Neurotoxicology

2 types of signal transmission:

Axonic transmission: impulse travels through a neuron. Greatest distance traveled is along
the axon.
-results from changes in the distribution of cations and anions across the plasma membrane
- when a neuron is at rest, the inside of the membrane has a slightly negative charge (-
70mv) The neuron is polarized.
-concentration of Na and K differ between the inside and outside (NA is higher outside than
inside, K is higher inside than outside)
- Ion-specific channels do not leak very fast. Otherwise, the Na-K exchange pump would
burn through huge amounts of ATP trying to maintain the concentration gradients.
- Change in membrane potential result from changes in membrane permeability.
- ejects 3 sodium, import 2 Potassium

Synaptic transmission: Signal passes across the synapse separating the axon terminal of a
presynaptic neuron from the post-synaptic membrane of another cell

2 types of changes in membrane potential

Graded potential: local change that gets weaker with distance
Action potential: long-distance change that does not get weaker with the distance it travels
(Axon has a lot, dendrites have none)
-carry nervous impulses only along axons
1. Local currents carry enough charge to the base of the axon to raise the potential of the
inside of the membrane to threshold voltage
2. When the threshold is reached, voltage-gated Na+ channels open up, sodium comes in.
and depolarize the membrane potential.
3. More sodium channels open up (positive feedback loop)
4. Peak voltage is somewhere around +30 +40
5. Whole process repeats until high Na concentration reach the synaptic terminals at the
end of the axon

2 Mechanisms that restores Na filled portion of an axon to resting potential

[Link] on ATP-powered active transport system to pump Na out of the axon
2. When membrane potential reaches its peak, some voltage-regulated K channels open and
the membrane returns to resting potential.(The method animals actually use)

Na - K exchange cleans up the K ions outside of the membrane and the Na ions cluttering up
in the inside of the axon. It consumes about two thirds of all the energy.

2 Advantages when myelin sheaths around an axon

1. Nerve impulses propagate faster under a myelin sheath. (Saltatory conduction, opposite
to continuous conduction)
2. No Na or K channel need to open under a sheath, so less action and energy consumption
is required by sodium-potassium exchange pumps.

2 celebrated toxins that plug up Na channel

1. Saxitoxin (has 2 positively charged N atoms, one is attracted to negatively charged amino
acids on the outer surface, and the other is drawn into the outer portion of the throat of Na
Channels) 5.7 ug/kg
2. Tetrodotoxin 10 ug/kg

Batrachotoxin(2ug/kg) keeps the Na Channels open

Strychnine (2.4-15 mg/kg)

Synaptic Transmission

2 groups of Neurotransmitters
1. Primarily in the central nervous system(brain + Spinal cord).
2. Peripheral nervous system.
- norepinephrine - serotonin, dopamine. melatonin
- Acetylcholine(ACh) - signals striated muscle and parasympathetic system targets
2 divisions of Autonomic Nervous System
1. Sympathetic - FIGHT or FLIGHT activates system you need to respond to a threat; throttles
back blood supply to optional systems.
2. Parasymapathetic - REST & DIEGEST wakes up housekeeping system that can be done
anytime but are not vital during emergencies. generates drool, tears

How do they work?

1. Ionotropic receptors - sits next to ligand gated ion channels
2. Metabotropic receptors - after receiving their ligand, they release an intracellular
messenger to turn on the gland.

Neurotransmitters and receptors in the Peripheral Nervous System

- Signals from CNS through PNS cross cholinergic synapses with nicotinic receptors on the
post-synaptic membranes except for the last synapse.
-When 2 Ach molecules bind to an AChR, Na channel opens. The resulting starts a weak
current that initiate an action potential

Latrotoxin, produced black widow spiders binds to neurexins and forms pores especially
permeable to Ca ions.

Boutulinum toxin - LD50 = 1-2ng/kg

Steps in Vesicle Fusion

1. Tethering
2. Docking
3. Priming
4. Fusion

Poisoning Cholinergic Synapses

-nAChR antagonists block the receptors so the signals carried across synapses by Ach are
never received by the post-synaptic membrane.

Nerve Agents
Sarin, VX, Tabun inhibit acetylcholinesterase(ACheE).

AChE in action
Lone pair of SER oxygen makes nucleophilic attack on carbonyl group of Ach, displacing
deprotonated choline as leaving group.
Water attacks the same carbonyl group removing acetic acid and regeneration AChE ready
for the next ACh molecule
Environmental Chemistry

Grouping Toxicants
1. Mechanisms, degree, chronic versus acute exposure
2. Intended use
3. Chemical groupings
4. Physical Properties

Commonly used groups

DNAPL - volatile
LNAPL - flammable
BTEX - benzene, toluene, ethylbenzene, o-,m, p-xylene
Liquid fossil fuels

Point sources - leaking, improper disposal, failure of storage, accident during transportation
non point sources - farm applications of fertilizers/wet and dry deposition from atmosphere

Environmental phases:
Vapor phases
Solid phases
Aqueous phases (dissolvable)
non-polar phases (liquid or solid)

[] = moles/liter

Partitioning:
X = moles of contaminant/ moles of all compounds in the NAPL phase

Predicting contaminant movement rate in Aquifers

1. how fast if the water moving
2. What is the K for the compound

Retardation Factors (the velocity of movement of a contaminant ):

V/Vc = 1+ PbKd/n

V= average linear velocity of groundwater

Vc = average linear velocity of contaminant
Pb = dry bulk density of aquifer solids
n = porosity
Kd = the soil distribution constant

Wellhead Protection Act:

Koc - pesticide stuck to non-moving soil particles so they will not leach fast
Biochemical half life - add the compound to soil and see how long it takes for the half of the
compound to disappear
Aqueous transport of highly lipophilic compounds
-compounds with high K face obstacles to transport in ground or surface water.

