non-cancer toxicology
DESCRIPTION
Non-Cancer Toxicology. Introduction to the Health Effects of Chemicals Neurotoxicology. Steven G. Gilbert, PhD, DABT & www.asmalldoseof.org www.toxipedia.org. “You cannot reach your full genetic potential with a damaged nervous system.” S.G. Gilbert. Introduction. What is Neurotoxicity. - PowerPoint PPT PresentationTRANSCRIPT
Introduction to Neurotoxicology
Introduction to the Health Effects of Chemicals
Neurotoxicology
Steven G. Gilbert, PhD, DABT &
www.asmalldoseof.orgwww.toxipedia.org
Non-Cancer Toxicology
A Small Dose of Toxicology Introduction to Neurotoxicology
Introduction
“You cannot reach your full genetic potential with
a damaged nervous system.”
S.G. Gilbert
A Small Dose of Toxicology Introduction to Neurotoxicology
An adverse change in the chemistry, structure or function of the nervous system during development or at maturity, following exposure to a chemical or physical agent.
What is Neurotoxicity
A Small Dose of Toxicology Introduction to Neurotoxicology
Even minor changes in the structure or function of the nervous system may have profound consequences for neurological, behavioral, and related body functions.
Nervous System Sensitivity
A Small Dose of Toxicology Introduction to Neurotoxicology
Developmental alterationsImmunological impairmentNeurobehavioral effectsKidney/liver dysfunctionMutagenesisReproductive impairmentMetabolic inhibition
Examples of non-cancer toxicity
A Small Dose of Toxicology Introduction to Neurotoxicology
Toxicant Delivery to target tissue
Interaction with target molecule
Cell dysfunctionand/or Injury
Tissuedamage
TOXICITY
Exposure
General Mechanisms of Non-Cancer Toxicity
A Small Dose of Toxicology Introduction to Neurotoxicology
Interference with receptor-ligand interactions Interference with membrane functions Interference with cellular energy production Binding to macromolecules Perturbation of calcium regulation Toxicity from selective cell loss Non-lethal genetic alterations
Are there general mechanisms?
A Small Dose of Toxicology Introduction to Neurotoxicology
Rough Endoplasmic Reticulum
LysosomesPeroxisomes Mitochondria
MembraneProtein
Nucleus Golgi
Ribosomes
Animal Cell
A Small Dose of Toxicology Introduction to Neurotoxicology
CellCell
Lipid bilayerLipid bilayer
ChannelChannelPumpPump
TransportTransportProteinProtein
Hydrophilic headHydrophilic head
Hydrophobic tailsHydrophobic tails
Interference with Membrane Function
A Small Dose of Toxicology Introduction to Neurotoxicology
Neuro Insulation
A Small Dose of Toxicology Introduction to Neurotoxicology
Ancient Awareness
“LEAD MAKES THE MIND GIVE WAY”
Dioscorides - GREEK 2ND BC
A Small Dose of Toxicology Introduction to Neurotoxicology
“The upsurge of interest in recent years in academia, industry, and government on the effects of toxic chemicals on the nervous system has created a new discipline of neurotoxicology.”
Peter S. Spencer & Herbert H. Schaumberg, in Experimental and Clinical Neurotoxicology, 1980
Current Awareness
A Small Dose of Toxicology Introduction to Neurotoxicology
1930’s – Ginger-Jake Syndrome• During prohibition, an alcohol beverage was
contaminated with TOCP (triorthocresyl phosphate) causing paralysis in 5,000 with 20,000 to 100,000 affected.
1950’s – Mercury poisoning• Methylmercury in fish cause death and sever
nervous system damage in infants and adults.
