THE ALUMNI MAGAZINE OF NORWICH UNIVERSITY
Photo: Seth Frisbie in chemistry lab

The environmental chemist and his wife and research partner, Erika Mitchell, PhD, have devoted much of their research careers to studying arsenic, manganese, and other toxic heavy metals found in drinking water and, more recently, infant formula. What they know is frightening. Far scarier are the outdated government regulations meant to protect us

BY SEAN MARKEY
NORWICH RECORD | Spring 2021

Nearly every day brought the same parade of human misery. Foot lesions. Hand lesions. Torsos and backs rippled with melanoma. In far-gone cases, gangrene or unseen internal malignancies, including bladder, liver, and lung cancers and vascular disease. Some victims were infants and children as young as one and a half years old. The majority were adults—older, but rarely very old. “I walked into one village where no one was over 30 years old,” Seth Frisbie, PhD, recalled. The sick didn’t know the true cause of their suffering. Some thought it was leprosy. Others suspected witchcraft. One thing was for certain, though. Death was stalking the villagers of Bangladesh.

Only a brilliant Indian dermatologist working in neigh-boring West Bengal correctly tied the melanosis and other symptoms to chronic arsenic poisoning. Tens of millions of Bangladeshis were drinking water contaminated with dangerous levels of arsenic and other unknown heavy met¬al toxins. In 1998, Frisbie was on a quest to identify that anonymous rogue’s gallery of poisons and their range across Bangladesh. A blue-collar plumber turned Ivy League PhD, he crisscrossed the country with a government tourist agency driver-cum-translator and a lab assistant from the International Centre for Diarrhoeal Disease Research in Dakha. Riding in an agency-issue rental car with no air conditioning, two horns, and right-hand steering wheel that echoed the country’s British colonial past, the environmental chemist was on an urgent mission to solve a public health emergency.

The previous year, the scientist had been part of a United States Agency for International Development (USAID) project to produce the first national survey of arsenic in the country’s drinking water, most of it drawn from 10 million deep, groundwater tube wells first dug in the 1970s. Some suggested the source of the arsenic came from wooden power poles supplied by the United States. But arsenic from such a source would seep just a few feet and couldn’t explain why Frisbie and geologist Don Maynard were finding the carcinogen as much as 900 feet underground and a dozen miles away. The arsenic was everywhere. The two investigators suspected the source was geologic.

That wasn’t the only problem in the water. Borrowing a lab at the national cholera hospital in Dakha, Frisbie conducted tests that suggested the presence of other previously unidentified toxic metals. Without better equipment, however, Frisbie had no idea what those additional contaminants might be or how widespread. Frisbie and Maynard had little doubt, however, that the health implications for tens of millions of people in Bangladesh were dire.

Frisbie and Maynard were so alarmed they approached representatives from the Bangladesh government, the World Health Organization, the European Union, and the World Bank. They even traveled to Washington, D.C., after returning to the States to speak with USAID staff.

“People just didn’t get it,” Frisbie said. Discoveries in science are usually a thrill, but in this case, it created an unimaginable burden that wore heavily on the Cornell-trained chemist. “Here he had discovered this huge problem and he couldn’t find anyone who was willing to listen,” said Erika Mitchell, PhD, his wife and long-time research partner.

The one person who finally did listen was Bibudhendra Sarkar, PhD, a researcher at the University of Toronto and The Hospital for Sick Children. An expert in metal-caused diseases, Sarkar had discovered the first treatment for Menkes syndrome, a rare and fatal disease caused by copper absorption that, left unchecked, kills newborn children within their first four years of life. Sarkar introduced Frisbie to analytical chemist Richard Ortega, who shared a keen interest in the effects of heavy metals on human health. Based at the University of Bordeaux in France, Ortega had access to an enviable lab of specialized equipment, including the university’s high-resolution imaging particle accelerator, one of only a few dozen instruments like it in the world. If Frisbie could gather the field samples, Ortega would analyze them. Working together, Frisbie, Ortega, Sarkar, and Mitchell hoped to reveal the cocktail of heavy metals poisoning the water supply of millions in Bangladesh.