Dissolved(if it goes through a 0.2 um filter) vs Suspended

Kdom = Cdom/CAqu and Kpom = Cpom/CAqu

Hysteretic Desorption

Reasons for departure from linearity:

1. many semipolar compounds stick to clay
2. Some pounds with polar substituents have a finite number of preferred sticking place in
soil and they become all occupied at high contaminant concentration
3. Very non-polar compounds can alter non-polar regions of organic matter by sticking to
them

4 states of natural Polymers in soil organic matter in increasing temperature

1. Crystalline
2. Glassy
3. Rubbery
4. Molten

Potentially troublesome ions

1. organic(cations, anions)
2. Inorganic (cations, nitrate)

The Rule of Nines

Primary Minerals - igneous rocks that formed from congealing magma.

Secondary Minerals - form slowly from primary minerals or precipitate out of solution in
soils.

Charges in Soils and Sediments

1. Permanent negative charge - most abundant in temperate-zone soils contains lots of
negative spots
2. pH - dependent charge - old clays, humic substance

Implication of Ionic contaminants;

1. Anionic contaminants repel the clays of temperate regions and leach rapidly to
groundwater.
2. in temperate-zone soils, cationic contaminants leach very slowly.
3. Clay-rich tropical soils over their usual pH ranges will slow the downward migration of
both cations and anions.
Environmental Remediation
Why don’t VOCs simply evaporate?
1. If TCE and VOC are within 1 cm or 2 of the surface they evaporate easily
2. water vapor below surface takes a long time to diffuse to the above ground
3. if water vapor has less than 99% relative humidity, the plant will wilt permanently during
the heat of the day and its leaves will fail to recover turgor overnight.

Plant leaves are indicators of how well equilibrated vapor-filled pores are with the above-
ground atmosphere. Wilted leaves = decent equilibration. Turgid leaves = not at equilibrium

Physical Remediation
Shallow contaminants:
- spills or leaks are discovered quickly, before vertical migration of contaminant have
occurred.
- contaminant may be too viscous to leach quickly
- An LNAPL spill may reach a shallow watertable.

Solution:
1. soil is excavated and disposed of as hazardous waste
2. LNAPL can be recovered by bailing

5 forms of Deep LNAPL Spills

1. free product
2. residual product above the watertable
3. residual product below the watertable
4. vapor-phase contaminants
5. Dissolved contaminants.

Zones below Ground

1. Watertable
2. Capillary fringe- a band of subsoil above the water table
3. Unsaturated zone - subsoil and soil above the Capillary fringe
4. Vadose zone - subsoil and soil above the water table
5. Phreatic zone - subsoil below the water table
6. Saturated zone - phreatic zone + capillary fringe

Phreatophyte - a plant that sends at least a tap root down deep to draw much of the
water used by the plant from groundwater (the phreatic zone). Mesquite roots will
descend as much as 40 m hunting for the watertable.
Deep contamination - two pump technique
1. one pump extract groundwater to act like a funnel concentrating LNAPL
2. second pump remove LNAPL from the bottom of the cone so more LNAPL slide down the
cone.
Advantage - maximizes the volume of free product that can be pumped off the water table
Disadvantage - when pumps are off, water table went back to normal, trapping lots of
hydrocarbons below it as residual product which requires water pumping to dissolve and
remove.

Soil Vapor Extraction (SVE)

Air pumped out of the center of the spill to remove hydrocarbons as vapors, leaving the
watertable undisturbed.

Watertables
- doesn’t stay at the same depth
- tend to rise during early spring
- watertables fall in summer due to transpiring water from plants
- water table rise during fall due to cool temperature and falling leaves reduce transpiration
demands for water
- stays still in winter because frozen

Impermeable barriers
- aquiclude - impermeable, horizontal below ground layer
- aquitard - slowly permeable version of an aquiclude. lie under much more permeable
layers

Aquifer Sparging
-injection of air bubbles into an aquifer with coarse-textured solids creates a cone of
bubbles rising towards the watertable carrying NAPL vapors inside.
-bubbles also carry NAPL-laced water to watertable
-once VOCs are in the unsaturated zone, they can be removed by SVE

Air stones emit silt-particle-sized bubbles are sold for the specific purpose of sparging
aquifers.

Problems with SVE and Aquifer Sparging

- only work well in sandy soils where air flow is uniform
- soils with more silt and clay are more resistant to air flow. If its forced with pressure, it
tends to follow preferential flow paths
- air exiting the soils needs to carry more of the contaminant with it
- contaminant that are located in distance, hard to be stripped from the soil
Thermal Conduction heating (TerraTherm and Maserati Method)
- fast but expensive
- heat generated from wells and pass slowly in to surrounding soil
- Slow SVE removes large amount of contaminants

In Situ Thermal Desorption (ISTD)

Steam cleaning
- steam injected into well for a while
-steam condenses into liquid, volume decreases by a lot
-causes a pressure drop, eliminates the force driving the water further from the well.
- DNAPL is effectively moved beyond the water condensation line and is concentrated there.

TCE - trichloroethylene
TCM = trichloromethane
BZ = benzene
CB = chlorobenzene
TCB = trichlorobenzene
PP = pahokee Peat
ZOI = zone of influence
LUST = leaky, underground storage tank
GAC - granular activated carbon
BTEX - benzene, toluene, ethylbenzene, o-,m, p-xylene