A Few Basic Facts
A normal human brain has approximately 86 billion neurons,
which is a lot even by mammalian standards.
What makes neurons special is that they are all interconnected by axons
and synapses that let neurons send and receive signals to other neurons quickly. Signals along the neuron and axon are
transmitted by electrical impulses that are enabled by ion channels that briefly
let charged ions cross the membrane of the cell. Synapses connect axon terminals to dendrites
in other neurons by molecules, called neurotransmitters, that are released from
axon terminals and interact with receptors on connected dendrites. Although the number of synapses each neuron
has varies tremendously, the average number is estimated to be over a thousand,
and the total number in the brain is estimated to be over 100 trillion (that’s 100,000,000,000,000).
Not all neurons are the same in structure or function. Some are closely associated with sensory
systems (e.g. eyes and ears), some with motivational systems (e.g. thirst,
hunger, fear, and sex), while still others are involved in controlling muscle
activity, and then there are neurons that are connected with everything in
general and nothing in particular. While
most neurons have short axons, some have long axons that connect to other
neurons, muscles, and senses that are far away. For example, there are neurons in the spinal cord
that have axons that run the length of both arms and legs.
Not all synapses are alike either. Some are excitatory, meaning they stimulate
the neurons they are attached to send a signal.
Others are inhibitory, meaning they act to prevent another neuron from
sending a signal. The neurotransmitters
used at different synapses also vary. While
there are 10 different main neurotransmitters, there are many other minor
transmitters as well.
Unlike most other cells in the body, most neurons are formed
either before birth or shortly afterward.
It’s all downhill after that – the number of neurons decreases to at
least some extent with age. On the other
hand, synapses some and go. Although
many synapses are formed when the brain is first developed, the formation of
new synapses throughout life is what makes learning and memory possible.
Disrupting Brain Function
There are many ways different substances can alter or impair
brain function. The most common and well
known mechanism is to either mimic or block the actions of neurotransmitters. Caffeine acts that way, and so do many legal
and illegal drugs. Alcohol probably acts
by generally impairing axonal transmission in all neurons. Even though the actions of many neuroactive
chemicals are temporary, an addiction can develop with prolonged use. That happens because the brain adapts to
having more or less of a particular transmitter, which means the brain will
then function abnormally without the drug.
Short term effects on neurons can also be fatal. For example, many pesticides act by
preventing the deactivation
of the neurotransmitter (acetylcholine) responsible for neuronal activation
of muscles, including those responsible for breathing.
But, some chemicals also have long term effects. Alcohol can cause neuronal cell death, which
is irreversible. Other toxic chemicals
can cause axons to degenerate, which may not grow back. But, perhaps the worst thing a toxic chemical
can do is to prevent the brain from developing in the first place. That can happen when a substance either
interferes with neuronal growth before or just after birth, or with the
development of synapses before birth or later in life. Methylmercury and lead are both examples of
developmental neurotoxicants.
Methylmercury is thought to act primarily before birth, while lead
exposure is thought to be most detrimental in young children. However, the exact mechanism responsible for the
effects of either lead or mercury is largely unknown.
Biochemical Neurotoxicology
There are bazillions of toxic molecules in the body. Let’s take methylmercury for instance. The average
methylmercury blood concentrations in the United States is about 1.3 µg/liter
and the blood volume of a pregnant woman (and fetus) is about 4 liters. So, an average pregnant women has about 5 µg
of methylmercury in her blood. Since the
molecular weight of methylmercury is 231 there are Avogadros number (6.2
x 1023) of methyl mercury molecules in 231 g, and 9.4 x 1012
molecules in the blood of average an average pregnant woman in the U.S. There’s
also mercury in other tissues, including the brain, so let’s just round to an
even bazillion. The main point here is that
there are a lot – even more than the number of neurons and about the same as the number synapses.
So, what happens if a molecule of methylmercury gets into
the blood? Usually, nothing. It hangs around for a few months and then
gets eliminated. But some of it crosses
the placenta and goes into the fetus.
But, even there nothing usually happens.
It may go back out again, or it may go into other tissues like muscle where
as far as anyone knows it isn’t toxic.
But some it gets into the brain of the fetus. But even there, most of it floats around
inside or outside the neurons and does nothing.
But, on some rare occasions, the molecule of methylmercury will bind to
something like an ion channel or a protein necessary for synaptic development,
and sometimes that may keep the neuron or synapse from developing as it
normally would. But even that's not necessarily so
bad. One neuron or one synapse among billions or
trillions isn’t going to be missed. On the other hand,
one molecule isn’t the problem. A
bazillion molecules may not really be much of an issue either. But a bazillion here, a bazillion there, and
pretty soon you are talking about a real problem where brain function is
reduced to a noticeable extent.
Thresholds
Toxicologists don’t ever prove there is absolutely no effect
– they can only show that if there is an effect it isn’t big enough to be detectable. Yet, they often suggest that somehow they
know that there is some dose of a toxic substance that does absolutely nothing,
which is called a threshold (e.g. Barnes and Dourson, 1988). There is no evidence for it, so the threshold theory is pretty
much just a fairy tale that is often repeated because people like to hear
it. It is true that for a number of
reasons, high level exposures can be much worse than low level exposures (e.g. cooperative binding, saturable metabolism), but
that’s not really the same thing as a threshold: If several bazillion molecules have a noticeable
effect, a bazillion or fewer probably do damage as well, only less. In toxicology, less is better than more, so that’s
good. But if you would like zero, well
you can’t have it. Anyone who says otherwise
is either lying or sadly mistaken.
In any case, the EPA has adopted the position that there is
no threshold for the effects of lead. In
fact, that is given as a reason for not having a Reference Dose for lead (EPA,
2004). On the other hand, the EPA supposes
that there is a threshold for methylmercury and gives that as a reason for having
a Reference Dose (EPA, 2001). I think the
EPA has it right for lead and wrong for methylmercury. At least that’s the way my synapses have it
sorted out.
References
Barnes DG and Dourson ML (1988). Reference Dose (RfD): Description and Use in
Health Risk Assessments. Regul Pharmacol Toxicol 8:471-486. Also at http://www.epa.gov/IRIS/rfd.htm
Environmental Protection Agency (2004). Lead
and compounds (inorganic); CASRN 7439-92-1
Official Post Soundtrack
Post Notes
Thesis Post #54. This is a part of the semi-lay toxicology series that i began last spring but have done nothing with since. I'm thinking a majority of by near future posts will be of this ilk, but we'll see. Besides providing a basic neuroscience overview, I am obviously taking on the threshold issue that still! has it hooks into the public and regulatory psyche. Dumb, dumb, dumb.
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