What are forever chemicals
Forever chemicals also known as PFAS or Perfluoroalkyl and Polyfluoroalkyl substances, are a group of man-made chemicals that includes perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), perfluorononanoic acid (PFNA), perfluoroalkyl acids (PFAAs), perfluoroalkane sulfonic acids (PFSAs), perfluorohexane sulfonic acid (PFHxS), perfluoroalkyl carboxylic acids (PFCAs), polytetrafluoroethylene (PTFE), also known as Teflon and many others (over 7800 forever chemicals identified to date) 1, 2, 3, 4, 5, 6, 7, 8. All forever chemicals contain at least one perfluoroalkyl moiety (CnF2n+1–) 9. Chemically, individual forever chemicals can be very different. However, they all have a carbon-fluorine bond, which is very strong and therefore, they do not degrade easily. Fully fluorinated aliphatic carbon chains are known as perfluoroalkyl substances while those with incomplete replacement of hydrogen atoms by fluorine are referred to as polyfluoroalkyl substances.
Forever chemicals have been manufactured and used in the aerospace, automotive, construction, and electronics industries around the world since the 1940s as chemicals that resist grease, oil, water, and heat 10, 11. Forever chemicals have been widely used for their water resistant (hydrophobic) and oil repellent (oleophobic) properties in consumer products such as disposable food packaging, cookware, outdoor gear, furniture, and carpet 12, 13, 14, 11. Certain forever chemicals are also authorized by the US Food and Drug Agency (FDA) for limited use in cookware, food packaging, and food processing equipment 5. Forever chemicals are also one of the main components (1–5% w/w) of aqueous film forming foams (fire-fighting foams) used frequently at airports and military bases in firefighting foam for firefighting and training activities 15, 16, 17, 18. Aqueous film forming foams (fire-fighting foams) contamination of groundwater is a major source of drinking water contamination and has been identified as a nationally significant challenge in countries such as the United States and Sweden 19, 20. Releases of PFAS to the environment can occur next to chemical manufacturing locations, at industrial sites where PFAS are used, and at various stages of product use and disposal. The carbon-fluorine bond in these compounds is extremely strong and thus many PFAS are not appreciably degraded under environmental conditions 21. This has resulted in their accumulation in the environment since the onset of production in the late 1940s 22. In 2015, the Centers for Disease Control and Prevention (CDC) National Health and Nutrition Examination Survey (NHANES) reported that forever chemicals were found in the blood of nearly all Americans sampled 23. US companies no longer manufacture the two best-known forever chemicals, perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) 24. But these legacy forever chemicals persist in the environment, even as thousands of others remain in production.
People can be exposed to forever chemicals in different ways, for example through food. Food can become contaminated through contaminated soil and water used to grow the food, through the concentration of these substances in animals via feed and water, through food packaging containing forever chemicals, or equipment that contained forever chemicals during food processing. Exposure to forever chemicals may lead to adverse health effects 25, 26, 27, 28.
Concerns about the public health impact of forever chemicals have arisen for the following reasons 29:
- Widespread occurrence. Studies find forever chemicals in the blood and urine of people, and scientists want to know if they cause health problems.
- Numerous exposures. Forever chemicals are used in hundreds of products globally, with many opportunities for human exposure.
- Growing numbers. Forever chemicals are a group of nearly 15,000 synthetic chemicals, according to a chemicals database maintained by the U.S. Environmental Protection Agency (https://comptox.epa.gov/dashboard/chemical-lists/PFASSTRUCT).
- Persistent. Forever chemicals remain in the environment for an unknown amount of time.
- Bioaccumulation. People may encounter different forever chemicals in various ways. Over time, people may take in more of the chemicals than they excrete, a process that leads to bioaccumulation in bodies.
Because there are many types of forever chemicals, which often occur in complex mixtures and in various everyday products, researchers face challenges in studying them. More research is needed to fully understand all sources of exposure, and if and how they may cause health problems. The research conducted to date reveals possible links between human exposures to forever chemicals and adverse health outcomes. These health effects include 30, 31, 32, 33, 2:
- altered metabolism,
- reduced fetal growth and increased risk of being overweight or obese,
- increased risk of some cancers,
- reduced ability of the immune system to fight infections.
Potential of forever chemicals to cause a wide range of negative health impacts depends of various factors, such as the conditions of exposure (dose/concentration, duration, route of exposure, etc.) and characteristics associated with the exposed target (e.g., age, sex, ethnicity, health status, and genetic predisposition) 34. Endocrine disruptive effects of forever chemicals have been reported to affect fertility, body weight control, thyroid and mammary gland function 35. Developmental effects have been observed in children such as alterations in the behavior or accelerated puberty but also in the newborns such as decreased birthweight 35. Increased risk of kidney, prostate and testicular cancer has been associated with long-term exposure to forever chemicals in the general population alongside with disturbances in the cholesterol metabolism or reduced efficiency of the immune system against infections 35.
Studies have shown that some forever chemicals are toxic for both animals and humans 36, 6, 7, 37, 38, 39, 40, 41. Certain forever chemicals such as perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS), perfluorononanoic acid (PFNA) and perfluorohexane sulfonic acid (PFHxS), don’t break down in the environment or in the human body, and can accumulate over time. Furthermore, the most frequently detected forever chemicals, perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA), are highly mobile once introduced to the aquatic environment 42 and are not removed by conventional wastewater treatment 43, 44. Forever chemicals therefore pose a severe threat to clean water supply worldwide 45.
In light of the past and current evidence of forever chemicals toxic effects, there is an increasing awareness and a general agreement that forever chemicals substances need to be regulated at multiple levels to minimize their adverse effects on human health and the environment. Manufacturers have phased out production of certain forever chemicals and in some cases replaced them with new forever chemicals or chemical substitutes 46. For example in textile treatments, many polymers containing long perfluoroalkyl side chains (more than seven perfluorinated carbons) were replaced by analogs containing short perfluoroalkyl side chains (six or four perfluorinated carbons) or fluorine-free moieties (e.g., siloxanes and hydrocarbon polymers) 47. Between 2000 to 2002, the main global manufacturer of forever chemicals (3M Company) voluntarily discontinued manufacturing of the parent chemical perfluorooctane sulfonyl fluoride (POSF) used to produce perfluorooctane sulfonic acid (PFOS) and its precursors perfluorooctane sulfonamide-based chemistry 48, 49. United States introduced a variety of programs to curb use of the most abundant environmental forever chemicals, including the PFOA Stewardship Program enacted in 2006 to end production of the longest chained compounds by 2015 11. Perfluorooctane sulfonic acid (PFOS) was added to the Stockholm Convention’s list of globally restricted Persistent Organic Pollutants (POPs) in 2009 11. A proliferation of new forever chemicals have been reported in the environmental literature as industry has rapidly replaced PFOS and PFOA with shorter chain length forever chemicals and new chemicals that are difficult to detect using standard methods 16. Emerging evidence from animal experiments suggests some of these alternative forever chemicals can be equally hazardous 50. Environmental health scientists thus face a considerable challenge in understanding the relative importance of diverse exposure pathways to forever chemicals in different human populations and their potential effects on human health in a rapidly changing chemical landscape 11.
Despite the many regulations to limit the forever chemicals spread and the phasing out the main forever chemicals substances (expressed in PFOS and PFOA), other compounds including PFAAs and related substances are still widely used in various industries including fire-fighting foams, photographic, semiconductor and others 51. Therefore, the detection of PFAS in human bodies have not decreased 51, 52, 53, 54.
