-ethyl O-4-nitrophenylphenylphosphonothioate (EPN), leptophos

      • Neuropathy Target Esterase (NTE) – Requires aging?, delayed for 7-10 days (after cholinergic signs)

    • Actions on Microtubules: Colchicine, vincristine, vinblastine, paclitaxel

      • Bind to tubulin, depolymerization of microtubules (or stabilization – paclitaxel)

  • Perhaps the best predictive capabilities


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Mechanisms of PNS Toxicity - Myelinopathy

  • Primary “Glial” Site of Action

    • Intramyelinic Edema: Hexachlorophene, acetylethyltetramethyl tetralin (AETT), ethidium bromide, triethyltin

      • Splitting of intraperiod line (PNS and CNS), Spongiosis of brain

    • Demylenation: Tellurium, amiodarone, disulfiram, lysolecithin, perhexilene, lead

      • Schwann cells lose ability to maintain myelin and/or die

      • Disassemble concentric layers of myelin

      • Largest axons > smaller axons

    • Metabolic Disruptors: 6-ANT, Metronidazole, fluroacetate/flurocitrate, methionine sulfoximine, disulfiram

      • Disrupt mitochondiral metabolism, TCA cycle, ATP production, glutamine synthetase, chelates cations

      • Altered glutamine metabolism


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Cell nutrients

Energy balance

Required co-factors

Axonal Transport

Biologic Interaction

f:(damage,repair)

Perturbation

Cell nutrients

Energy balance

Protein synthesis/activity

Ca+2 balance

ROS

Ion gradients

Metabolic inhibition (MT)

DNA/Protein disruption

Excitotoxicity

Membrane turnover

?

Toxic Pathway(s)

Exposure

ADME

Neuronal Death

?

NTE inhibition

X-linking

Neurofilaments

Trophic factors

Glutamine metabolism

Lipid metabolism

Supportive function

Ion gradients

Glial effects


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Challenges for the Future – Systems Biology and QSAR

  • System-level understanding of biological processes

    • Initiating events and subsequent downstream critical events

  • Model Components:

    • Structure of the system (gene regulatory systems, biochemical networks, and physical structures)

    • Dynamics (changes over time) of the system, both quantitatively and qualitatively

      • Theory/model needs predictive capability

    • Biological controls of the system

  • Appropriate tools to design the system


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Physiological Systems & Function

Top-Down

Systems

Organs

Middle-Out

Cells

Tissues

Pathways

Organelles

Bottom-Up

Molecular Data & Mechanisms

Moving to the Future - Modeling Strategies

Modified From: Noble, 2003



Toxic pathway s17 l.jpg

  • Loss of ion gradients – mitochondrial uncoupling

  • Altered lipid metabolism

  • Metabolic disruption

  • Altered glutamine metabolism

  • ?

Toxic Pathway(s)

  • Membrane turnover

  • Inhibition of NTE

  • ?

  • Neurofilament X-linking

  • Axonal transport

  • Lack of “cell constituents”

  • Ion chelation

  • ?


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Types of Validity

  • Content Validity: Does the effect result from exposure to a substance (dose-related)

  • Construct Validity: Does the test measure what we think it does? Is the effect adverse or toxicologically relevant?

  • Concurrent Validity: Correlative measures among other endpoints (biochemical, physiological, behavioral, pathological)

  • Predictive Validity: Do the results predict what will happen under various conditions? Are the results predictive of human effects?


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