25 years after Karen Wetterhahn died of dimethylmercury poisoning, her influence persists

In another universe, you could be reading an article celebrating Karen Wetterhahn’s retirement from Dartmouth College. She would be 73.

A chemist, Wetterhahn started her career at Dartmouth in 1976, when she was the first woman hired into a tenure-track position in the Chemistry Department. Her research focused on understanding how the heavy metal chromium damages DNA and causes cancer. In 1995, she established Dartmouth’s Toxic Metals Superfund Research Program. Perhaps this work would have earned her a Priestley Medal, the highest honor awarded by the American Chemical Society, which publishes C&EN.

Wetterhahn also took on administrative roles, rising to dean of the faculty of arts and sciences, the number 3 position at the university in 1995. “She would have been an exceptional university president,” says James Wright, her former colleague and a past Dartmouth president.

Or her talents could have taken her away from academia. “The [US National Institutes of Health] and White House are interesting possibilities where her expertise and thoughtful decisiveness would have had a very positive impact,” says Dean Wilcox, chair of Dartmouth’s Chemistry Department.

Then again, Wetterhahn’s colleagues say, she loved her research, and it’s hard to imagine her giving up her lab for any other position. “Where I saw her joy was in convening people for big science and mentoring,” says Carol Folt, one of Wetterhahn’s collaborators and now the president of the University of Southern California.

But we don’t know what path Wetterhahn’s life might have taken to retirement. She died in 1997 from dimethylmercury poisoning after exposure in her lab.

Wetterhahn was talented and ambitious. She was also kind and generous to her colleagues and friends. Her death caused shock, horror, sorrow, and disbelief that spread through her research group and the Dartmouth Chemistry Department, out into the larger college, and beyond—to Wetterhahn’s collaborators, colleagues, and friends, as well as strangers around the world.

Brooke Martin, Wetterhahn’s last graduate student to earn a PhD and now a researcher of toxic metals at the University of Montana, says the tragedy remains a clear inflection point: “It’s something that happens in your life, and it’s an epoch. Things are not the same after.”

The poignancy of Wetterhahn’s death has not waned in 25 years. But those years do provide the perspective to better appreciate the facets of Wetterhahn’s legacy. Some aspects, like her contributions to understanding chromium toxicity or her efforts to help women succeed in science, were apparent while she was alive. Others, like changes to laboratory safety practices, emerged only after she died. Taken together, these elements help define a trailblazer whose influence will continue to be felt in different ways for years to come.

Exposure

On Aug. 14, 1996, Wetterhahn was working in a fume hood in her research group’s lab. By that point in her career, she didn’t get to spend much time at the bench, but this was a task she didn’t want anyone else doing.

She was preparing for some mercury experiments she planned to run. Much of Wetterhahn’s work to that point had focused on the heavy metal chromium and its toxic effects on people. Chromium’s links to cancer were central to the high-profile environmental justice suit led by activist Erin Brockovich in California in 1993. Scientists knew that chromium damaged DNA, but at the time they didn’t know how.

Wetterhahn was collaborating with colleagues at Harvard University and the Massachusetts Institute of Technology to study zinc proteins that repair DNA damage. Understanding DNA-repair mechanisms could yield insight into how the damage occurs. They wanted to study small-molecule analogs of the zinc-binding sites of the proteins by nuclear magnetic resonance spectroscopy. But zinc isn’t easily seen by NMR, so they made the compounds using mercury, whose ^¹⁹⁹Hg isotope can be measured with NMR.

First, Wetterhahn needed to calibrate the NMR instrument at Dartmouth to accurately detect mercury’s signals. Her group had initially tried to do so using a mercury chloride standard, but she wasn’t satisfied with those results. To ensure accurate readings, she turned to the consummate—and most dangerous—substance for a mercury NMR standard: dimethylmercury.

Dimethylmercury had long been known to be toxic. Like other organic mercury compounds, it is easily absorbed by the body, even through the skin. In the body, it is converted to methylmercury and binds to proteins and peptides, allowing the heavy metal to travel across the blood-brain barrier. Once in the brain, methylmercury interferes with the processes that protect neurons from oxidation, and it stimulates an immune response that attacks proteins key to brain function.

After discussing the procedure for preparing the standard with a postdoctoral researcher, Wetterhahn decided to do it herself. So she was the one in the lab that day transferring dimethylmercury from a sealed glass ampoule into an NMR tube. A material safety data sheet for dimethylmercury found in Wetterhahn’s lab recommended wearing “rubber” gloves. So when a few drops slipped from the pipette she was holding in one hand onto the back of her other hand, they landed on latex, the standard lab glove material at the time.