Historical Events
A Small Dose of Toxicology Introduction to Neurotoxicology
Case Studies
Lead – damages developing brain
Alcohol – Fetal alcohol syndrome
MPTP – similar to Parkinson’s disease
A Small Dose of Toxicology Introduction to Neurotoxicology
Lead In Homes
A Small Dose of Toxicology Introduction to Neurotoxicology
Nervous Systems Effects
Developmental Neurotoxicity Reduced IQ Impaired learning and memory
Life-long effects
Lead Neurotoxicity
A Small Dose of Toxicology Introduction to Neurotoxicology
Alcohol (ethanol)
CH
H
H
OH
Ethyl Alcohol
C
H
H
A Small Dose of Toxicology Introduction to Neurotoxicology
Vulnerability of Developing Nervous System
FAS – Fetal Alcohol SyndromeFAE – Fetal Alcohol Effects
What is a save level of consumption during pregnancy?
Alcohol
A Small Dose of Toxicology Introduction to Neurotoxicology
Vulnerability of Developing Nervous SystemFAS – Fetal Alcohol SyndromeFAE – Fetal Alcohol Effects
ALCOHOL
What is a safe level of ethanol consumption during pregnancy?
http://www.fetalalcohol.com/what-is-fase.htm http://www.alumni.ca/~syed4s0/discussion.htm
A Small Dose of Toxicology Introduction to NeurotoxicologyFAS Child
A Small Dose of Toxicology Introduction to Neurotoxicology
MPTP
N
CH3
1-methyl-4-phenyl-1,2,3,6-tetrahydrophyridine
A Small Dose of Toxicology Introduction to Neurotoxicology
• 1980s – Designer Drug• Caused effects similar to
Parkinson’s disease• Damaged neurons that
secrete dopamine
MPTP Effects
A Small Dose of Toxicology Introduction to Neurotoxicology
• MPTP – 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine: a contaminant in
“synthetic heroin”
• Parkinson’s Disease-like symptoms in drug addicts
• Loss of neurons in the substantia nigra which synthesize and secrete dopamine
• MPTP-->MPP+ ---> oxidative stress
MPTP
A Small Dose of Toxicology Introduction to Neurotoxicologyhttp://www.swmed.edu/stars/resources/neurodisslides.html
MPTP – Real People
A Small Dose of Toxicology Introduction to Neurotoxicologyhttp://www.swmed.edu/stars/images/neurodisslides/Slide26.JPG
A Small Dose of Toxicology Introduction to Neurotoxicologyhttp://www.swmed.edu/stars/images/neurodisslides/Slide29.JPG
PD Brain
A Small Dose of Toxicology Introduction to Neurotoxicology
• CNS – Central Nervous System• PNS – Peripheral Nervous System• Blood brain barrier• Neuronal cells• Neurotransmitters & receptors• 10-100 billion cells with 1015
connections
Nervous System Biology
A Small Dose of Toxicology Introduction to Neurotoxicology
Nervous System – CNS & PNS
Central Nervous System (CNS)• Brain & Spinal Cord
Peripheral Nervous System (PNS)• Afferent (sensory) Nerves – Carry
sensory information to the CNS
• Efferent (motor) Nerves – Transmit information to muscles or glands
A Small Dose of Toxicology Introduction to Neurotoxicology
Nervous System
Nervous System
CNSCentral Nervous System
PNSPeripheral Nervous System
Autonomic Somatic
Sympathetic Parasympathetic
A Small Dose of Toxicology Introduction to Neurotoxicology
Central Nervous System
Central Nervous System (CNS)(Brain and Spinal Cord)