With no time to waste, the scientists decided to fund the research themselves. Frisbie and Mitchell both quit their existing jobs in the U.S. so Frisbie could devote the next year to field research in Bangladesh. To support the project, Mitchell, who holds a PhD in linguistics and understands 15 languages, soon landed a job teaching English at Zayed University, a start-up college for Emirati women in Dubai in the oil-rich United Arab Emirates. The couple plowed most of her salary into their research.

Taking the advice of a colleague in Dakha, Frisbie timed his field work for Ramadan, when Muslims throughout the country would fast from sunup to sundown, a time when chronic civil unrest in the country calmed. Like his hosts, Frisbie fasted and refused water during the day. At night, he would collapse from sheer exhaustion, often sleeping through the evening meal. After four weeks, he had lost 20 pounds.

Frisbie and his two companions visited three or four villages a day, some only accessible by foot, reached via a dirt path or by balancing atop the dikes of rice paddies. Upon entering, Frisbie would sample local wells and ask to meet the village elder. He would soon find himself seated in the center of the community, as residents described their suffering. Even normally modest Muslim women came forward to expose skin malignant with cancer. Chronic arsenic poisoning can be reversed if it’s caught in time, but only before it manifests as cancer or severe vascular disease. Otherwise, the metal continues to accumulate in the proteins in the skin and begins to destroy blood vessels throughout the entire body, leading to gangrene and far worse cancers in the body’s internal organs.

“These people were desperate. They were sick and they had no idea why,” Frisbie said. The villagers he spoke with were grateful to see someone who cared, who knew what was happening, and who offered some solutions to their problem.

But his fieldwork was paying off, providing the water samples and mapping data he and his colleagues were looking for. At his lab in Bordeaux, Ortega began analyzing the water Frisbie flew back from Bangladesh. Sample after sample confirmed the same grim results. Half of the country’s 120 million people were drinking water with unsafe concentrations of arsenic. Another 60 million people were drinking water with unsafe concentrations of manganese, a potent neurotoxin, with some overlap between the two groups.

The presence of manganese was especially troubling. An essential nutrient in trace amounts, in higher exposures manganese becomes toxic. Only recently have scientists begun to understand its effect as a powerful developmental neurotoxin in children, one linked to lower IQs, impaired memory function and academic skills, attention deficit hyperactivity disorder, violent behavior, and a welter of other behavior and attention problems.

The discovery marked the first time that manganese had been identified in drinking water and found to be wide-spread, and it gave the researchers pause. “There were four people on Earth who knew that there might be another toxin in Bangladesh’s drinking water,” Frisbie said. How could anyone walk away from a problem like that? Frisbie and his colleagues knew they could never live with themselves if they did.

“We had no idea what Seth would find in Bangladesh and how important this would be,” Mitchell said. The more they discovered, the more the scientists found there was to learn and bring to the world’s attention. “It was just opening a can of worms, and we dove right in.”

Photo: feet damaged by chronic arsenic poisoningFrisbie and Mitchell spent five years in Dubai, in all, with frequent return trips to Bangladesh. The researchers proposed a testing strategy to the government of Bangladesh that could provide safe drinking water to 85 percent of the population: Wells with arsenic levels sufficiently low enough to be considered safe by Bangladesh government standards would be painted green. Wells considered unsafe would be painted red. For the remaining 15 percent of the population, water could be treated or sourced from newly dug, safer wells.

The couple also founded a nonprofit, Better Life Laboratories, in 1997, which continues to operate today. It provides research, technical training, and equipment to help people in Bangladesh and other underserved regions access safer drinking water.

Today, the scientists focus much of their research energy on topics related to drinking water and public health, particularly the safety standards national governments and global health organizations set for naturally occurring heavy metals in groundwater.

Frisbie, who joined the chemistry faculty at Norwich in 2006, is a sought-after expert in the field, one who has ad-vised the Canadian government on its drinking water safety standards for copper and uranium. He has also pointed out math errors in drinking water standards set by the World Health Organization. Frisbie and Mitchell collaborate with colleagues at MIT, the Harvard School of Public Health, and other institutions on projects around the world, from Nepal, India, and Rwanda to South America, Honduras, and the United States. Susan Murcott, a research engineer and lecturer at MIT’s D-Lab, who works on global water, sanitation, health, and climate change issues and is a frequent collaborator, describes him as a “world class” chemist.