No one interviewed by C&EN recalls Wetterhahn’s mentioning the spill when it happened. Perhaps, after stripping off the gloves and washing her hands, she thought little of it. Accidents happen, after all, and she had worn what she thought was appropriate personal protective equipment.

It was 5 full months before the consequences of that spill became apparent. Wetterhahn developed stomach problems, then began having trouble walking and speaking clearly. A friend, nurse Cathy Johnson, recalls a lunch date in early January 1997 when she urged Wetterhahn to see a doctor.

Within a few weeks, Wetterhahn was in a coma. On June 8, 1997, she died. She was 48 years old.

Dimethylmercury’s toxicity

Lab work can be dangerous, especially for researchers interested in toxic substances like heavy metals, as Wetterhahn clearly knew. But until her death, very few people realized just how deadly dimethylmercury was or how inadequate laboratory safeguards were.

Dimethylmercury wasn’t used often in most chemistry labs, but it wasn’t unheard of either. Thomas V. O’Halloran, now a chemistry professor at Michigan State University, had recently published several papers describing ^¹⁹⁹Hg NMR work. “We knew [dimethylmercury] was toxic,” O’Halloran says. “We didn’t have any idea how incredibly toxic it could be.”

Dimethylmercury’s physical properties contribute to its danger. It’s volatile and heavy, about three times as dense as water. It’s nonpolar, so it has little surface tension. Together, those properties would have made it easy for a drop or several to escape from the pipette tip as Wetterhahn manipulated it in the fume hood. The liquid purchased by Wetterhahn to make the NMR standard was 98% dimethylmercury.

No one knows exactly how many drops of dimethylmercury landed on Wetterhahn’s glove, or how much her body absorbed. A blood sample taken in late January showed she had 4,000 μg/L of mercury in her body (N. Engl. J. Med. 1998, DOI: 10.1056/NEJM199806043382305). A healthy adult has 1–8 μg/L. Toxicologists consider over 200 μg/L to be a lethal dose. The symptoms of dimethylmercury poisoning start, as Wetterhahn’s did, with loss of coordination and slurred speech. Loss of vision and hearing follows, and then an irreversible coma.

Many chemists were stunned by the idea that only a few drops of the substance, spilled from a pipette, could have killed their colleague. Russell Hughes was one. An organometallic chemist, he joined Dartmouth’s faculty the same year as Wetterhahn, and the two taught an inorganic chemistry course together. Unlike Wetterhahn, he was no stranger to dimethylmercury, he says, although he never worked with it himself. “I know people who’ve made bucketloads of this,” Hughes remembers thinking. Synthetic chemists have at times used organic mercury compounds as sources of alkyl groups, although safer alternatives, like Grignard reagents, have largely replaced them. “Frankly, I was surprised there was not a trail of bodies back through history,” he says.

Twenty-five years later, experts agree it is hard to understand Wetterhahn’s death. “I don’t see any evidence that points to anything other than a laboratory accident, but I agree that it’s difficult to think that just a couple of ‘drops’ of anything could lead to the symptoms that Wetterhahn displayed,” mercury toxicity expert Christy Bridges, a professor at Mercer University’s School of Medicine, tells C&EN in an email. Bridges reviewed reports of Wetterhahn’s accident and illness at C&EN’s request. “I think the extreme toxicity of dimethylmercury was a surprise,” Bridges adds.

Even today, experts like Bridges know little about the effects of dimethylmercury poisoning. Wetterhahn’s death is one of only four reported in scientific literature (Int. Arch. Arbeitsmed. 1974, DOI: 10.1007/BF00538936; Chem. Br., July 1989, page 702), although many other people have been sickened or killed by methylmercury, which has similar effects. With so little information, it isn’t easy to put Wetterhahn’s illness in context.

“Unfortunately, we don’t have enough data regarding the toxicity of dimethylmercury to fully understand how it affects the human body,” Bridges writes. And, she adds, the compound is so dangerous that future studies are unlikely, even in animals.

At the time of Wetterhahn’s death, investigators took steps to rule out other possible explanations for her mercury exposure. Her family and other members of her research group were tested for mercury; all were within the normal range. The only place mercury was detected in her lab was in the hood she used.

Besides Wetterhahn’s recollections when she became ill, one other key piece of evidence was available to the scientists who studied her death. Doctors collected a sample of Wetterhahn’s hair in the hospital, since organic mercury compounds accumulate in hair and nails. As those tissues grow, they become a record of exposure over time. A strand of Wetterhahn’s hair showed a rapid increase in mercury levels corresponding to when she recalled her exposure, followed by a slow decrease. That pattern fits the idea that the lab accident was the source of her mercury poisoning.