Figure 1. Forever chemical structure
Footnote: A general structural formula for perfluoroalkyl substance (PFAS), containing a hydrophobic perfluorinated alkyl tail, and a hydrophilic functional (R) group outlined in a red box. The general structure of non-polymeric, perfluorinated PFAS substances. Non-polymeric PFAS are compounds of variable composition and physicochemical properties that however share two common features. These are represented by the hydrophobic tail, composed by a variable number of carbon atoms at different degree of fluorination, and the hydrophilic head, which contains polar groups. The specific combination of these chemical determinants, namely the carbon chain length, the type of functional groups and the number of fluoride atoms, generates an enormous number of different PFAS molecules with ample downstream applicability. Some of the most common polar groups, are shown.[Source 35 ]
Figure 2. Forever chemicals classification9 ]
Figure 3. Forever chemicals substances
Footnote: Examples of non-polymeric and polymeric Forever chemicals substances substances. (A,B) Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS), two well-known non-polymeric PFAS are shown. Both these compounds possess a relatively long tail containing eight fluorinated carbon atoms, but differ in the chemical composition of the polar head group, which is a carboxylic acid for PFOA and a sulfonic acid for PFOS. Under specific pH environmental conditions, these functional groups can dissociate into the respective anion forms (i.e., carboxylate and sulfonate). (C) Exemplary structure of Polytetrafluoroethylene (PTFE), also known as Teflon, a polymeric PFAS belonging to the subgroup of fluoropolymers. This type of compound is constituted by a moiety of (CF2-CF2)n atoms which is repeated up to thousands of times; (D) Exemplary structure of a lubrificant also known as Krytox, which is a polymeric PFAS belonging to the subgroup of perfluoropolyethers. In this case the (CF[CF3]−CF2−O)n moiety is repeated between 10–60 times.[Source 35 ]
Figure 4. Forever chemicals emission sources
Footnotes: Schematic illustration of the forever chemicals (PFAS) environmental distribution and exposure routes for humans and biota. The environmental distribution of forever chemicals (PFAS) substances involves multiple dispersion routes and exposure pathways that link the sources to the final receptors, represented by humans and wildlife. Industrial manufacture processes, industrial uses and recycling activities, represent primary sources of forever chemicals (PFAS) emissions. Other indirect sources are the landfilling or the application of contaminated sludge to agriculture land. Volatilization, deposition, leaching and run off processes regulate the redistribution of forever chemicals (PFAS) between air, soil, water and sediment compartments. Collectively, these pathways contribute to the short-term and long-term exposure of aquatic ecosystems, terrestrial ecosystems and humans to forever chemicals (PFAS) substances, that can also enter into the food chain through bioaccumulation and indirect human exposure via the ingestion of contaminated food sources.[Source 35 ]
Table 1. List of main Forever chemicals categories and subgroups
|Non-Polymeric Forever Chemicals|
|Perfluorinated forever chemicals||Polyfluorinated forever chemicals|
|Perfluoroalkyl acids (PFAAs)|
Perfluoroalkane sulfonic acids & sulfonates (PFSAs)
Perfluoroalkane sulfnic acids (PFSIAs)
Perfluorocarboxylic acids & carboxylates (PFCAs)
Perfluoroalkyl phosphonic acids (PFPAs)
Perfluoroalkyl phosphinic acids (PFPIAs)
|PFBS, PFHxS, PFOS|
PFBA, PFHxA, PFOA
|Fluorotelomer compounds (FT)||6:2 FTO, 8:2 FTI|
|Perfluoroalkane sulfonamido compounds|
|Perfluoroalkyl ether acids (PFEAs)||GenX, Adona, F-53B|
|Perfluoroalkane sulfonamides (FASA)||FOSA|
|Perfluoroalkane sulfonyl fluorides (PASFs)||PBSF, POSF|
|Perfluoroalkyl iodides (PFAIs)||PFHxI|
|Perfluoroalkanoyl fluorides (PAFs)||POF|
|Perfluoroalkyl aldehydes (PFALs)||PFNAL|
|Polymeric Forever Chemicals|
|Fluoropolymers||PVDF, FEP, PFA, ETFE, PTFE (Teflon)|
|Side-chain Fluorinated Polymers||Fluorinated urethane/acrylate/methacrylate/oxetane plolymers|
|Perfluoropolyethers (PFPEs)||PFPE-BP, Fluorolink-PFPE|
Table 2. List of Forever Chemicals extended chemical names and acronyms
|Forever chemicals Chemical Name||PFAS Acronym||Forever chemicals Chemical Name||PFAS Acronym|
|Perfluorooctanoic acid||PFOA||N-ethyl perfluorooctane sulfonamide||Et-FOSA|
|Perfluorooctane sulfonic acid||PFOS||N-methyl perfluorooctane sulfonamide||Me-FOSA|
|Perfluorooctanesulfonamide||PFOSA/FOSA||N-ethyl-perfluorooctane sulfonamido acetic acid||N-Et-FOSAA|
|Perfluorooctane sulfinic acid||PFOSI||N-methyl-perfluorooctane sulfonamido acetic acid||N-Me-FOSAA|
|Perfluorononanoic acid||PFNA||2-(N-Methyl-perfluorooctane sulfonamido) acetic acid||Me-FOSAA/Me-PFOSA-AcOH)|
|Perfluorononanal||PFNAL||2-(N-Ethyl-perfluorooctane sulfonamido) acetic acid||Et-FOSAA/Et-PFOSA-AcOH|
|Perfluorononane sulfonic acid||PFNS||perfluorooctane sulfonamido ethanol||FOSE|
|Perfluoroundecanoic acid||PFUnDA||N-ethyl perfluorooctane sulfonamido ethanol||Et-FOSE|
|Perfluorodecanoic acid||PFDA||bis(perfluorooctyl)phosphinic acid||C8/C8-PFPiA|
|Perfluorododecanoic acid||PFDoA||6:2 Fluorotelomer olefin||6:2 FTO|
|Perfluorodecane sulfonic acid||PFDS||6:2,8:2,10:2 fluorotelomer alcohol||6:2,8:2,10:2 FTOH|
|Perfluorobutanoic acid||PFBA||6:2,8:2 fluorotelomer sulfonic acid||6:2,8:2 FTSA|
|Perfluorobutane sulfonic acid||PFBS||6:2 fluorotelomer thioether amido sulfonate||6:2 FtTAoS|
|Perfluorophosphonic acid||PFPA||8:2 fluorotelomer iodide||8:2 FTI|
|Perfluoropentanoic acid||PFPeA||8:2 fluorotelomer unsaturated carboxylic acid||8:2 FTUCA|
|Perfluoropolyether-benzophenone||PFPE-BP||9-chlorohexadecafluoro-3-oxanone-1-sulfonic acid||6:2 Cl-PFESA (F-53B)|
|Perfluorohexanoic acid||PFHxA||1-chloroeicosafluoro-3-oxaundecane-1-sulfonic acid||8:2 Cl-PFESA|
|Perfluorohexyl iodide||PFHxI||Polyvinylidene fluoride||PVDF|
|Perfluorohexane sulfonic acid||PFHxS||Fluorinated ethylene propylene||FEP|
|Perfluoroheptanoic acid||PFHpA||Perfluoroalkoxy polymer||PFA|
|Perfluoroheptane sulfonic acid||PFHpS||Ethylene tetrafluoroethylene||ETFE|
|Perfluorooctanoyl fluoride||POF||Hexafluoropropylene oxide dimer acid||HFPO-DA/GenX|
|Perfluorobutane sulfonyl fluoride||PBSF||3H-perfluoro-3-[(3-methoxy-propoxy)] propanoic acid||ADONA|
|Perfluorooctane sulfonyl fluoride||POSF||Ammonium pentadecafluorooctanoate||APFO|
Forever chemicals Uses
The exceptional strength of the Carbon-Fluorine bond confers very high thermal and chemical stability to forever chemicals molecules while the presence of hydrophobic and hydrophilic properties along with the variability in the carbon chain length and chemical composition generates an enormous range of different molecules with useful physicochemical properties. For this reason, since 1940’s, forever chemicals substances have been frequently employed in a vast number of industrial or consumer’s products covering more than 100 sectors of use. Some of the most common forever chemicals applications include Teflon, pesticide formulation, firefighting foams, surfactants, lubricants, paints, waxes, cosmetics, aerospace, aviation, automotive, textiles coating, water and stain-repellent fabrics, oil production, medical products, food processing, building and construction, energy, paper and packaging, cables and wiring, electronic and semiconductors (see Table 3) 55, 56, 57.
