Sulfur Hexafluoride Lipid-Type A Microspheres

By Mark Jones It looks innocuous in my hand, yet there are growing calls to ban it. It may use technology created for the Manhattan Project, but, in my hand, it doesn’t feel like a weapon. It feels natural, in spite of the very unnatural materials it may contain. I’m not at all cautious as I open it. Reaching in, I grab a slice. I do love pizza. Pizza predates the Manhattan Project. Although pizza technically isn’t the problem, it’s the box. Cardboard for pizza boxes have been made resistant to both grease and steam using fluorocarbons. Five years ago, almost certainly, per- or polyfluorinated alkyl substances, PFAS, would have been used. Some states have now banned PFAS in things like pizza boxes. I’m not in one of those states. I can’t be sure whether the box in my hand uses PFAS or not. PFASes were initially identified as a health concern at hotspots. There are many maps with markers locating these hotspots contaminated most commonly by some intense use of PFAS in manufacturing or firefighting. Realization of widespread contamination from use in paper may ultimately be the trigger for bans gaining traction. PFASes are under intense scrutiny, with high-profile calls for a complete ban becoming more common. At the same time, just to muddy things up, there are at least nine competing definitions of PFAS. One thing is certain: they are now everywhere. Hardly a day goes by without another report of concerning levels being found in food wrappers, bottled water, toilet paper, food, cosmetics, ski wax, or some other product. (Note from Medical Design & Outsourcing: A PTFE reformulation played a role in a string of serious medical device guidewire recalls in the 2010s.) A review of history shows how we got to this point. It is a story of overcoming daunting challenges, of incredible R&D efforts. It is a story of innovation, of invention put to practice. It is a story of solving difficult challenges. It is also a story of hubris, of actions driven by flawed beliefs. The beginning of PFASes The Manhattan Project team turned to gaseous diffusion to produce fissionable uranium. Uranium hexafluoride, UF6, was the only gaseous uranium compound known at the time. Handling UF6 was, and remains, a daunting task. It is corrosive to many common construction materials and reacts with moisture-liberating HF. Tasked with handling this troublesome material, the Manhattan Project scientists rapidly developed fluorocarbon polymers, fluids, and waxes. After the war, chemists at 3M and DuPont went wild synthesizing new compounds. Applications exploded due to the unique properties of highly fluorinated materials. Many new applications made use of inertness. Many didn’t. We’ve all learned oil and water don’t mix. Things either like oil or they like water. Turns out highly fluorinated materials don’t like either. They don’t want to be near oil, they don’t want to be near water. This trait made them attractive in a range of applications. Highly fluorinated materials are completely artificial, unlike anything made in nature. Their stability is remarkable. Environmental and biological systems do not degrade them. Their remarkable stability led to the defining fluorocarbons as more than safe — they were innocuous. Environmental release was okay because they were safe. Placement in consumer products was okay because the materials were safe. While originally seen as a remarkable benefit, we’ve come to recognize stability is a problem. The Stockholm Convention is recognition that persistence of synthetic materials is a risk. Production of perfluorinated C8 compounds exploded in the time between the War and the 1990s. 1968 marks the year of the first reports of persistent fluorocarbon species in human blood. Much of the world bore the evidence of exposure more than 50 years ago. The explosion in use was, in part, based on assumptions these inert materials were biologically benign. By 2000, this changed. Reports of liver changes correlated with exposure were made public. Compounds were voluntarily removed from the market, in 2000 by 3M and in 2006 by other U.S. manufacturers. A 2022 National Academies’ report clearly implicated six negative health outcomes with exposure. Our understanding of the health and environmental impacts continues to grow, as does our understanding of where these materials are present in the environment. Not just stable, but resistant The Manhattan Project valued the stability and resistance to aggressive, corrosive materials. But fluorocarbons are in the pizza box due to characteristics unrelated to stability. Functionalized fluorocarbons, when added to pulp (even at only around 1%), make the cardboard repel both oil and water. Their use has nothing to do with stability. They make paper grease- and water-resistant. They are used in coated papers too, keeping coatings from sinking in too much when being applied. Let that sink in. One of the lowest-value uses of PFAS grew to be the largest single market for fluorochemicals. Paper intended to be thrown away after a single use was, and may remain, where most PFAS gets used. Paper factories are one of the places where high levels of PFAS contamination are found, but the presence in biosolids and compost points to paper being a major source of widespread, low-level contamination. PFAS used to be a concern only in places where high levels were found. Two things have happened. As analytical chemists look more and more places, PFASes are found in more and more places. They are pretty much everywhere. At the same time, levels of concern have dropped from parts-per-million to parts-per-quadrillion. Fabric coating, making fabrics stain and water resistant, is similar to paper coating. Application to fabric at very low levels significantly modifies properties. High levels of fluorocarbons are associated with textile, leather, and paper manufacturing. Fluorocarbon foams extinguish flammable liquid fires amazingly well. Highly fluorinated materials repel both water and oil. Applied to flammable liquids, they suppress formation of flammable vapors. Foams made with them rapidly suppress fires and keep them from reigniting. Use at refineries, airports, and military bases led to very high levels of contamination. Those same materials, especially the C8 materials referred to PFOS and PFOA, were also used as processing aids in making polymers. Contamination from manufacturing of fluoropolymers have created some huge environmental issues, too. PFAS negative health impacts came to light in populations near fluorocarbon polymer manufacturing sites with significant groundwater contamination. Continued use of fluorocarbon polymers will require overcoming this legacy, showing that fluorocarbon polymers can be produced without environmental emissions. In addition to these major uses, there are many minor uses. They are common in coatings and used in metal plating. They are