Lab safety

Wetterhahn’s death showed many chemists that they might not fully understand how toxic some chemicals can be or how protective their safety procedures and equipment are. That legacy of laboratory safety might be the one most strongly attached to Wetterhahn’s memory for many in the chemistry community.

Although Wetterhahn had not worked with dimethylmercury before, she had resources that should have helped her handle the dangerous chemical. Federal law requires manufacturers and suppliers to provide safety data sheets—formerly called material safety data sheets—with hazardous chemicals. These documents describe chemicals’ basic properties, their dangers, and what precautions to take when handling them.

Three material safety data sheets for dimethylmercury were available to Wetterhahn, according to investigation reports (Appl. Occup. Environ. Hyg. 2001, DOI: 10.1080/104732201460389). One recommended wearing rubber gloves, another wearing “appropriate chemical-resistant gloves.” A third recommended wearing neoprene gloves.

Wetterhahn recalled wearing latex gloves on the day of her accident. Like the molecules in latex rubber, dimethylmercury is nonpolar. “Of course I can imagine it going through latex,” says John Winn, a Dartmouth professor emeritus of chemistry, who was chair of the department when Wetterhahn died.

Michael Blayney, who led Dartmouth’s environmental health and safety office at the time and is now executive director of research safety at Northwestern University, commissioned an independent lab to test the different types of gloves found in Wetterhahn’s lab to see how quickly dimethylmercury passed through them.

And just as dimethylmercury was more toxic than people realized, it penetrated gloves faster than anyone expected. The lab, Intertek Testing Services, had to shorten its sampling intervals because the gloves degraded so quickly. Dimethylmercury penetrated every brand of latex glove tested in less than 20 s, and most in less than 15 s. Even neoprene gloves lasted less than 10 min. The only reliable protective equipment Blayney and Intertek were able to identify was a neoprene glove worn over a laminated plastic glove.

As the doctors and researchers involved in Wetterhahn’s case were beginning to understand the twin dangers of the chemical and the gloves, they undertook an aggressive effort to let other chemists know what they were learning.

Wetterhahn herself was actively involved. Winn remembers visiting her in the hospital after doctors realized that it was mercury making her sick. “She asked me two things. One, to make sure everyone in her lab was tested,” he says. “Then she asked that we do our best to get the word out to the chemistry community.”

Her colleagues started with a letter to C&EN, which ran in the May 12, 1997, issue, while Wetterhahn was still alive, although incapacitated.

In the letter, Blayney, Winn, and David Nierenberg, a doctor at Dartmouth Hitchcock Medical Center with clinical toxicology training who cared for Wetterhahn, briefly described Wetterhahn’s accident and illness. They also described what they had found about the inadequacy of latex gloves for handling alkyl mercury compounds. “All laboratories working with such compounds are strongly encouraged to conduct an assessment of existing work practices and precautions,” they wrote. “We urge the Hg NMR community to consider a safer standard compound.”

Michigan State University’s O’Halloran was doing just that. “When this happened, the first thing I did was I got my group together, and I said, ‘Why did we not try other mercury standards?’ ” he remembers. His group had just published a series of mercury NMR papers, and he wanted to make sure no one else had an accident like Wetterhahn’s.

O’Halloran’s group found a few papers from the 1960s and ’70s that reported using mercury perchlorate salts as standards. His group used those references to write new procedures for calibrating NMR spectrometers with mercury perchlorate instead of dimethylmercury. Thanks to that and other alternatives developed after Wetterhahn’s death, dimethylmercury standards are almost unheard of in mercury NMR today.

Wetterhahn’s Dartmouth colleagues also contacted the US Occupational Safety and Health Administration (OSHA) in February 1997. As a matter of course, OSHA opened an investigation into the accident. It ultimately fined Dartmouth $9,000 and required that the college hire a new chemical safety official and revise laboratory safety procedures.

Maybe more importantly, in 1998, OSHA published a bulletin recommending that chemists use alternative mercury NMR standards and sharing what Blayney and his colleagues had learned about lab gloves.

Scientific method

Wetterhahn also left a legacy of solving scientific problems by rigorously evaluating data and seeking a variety of perspectives.

It isn’t clear what drew Wetterhahn to heavy-metal toxicity and chromium in particular. Her sister, Charlotte Archabald, a retired high school biology teacher, says she has often wondered if their grandmother’s death from cancer in her 70s steered Wetterhahn toward questions about human health, but she never asked.