Many forever chemicals are used as surfactants 9. Traditional surfactants comprise a water-soluble hydrophilic portion and a water-insoluble hydrophobic portion. Surfactants lower the surface tension of a liquid, or the interfacial tension between 2 liquids, or between a liquid and a solid. In fluorinated surfactants, the hydrophobic portion contains F bound to C, often as a perfluoroalkyl moiety. The extent of fluorination and location of the F atoms affect the surfactant properties. Forever chemicals surfactants, often referred to as “fluorinated surfactants,” “fluorosurfactants,” “fluorinated tensides,” or “fluorotensides,” are superior in their aqueous surface tension reduction at very low concentrations and are useful as wetting and leveling agents, emulsifiers, foaming agents, or dispersants 13, 58, 14. The term “tenside” is encountered most frequently in publications of German origin, and the synonym “surfactant” is preferred in English.
Table 3. Forever chemicals uses in industrial and consumers products
|SECTOR OF USE||TYPE OF USE|
|Non-Polymeric Forever chemicals|
|Fire prevention||Fire-fighting foams such as foams based on aqueous films (Acqueous Film-Forming Foams, AFFs)|
|Biocides||Active products in plants grow regulators (PGRs)|
Active or inert (emulsifiers, solvents, carriers, aerosol propellants) ingredients in pesticides
|Aviation and Aerospace||Additives for hydraulic fluids|
|Metal plating||Humectants and anti-fog agents|
|Household Products||Surfactants in floor cleaning; treatment for textiles, leather, carpets; car waxes|
|Building and Construction||Additives in coatings and paints|
|Medical Products||Stain-resistant and water-repellent articles, X-ray film|
|Personal care products||Cosmetics, makeup, nail polish, shampoo|
|Metal plating||Wetting agent, anti-mist agents|
|Oil and mining production||Surfactants used in oil-well production and mining flotation|
|PFAS synthesis||Use as monomers for the synthesis of fluoropolymers with fluorinated side chain|
|Automotive||Treatment for external surfaces and internal leather coatings, textiles or carpets|
|Textiles and leather||Treatment aimed to create a coating with oil-water-stain-repellent properties|
|Semiconductors||Use in the production of semiconductor chips|
|Polymeric Forever chemicals|
|Fire prevention||Raw materials for firefighting equipment, protective clothes and fuel repellents|
|Electronic||Insulators and materials for welding|
|Aviation and Aerospace||Insulators, sleeves|
|Household Products||Non-stick coatings|
|Building and Construction||Coating of architectural materials, additives in paints, dyes, stains and sealants|
|Medical Products||Use in surgical patches, biocompatible human implants and medical prosthesis|
|Personal care products||Use in dental floss and lotions|
|Oil and mining production||Use in lining of gas pipes|
|Automotive||Mechanical components, seals and lubricants|
|Textiles, leather and clothing||Use in the manufacture of clothing and housewares as well as in coatings having oil-water-repellent properties|
|Semiconductors||Use as fluids in mechanical vacuum pumps|
|Energy||Film for solar panels|
|Paper and packaging||Use in water-oil-repellent materials, paperboard, and bags for food packaging|
|Cables and wiring||Coatings resistant to weathering, flame and soil|
|Food processing||Production of materials used for cooking (non-stick pans) and food storage (containers)|
How are humans exposed to Forever Chemicals?
The widespread use of forever chemicals and their persistence in the environment means that forever chemicals from past and current uses have resulted in increasing levels of contamination of the air, water, and soil. Over time, forever chemicals may leak into the soil, water, and air. Human exposure to forever chemicals is widespread and variable by geography and occupation. Because forever chemicals break down slowly, if at all, people and animals are repeatedly exposed to them, and blood levels of some forever chemicals can build up over time. People are most likely exposed to forever chemicals chemicals by consuming forever chemicals-contaminated water or food, using products made with forever chemicals, skin contact or breathing air and dust particulate containing forever chemicals 59. Despite the presence of some gaps in our understanding, it is generally accepted that the dietary intake and the consumption of drinking water represent major pathways for the general population 60, 61 while inhalation and dermal contact is far more relevant in case of occupational exposure 62, 63, 64. In total, 67 to 84 percent of exposure to perfluorooctanoic acid (PFOA) and 88–99% of exposure to perfluorooctyl sulfonic acid (PFOS) in humans come from food products 65. Furthermore, the home environment plays a crucial role in total exposure to forever chemicals. Home air was found to be responsible for 40% of exposure to PFOA in 25% of women who lived in environments with high dust concentrations 66.
Forever chemicals food consumption rates vary by age, geography and culture but typical exposure factors are relatively well known 67. Forever chemicals concentrations have been reported in milk, meat, vegetables, fruits, and bread in the sub- to low nanogram/g range, while the majority of food samples analyzed contained forever chemicals below detection limits 68, 69. In homogenized whole meals, a similar concentration range was reported, although the maximum concentration observed was 118 ng PFOA per gram of fresh food 70. Food can become contaminated through contaminated soil and water used to grow the food, through the concentration of these substances in animals via feed and water, through food packaging containing forever chemicals, or equipment that contained forever chemicals during food processing. The major exposure pathways for perfluorooctane sulfonic acid (PFOS) for the general population in Europe and North America are food and water ingestion, dust ingestion, and hand-to-mouth transfer from mill-treated carpets 71. For perfluorooctanoic acid (PFOA), major exposure pathways are oral exposure resulting from migration from paper packaging and wrapping into food, general food and water ingestion, inhalation from impregnated clothes, and dust ingestion 71. Exposure pathways for other forever chemicals such as perfluorohexane sulfonic acid (PFHxS) and perfluorononanoic acid (PFNA) are less extensively studied but expected to be similar to perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS). A study reported that forever chemicals can pass through the placenta to the fetus 72. A total of 123 pairs of samples of mothers’ blood and omphalic cord blood were obtained at the Oslo University Hospital. Maternal blood was collected at the 37th week of gestation for the detection of seven forever chemicals compounds. The level of forever chemicals measured in cord blood was 30–79% of that of the pregnant mother 72.
Since the 1960s, the US Food and Drug Agency (FDA) has authorized specific forever chemicals for use in specific food contact applications 73. Some forever chemicals are used in cookware, food packaging, and in food processing for their non-stick and grease, oil, and water-resistant properties. To ensure food contact substances are safe for their intended use, the FDA conducts a rigorous scientific review before they are authorized for the market 73.
