--In Honor of Dr. Karen Wetterhahn, PhD, Dartmouth College. Case published N Engl J Med 1998; 338:1672-1676.--
A Scientist Spilled 2 Drops of Organic Mercury On Her Hand.
This Is What Happened To Her Brain.
KW is a 48 year old woman, presenting to emergency room with a progressive deterioration in balance,
gait and speech.
She tells the admitting nurse that she had lost 15 pounds (6.8 kg) over the last 2 months, and
experienced several brief episodes of nausea and abdominal discomfort.
You see, KW was a chemistry professor who researched toxic metal exposure.
She had an influential career at a prestigious institution, and there were few, maybe none,
in the world who knew the subject better than her.
About 5 months earlier, she was transferring liquid dimethylmercury from a container when
suddenly 2 drops from the tip of the pipette were spilled onto the dorsum, or backside,
of her gloved hand.
To her, this was an incident she had to actively recall as it was so minor and incidental she
didn’t give a second thought to it.
She tells the nurse that she had cleaned up after the spill properly per protocol.
Her hands were in gloves so long, it was sweaty inside.
She was pretty sure she didn’t have any physical contact without barrier with any
chemicals.
Over the next few weeks, KW noticed something wrong when she would walk into walls.
Maybe she wasn’t paying attention she thought.
One day, she almost got into a car accident.
She started asking her husband to drive her to university.
Maybe she hadn’t slept well, she thought.
Skin-deep, KW appeared to be healthy.
But, at physical examination, she exhibited upper-extremity dysmetria.
Dys meaning wrong and metria meaning length.
Her movements in the limbs above her waist were uncoordinated, with intended positioning
often missing the target at varying lengths.
Similarly, she had ataxic gait.
A meaning without and taxic meaning order.
Gait being her walk.
It was awkward, imbalanced, disorderly.
Both of these were combined with dystaxic handwriting and slurred speech, all of which
can point to some potential neurodegeneration given her past exposure to mercury.
She was right to be concerned about her condition.
As the days continued, KW reports that she has a tingling in her fingers that’s getting
stronger.
She sees brief flashes of light in both eyes.
She introduces a concept of white background noise that begins to wash away her normal
hearing in both ears.
Her gait becomes more ataxic, speech more slurred, field of vision more narrowed.
A blood test reveals KW’s blood mercury levels are over 4000 micrograms per liter,
4,000 times greater than the upper limit of normal.
We can conclude here that KW’s neurologic decline is because of mercury toxicity.
But, something’s wrong.
Typically, signs and symptoms of this poisoning are resolved after exposure has ceased.
She hasn’t been in the lab for months now but those signs and symptoms are still present
and her neurologic decline is accelerating.
KW’s mercury toxicity is acute in nature, meaning there wasn’t a constant source of
exposure to her, and that the one episode of accidentally spilling on the dorsum of
her gloved hand was enough to lead her to where she is now.
We can prove this.
We estimate her total blood volume to be about 4.5 liters given her weight of 70 kilograms,
measured at admission.
This means there are 18 mg of mercury in her blood.
But, for dimethylmercury, studies estimate that only 5% of the absorbed amount is in
the blood, a bit troubling given that 18mg is already 4,000 times the upper limit of
normal.
So, where is the other 95%?
Well, there’s a bit of basic chemistry to be known here.
Elemental Mercury is a metal.
But dimethylmercury, the compound KW was exposed to is an organic mercury, something that does
absorb well into body tissue.
The dimethyl moiety means that it is highly lipophilic.
Philic meaning affinity for and Lipo meaning fat, so it preferentially mixes with fat tissue
in the body.
Because blood is mostly water, then dimethylmercury would be found more in tissues and organs
that contain a lot of fat instead of the blood.
So if 18 mg is 5%, then there is really a total of 360 mg mercury accumulated in her
body at 5 months post exposure.
Given that the lethal amount in the body is around 400 mg and her neurologic condition
is quickly deteriorating, KW is in trouble.
Is there a way that we could somehow remove the mercury from her body?
Maybe.
This brings us back to lipophilicity.
Your body removes chemicals and drugs through a process called metabolism.
The central idea behind that is to make the chemical in question more water soluble, meaning
it can dissolve in the water, concentrate in the urine and be excreted through the kidneys.
