What happens when a scientist makes a minor mistake? This story of one such scientist is well known by toxicologists, but perhaps you've never heard the cautionary tale about workplace safety.
Watch the video above or read the transcript below to find out.
A scientist spilled two drops of organic mercury on her hand. This is what happened to her brain. KW [Karen Wetterhahn, PhD] is a 48-year-old woman presenting to the emergency room with a progressive deterioration in balance, gait, and speech. She tells the admitting nurse that she has lost 15 pounds 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 two 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 wearing gloves so long that 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, "-taxic" meaning order, and gait being her walk, it was awkward, imbalanced, and 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 the concept of white background noise that begins to wash away her normal hearing in both ears. Her gait becomes more ataxic. Her speech becomes more slurred; her field of vision, more narrow.
A blood test reveals that her blood mercury levels are over 4,000 mcg/L -- 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 is 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 that one episode of accidentally spilling on some on her left hand was enough to lead her to where she is now.
We can prove this. We estimate her total blood volume to be about four and a half liters, given her weight of 70 kg 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 18 mg is already 4,000 times the upper limit of normal. Where are the other 95%?
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 the body tissue. The dimethyl moiety means that it's highly lipophilic: "philic" meaning an affinity for, and "lipo-" meaning fat; it preferentially mixes with the fat tissue in the body.
Because blood is mostly water, dimethylmercury would be found a lot more in the tissues and organs that contain a lot of fat, instead of the blood. If 18 mg is 5%, then there's really a total of 360 mg mercury accumulated in her body at 5 months postexposure. 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 can somehow remove the mercury from her body? Well, maybe. This brings us back to lipophilicity. Your body removes chemicals and drugs through metabolism. The central idea behind it is to make the chemical in question more water-soluble, meaning it can dissolve in 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's known to bind to tissue and cause free radical damage and oxidative stress, and form complexes that accelerate cell death.
The best solution here is to trap the mercury inside a molecule that's water-soluble on the outside -- i.e., chelation, the use of a ligand that binds to organo-mercury molecules. The shape of the 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 three doses over 24 hours. It's found to be working because the mercury levels in her urine increased by 160 times the next day; this is repeated for several days.
But it's not enough. It's a week later and neuropsychiatric consult now finds severe cognitive deficits in KW. 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? 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 any better. Her deteriorating condition has little to do with a lower number from the lab. Removing mercury from her blood isn't removing it from her organs.
We've established two things: First is that the organic mercury KW came into contact with and its metabolite are lipophilic. The second is that the bulk of the mercury definitely isn't in her blood, but rather, in fat tissue.
Which tissue is the mercury in exactly? It couldn't be the 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 that the methylmercury is accumulating, causing oxidative stress, forming protein complexes, and inducing cell death, manifesting as her neurologic decline.
But it's not limited to just one organ -- it's going through her entire nervous system. The axons of the nerves that feed the brain stimuli are covered by a myelin sheath, which helps conduct signals. Myelin is also 60% fat. This mercury is accumulating, forming complexes and damaging cells, disrupting her movements, reflexes, speech, and 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 -- i.e., pupillary reflex -- and is modulated by cognitive factors. When it's slow, it suggests impaired cognition. 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, 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. In two millimeter increments of simple 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 days with a period of 75 means that two half-lives have passed since initial exposure at the time of measurement when she had 4,000 mcg/L in [her] blood. Instead of 360 mg total, KW was initially exposed to four times that amount or 1,480 mg. That's almost four times the lethal amount in [her] blood and means that at one point her blood mercury levels were like 16,000 times the upper limit of normal.
Given that the mean mercury concentration of fresh Atlantic salmon is measured to be .022 ppm or .022 µg of mercury per gram of fish, then to get to 1,440 mg of mercury means that you need to eat 65,000 kg or 144,000 pounds of salmon in one 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, and the 1.44 g of mercury exposure comes out to be about half a milliliter of liquid. Because it's three times more dense than water and comes in a 95% solution, about two to three drops contain 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 of 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, used today in patients at risk for stroke, reduces that risk by thinning the blood, preventing it from forming clots.
In a healthy person, bumping your arm forms a bruise, 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 that bleeding doesn't stop in patients who take too much warfarin. 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, with blood leaving the body in fatal amounts.
Because fat doesn't flow as freely in your body as water, the residence time of lipophilic drugs into fat tissue can be a longer timescale 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 three other cases of dimethylmercury poisoning were documented in history. In 1865, two lab assistants who were synthesizing it for the first time passed away several weeks after doing so. In the 1960s, another lab worker was exposed to it and he too suffered a delayed neurologic decline in the same fashion as KW.
In general, it's a good rule to not touch things if you don't know what they are. Be cognizant of what comes in contact with your skin. Unless you're a chemist, you probably won't come into direct contact with dimethylmercury the way that KW did. 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 six times that of the presence in blood, as the lipophilicity of methylmercury allowed it to access into the nervous system. There was little that could be done that day when 4,000 mcg/L of 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 that 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 every day.
Today, those who handle dimethylmercury are expected to wear two pairs of gloves -- a highly resistant, laminate type that's found underneath another 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.