Forever chemicals that are authorized for use in contact with food generally fall into four application categories 73:
- Non-stick cookware: Forever chemicals may be used as a coating to make cookware non-stick.
- Gaskets, O-Rings, and other parts used in food processing equipment: Forever chemicals may be used as a resin in forming certain parts used in food processing equipment that require chemical and physical durability.
- Processing aids: Forever chemicals may be used as processing aids for manufacturing other food contact polymers to reduce build-up on manufacturing equipment.
- Paper or paperboard food packaging: Forever chemicals may be used as grease-proofing agents in fast-food wrappers, microwave popcorn bags, take-out paperboard containers, and pet food bags to prevent oil and grease from foods from leaking through the packaging.
The FDA reviews new scientific information on the authorized uses of food contact substances to ensure that these uses continue to be safe 73. When the FDA identifies potential safety concerns, the agency ensures that these concerns are addressed or that these substances are no longer used in food contact applications. The FDA can work with industry to reach voluntary market phase-out agreements for such food contact substances. The FDA can also revoke food contact authorizations when the agency determines that there is no longer a reasonable certainty of no harm from the authorized use of a food contact substance 73.
One report by the Centers for Disease Control and Prevention, using data from the National Health and Nutrition Examination Survey (NHANES), found forever chemicals in the blood of 97% of Americans 23. Another National Health and Nutrition Examination Survey (NHANES) report suggested blood levels of PFOS and PFOA in people have been reduced since those chemicals were removed from consumer products in the early 2000s. However, new forever chemicals have been created and exposure to them is difficult to assess. The US Food and Drug Agency (FDA) is undertaking a study of PFAS in food 74.
Dietary exposure to forever chemicals has primarily been estimated using the exposure factor approach by measuring forever chemicals concentrations in various foods and multiplying by food consumption rates for a given population or demographic group 46. A number of studies have estimated dietary exposure to forever chemicals using the exposure factor approach.
Several studies have used the epidemiologic approach to associate serum forever chemicals concentrations with different food sources. For example, one study found associations between serum concentrations of several forever chemicals and fish/seafood consumption in Norway 75. In a cohort of 941 American adults with blood sampled between 1996 and 1999, investigators reported positive associations of several forever chemicals in plasma with consumption of “meat/fish/shellfish (especially fried fish, and excluding omega-3 fatty acid rich fish), low-fiber and high-fat bread/cereal/rice/pasta, and coffee/tea,” but inverse associations with some other foods such as vegetables and fruit 76. Another study reported associations between serum perfluorooctanoic acid (PFOA) and perfluorononanoic acid (PFNA) and fast food consumption and take-out coffee in the USA using data from the US National Health and Nutrition Examination Survey (NHANES), suggesting a role for food contact materials 77. A different study also based on the US National Health and Nutrition Examination Survey (NHANES) data reported associations between serum forever chemicals concentrations and fast food restaurant meals as well as microwave popcorn 78. A small (n=61) but remarkable Norwegian study examined food consumption using several approaches but report few significant correlations with forever chemicals in blood 79. While diet is likely an important route of exposure for many people, it is difficult to estimate and thus uncertain 46. Statistically representative surveys of dietary exposure to forever chemicals are therefore needed as well as better data on the sources of PFAS found in food and links to those present in food contact materials 46.
Human exposures to perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) have been declining in western countries and Japan over the last decade due to these regulatory interventions because of their adverse effects on human health 80, 81, 82, 83, 84.
Forever Chemicals Health Effects
While the science surrounding potential health effects of forever chemicals is developing, exposure to some types of PFAS have been associated with serious health effects such as liver toxicity, reproductive disorders, neurotoxicity and immunotoxicity 85. Forever chemicals are potentially capable of producing a wide range of adverse health effects depending on various factors, such as the conditions of exposure (dose/concentration, duration, route of exposure, etc.) and factors associated with the individuals exposed (e.g., age, sex, ethnicity, health status, and genetic predisposition) 34. Moreover, the mechanisms underlying toxic health effects attributed to forever chemicals in humans are not well understood 3. There is strong evidence that forever chemicals toxic effects that are observed in rodents include liver damage (hepatotoxicity), damage to the immune system (immunotoxicity) and developmental toxicity (e.g., increased fetal and/or neonatal mortality and reduction in fetal weight and/or postnatal growth), involve the activation of peroxisome proliferator-activated receptor-alpha (PPARα); however, humans and nonhuman primates are less responsive to peroxisome proliferator-activated receptor-alpha (PPARα) than rodents 86, 80. In addition, peroxisome proliferator-activated receptor-alpha (PPARα)-independent mechanisms are also involved, and it is not known if species differences exist for these mechanisms 4.
- Increased cholesterol levels (PFOA, PFOS, PFNA);
- Changes in liver enzymes (PFOA, PFOS, PFHxS);
- Decreased vaccine response in children (PFOA, PFOS, PFHxS);
- Increased risk of high blood pressure or preeclampsia in pregnant women (PFOA, PFOS); and
- Decreases in infant birth weights (<20 g (0.7 ounces) fall in birth weight per 1 ng/ml elevation in PFOA or PFOS in blood).
Selected human studies (published since 2010) investigating toxic effects of forever chemicals are presented in Table 4. Majority of the human studies explored the linkage between forever chemicals concentration and lipid status, mainly cholesterol level 87, 88, while a study was also conducted to assess the connection between forever chemicals and cholesterol at the gene expression level 89. Multiple studies find significant associations between forever chemicals exposure and adverse immune outcomes in children 11. Abnormally elevated cholesterol or fats in the blood (dyslipidemia) is the strongest metabolic outcome associated with forever chemicals exposure. Eriksen et al. 87 discovered substantial positive relationships between PFOS, PFAS, and total cholesterol in 753 individuals, while sex and prevalence of diabetes were suggested to influence the connection between these two substances and cholesterol. Fletcher et al. 89 observed an inverse relationship between serum PFOA levels and the expression level of genes involved in cholesterol transport in whole blood (NR1H2, NPC1 and ABCG1). A positive correlation was found between PFOS and a transcript involved in cholesterol mobilization (NCEH1), while a negative relationship was seen between PFOS and a transcript involved in cholesterol transport (NCEH2). Sex-specific effects were also noticed in Fletcher et al. study 89. On the other hand, in a study involving 815 participants ≤18 years of age, Geiger et al. 88 found that serum PFOA and PFOS were related with high total cholesterol and LDL-C levels, regardless of age, gender, race-ethnicity, body mass index, yearly family income, physical activity, or serum cotinine levels. PFOA and PFOS were not shown to be substantially linked with aberrant HDL-C and triglyceride levels.
Other studies explored the link between forever chemicals concentration and different hormones, such as thyroid 90, 91 and sex hormones 91, 92, 93, as well as development 94, 92. By assessing the connection between the levels of 14 forever chemicals in healthy men from the general population and different sex hormones and semen sample quality, Joensen et al. 95 found that only PFOS levels were negatively associated with testosterone, calculated free testosterone (FT), free androgen index (FAI) and ratios of T/LH, FAI/LH and FT/LH. Other forever chemicals were found at lower levels than PFOS and did not exhibit the same associations 95. Also, after measuring forever chemicals levels in 1682 males and females 12 to 80 years of age, Lewis et al. 90 found no significant relationships between any of the forever chemicals and testosterone. Forever chemicals were suggested to be associated with increases in FT3, TT3, and FT4 among adult females. The authors concluded that, during the adolescence, forever chemicals may be related to increases in TSH among males and decreases in TSH among females, suggesting sex-specific effects 90. In contrast, Li et al. 91 discovered no associations between forever chemicals and thyroid hormones in adults and seniors in 3297 participants from Ronneby, a municipality with highly contaminated drinking water by forever chemicals (exposed group), with the exception of a positive association between forever chemicals and fT4 in males over 50. Thyroid hormone levels were observed to be higher in Ronneby preteen children compared to the control group. Weak evidence of a link between increasing forever chemicals levels and lower fT3 in preteen boys and lower TSH in adolescent men was found 91.