This breakdown usually takes place in the liver, where chemicals are delivered by your
blood as they flow through your body.
The problem with dimethylmercury is that in the liver, it’s broken down to methylmercury,
which is still lipophilic.
Even worse, it is known to bind to tissue, cause free radical damage and oxidative stress,
and form complexes which accelerate cell death.
The best solution here we can do is trap the mercury inside a molecule that is water-soluble
on the outside.
This is called chelation— the use of a ligand that binds to organomercury molecules.
The shape of that molecule is important to fit the organic metal inside.
KW is given succimer.
The shape of the molecule traps the organic mercury inside.
The outside mixes well with water, allowing it to be removed by the kidneys.
She receives 3 doses over 24 hours, and it’s found to be working, because mercury levels
in KW’s urine increased by 160 times the next day.
It is repeated for several days.
But, it’s not enough.
It’s a week later, neuropsychiatric consult finds severe cognitive deficits in KW now.
Her husband tries to speak to her, but she sometimes stares blankly into a void.
If we’re removing the mercury from her blood now, why is she getting worse.
Less mercury is good, right?
Well, in this case, it might not be.
Chasing a lower blood mercury level is just chasing a lower laboratory value.
Clearly just by looking at her, she’s not getting better.
Her condition deteriorating has little to do with a lower number from the lab.
Removing mercury from her blood, isn’t removing it from her organs.
So, we’ve established 2 things.
First is that the organic mercury KW came into contact with, and it’s metabolite are
lipophilic.
Second is the bulk of the mercury definitely isn’t in her blood, but in fat tissue.
But which tissue is it in, exactly?
It couldn’t be her heart, as that’s mostly muscle.
It couldn’t be her kidneys, as those are not made of fat.
But how about the brain?
The brain is 60% fat, and it’s there the methylmercury is accumulating, causing oxidative
stress, forming protein complexes, and inducing cell death manifesting as her neurologic decline.
It’s not limited to just 1 organ though, it’s going through her entire nervous system.
The axons of the nerves, which feed the brain stimuli are covered by something called a
myelin sheath, which helps conduct signals.
Myelin is a substance that is also 60% fat.
This mercury is accumulating, forming complexes and damaging cells, disrupting her movements,
reflexes, her speech, and her senses.
At 3 weeks time after initially presenting to the emergency room, KW becomes unresponsive
to verbal, visual and touch stimuli.
Spontaneous and unprovoked eye-openings are observed.
In someone who is not neurologically impaired, shining a light on their eye would cause the
pupil to constrict so as to limit the amount of light entering the eye.
This is called pupillary reflex and it’s modulated by cognitive factors.
When it is slow, it suggests impaired cognition, and in KW, it’s slow.
From the depths of her coma, she is sometimes found yawning spontaneously, with brief episodes
of agitation— screaming, crying and unprompted, sudden and jerky limb movements.
There’s someone inside, but that person is trapped in a prison of her own comatose
body.
At the time of diagnosis, her colleagues believed that her work with mercury salts in the past
were the culprit.
That maybe she accidentally breathed in mercury vapors causing the toxicity.
But further analysis showed otherwise.
Mercury is detectable in the hair, and in 2mm increments of sample strands, the
amount of free mercury found in her body halved every 75 days, with a maximum excretion recorded
roughly 150 days before presenting to the emergency room.
150 days coincides with the 5 month time period she gave the admitting nurse.
Dividing 150 day with a period of 75 means that 2 half-lives passed since initial exposure
at the time of measurement, when she had 4000 micrograms per liter.
So instead of 360 mg total, KW was initially exposed to 4 times the amount, or 1440 mg.
That’s almost 4 times the lethal amount in blood, and means at one point, her blood
mercury levels were likely 16,000 times the upper limit of normal.
Given that the mean mercury concentration of Fresh Atlantic Salmon is measured to be 0.022 parts per million
or 0.022 micrograms mercury per g fish, then to get 1440 milligrams of
mercury means you’d need to eat 65,000 kilograms, or 144,000 pounds of salmon in 1 sitting
to reach KW's exposure.
Not only are the number of days physiologically consistent with KW’s recollection of exposure,
but the amount was too.
The density of dimethylmercury is about 3 g / mL at room temperature, the 1.44 g of
mercury exposure comes out to be about half a milliliter liquid.
