September 1, 2019 0

A Scientist Spilled 2 Drops Organic Mercury On Her Hand. This Is What Happened To Her Brain.

–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.–

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