Peripheral Nervous System(PNS)
Autonomic Somatic
Sympathetic Parasympathetic
Afferent (sensory) Nerves(Carry sensory information to the CNS)
Efferent (motor) Nerves(Transmit information to muscles or glands)
A Small Dose of Toxicology Introduction to Neurotoxicology
Peripheral Nervous System
Peripheral Nervous System (PNS)• Efferent (motor) Nerves –
• Transmit information to muscles or glands Somatic Nervous System
• Stimulates Skeletal muscles Autonomic Nervous System
• Stimulates Glands and Organs (e.g. heart)• Sympathetic
- Adrenergic – stress response
• Parasympathetic - Cholinergic –
basic functions
A Small Dose of Toxicology Introduction to Neurotoxicology
Cells of the Nervous System
Neurons• Information conductors
Supporting Cells (Glia cells)• Astrocytes (CNS – blood brain barrier)
• Oligodendrocytes (CNS – link cells)
• Schwann cells (PNS – wrap cells)
A Small Dose of Toxicology Introduction to Neurotoxicology
Blood-brain Barrier
Not an absolute barrier• Caffeine (small)• Methylmercury cysteine complex• Lipids (brain is a ball of fat)
Anatomic Characteristics• Capillary endothelial cells are tightly joined –
no pores between cells• Capillaries in CNS surrounded by astrocytes• Low protein concentration in CNS fluid• Active ATP-dependent transporter – moves
chemicals into the blood
A Small Dose of Toxicology Introduction to Neurotoxicology
Neuronal Cells
Axon
Myelin (Schwann cell)
Synapse
Dendrite
Cell Body
Nucleus
A Small Dose of Toxicology Introduction to Neurotoxicology
DopamineTransmitter Cell(Excitatory Neuron)
DopamineReceptor Cell(Post-synaptic receptor)
DopamineReceptor
Synaptic Cleft
Synaptic Vesicles
Neurotransmission
A Small Dose of Toxicology Introduction to Neurotoxicology
Neuronal Transmission
+ + - + +
+ + - + +
+ + - + +
+ + - + +
- - + - -- - + - -
- - + - -- - + - -
- - - - -+ + + + +- - - - -+ + + + +
++
++
+ + +++ +
++ +-
--
- -- ----
-K+
K+
Na+
Cl-
-- -
-
-
--
-
- -
Inhibitory Synapse
Excitatory Synapse
+400
-40-70
+400
-40-70
Action Potential IPSP
EPSP
Action Potential
No Action Potential
A Small Dose of Toxicology Introduction to Neurotoxicology
• Inhalation (e.g. solvents, nicotine)
• Ingestions (e.g. lead, alcohol)• Skin (e.g. pesticides, nicotine)• Physical (e.g. load noise)
Exposure Issues
A Small Dose of Toxicology Introduction to Neurotoxicology
What causes neurotoxicity?
Wide ranged of agents – chemical and
physical
A Small Dose of Toxicology Introduction to Neurotoxicology
Types Of Neurotoxicity
Neuronopathy• Cell Death. Irreversible – cells not replaced.• MPTP, Trimethytin
Axonopathy • Degeneration of axon. Reversible.• Hexane, Acrylamide
Myelinopathy• Damage to myelin (e.g. Schwann cells)• Lead, Hexachlorophene
Transmission Toxicity• Disruption of neurotransmission• Organophosphate pesticides, Cocaine, DDT
A Small Dose of Toxicology Introduction to Neurotoxicology
Neurotoxic Injury
Neuron
Normal
Neuronopathy
Axonopathy
Myelinopathy
Transmission
Axon
Synapse
Myelin
A Small Dose of Toxicology Introduction to Neurotoxicology
Examples of Neurotoxicology
DiseasesParkinson's, Alzheimer's, MS, ALS..
