Scientists and regulators are divided over the threat posed by rising levels of a chemical called TFA.
Whenever rain or snow falls from the skies, a human-made chemical called trifluoroacetic acid (TFA) falls with it. Across the world, this chemical has been detected in lakes, rivers, bottled water, beer, cereal crops, animal livers, and even human blood and urine. And wherever researchers measure changes in TFA levels, they find that concentrations are rising.
Over the past four decades, TFA levels have risen five- to tenfold in the leaves and needles of tree species in Germany2,3. Researchers have also documented increasing levels of TFA in Canadian Arctic ice cores4 and in groundwater in Denmark5.
TFA accumulates partly because natural processes can’t break its strong carbon–fluorine bonds. By some definitions, TFA is the smallest example of per- and poly-fluoroalkyl substances (PFASs), which persist for so long that scientists have termed them forever chemicals (see ‘TFA: a controversial molecule’ and ‘Rising levels of TFA’).
Some PFASs are already linked to higher risks of health harms and are banned internationally. Many countries are restricting the levels of certain PFASs in drinking water and undertaking costly cleanup operations.
But the health impacts of TFA are less clear. The few animal studies that exist suggest that current levels are thousands of times lower than those shown to exert biological effects. The United Nations Environment Programme (UNEP), which has been assessing the risks of TFA since 1998, states that it considers the chemical to pose minimal risk for now, and at least until 2100 — although UN member states requested that it re-evaluate its assessment last year.
However, some countries have already begun clamping down on TFA. And in June 2024, two German federal agencies petitioned the European Chemicals Agency (ECHA) to label TFA as a reproductive toxin and a very persistent and very mobile substance. The ECHA has opened this petition for public comment, which closes on 25 July.
In October 2024, worried European environmental scientists declared that rising levels of TFA could cause irreversible harm, calling the chemical a threat to ‘planetary boundaries. They support a widespread ban on all PFASs that the ECHA is considering, which covers TFA.
However, other scientists argue that TFA shouldn’t be included in the definition of PFASs, partly because it doesn’t accumulate in humans and animals like other PFASs do. The US Environmental Protection Agency, for instance, doesn’t currently consider TFA to be a PFAS.
The stakes are high because regulating TFA could have a far-reaching impact on powerful industries, including the refrigeration, agrochemical, and pharmaceutical sectors.
Here, Nature explains the fight that’s brewing over this small but controversial molecule.
Simple molecule, complex origins
TFA enters the environment in many ways. It’s used in academic research, for example, to prepare peptides for biology studies, says Reza Ghadiri, a chemist at the Scripps Research Institute in La Jolla, California. More widely, however, the agrochemical, pharmaceutical, and fine-chemical industries utilise TFA as an ingredient to produce larger fluorine-containing molecules, which can escape from industrial facilities.
In Germany, for instance, interest in TFA was sparked in 2016 after researchers at the German Water Centre (TZW) in Karlsruhe found high levels of the chemical in a river and traced it to a chemical plant.
Industrial discharges are just one source of TFA pollution6. Other chemicals can also break apart to create TFA as they languish in the environment. These precursor chemicals include pesticides, PFASs leaching from discarded or landfilled consumer products and excreted medications that pass through sewage plants (see ‘TFA’s precursors’). This all adds TFA to terrestrial water, but not to rain; when water evaporates, TFA — like a salt—is left behind.
The TFA in rain originates from various sources, primarily fluorinated gases (F-gases), including those used as refrigerants and in building insulation. These gases leak from air-conditioner units and insulation foam, mostly when products are in use or being discarded.
Scientific interest in TFA began after the Montreal Protocol came into force in 1989, when the world agreed to restrict gases, including chlorofluorocarbons (CFCs), used as refrigerants and aerosol propellants, because they damaged the Earth’s protective ozone layer.
Industry users launched a massive effort called the Alternative Fluorocarbon Environmental Acceptability Study (AFEAS) to assess the environmental impact of the F-gases proposed as substitutes for fluorocarbons. A few of those — including the widely used HFC-134a — were soon found to break up into TFA in the lowest layer of Earth’s atmosphere.
Concerned that the F-gas substitution would introduce a foreign substance to the planet, researchers began studying TFA intensively. Unexpectedly, they discovered that TFA already existed in rain, springs, and rivers at appreciable levels, suggesting that there were other sources of contamination. Indeed, later analysis of ice cores from the Arctic shows that TFA was deposited with snow there as long ago as 19694.
The missing TFA
That kicked off a search in the 1990s for other TFA precursors. Surprisingly, these included anaesthetic gases that have been used since the 1950s, and that are exhaled or vented into the atmosphere.
A twist in the tale emerged in 2002, when AFEAS-funded researchers measured substantial TFA in the Atlantic and Southern oceans8. In 2005, an international team of researchers found similar TFA levels in 22 spots in the Atlantic, Arctic, and Pacific oceans. They extrapolated that the oceans held huge quantities of TFA, ranging from 60 million to 200 million tonnes.
That was far too much TFA to explain with known human-made sources. The authors of both studies suggested that TFA might be a naturally occurring salt in the oceans.
Some industrial firms use this theory to argue that any anthropogenic TFA would wash away into oceans and increase the large amounts of natural TFA there by unnoticeable fractions. Panels of scientists convened by UNEP have repeatedly relied on this argument when concluding that TFA poses minimal risks at current environmental levels.
In October 2024, worried European environmental scientists declared that rising levels of TFA could cause irreversible harm, calling the chemical a threat to ‘planetary boundaries. They support a widespread ban on all PFASs that the ECHA is considering, which covers TFA.