One of the more recent lines of inquiry undertaken by the husband and wife research team has been the manganese content in powdered infant formulas and so-called toddler “follow on” drinks marketed to parents of children under age 3. The parallels to their early experience in Bangladesh has, at times, been unsettling. Only instead of tens of mil¬lions of impoverished people living in a far-away country in Southern Asia, the exposed population are infants and toddlers in the United States and France.

In a series of three landmark papers, the latest of which was published earlier this year, the scientists shared the results of a year-long research sabbatical in France working with their friend and long-time collaborator Richard Ortega. One of the challenges in analyzing powered infant formula is its insolubility. (This may seem counterintuitive to parents, but from a chemistry perspective, it is true.) Standard chemical analyses using traditional instruments doesn’t work well. Which may explain why such studies are novel. It also shows where having a colleague based at the University of Bordeaux with access to a warehouse-size, multimillion-dollar, high-resolution imaging ion beam particle accelerator called PIXE at the Bordeaux-Gradignan Center for Nuclear Studies comes in handy.

As with the best telescopes in the world, research time on PIXE is competitive and coveted. During their year-long sabbatical, Frisbie and Mitchell only had a week of “beam time,” and even then had to share time with other scientists working on other projects. Using PIXE, Frisbie and Mitchell’s team analyzed the manganese content of 44 brands of powdered infant formula and toddler drinks bought off the shelf in the United States and France. The formulas reflected a range of drinks derived from soy, rice, chocolate, cow’s milk, and goat’s milk-based protein.

Tell-tale X-ray and Rutherford backscattering signatures revealed that manganese levels in the products were 32 to 1,000 times greater than that found in natural breast milk. The worst offenders were supplemented with manganese salts, such as manganese chloride, manganese citrate, manganese gluconate, or manganese sulfate. A vital nutrient in the faintest trace amount, manganese is also a toxic metal. Only in the last 15 to 20 years has the research community begun to fully understand its function as a potent neurotoxin on child brain development and, more generally, on adults.

According to Maryse Bouchard, a researcher and professor at the University of Montreal’s School of Public Health, school-age children with elevated manganese levels have been found to have lower IQs, impaired memory function and academic skills, lower visual-spatial ability, impaired motor function, impaired olfactory function, and atypical brain structure or function. High manganese exposure is also linked to increased risk of attention deficit hyperac¬tivity disorder, behavior, and attention problems.

In adults, manganese can cause Parkinson’s-like tremors, liver and kidney damage, hearing loss, violent behavior, and depression. Research has shown that the hair of violent offenders in California contains higher levels of manganese than control groups.

As humans, our need for manganese is so minute that we acquire it in sufficient amounts simply from the dust in the air we breathe, Frisbie notes. For nursing infants, their mother’s natural breast milk is an ideal source of manganese.

Yet, a 40-year-old regulation by the federal Food and Drug Administration written in 1980 still governs the manganese content in infant formula sold in the United States. It requires a minimum of 5 micrograms of manganese per 100 kilocalories of infant formula, approximately five times the concentration of breast milk. In Europe, the standard is 1 microgram per 100 kilocalories, which approximately equals the concentration of breast milk.

Most troubling, however, is that U.S. regulations set no maximum ceiling or limit on the amount of manganese that manufacturers can add to infant formulas and related products. As a result, many appear to have followed the erroneous approach that “if some is good for you, more must be better,” adding tens if not hundreds times more manganese that necessary. In light of their studies, Frisbie and Mitchell have urged that all manufacturers stop adding supplemental manganese to infant formula.

Their findings highlight the grave disconnect that often exists between science and the latest research and government regulators. As Frisbie and Mitchell wrote in a recent paper, “Evidence-based public policy often comes years or decades after the underlying scientific breakthrough.”

“What we’re seeing over and over again is that many of these regulations that have been designed to protect public health are based on outdated science that’s sometimes 40 years old or even older,” Mitchell said.

“It’s a very underserved area of science,” Frisbie said. “Regulations get set and they become written in stone. They don’t seem to change as science advances.”