EnvironmentalLead, Methylmercury, PCBs
OccupationalSolvents, Pesticides
Drugs - ClinicalVincristine, cisplatin
Drugs - SocialAlcohol, cocaine, nicotine
A Small Dose of Toxicology Introduction to Neurotoxicology
Cognitive Effects - memory, learning, confusion
Motor Effects- weakness, convulsion, paralysis
Sensory Effects- vision, auditory, touch, balance
Mood and Personality Effects- sleep, depression, irritability, excitability
General Effects- loss of appetite, fatigue
Neurotoxic Effects
A Small Dose of Toxicology Introduction to Neurotoxicology
Classification of Neurotoxicant
Temporary inhibition of nerve function• Agents which alter membrane
function• Agents with interfere with synaptic
transmission
Mechanism of action
A Small Dose of Toxicology Introduction to Neurotoxicology
Classification of Neurotoxicant
Permanent inhibition of nerve function• Agents which cause Anoxia
• Anoxic anoxia (e.g. CO2 asphyxiation)• Ischemic anoxia (e.g. blood clot)• Cytotoxic anoxia (e.g. cyanide)
• Agents which damage myelin formation• Oligodendroglia (CNS)• Schwann cells (PNS)
• Agents which damage peripheral axons• Agents which damage nerve cell body• Agents which cause localized CNS lesions
Mechanism of action
A Small Dose of Toxicology Introduction to Neurotoxicology
1. Autonomic function (lacrimation and salivation, piloerection and exophthalmus, urination and defecation, pupillary function, palpebral closure)
2. Convulsions, tremors, or abnormal motor movements3. Reactivity to general stimuli such as removal from the cage or handling
(no reaction to hyperreactivity)4. Arousal level (from coma to hyperalertness)5. Posture and gait abnormalities (home cage and open field)6. Forelimb and hindlimb grip strength7. Landing foot splay8. Sensorimotor responses to stimuli (a tail-pinch, tailflick, hot-plate,
acoustic startle response )9. Body weight10. Any unusual or abnormal behaviors, excessive or repetitive actions
(stereotypies), emaciation, dehydration, hypotonia or hypertonia, altered fur appearance, red or crusty deposits around the eyes, nose, or mouth, and any other observations that may facilitate interpretation of the data.
Functional Observational Battery (FOB)
A Small Dose of Toxicology Introduction to Neurotoxicology
1. Count of rearing activity on the open field. 2. Ranking of righting ability. 3. Body temperature. 4. Excessive or spontaneous vocalizations. 5. Alterations in rate and ease of respiration,
e.g., rales or dyspnea. 6. Sensorimotor responses to visual or
proprioceptive stimuli.
Functional Observational Battery (FOB)
A Small Dose of Toxicology Introduction to Neurotoxicology
• Memory and learning tests (e.g. radial maze, Morris water maze)
• Conditioned stimulus/responses• Other supportive techniques:• Histopathology/Quantitative Stereology• EEG, EMG, Functional MRI:
CBV-fMRI of rat brain induced by electrical stimulation of both forepaws. T. Reese, A. Sauter, N. Beckmann, M. Rudin et al.Novartis Pharmaceutical, Basel, Switzerland
http://www.bruker-biospin.de/MRI/applications/bio29.html
Other measures
A Small Dose of Toxicology Introduction to Neurotoxicology
WHAT IS THIS?
N
NN
N
CH3
CH3
CH3
O
O
1
3
7
A Small Dose of Toxicology Introduction to Neurotoxicology
Dependence on oxygen• Little anaerobic capacity• CO – less available oxygen• Cyanide – inability to use oxygen
Dependence on glucose• Sole energy source
High metabolic rate
Physiological Sensitivity
A Small Dose of Toxicology Introduction to Neurotoxicology
H+
H+
H+
I III IV V
+++++++ +++++++++++++ +++ ++++++
- - - - - - - - - - - - - - - - - - - - - - - - - -- - -
NAD+NADH + H+
O2 + 4H+
2H2O
Matrix
Intermembrane Space
3 ATP
H+
Interference with Energy Production
A Small Dose of Toxicology Introduction to Neurotoxicology
Carbon monoxide, nitrites Affect oxygen delivery to tissues
Nitrophenols, organotins, mercurials Uncouple oxidative
phosphorylation Rotenone, antimycin A, cocaine
Inhibit electron transport
Energy Production Inhibitors
A Small Dose of Toxicology Introduction to Neurotoxicology