Lopez-Espinosa et al. 94 aimed to investigate whether PFOS and PFOA were linked to the markers of sexual development. Their study included 3076 boys and 2931 girls aged 8–18 years. For boys, there was a link between increased PFOS and a lower chance of reaching puberty. Higher PFOA or PFOS concentrations in girls were related to a lower risk of post menarche 94. The same group of researchers examined the link between forever chemicals levels and estradiol, total testosterone, and IGF-1 in 2292 children. In boys, PFOA concentrations were substantially related to testosterone levels; PFOS concentrations were related to estradiol, testosterone, and IGF-1, while PFNA concentrations were linked to IGF-1. Significant linkage was discovered in girls between PFOS and testosterone and IGF-1, as well as PFNA and IGF-1 96. Furthermore, Wang et al. 92 concluded that forever chemicals may affect estrogen homeostasis and foetal growth during pregnancy, and that estrogens may mediate the relationship between forever chemicals exposure and foetal growth after examining 424 mother-infant pairs.
Some of the studies also explored the linkage between the forever chemicals exposure and liver function 97, 98, 99. In 47,092 adult participants, Gallo et al. 100 found a positive association between PFOA and PFOS concentrations and serum ALT level. On the other hand, the relationship with bilirubin appeared to increase at low levels of PFOA and decrease at higher levels 100. In 1002 individuals from Sweden, Salihovic et al. 101 have also found a positive association of PFHpA, PFOA, PFNA, and PFOS concentrations and ALT activity, but also positive associations of PFHpA, PFOA, PFNA, PFDA, and PFUnDA with ALP. These authors noted that the changes of investigated forever chemicals concentrations were positively associated with gamma glutamyl transferase (GGT) levels and inversely associated with the changes in circulating bilirubin 101. On the other hand, in 2883 participants, (1801 non-obese and 1082 obese), Jain and Ducatman 102 investigated the connection between liver function alterations and various forever chemicals. They concluded that connections might only be observed in the obese participants: alanine aminotransferase (ALT) was positively associated with PFOA, PFHxS, and PFNA. On the other hand, PFOA and PFNA were associated with GGT 102. Epidemiological studies revealed a connection between forever chemicals and decrease in vaccination antibody production in early infants and children, especially having in mind that, if breastfed, they have a relatively high exposure and may be more susceptible as their immune system develops. Abraham et al. 93 found significant associations between the concentration of PFOA, but not PFOS, and adjusted levels of vaccine antibodies against Haemophilus influenza type b, tetanus and diphtheria for which no observed adverse effect concentrations (NOAECs) were 12.2, 16.9 and 16.2 µg/L, respectively. Furthermore, PFOA levels were shown to be inversely related to the interferon gamma (IFN-γ) production of ex-vivo lymphocytes after stimulation with tetanus and diphtheria toxoid 93. Furthermore, Budtz-Jorgensen E and Grandjean P 103 found an approximate BMDL of 1 ng/mL serum for both PFOS and PFOA for the serum concentrations of specific IgG antibodies against tetanus and diphtheria at ages 5 and 7 as outcome parameters. These authors proposed the reference concentration of about 0.1 ng/mL as the serum-based target, a level which is below the most reported human serum-forever chemicals concentrations 103. Grandjean et al. 104 discovered that prenatal exposure to forever chemicals had an inverse relationship with antibody concentrations five years later, while concentrations measured at 3 and 6 months of age had the highest inverse relationships with antibody concentrations at 5 years of age, especially for tetanus. The same authors have found that diphtheria antibody concentrations dropped at higher forever chemicals concentrations at 13 and 7 years after booster vaccinations at 5 years of age; the correlations were statistically significant for PFDA at 7 years and PFOA at 13 years, implying a 25% decrease for each doubling of exposure 98.
Evidence for cancer is limited to manufacturing locations with extremely high exposures and insufficient data are available to characterize impacts of forever chemicals exposures on neurodevelopment 11. The International Agency for Research on Cancer concluded that perfluorooctanoic acid (PFOA) is possibly carcinogenic to humans (Group 2B) and the United States Environmental Protection Agency indicated that there was suggestive evidence of cancer causing potential of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS) in humans 105, 106, 107, 108. Increases in testicular and kidney cancer were noted in highly exposed humans 109, 110, 111.
Figure 5. Forever chemicals effects on human health2 ]
Table 4. Forever Chemicals human studies exploring the toxicity
population; 753 individuals (663 men and 90
women), 50–65 years of age, nested within a Danish cohort of 57,053 participants
|serum levels of|
|Statistically significant positive associations between PFOS, PFAS and total cholesterol level|
Sex and prevalent diabetes modified the association between PFOA and PFOS and cholesterol
|815 participants ≤18 years of age from the National|
Health and Nutrition Examination Survey 1999–2008
total cholesterol >170 mg/dL, low-density lipoprotein cholesterol (LDL-C) >110 mg/dL, high-density lipoprotein
cholesterol (HDL-C) <40 mg/dL or triglycerides >150 mg/dL.
|Serum PFOA and PFOS-positively associated with high total cholesterol and LDL-C, independent of age, sex, race-ethnicity, body mass index, annual household income, physical activity and serum cotinine levels|
PFOA and PFOS-not significantly associated with abnormal HDL-C and triglyceride levels.
|290 individuals (144 men + 146 women) exposed to background levels of PFOS and elevated concentrations|
of PFOA through drinking water,
aged between 20 and 60 years
|expression of genes involved in cholesterol|
|Inverse associations between serum PFOA levels and the whole blood expression level of genes involved in cholesterol transport (NR1H2, NPC1 and ABCG1)|
A positive association between PFOS and a transcript involved in cholesterol mobilisation (NCEH1), and a negative relationship with a transcript involved in cholesterol transport (NR1H3)
Reductions in the levels of mRNAs involved in cholesterol transport were seen with PFOA in men (NPC1, ABCG1, and PPARA) and in women (NR1H2 expression)
Increase in the levels of a cholesterol mobilisation transcript (NCEH1) in women.
PFOS was positively associated with expression of genes involved in both cholesterol mobilisation and transport in women (NCEH1 and PPARA)
|2883 participants, (1801 non-obese and 1082 obese), aged more than or equal to|
20 years old
|liver function parameters: AST, ALT, GGT, ALP, and total bilirubin (TB)||Among obese participants only, alanine aminotransferase (ALT)-positively associated with PFOA, PFHxS, and PFNA|
PFOA and PFNA were associated with gamma GGT in obese participants
|14 PFCs||Healthy men from the general population, median age of 19 years||total testosterone (T), estradiol (E), sex hormone-binding globulin (SHBG),|
luteinizing hormone (LH), follicle-stimulating hormone (FSH) and inhibin-B and
Semen samples analysis
|PFOS levels-negatively associated with testosterone, calculated free testosterone (FT), free androgen index (FAI) and ratios of T/LH, FAI/LH and FT/LH|
Other PFCs were found at lower levels than PFOS and did not exhibit the same associations.