Regardless, even in her relatively short career, Wetterhahn was well established as a giant. “Karen was one of the best in the field of metal toxicology; but she was unsurpassed when dealing with chromium,” William A. Suk, then director of the National Institutes of Health’s National Institute of Environmental Health Sciences (NIEHS), wrote in a eulogy for Wetterhahn.

In particular, Wetterhahn developed what is known as the uptake-reduction model of chromium toxicity. Cells take up chromium in its +6 oxidation state, a form that isn’t itself toxic. Wetterhahn discovered the metabolic processes that reduce Cr^VI to Cr^III (J. Am. Coll. Toxicol. 1989, DOI: 10.3109/10915818909009118). The reduction produces reactive intermediates and oxygen radicals that damage DNA.

That work helped define the way scientists thought about chromium toxicity. “She was the top scientist in her field, but it wasn’t a field before,” says Martin of the University of Montana.

One of the things that made her such a successful researcher was her approach to science, colleagues say. “She was very good about being neutral and objective,” says Diane Stearns, who was one of Wetterhahn’s postdocs and is now provost of Tarleton State University.

“She had an incredible amount of personal and professional integrity,” Martin says. “If we ever discovered something, the first thing she’d say is, ‘Go and repeat it.’ ”

Next to her chromium work, Wetterhahn’s longest-lasting scientific mark was the NIEHS grant she won in 1995 to establish the Dartmouth Toxic Metals program. The project studied the effects of heavy metals at locations in Vermont and New Hampshire designated as US federal Superfund sites—areas where the Environmental Protection Agency will oversee cleanup. The $7 million grant was the largest in Dartmouth’s history, and the program continued until March 2022.

It wasn’t the dollar amount that made the project unique, however. It was Wetterhahn’s interdisciplinary approach. Large-scale team science was in its infancy and almost totally foreign to chemistry.

“She sent out an email to people in all these departments,” recalls USC’s Folt, who was then a young biology professor at Dartmouth. Wetterhahn included biologists, physicists, and medical doctors. Folt remembers the email saying something simple, like, “If you’re interested in metals, come to a meeting.” She recalls the meeting room being filled.

Folt, who became a principal investigator on the project, says it was a testament to Wetterhahn’s reputation that so many people trusted her leadership and wanted to be part of the project.

The project also showed Wetterhahn’s innovative approach to science.

“She was absolutely a pioneer in big-team, interdisciplinary, problem-based science,” Folt says, adding that Wetterhahn also understood the need to address public policy and community education in research programs on this scale.

Wetterhahn talked about the Superfund project in 1996 with reporter Karen Endicott of Dartmouth Alumni Magazine. The article was never published, but Endicott used some of the material in a story about Wetterhahn’s death and shared her interview notes with C&EN. Wetterhahn told Endicott she liked the Superfund project “as a model for how we can bring together people from different departments and schools,” according to those notes. And she affirmed her commitment to an interdisciplinary approach: “If I have to learn chemistry, biophysical kinetics, whatever I need to understand a problem, I’ll do it,” Wetterhahn told Endicott, according to the notes.

One researcher continuing some of Wetterhahn’s work is metal toxicity researcher Ke Jian “Jim” Liu of the University of New Mexico. In the 1990s, Liu was a professor at Dartmouth using electron paramagnetic resonance spectroscopy to study the effects of heavy metals like chromium in the body. He called Wetterhahn after reading one of her papers, and she proposed a collaboration. They had been working for only about a year when Wetterhahn got sick, but he is still working on those questions.

Liu, the immediate past president of the metal research section of the Society of Toxicology, says Wetterhahn was a leader, helping people see how important metals are in human health and understanding the need for an interdisciplinary attack on those problems. “I wish Karen was still doing this,” he says.

Women in science

Another of Wetterhahn’s legacies is Dartmouth’s Women in Science Project (WISP), a mentoring and research experience program she helped start in the early 1990s. The initiative may have sprung at least in part from her own experiences as a woman in a field that was—and still is—dominated by men.

Carol Muller, WISP’s cofounder, recalls that Wetterhahn was not allowed to join the science honor society Sigma Xi as an undergraduate at St. Lawrence University in the 1960s because the chapter was men only. “That experience for Karen at that early stage made her more mindful of the discrimination women encounter and determined to do something about it,” Muller says. Muller was an assistant dean at Dartmouth’s engineering school and later an administrator at Stanford University until she retired.

Folt recalls Wetterhahn saying things like, “I’m going to make the path for the women that come after me much smoother than for the women who came before.”