In late 2019, after they published their first paper on manganese in infant formula, Frisbie and Mitchell reached out to the office of U.S. Congressman Peter Welch (D-Vt.) with the aim of alerting legislators and the FDA to the risks posed by excessive manganese in infant formula. Four hours after they submitted a constituent web query, a PhD biochemist on Welch’s staff called them at home. Finally, people were paying attention. (In February of this year, an unrelated U.S. Congressional report characterized heavy metals in baby food as “highly dangerous.” That report, plus a self-study on heavy metals in baby food, requested by the FDA from large U.S. producers, suggest greater regulatory scrutiny if not a wholesale overhaul may finally be on the horizon.)

In January, the couple learned that their latest paper, a critical review of international regulations relevant to manganese ingestion in infants, had been accepted by The Journal of Trace Elements in Medicine and Biology. Full of technical detail and dense analysis of the scientific studies used by the U.S. Environmental Protection Agency, World Health Organization, European Union, and the Institute of Medicine (IOM) to set limits for manganese in drinking water, it is not exactly coffee table material. But it’s the kind of work that one might expect people in the right places, i.e., the staffs of our government representatives and federal regulatory agencies, to read and pay attention to. At least, one would hope.

As the scientists point out in their paper, digging to find the original research upon which government regulations are based, in this case manganese, often reveals old and outdated studies. Often they offer “very little scientific basis” to guide regulation, Mitchell says. The Institute of Medicine (since renamed the National Academy of Medicine), for example, set the upper limit for the ingestion of manganese on a single Canadian study from 1982. “They did a dietary survey for three days of a hundred university women,” Mitchell says. “What did you eat for food? Okay, the [person] who ate the most manganese, that’s the upper limit. They didn’t measure any health outcomes. They didn’t even measure weight in this dietary study. So, there was no idea of how long the exposure had been going on. They didn’t measure or look for any health outcomes for either the low ingestion levels or the high ingestion levels. Looking at the entire study, there was … probably around 10 women [who] supposedly ingested 10 milligrams per day, with no measurements of whether or not this affected their health. And the IOM used this to set an upper limit [for manganese]. And then the World Health Organization used the IOM figure for setting their drinking water regulation.”

One of the other major takeaways from Frisbie and Mitchell’s work is that safety standards used by rich and poor countries to govern the amount of arsenic in drinking water is often not governed by the amount that is deemed safe, or reasonably so, for humans. Rather it is often set at the minimum level that most laboratories can easily detect. To put that another way, it is like setting the speed limit around school zones at 80 m.p.h. simply because our police don’t have better radar detectors.

Photo: Boy with melanosis caused by chronic arsenic poisoningWhen he left high school, Frisbie didn’t imagine he would attend college. He trained briefly as machinist and, later, as a plumbing apprentice, going to work for his parents’ plumbing business in Marshfield, Mass. One day, while working on a job at an area hospital, a piece of Sheetrock fell from the ceiling as Frisbie reached for a tool. The slab made “a perfect on-edge karate chop” against his spine. Seriously injured, Frisbie couldn’t walk for three days and was sidelined for months afterward. His orthopedic surgeon refused to operate, believing there was an equal chance he would make matters worse, not better. The doctor told Frisbie he needed to find a different line of work, one where he used his brain instead of his back.

Frisbie followed that advice and ignored his father’s— who thought college was an escape for young people avoiding life—and put himself through the University of Massachusetts at Amherst. His finances were so tight, he could only afford the college’s 10-meal-a-week dining plan. He would eat two meals a day during the week and fast on weekends. If he made tea, he would save the bags and eat the leaves inside. If he had dined better, he may never have met his future wife. “I saw this guy gorging himself on Friday nights, eating two or three meals in one sitting,” Mitchell recalled. “I thought, what is going on here?” The two got to talking and when Mitchell realized the tall freshman didn’t have enough to eat, she started bringing rice and beans to him in his dorm room on Saturday nights.

Frisbie’s academic skills were rusty at first. But he soon proved himself to be an outstanding student, graduating among the top 12 students in his entire class and earning a scholarship to attend graduate school at Cornell. Mitchell followed him there, writing her 900-page doctoral thesis on Finno-Ugric languages. After graduation, Frisbie worked as a chemist at three different engineering firms, until his experience in Bangladesh forever altered the course of both their lives. As Frisbie likes to joke now, he rescued his wife from a life of prosperity.