PFC levels were not significantly associated with semen quality
PFOS PFHxS PFNA
|1682 males and|
females 12 to
80 years of age
|testosterone (T), thyroid stimulating hormone (TSH), and free and|
total triiodothyronine (FT3, TT3) and thyroxine (FT4, TT4)
|Exposure to PFAS may be associated with increases in FT3, TT3, and FT4 among adult females|
During adolescence, PFAS may be related to increases in TSH among males and decreases in TSH among females
No significant relationships were observed between PFAS and T in any of the models
|3076 boys and 2931|
girls aged 8–18 years
|subjects were classified as having reached puberty based on either hormone|
levels (total >50 ng/dL and free >5 pg/mL testosterone in boys and estradiol >20 pg/mL in girls) or onset of menarche
|For boys, there was a relationship of reduced odds of reached puberty (raised testosterone) with increasing PFOS (delay of 190 days between the highest and lowest quartile)|
For girls, higher concentrations of PFOA or PFOS were associated with reduced odds of postmenarche (130 and 138 days of delay, respectively)
|2292 children (6–9 years of age)||estradiol, total testosterone,|
|In boys, PFOA concentrations were significantly associated with testosterone levels; PFOS with estradiol, testosterone, and IGF-1; and PFNA with IGF-1|
In girls, significant associations were found between PFOS and testosterone and IGF-1; and PFNA and IGF-1
|424 mother-infant pairs||estrone (E1), b-estradiol (E2), and estriol (E3),|
infants: head circumference,
body weight, body length
|PFOS was positively related to E1 and E3, but negatively related to E2|
Serum PFOA was positively related to serum E1 and negatively related to head circumference at birth
Serum E2 was negatively related to head circumference, body weight, and body length at birth and serum E3 was positively related to body weight
Serum E3 mediated the relationship between serum PFOS and body weight
PFAS could affect estrogen homeostasis and fetal growth during pregnancy and estrogens might mediate the association between exposure to PFAS and fetal growth
|alanine transaminase (ALT), γ-glutamyltransferase (GGT), direct bilirubin||Positive association between PFOA and PFOS concentrations and serum ALT level, a marker of hepatocellular damage.|
The relationship with bilirubin appears to rise at low levels of PFOA and to fall again at higher levels.
|1002 individuals from Sweden (50% women) at ages 70, 75 and 80||bilirubin and hepatic enzymes alanine aminotransferase (ALT), alkaline|
phosphatase (ALP), and γ-glutamyltransferase (GGT)
|Positive associations of PFHpA, PFOA, PFNA, PFDA, and PFUnDA with ALP|
Concentrations of PFHpA, PFOA, PFNA, and PFOS were positively associated with the activity of ALT
The changes in PFAS concentrations were positively associated with GGT and inversely associated with the changes in circulating bilirubin
|3297 participants from Ronneby, a municipality with drinking water highly contaminated by forever chemicals (exposed group)||thyroid hormone levels, with adjustments for age, sex and BMI||No associations between PFAS and thyroid hormones in adults and seniors except for a positive association between PFAS and fT4 in males over 50|
Higher thyroid hormone levels in the preteen children from Ronneby compared to the reference group
Weak evidence of associations between increased PFAS levels and decreased fT3 in preteen boys, and decreased TSH in teenage males
|101 healthy 1-year-old children||Antibodies against haemophilus infuenza type b, tetanus and diphtheria, interferon gamma, cholesterol||Significant associations between PFOA, but not PFOS concentrations, and adjusted levels of vaccine antibodies against haemophilus influenza type b, tetanus and diphtheria|
PFOA levels inversely related to the interferon gamma (IFN) production of ex-vivo lymphocytes after stimulation with tetanus and diphtheria toxoid
No infuence of PFOA and PFOS on infections and cholesterol level during the frst year of life
|1146 children||serum concentrations of specific IgG antibodies against tetanus and diphtheria at ages 5 and 7||Approximate BMDL of 1 ng/mL serum for both PFOS and PFOA for the serum concentrations of specific IgG antibodies against tetanus and diphtheria at ages 5 and 7|
Proposed reference concentration of about 0.1 ng/mL as the serum-based target
|PFHxS, PFOS, PFOA, PFDA, PFNA||275 males and 349 females participated in clinical examinations and provided blood samples at ages 18 months and 5 years||serum concentrations of antibodies against tetanus and diphtheria vaccines determined at age 5||Pre-natal exposure showed inverse associations with the antibody concentrations five years later, with decreases by up to about 20% for each two-fold higher exposure|
Associations for serum concentrations at 18 months and 5 years were weaker
Concentrations estimated for ages 3 and 6 months showed the strongest inverse associations with antibody concentrations at age 5 years, particularly for tetanus
Joint analyses showed statistically significant decreases in tetanus antibody concentrations by 19–29% at age 5 for each doubling of the PFAS exposure in early infancy
|PFHxS, PFOA, PFOS, PFNA, PFDA.||516 subjects||Forever chemicals serum concentrations and concentration of antibodies against diphtheria and tetanus||Diphtheria antibody concentrations decreased at elevated PFAS concentrations at 13 y and 7 y; the associations were statistically significant for perfluorodecanoate (PFDA) at 7 y and for perfluorooctanoate (PFOA) at 13 y, both suggesting a decrease by ∼25% for each doubling of exposure|
Structural equation models showed that a doubling in PFAS exposure at 7 y was associated with losses in diphtheria antibody concentrations at 13 y of 10–30% for the five PFAS
Forever Chemicals Cholesterol and Metabolic effects
Cross-sectional and longitudinal studies published between 1996–2020 based on human populations in Australia, Canada, China, several European countries, Japan, South Korea, Taiwan, UK and the U.S. found consistent evidence of modest positive associations between elevated serum forever chemicals concentrations and detrimental lipid profiles, such as elevated total cholesterol and low-density lipoprotein cholesterol (LDL-C), or reduced high-density lipoprotein cholesterol (HDL-C) in adults and children, although the magnitude of the cholesterol effect is inconsistent across different exposure levels 11, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131. Perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) exhibit the most consistent finding across studies. The effect size varies across studies, which can be a result of different exposure levels. Increases in serum PFOA and PFOS from the lowest to the highest quintiles among children in C8 health project was associated with 4.6 and 8.5 mg/dL total cholesterol (reference level for children is <170 mg/dL) 131. Among the National Health and Nutrition Examination Survey (NHANES) 2003–2004 participants, increases in serum PFOA and PFOS from the lowest to the highest quartiles were associated with 9.8 and 13.4 mg/dL total cholesterol (reference level for adults is <200 mg/dL) 114. Maisonet et al. 132 reported a non-linear relationship between prenatal PFOA concentrations and total cholesterol at ages 7 and 15 of the child.
Studies of large populations, featuring wide exposure ranges, demonstrate that serum lipids rapidly increase beginning at background forever chemicals (1–10 ng/mL) serum concentration and then are followed by attenuating (“plateaued”) cholesterol measurements as (log-transformed) exposures to long-chain forever chemicals increase 126, 113, 131. These findings suggest partially saturable mechanisms; thus, the cholesterol dose response at pharmacologic or acutely toxic doses should be viewed with caution; associations can be missed or may be misleading when an environmental range of exposure is absent. At background forever chemicals exposure levels, residual associations may be more detectable in obese participants 133, 134, a finding congruent with experimental forever chemicals outcomes in rodents fed “Western” or high-fat diets laced with forever chemicals 135, 136, 137. Human gene expression pathways provide support for an interaction of obesity and forever chemicals exposures and suggest possible sex differences 138. A pharmacokinetic model predicts that approximately half of the PFOS-exposed population would experience a >20% rise in serum cholesterol 139. Risk-assessment implications for low-forever chemicals dose increases in cholesterol have been noted 140, 126 and a review of population and toxicity data concluded that dyslipidemia is the strongest metabolic outcome of forever chemicals exposure 11.