In 1989, Dartmouth announced that Wetterhahn would become associate dean for sciences, the first woman to hold the position.

Muller recalls Wetterhahn listing three priorities in the press release about her new role: constructing a new chemistry building, creating a new biology curriculum, and encouraging women in science fields.

Muller proposed to Wetterhahn that they work on that last problem together. They quickly developed the framework for WISP. Wetterhahn wanted it to have a research component so that undergraduate women interested in science could get lab experience and develop relationships with faculty and peers. WISP also began to facilitate peer mentoring for students to share knowledge and build relationships.

Three decades later, almost 2,300 students have participated in WISP. There were only a few such programs like it at its founding, but WISP quickly gained national prominence, and its model was replicated at more than 100 other schools.

Many of Wetterhahn’s contemporaries were struck by her commitment to WISP. “She didn’t have to do this,” says Mary Pavone, whom Wetterhahn and Muller helped hire as WISP’s first director. “She could have made some pronouncement at the outset: ‘Dartmouth should be doing something about this.’ ” Instead, Pavone says, Wetterhahn used her influence, administrative position, and skills as an organizer and leader to help bring WISP into being, including securing the US National Science Foundation grant that paid for Pavone.

Folt recalls other, less formal ways that Wetterhahn helped smooth the path for women around her.

Shortly after Folt arrived at Dartmouth in 1982, Wetterhahn invited her to lunch with the other women faculty members in science. There were only five of them. “We realized how few we were,” Folt says. But they also realized they had one another and Wetterhahn, who was already established as a researcher. “She gave us all a boost.” Wetterhahn’s message to Folt and other women was that they could do it—whether that was having kids or taking on a role in the administration or both—and that she was there to help. Wetterhahn, Folt says, was an inspiration.

Mentor

A lot of people felt that way about Wetterhahn. Her group members and colleagues alike saw her as a mentor. Her mentorship didn’t produce any papers or interdisciplinary research projects, but those people show that its impact was very real nonetheless.

Martin remembers that, as busy as Wetterhahn was, she gave anyone with whom she met all her attention. Her graduate students had only 30 min a week scheduled with her, but during that time, she was all theirs. “You got to talk about anything you want. She was intensely there for you,” Martin says.

Martin also remembers how demanding Wetterhahn could be, making her group members show that they could repeat results or making them rewrite sections of research papers over and over. Martin admits she sometimes chafed at those demands, but she says now she understands that Wetterhahn held herself and her group to a high standard—and Martin tries to do the same with her own research group.

Folt remembers calling Wetterhahn, who already had kids, after finding out she was pregnant. Folt had a tenure-track position and says having kids before getting tenure wasn’t seen as a smart move. People asked her if she was planning to quit.

Wetterhahn’s positivity and practicality gave Folt the confidence she needed. The first thing Wetterhahn told her was to find a good day care, Folt remembers. “It was, ‘You got this. We can do this.’ ”

Stearns, one of Wetterhahn’s former postdocs, says that like Folt, Martin, and others passing on Wetterhahn’s lessons, Wetterhahn herself was channeling the lessons of her mentors. “She also had strong mentors and advocates,” Stearns says, and those helped get her to where she was. She felt strongly that she had a responsibility to mentor others in turn, Stearns says.

Folt is a case in point. She says not a lot of women were running big science projects when Wetterhahn won her grant to start the Superfund research program. She made sure other women were on the project leadership team, including Folt, who was one of the project’s original PIs. Wetterhahn’s confidence and positive attitude helped all those women feel that they could succeed as leaders, Folt says.

And facilitating other women’s success didn’t end with Folt. One of Folt’s postdocs, Celia Y. Chen, began a research project to study toxic metals in aquatic environments. Then Chen took over Folt’s research program after Folt left. And Chen became the last director of the Dartmouth Toxic Metals Superfund Research Program, the same position Wetterhahn herself had held.

What Wetterhahn might have accomplished, or might have become, we will never know. But what she did, who she was, and what she left behind are things that live on through her colleagues, collaborators, and the wider world.

A group of those people, including many interviewed by C&EN, gathered at Dartmouth in late May 2022 to remember Wetterhahn. One by one, trainees and colleagues described the profound impacts she had on their lives. Many paused to hold back tears as they did so.

Former Dartmouth president Wright recalled that in his eulogy for Wetterhahn, he had remarked that he didn’t expect to meet anyone like her ever again. Twenty-five years later, he said, “I can say those expectations have been confirmed.”

Sam Lemonick is a freelance reporter living in Maine. A version of this story also appeared in ACS Chemical Health & Safety.