However, other scientists argue that TFA shouldn’t be included in the definition of PFASs, partly because it doesn’t accumulate in humans and animals like other PFASs do. The US Environmental Protection Agency, for instance, doesn’t currently consider TFA to be a PFAS.
However, many scientists disagree that unexplained large amounts of TFA in the oceans necessarily indicate that it’s natural. “Ten measurements from a few locations should not be extrapolated to entire oceans,” says Cora Young, an environmental chemist at York University in Toronto, Canada, whose team has documented TFA’s rising levels in Arctic ice cores (see ‘TFA in ice cores’)4.
And no one has reported a plausible mechanism for TFA to form naturally, says Scott Mabury, an environmental chemist at the University of Toronto, who has identified precursors of TFA.
David O’Hagan, a fluorine chemist at the University of St Andrews, UK, who studies naturally occurring fluorinated compounds, says that he remains “truly unsure” about whether TFA could occur naturally. A few microorganisms do make fluorinated molecules, but because these have only one fluorine atom — not three — O’Hagan doesn’t think microbial processes would create TFA. Scientists have yet to identify possible geological mechanisms, he adds.
New data support the decades-old findings that the oceans could harbour large amounts of TFA. Last year, the German environmental agency published measurements of TFA levels from 31 locations in the Atlantic Ocean, which are higher than those reported in 2005 (it is too soon to tell whether ocean TFA levels are rising, however).
However, in the end, it doesn’t matter whether natural TFA exists in the oceans, says Finnian Freeling, an analytical chemist at TZW, who conducted both the Atlantic Ocean and German-tree studies. What’s essential is the drastic rise in TFA levels on land. “These steep increases, they have to come from anthropogenic activities,” he says.
Even if some TFA turns out to be naturally occurring, that doesn’t make it safe and doesn’t make it OK to add more, says Mark Hanson, an ecotoxicologist at the University of Manitoba in Winnipeg, Canada, who serves on the current UNEP panel.
Researchers, including Shira Joudan, an environmental chemist at the University of Alberta in Edmonton, Canada, suggest that TFA emissions from sources other than F-gases have been underestimated.
These researchers are investigating how much and how quickly precursors such as pesticides and pharmaceuticals break down into TFA. “If we’re going to make any decisions on limiting emissions, we need to know where it’s coming from,” Joudan says.
Is TFA harmful?
In the 1990s, AFEAS researchers concluded that TFA is not acutely toxic, citing earlier studies that had administered TFA to mice and rats. 7 Huge quantities were needed to kill the animals. By that metric, TFA was found to be “about as toxic as table salt”, says Thomas Cahill, an environmental toxicologist at Arizona State University in Tempe.
TFA’s molecular structure differs from that of the well-established PFAS pollutants. The typical structure of molecules linked to health harms features a hydrophilic head and a long hydrophobic tail, often swaddled in fluorine atoms. TFA has a mere stub of a tail, with just one fluorine-bearing carbon atom.
For this reason, some scientists believe that TFA shouldn’t be considered a PFAS. Due to its small size, TFA is highly water-soluble, enabling mammalian bodies to excrete it efficiently. In 1976, to investigate whether TFA is a harmful metabolite of the anaesthetic halothane, researchers injected two volunteers with TFA and recovered all of it in urine within three days. Many scientists believe that TFA does not accumulate in organs and tissues, but instead behaves like a salt. “I view it like chloride,” says Mabury.
However, TFA levels could still rise in humans because the molecule is constantly consumed through food and water, and levels in those sources are rising, says Freeling. After measuring TFA in human urine samples, he thinks that dietary exposure is higher than many scientists assume. Cahill, who has found TFA in dozens of foodstuffs, agrees.
And evidence is mounting that TFA can exert biological effects. In March, Ghadiri’s team reported, in a preprint, the accidental discovery that TFA is a bioactive component that lowers lipid and cholesterol levels in mice12. In a 1999 study, researchers observed that, as a laboratory contaminant, TFA inhibited the proliferation of specific bone cells in Petri dishes13. Ghadiri emphasises that there is no human data on TFA; his takeaway is simply that it should not be treated as innocuous.
Most significant are the animal data that German agencies are now relying on to convince the ECHA to label TFA as a reproductive toxin.
In 2017, the ECHA told some firms that were registering TFA as a ‘high production volume’ chemical (to comply with updated European chemicals legislation) to provide more data on safety risks. That included data on reproductive toxicity, which the AFEAS hadn’t assessed. Industry groups commissioned safety studies from a contract lab that fed TFA to rats and rabbits and assessed their offspring. Animals given higher doses of the chemical had fetuses with lower weights and more deformities, particularly in the eyes, compared with those on lower doses. (The studies are not published, but the data were made public with the German petition.)
However, those animals were given TFA at levels that are hundreds of thousands of times higher than researchers have measured in drinking water.
Although these outcomes may not be observed in humans, the studies indicate that high levels of TFA could harm human health, says Jamie DeWitt, a toxicologist at Oregon State University in Corvallis. DeWitt is planning to initiate 30-day studies that expose mice to TFA through their skin, aiming to investigate its effects on the immune system.
Some researchers are more worried about the effects of TFA on plants and ecosystems. Plants take up TFA along with water through their roots, but the TFA doesn’t leave the plant together with transpired water vapour. “It can’t evaporate,” Cahill says. “It’s stuck.”
AFEAS researchers attempted to address these concerns in the 1990s by growing crops, including sunflower, wheat, maise (corn), rice, and soybeans, in TFA-contaminated soil and water. Apart from inhibiting growth at high levels (above 1 milligram per litre), the researchers found little else.