Because it is 3 times more dense and comes in a 95% solution, about 2-3 drops contained
the dosage that the professor came into contact with, and gave us this outcome.
It was found after the fact that, dimethylmercury does in fact diffuse through the type of gloves
KW wore that day, and it does so within seconds.
The small exposure equivalent to a few drops absorbed into her skin, embedded into her
body and caused delayed onset cerebral disease.
It’s difficult for people sometimes to realize the extent of injury that can present with
what seems like trivial exposure.
Even in KW’s case, gloves get sweaty, so she may not have even felt any liquid that
spilled onto the outside of the glove on her hand.
The concept of a delayed onset of disease several weeks to months after initial exposure
is not uncommon.
You’ve experienced it yourself.
Infectious diseases famously have an incubation period that can range from a few hours to
nearly a year before manifesting clinical symptoms.
It happens every year when there’s a new flu floating around.
But can be extreme like during the bubonic plague in Europe where transmission can occur
through touch and manifest itself within hours.
Today, in China and Iran, farmers were unknowingly exposed to superwarfarins, used as rat poison.
Warfarin is a drug commonly used today in patients who are at risk for stroke.
It reduces that risk by ‘thinning’ the blood, preventing it from forming clots.
In a healthy person, bumping your arm forms a bruise, which is a form of bleeding.
That bleeding stops due to clotting.
Clots can break off and block blood vessels like those in the brain, causing stroke.
Stopping clotting means bleeding doesn’t stop in patients who take too much warfarin.
And those farmers who were poisoned with superwarfarins were found with massive abdominal hemorrhaging,
accompanied with hematuria, the urination of blood, before expiring in the hospital due
to exsanguination.
The process of blood leaving the body in fatal amounts.
Because fat doesnt flow as freely in your body as water, residence of time of lipophilic
drugs into fat tissue can be on a longer time scale than hydrophilic drugs, allowing for
things like superwarfarin and dimethylmercury to accumulate in the fat, metabolize slowly
in the liver, and then release amounts into the blood until it reaches a lethal dose.
Only 3 other cases of dimethylmercury poisoning were documented in history.
In 1865, 2 lab assistants who were synthesizing it for the first time passed away several
weeks after doing so.
In the 1960’s, another lab worker was exposed to it.
He too suffered a delayed neurologic decline in the same fashion as KW.
In general, its a good rule to not touch things if you don’t know what they are.
Be cognizant of what comes in contact with the skin.
Unless you’re a chemist, you probably won’t come into direct contact with dimethylmercury
the way KW did.
And don't forget, you would have to eat 65,000 kg of Fresh Atlantic Salmon
in one sitting to get you to where she was.
For KW, extremely high levels of mercury were found at autopsy in the frontal lobe of her
brain.
Microscopes revealed extensive neuronal loss and gliosis, an inappropriate proliferation
of nerve supporting cells, throughout her cerebellum which controls motor function,
explaining her dystaxia, dysmetria, and ataxic gait.
Neuronal loss was found bilaterally across her visual and auditory cortices, explaining
her narrowing field of vision as well as the white noise as it began to wash away her hearing
before she slipped into coma.
As expected, the amount of mercury found in her brain was 6 times that of the presence
in blood, as the lipophilicity of methylmercury allowed it access into the nervous system.
There was little that could be done that day when 4000 micrograms per liter mercury was
found in her blood.
Because KW was a world-renowned expert in her field, she knew at diagnosis what was
to become of her.
Once symptoms appear in mercury toxicity this serious, there’s very little chelation therapy
can do as the toxin has started to absorb into neurologic tissue.
The delayed onset served as a means for her to give advanced directives- to notify others
about her story and warn them of the occupational hazards they face everyday.
Today, those who handle dimethylmercury are to wear 2 pairs of gloves-- 1 a highly resistant
laminate type that’s found under a pair of long cuffed neoprene or nitrile gloves.
Her colleagues in the science community, as well as her family, and the United States
government all worked together to bring about an extreme awareness of safety in science,
a legacy that lives on today, decades later.
KW, in both her science and her story, transcends the boundary of time.
Thank you so much for watching.
Take care of yourself.
And be well.
--In Honor of Dr. Karen Wetterhahn, PhD, Dartmouth College. Case published N Engl J Med 1998; 338:1672-1676.--