Human forever chemicals lipid findings may be related to experimental findings of induced adipogenesis, impaired bile acid metabolism/synthesis, strongly decreased CYP7A1 enzyme activity, altered fatty acid transport, and intracellular lipid accumulation with steatosis, including in PPAR-α-null or PPAR-α-humanized animals 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151. Independent of forever chemicals exposure, similar alterations in metabolic pathways have been related to disrupted fatty acid beta-oxidation and increased free cholesterol in toxicology studies 152.
Emerging longitudinal and diabetes clinical trial data indicate that forever chemicals may increase human insulin resistance, associated with dysregulated lipogenesis activity 153, 127. Longitudinal studies of clinically diagnosed diabetes patients have sometimes associated forever chemicals exposures with diabetes 154 or with small changes in glycemic markers 155; however, diabetes associations to date are not consistent 156, 157, 155. Future studies should consider whether forever chemicals may instigate autoimmune diabetic outcomes in humans, as shown in experimental studies 158. Experimental data reveal that forever chemicals activate G protein-coupled receptor 40, a free fatty acid-regulated membrane receptor on islet ß cells, stimulating insulin secretion 159, 160.
There is some but much less consistent evidence of a modest positive correlation with metabolic diseases such as diabetes, overweight, obesity and heart diseases 11. The majority of studies are cross-sectional, which have limited causal interpretation 161. A few studies provided stronger evidence than observational studies, such as Diabetes Prevention Program Trial where at baseline, a doubling in plasma perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) concentrations was associated with small differences in markers of insulin secretion and β – cell function. However, there was limited evidence suggesting that forever chemicals concentrations are associated with diabetes incidence or changes in glycemic indicators during the follow-up period 155. And in the diet-induced weight-loss trial, higher baseline plasma forever chemicals concentrations were associated with a greater weight regain, especially in women 30.
An odds ratio (OR) represents the odds that an outcome will occur given a particular exposure, compared to the odds of the outcome occurring in the absence of that exposure 162:
- Odds Ratio (OR) = 1 Exposure does not affect odds of outcome
- Odds Ratio (OR) greater than 1 means Exposure is associated with higher odds of outcome
- Odds Ratio (OR) less than 1 means Exposure is associated with lower odds of outcome
Eighteen studies have examined the associations between forever chemicals exposures and glucose metabolism, insulin resistance and diabetes. Overall the results across different studies are inconclusive 11. Lin et al. 163 was the first to report a positive association between serum forever chemicals concentrations and glucose homeostasis among adults and adolescents in the National Health and Nutrition Examination Survey (NHANES). They reported a considerable effective size – doubling serum PFNA concentrations was associated with hyperglycemia odds ratio (OR) of 3.16 163. Later studies tend to report smaller effect sizes. Exposure during pregnancy may affect the mother and child during gestation and later in life. In a small pregnancy cohort in the U.S., each standard deviation of increase in PFOA was associated with a 1.87-fold increase of gestational diabetes risk 164. In a larger Spanish cohort 165, a null result was reported for PFOA, but PFOS, PFHxS and gestational diabetes had positive associations: Odds Ratio (OR) per log10-unit increase=1.99 and Odds Ratio (OR)=1.65, respectively.
Results for hypertension and other vascular diseases including stroke are also inconsistent 11. Two of the earliest studies examined the relationship between forever chemicals exposure and hypertension among NHANES and found different results for children and adults. Adjusted Odds Ratio (OR)=2.62 for hypertension comparing 80th vs. 20th percentiles serum PFOA among NHANES adults in the U.S. 166, while among children a null finding was reported 167. In some later cohort studies, null results and even protective effects associated with forever chemicals exposure and hypertension were reported 168, 169. A cross-sectional study on carotid artery intima-media thickness in adolescents reported increased risks with increase in plasma perfluorooctanesulfonic acid (PFOS) 170. However, a more recent study on artery stiffness found protective effects of PFOA and PFNA among children and adolescents enrolled in the World Trade Center Health Registry 124.
Other metabolic endpoints include thyroid disease (which could also be considered an endpoint for endocrine disruption), cardiovascular diseases, uric acid metabolism, and body weight. Except for uric acid metabolism, most results are inconclusive 11. An increase in hyperuricemia risks and PFOA exposure was observed in all four studies (two from NHANES and two from C8 Health Project) 11.
In summary, the strongest evidence for a relationship between forever chemicals exposure and metabolic outcome is in the area of dyslipidemia 11. Animal studies have found decreases in serum cholesterol levels associated with increased forever chemicals exposures, which contradicts epidemiological findings 11. The difference may lie in different levels of expression for nuclear receptors involved in the toxicological pathway, such as peroxisome proliferator-activated receptor (PPAR)-alpha. It may also be related to differences in exposure levels. Dietary factors can influence metabolic outcomes 171, introducing bias into observed relationships if not controlled for properly. Explanations for null findings include healthy worker effects and non-linear relationships, such as a decreasing slopes as exposure increases (log-linear relationships) 172.
Forever Chemicals Liver effects
The liver is a primary target organ for long-chain forever chemicals storage, and accompanying experimental evidence of toxicity includes hepatocyte fat infiltration, specific P450 (CYP) pathway induction, apoptosis, hepatocellular adenomas and carcinomas, and disrupted fatty acid trafficking that can be peroxisome proliferator-activated receptor alpha (PPARα)-dependent or -independent and present across species 173, 174, 175, 176, 177, 178, 143, 179.
Population studies demonstrate significant associations of long-chain forever chemicals (>6 fluorinated carbons) exposure to higher liver enzymes, such as alanine aminotransferase in adults and adolescents 180, 181, 182, 183, 184, 185, including in longitudinal studies 186, 187. Following low-dose exposures, these associations may be more evident in obese participants 172, 181, 188.
Based on experimental data, nonalcoholic fatty liver disease (NAFLD) has been investigated as a clinical outcome of forever chemicals exposure mediating consistent population forever chemical-altered liver enzyme findings 189, 190, 191, 145. Studies with nonalcoholic fatty liver disease (NAFLD) cytokeratin C18 biomarkers have provided supportive evidence for forever chemicals inducing steatosis 192. Metabolomic studies have been directed at potentially explanatory human glycerophosphocholine and fatty acid profiles 193, 144, 194. Processes which favor steatosis promote advanced liver disease including liver cancer in humans 195. Associations of forever chemicals with advanced human liver disease and liver cancer are technically hard to study for reasons including (and not limited to) lethality, selection of comparison populations, and alterations of excretion mechanics associated with disease states. In a clinic-based study, mostly obese (85%) children aged 7 to 19 years with biopsy-proven NAFLD had more advanced disease associated with PFOS and PFHxS exposure as well as associations with lipid and amino acid pathways linked to NAFLD pathogenesis 196. However, an adult study reported that serum PFHxS was inversely associated with hepatic lobular inflammation in morbidly obese bariatric surgery patients 197. A study of heavily exposed workers (n = 462, geometric mean serum PFOA of 4048 ng/mL) detected significantly increased incident mortality for cirrhosis and liver cancer compared to a regional population 198, whereas no forever chemicals association to cancer or advanced liver disease was reported in a 3M worker cohort or in the C8 Health study population 199, 200, 201.