One of his biggest challenges today is time. “I have more work than I can do in a hundred years,” he says. Teaching at Norwich to train and inspire the next generation of chem¬istry leaders is one way Frisbie hopes to solve the problem.

U.S. Army Medical Corps 2nd. Lt. Gregory Wilkins ’18, is a former student now in dental school at NYU. Wilkins describes Frisbie as a committed educator and dedicated mentor who involves students in consequential research. As an undergraduate, Wilkins spent three years helping Frisbie build a novel instrument to detect arsenic in drinking water at concentrations a thousand times lower than that detected by most routine laboratory tests.

Frisbie’s other projects include an inexpensive spectrophotometer designed in collaboration with electrical and computer engineering Prof. Michael Prairie, PhD. While commercial devices run many thousands of dollars, their instrument uses just $64 in parts. The price point has opened new applications in many low-income countries, including projects to test drinking water for uranium in India and to screen patients for diabetes in Honduras.

Former biochemistry major Kenneth Sikora ’16, who is now studying for his medical degree at Dartmouth’s Geisel School of Medicine, says meeting Frisbie during a campus visit in high school was what inspired him to attend Norwich. He describes his former professor and mentor as a model of “scientific excellence and integrity, empathy, service, and ethical responsibility.”

Thomas Bacquart, a French research scientist based at the National Physical Laboratory in England who has collaborated with Frisbie over the years, says Frisbie’s work is distinguished by its innovation and cutting-edge ideas. While the trend in research today is to tackle increasingly complex and esoteric areas of inquiry, Frisbie’s are always grounded in a practical focus on improving the well-being of people. Striving “to link accurate and pertinent scientific research with actual human life improvements is probably what … impress[es] me most when I look at Dr. Frisbie’s work,” he notes.

“I tell my students who are interested in public health that you have the potential to benefit many millions of people and that you also have the potential to harm many millions of people,” Frisbie said. “The people who advocated to install these deep-water wells in Bangladesh—without testing a single drop of water for naturally occurring metals—did this with the best of intentions. However, they did not think it through, and this has caused tremendous suffering for people.”

As research couples go, Frisbie and Mitchell are exceptionally well matched. Frisbie can be phenomenally detail focused. “A spreadsheet with a thousand datapoints, and he sees the one with the typo,” is how Mitchell puts it. While Frisbie tackles the extremely difficulty chemistry questions, Mitchell delves deeply into literature reviews around the health aspects of their research. “She sees the big picture,” Frisbie says. “It has happened over and over. I’ve been immersed in the minutiae and she understands the significance of what we’re doing.”

One of the more intriguing ideas that Mitchell has landed on recently is the effect that drinking water drawn from deep underground has on human health. Over the course of human evolution, our species has relied almost exclusively on drinking water drawn from lakes, rivers, streams, and other surface water sources. While such sources can be rife with disease caused by parasites and bacterial pathogens, they do offer an advantage when it comes to naturally occurring heavy metals. Exposed to oxygen, many of these metals become insoluble and precipitate out of the water.

But, as Mitchell points out, three technological revolutions that occurred within the span of just seven years in the mid-1800s sparked a tipping point that would irrevocably change where most of the world’s population obtained their drinking water. A source we didn’t evolve to consume. The first innovation came during the London cholera outbreak in 1854, when a scientist by the name of John Snow conceived the germ theory of disease, suggesting correctly that cholera was transmitted by bacteria that contaminated drinking water. The second innovation came just two years later, also in England, when inventor and engineer Henry Bessemer devised a new, inexpensive way to manufacture steel. The final innovation came during the Civil War in the United States, when Union Army officer Col. Nelson W. Green drilled deep, steel tube wells to tap water in underground aquifers to supply safe drinking water that wouldn’t spread dysentery and other diseases among his soldiers.

Water sourced from deep underground is now a major source of drinking water for much of the world’s population. “For the first time in our evolutionary history, a large number of us are drinking deep well water that can’t interact with the oxygen gas in the atmosphere. The deep well water often has naturally occurring metals at high concentrations,” Frisbie says. “This has been an uncontrolled experiment that humans have been participating in for 150 years.”

As that experiment continues, Frisbie and Mitchell will continue to answer the call to use science to help people find safe water to drink.

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