The Horror of Organic Mercury

Video Transcript:

A scientist spilled two drops of organic mercury on her hand. This is what happened to her brain. KW 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 had lost 15 pounds over the last two 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 five months earlier, she was transferring liquid dimethyl mercury from a container when suddenly two drops from the tip of the pipette were spilled onto the door-some, 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 a taxic gate, a meaning without, and taxic meaning order. Gate being her walk, it was awkward, imbalanced, disorderly. Both of these were combined with dystastic 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 is 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 gate becomes more a taxic, speech more slurred, field of vision more narrowed. A blood test reveals KW's blood mercury levels are over 4,000 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 that one episode of accidentally spilling on the door some of her blood 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 milligrams of mercury in her blood, but for dimethyl mercury studies estimate that only 5% of the absorbed amount is in the blood, a bit troubling given that 18 milligrams is already 4,000 times the upper limit of normal. So where are the other 95%? Well there's a bit of basic chemistry to be known here. Elemental mercury is a metal, but dimethyl mercury, the compound that 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 affinity for and lipo, meaning fat, so it preferentially mixes with the fat tissue in the body. Because blood is mostly water, then dimethyl mercury would be found a lot more in the tissues and organs that contain a lot of fat instead of the blood. So if 18 milligrams is 5%, then there's really a total of 360 milligrams mercury accumulated in her body at 5 months post exposure, given that the lethal amount in the body is around 400 milligrams 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? Well, maybe. This brings us back to lipophilicity. Your body removes chemicals and drugs through a process called metabolism. The central idea behind it is to make the chemical and 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 dimethyl mercury is that in the liver, it's broken down to methyl mercury, which is still lipophilic, and even worse, it's 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 to trap the mercury inside a molecule that's water soluble on the outside. This is called chelation. The use of a ligand that binds to organo mercury 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 three doses over 24 hours and it's found to be working because the mercury levels in KW's urine increased by 160 times the next day and it's repeated for several days. But it's not enough. It's a week later. Neurocyciatric consult finds severe cognitive deficits in KW now. Her husband tries to speak to her, but she sometimes stares blankly into avoid. 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. Reasing 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 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 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 in fat tissue. Which tissue is it 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 methyl mercury is accumulating, causing oxidative stress, forming protein complexes, and inducing cell death, manifesting as her neurologic decline. But it's not just limited to one organ, though. It's going through her entire nervous system. The axons of the nerves, which feed the brain's 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 three weeks time after initially presenting to the emergency room, KW becomes unresponsive to verbal, visual, and touch stimuli. Ideas and unprovoked eye openings are observed. In someone who's 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's 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 their own comatoz 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 two millimeter 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 five-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 micrograms per liter in blood. So instead of 360 milligrams total, KW was initially exposed to 4 times that amount, or 1,440 milligrams. 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 1.022 parts per million, or 0.022 micrograms of mercury per gram of fish, then to get to 1,440 milligrams of mercury means that you would need to eat 65,000 kilograms, 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 two. The density of dimethyl mercury is about 3 grams per milliliter at room temperature, and the 1.44 grams 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 contained the dosage that the professor came into contact with and gave us this outcome. It was found after the fact that dimethyl mercury does infect 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 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 super warfarin's used as rat poison. Grifrin is a drug that's commonly used today in patients where it risks 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 that bleeding doesn't stop in patients who take too much warfarin, and those farmers who were poisoned with super warfarin were found with massive abdominal hemorrhaging, accompanied with hemateria, the urination of blood, before expiring in the hospital due to exanguination, the process of blood leaving the body in fatal amounts. Because fat doesn't flow as freely in your body as water, the resident's time of lipophilic drugs into fat tissue can be on a longer time scale than hydrophilic drugs, allowing for things like super warfarin and dimethyl mercury 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 dimethyl mercury 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 dimethyl mercury the way that KW did. And don't forget, you would have to eat 65,000 kilograms of fresh elanic 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. Neuronolos 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 lipofalicity of methyl mercury allowed it to access into the nervous system. There was little that could be done that day when 4,000 micrograms per liter 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 that they face every day. Today, those who handle diemethyl mercury are to wear two pairs of gloves. One, a highly resistant, laminate type that's found underneath another pair of long-coft, 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 and 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.