immersion heat transfer fluids, effective at removing heat while not interacting with substrates. They are used as vapor degreasing agents, non-flammable and presumed safe. They are used in cosmetics, where properties such hydrophobicity and film-forming ability are desired. PFASes make products apply easier and makes them more durable. All of these uses are sources of potential exposure and near-certain environmental release. PFASes are used in a way where there is at least some release to the environment. Essential is a word now getting applied to describe some PFAS uses and as an argument against bans. It is easy to argue for banning some applications. There are other technologies for pizza boxes. The same is true for fabric and leather protection. Cosmetics seem firmly in the non-essential use bucket. There are, however, areas where PFASes are used where replacements aren’t so readily apparent. My first project in an industrial lab was to automate an oxidizing titration. I used a cell made of Kynar with sapphire windows sealed with Viton O-rings. Regents were controlled by PTFE valves and flowed into the cell through FEP tubing sealed to the cell with Tefzel ferrules. A Teflon-coated stirrer insured complete mixing. Pipe threads were lubricated with Teflon tape. Kynar, polyvinylidene fluoride, would be gone with a PFAS ban. So would Teflon (polytetrafluoroethylene[PTFE]), Viton (vinylidene fluoride and hexafluoropropylene copolymer), FEP (copolymer of hexafluoropropylene and tetrafluoroethylene), and Tefzel (copolymer of ethylene and tetrafluoroethylene). All the working definitions of PFAS include fluorocarbon polymers. What was possible in the 1990s would be unconstructable in a post-PFAS polymers world. All the polymers would be banned. Many other polymers are PFASes: Gore-Tex (expanded PTFE), Neoflon (polychlorotrifluoroethylene and formerly sold as Kel-F), Krytox grease (polyhexafluoropropylene oxide), and more would all be banned. Nafion membranes (sulfonated polyfluoroethylene) enables the chlor-alkali process foundational to the chemical industry, and fuel cells and membrane electrolyzers. I am writing this on a laptop with a lithium-ion battery containing polyvinylidene fluoride as an electrode binder, with semiconductors likely processed with PFAS heat transfer fluids, and with a main board that may have been soldered using vapor reflow soldering using temperature-stable, nonflammable fluorocarbons. Bye-bye to all if PFASes are banned. Manufacturers of polymers are pushing back against the bans. Polymers, they argue, are too big to cause health issues and they don’t decompose to make smaller, ingestible PFAS species. The hazards presented by polymers are small and the benefits more than worth the risk. Historic manufacturing carelessly released PFAS. Not anymore, manufacturers say. Emissions are or can be eliminated. On the other end of the spectrum from polymers are the more lightly fluorinated small molecules used a drugs or agricultural chemicals. There are many compounds currently in wide use that some would ban and others would argue aren’t even a PFAS, depending on the PFAS definition. Some of the most used drugs have a perfluorinated alkyl group. Prozac does. Health studies on this widely prescribed drug stretching back decades fail to show the health impacts attributed to PFAS even though serum levels are high compared with current PFAS levels of concern. New drugs, such as the COVID treatment Paxlovid is a PFAS by many of the definitions. Same with the widely used agrochemicals diflufenican and fluopyram. Studies show all are transient in the environment, that the bioaccumulation observed for PFASes like PFOA and PFOS do not occur. The environmental fate is still a research topic. It is pretty clear mineralization, where the carbon-fluorine bonds are broken and the fluorine becomes an inorganic fluoride, either do not occur or occur only very slowly. That’s bad. It means nature is likely transforming one PFAS into others. Studies on compounds with trifluoromethyl groups indicate production of trifluoroacetic acid. Again, more research is needed to better understand both the degradation and the hazard it presents. For most years over the last decade, fluorinated pharmaceuticals account for between one quarter and one third of all new small molecule drug registrations. The numbers are similar for agrochemicals. Many very popular drugs, including the Lipitor, the most prescribed drug of all time, are fluorinated. Removing fluorine from the pharmaceutical chemist’s toolbox will have negative consequences. Just as with the polymers, some want to name the materials essential and allow continued use. Others argue they shouldn’t be lumped in with more highly fluorinated PFAS. There is no clearly right answer. We are not in a good place. The talk of banning a class of materials when there is disagreement about what is in the class is certainly problematic. Those seeking essential use exemptions will surely face scrutiny about the definition of essential. Fluoropolymers are amazing materials, so amazing it is hard to imagine a world without them. All evidence points to the polymers being benign. Manufacturers still need to prove the manufacturing is similarly benign, that polymer production can be done without PFAS release. Drugs proven safe over decades of use may be banned by association. Potential new treatments and new agrochemicals will never get to market. We are where we are because of hubris — because strong beliefs that fluorochemicals were inert meant they were safe. We must do better moving forward. The pizza is gone. I’m now stuck deciding what to do with the box, while pondering the implications. Widespread use of PFASes for something as inconsequential as a pizza box is clearly responsible for some of the near universal contamination we now face. That contamination is driving a response that may remove some very useful, even essential materials and compounds from use. If PFAS is present in my pizza box, someone else made the decision to use it. It is my hand that determines the fate of the PFAS in the box. Recycle bin or trash bin are the options available. I’m writing this in Washington, D.C. Trash here goes one of two places, either to waste-to-energy facilities or to a landfill, and I don’t control that decision. There are concerning reports that waste-to-energy facilities fail to destroy PFASes. Some data show they actually spread the materials to the environment. Recycling, putting the paper fiber back into the circular economy, will put PFAS into the recycle stream where it will continue to build. There are qualitative tests I could run in hopes of determining whether PFAS is present in the cardboard. Instead, I tear the box in half. Half into recycling, half goes into the trash. Faced with two bad options, I choose a bit of both. This story originally ran on our WTWH Media sister site R&D World.