Binding to macromolecules
Interference with enzyme functionMethotrexate (DHFR inhibitor)Hydroxyurea (Ribonucleotide reductase)
Formation of lipid hydroperoxides, free radical generationCarbon tetrachloride, paraquat, ozone
Nucleic acids (DNA, RNA)Cyclophsophamide, MNU, MMS
A Small Dose of Toxicology Introduction to Neurotoxicology
Oxidative stress Depletion of GSH (DEM, BSO, metals) Oxidation of protein thiols (metals)
SS
Hg S
S
Hg
Active Inactive
Binding to macromolecules
A Small Dose of Toxicology Introduction to Neurotoxicology
Structure• Long cell requires extensive
intracellular transport
Blood-Brain BarrierDevelopmental stage
(lead and alcohol)
Physiological Sensitivity
A Small Dose of Toxicology Introduction to Neurotoxicology
Neurons CANNOT divide and replace themselves
Neurons CAN repair limited axonal damage
Most Recovery• Redundancy of Function• Plasticity of Organization
Reversibility of Damage
A Small Dose of Toxicology Introduction to Neurotoxicology
Classification of neurotoxicants by mechanism of action
Permanent inhibition of nerve function• Agents which cause Anoxia
• Anoxic anoxia• Ischemic anoxia• Cytotoxic anoxia
• Agents which damage myelin formation• Oligodendroglia (CNS)• Schwann cells (PNS)
• Agents which damage peripheral axons• Agents which damage nerve cell body• Agents which cause localized CNS lesions
A Small Dose of Toxicology Introduction to Neurotoxicology
Neurological and Behavioral Effects of Exposure to Toxic Substances
Motor Effects - Convulsions, weakness, tremor, twitching, lack of coordination, unsteadiness, paralysis, reflex abnormalities, activity changes
Sensory Effects - Equilibrium changes, vision disorders, pain disorders, tactile disorders, auditory disorders
Cognitive Effects - Memory problems, confusion, speech impairment, learning impairment
Mood and personality effects - Sleep disturbances, excitability, depression, irritability, restlessness, nervousness, tension, delirium, hallucinations
General effects - Loss of appetite, depression of neuronal activity, narcosis stupor, fatigue, nerve damage
A Small Dose of Toxicology Introduction to Neurotoxicology
ReceptorReceptor
LigandLigand
Cell MembraneCell Membrane
Signal ProteinSignal Protein
Positive ResponsePositive Response
Outside CellOutside Cell
Inside CellInside Cell
Ligand binds to receptorLigand binds to receptor
11
33
22
Normal Receptor-Ligand Interaction
A Small Dose of Toxicology Introduction to Neurotoxicology
ToxicantToxicant11
Toxicantinactivates
receptor
Toxicantinactivates
receptor
No ResponseNo Response
3322
Inactivation of Receptor by Toxicant
A Small Dose of Toxicology Introduction to Neurotoxicology
Toxicant1
No Response
32
Ligand
Toxicant out competes normal ligand
Ligand cannot bind receptor
Competition For Receptor
A Small Dose of Toxicology Introduction to Neurotoxicology
Who Is Vulnerable?
Young or OldMale or FemaleGenetics - Individual Diff.Species
A Small Dose of Toxicology Introduction to Neurotoxicology
Fetal Nervous System
Developing Nervous System
Mature Nervous System
Aging Nervous System
Vulnerability / Sensitivity
A Small Dose of Toxicology Introduction to Neurotoxicology
A Small Dose of ™ Neurotoxicity
A Small Dose of Toxicology Introduction to Neurotoxicology
Additional Information
Web Sites• U.S. National Institute of Health - National Institute
of Neurological Disorders and Stroke (NINDS). Online. Available HTTP: <http://www.ninds.nih.gov/> (accessed: 10 April 2003).
• Natural Resources Defense Council (NRDC). Online. Available HTTP: <http://www.nrdc.org/health/kids/cfqpa0599.asp> (accessed: 10 April 2003). NRDC site provides information on children’s health and neurotoxicology.
Other Chapters• Mercury, lead, pesticides
A Small Dose of Toxicology Introduction to Neurotoxicology
Authorship Information
For Additional Information ContactSteven G. Gilbert, PhD, DABT
E-mail: [email protected]: www.asmalldoseof.org
This presentation is supplement to “A Small Dose of Toxicology”