Emerging animal toxicology and histology and human population data provide mechanistic clues that forever chemicals disrupt hepatic metabolism, leading to increased bile acid reuptake and lipid accumulation in liver 202, 141. A review of NAFLD and toxicant exposure concluded that forever chemicals are associated with early steatosis (“fatty liver”), the preclinical stage of NAFLD 203.
Forever Chemicals Neurodevelopmental effects
In vitro studies suggest perfluorooctanesulfonic acid (PFOS) can trigger the “opening” of tight junction in brain endothelial cells and increase the permeability of the blood brain barrier 204. There has therefore been some interest in investigating the neurotoxic effects associated with forever chemicals exposures. In laboratory animals, it has been reported that PFOS, PFOA and PFHxS exposures during the peak time of rapid brain growth in mice resulted in an inability to habituate in unfamiliar environment 205. A few studies reported neurotoxicity of PFOS, PFHxS, and PFOA in cell culture systems 206, as well as altered behavioral responses 207 and deficits in learning and memory ability in rodents 208. In contrast, no significant developmental neurotoxic effects were seen from prenatal exposure to PFOS in US EPA guideline-based studies with rats 209.
Liew et al 210 reviewed 21 epidemiological studies in 2018 and concluded that evidence is mixed regarding neurodevelopmental effects of forever chemicals exposures. Health outcomes examined included developmental milestones in infancy, attention-deficit/hyperactivity disorder (ADHD) and behaviors in childhood, and neuropsychological functions such as IQ and other scales or scores 210. Neurodevelopmental trajectories are highly complicated and there is great heterogeneity in the instruments and methods to evaluate neurodevelopmental endpoints. Existing evidence suggests that forever chemicals can impact the nervous system, with particularly harmful effects from developmental exposures or exposures in sensitive populations 211. However, the limitations and inconsistencies in the current research make the severity of the neurotoxicological ramifications of forever chemicals exposure largely unknown 211. Additional research is needed to establish a link between neurodevelopmental outcomes and forever chemicals exposures.
Forever Chemicals Immune effects
Immunotoxicity of forever chemicals has been demonstrated in multiple animal models, including rodents, birds, reptiles and other mammalian and non-mammalian wildlife. Epidemiological data is relatively sparse but mounting evidence suggests that the immunotoxic effects in laboratory animal models occur at serum concentrations that are comparable to body burden of highly exposed humans and wildlife 212.
The health outcomes related to forever chemicals immunotoxicity include both molecular-level (i.e. antibody concentrations) and organ/system-level (i.e. infection of respiratory system). In general, more consistent results across different studies were reported for molecular-level health endpoints such as vaccine antibody or other immune markers such as immunoglobulin 11.
Five studies examined the association between forever chemicals exposure and suppression of antibody response to vaccination among children, adolescents or adults. Four out of the five found statistically significant associations between higher forever chemicals exposure and suppressed immune response 11. Grandjean et al. 213 was the first to link forever chemicals exposure in children to deficits in immune function. The authors reported a 2-fold increase in perfluorooctane sulfonate (PFOS) in child serum was associated with a −49% decline in tetanus and diphtheria antibody concentrations 213. Decreased immunological response persisted at age 13 years 214. This effect size is larger than later studies and can be attributed to different exposure levels, different vaccine strains, and different times elapsed since vaccination (peak antibodies vs residual antibodies). Adverse associations have also been found in forever chemicals exposure and other childhood vaccinations such as rubella, mumps, and Hemophilus influenza vaccinations in children 215, 216, 217 and adult influenza vaccination such as FluMist 218 and anti-H3N2 219. In a single study, modest down-regulation of C-reactive protein response, a marker of human systemic inflammation, was also reported to be associated with perfluorooctanoic acid (PFOA) blood levels 220.
Disease outcomes linked with immunosuppression such as clinician-recorded diagnoses of childhood infections have also been associated with prenatal exposures to PFOS and perfluorohexane sulfonate (PFHxS) 221. A pregnancy cohort study prospectively detected increased risk of airway and throat infections and diarrhea in children through age 10 yr, correlated with cord-blood forever chemicals measurements 222. A recent review concluded that exposure to forever chemicals in infancy and childhood resulted in an immunosuppressive effect characterized by an increased incidence of atopic dermatitis and lower respiratory tract infections 223. Some of the immunological effects were sex-specific, but the authors cautioned that there were inconsistencies across studies 223. Overall, available data provide strong evidence that forever chemicals exposure can suppress the human immune response.
Population studies of immune hyperreactive diseases have resulted in mixed findings. Studies on childhood allergy and asthma outcomes have shown no association with forever chemicals 224, 222, whereas others have found substantial effects, including provocative evidence that subgroups of individuals not adequately immunized may be at an increased risk for disease a priori 225, 226. For example, a case-control study of Taiwanese children compared the first and fourth quartiles of serum measurements for 11 forever chemicals with asthma and other immune markers and reported confidence intervals well above 1.0 for PFOA and others 225. However, review articles concerning forever chemicals and childhood allergy and asthma offer nuanced, age- and sex-specific interpretations and advise against firm conclusions 223.
Chronic autoimmune outcomes, including thyroid disease and inflammatory bowel disease (IBD), have also been considered. A study in contaminated communities (n = 32 254) detected an association between both prevalence and incidence of ulcerative colitis (UC) and PFOA exposure 227. A worker study (n = 3713) found a higher prevalence and incidence of ulcerative colitis (UC) with increasing log PFOA serum concentrations 169. A case-control study of children and young adults from a background exposure community in Atlanta, Georgia, USA, also found higher serum PFOA levels in patients with ulcerative colitis (UC) 228. In contrast to PFOA-related associations in US populations, a study of a contaminated community in Sweden (n = 63 074) did not show a consistent association of inflammatory bowel disease (IBD) with any forever chemicals exposure 229.
- There is concordance between animal studies and human epidemiological observations that forever chemicals modify the immune response, and
- There are noted complexities in assuming dose-response continuums, including possible differences in life-stage vulnerability.
- Authors of these reviews note uncertainty about which outcome will be of most importance but agree that immunotoxicity should be included among sensitive human forever chemicals toxicity endpoints.
Forever chemicals and Cancer
Numerous studies have investigated forever chemicals carcinogenicity, mainly focusing on perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA). Perfluorohexanoic acid (PFHxA) is the only other forever chemical that has been investigated in an animal study and null findings were reported 233. Human studies for PFOS and PFOA include chemical workers, communities with contaminated drinking water, and the general population. A 3.3-fold increase in prostate cancer mortality was reported for each month spent in the chemical division with PFOA production was observed among occupationally exposed workers, but the number of cases was small 234. Later data from this occupational cohort did not support an association between occupational exposure and cancer mortality or incidence 235. The strongest evidence for increased cancer risk has been reported by studies among community members whose drinking water was contaminated by PFOA. Barry et al 200 and Vieira et al 201 showed a positive association between PFOA levels and kidney and testicular cancers among participants in the C8 Health Project. These studies form the foundation of the overall conclusion from the C8 Health Project. Results among studies conducted in general population are inconsistent. Eriksen et al 236 was a the first to examine PFOA exposure and cancer in the general population and they did not find an association between plasma PFOA or PFOS concentration and prostate, bladder, pancreatic or liver cancer.
The International Agency for Research on Cancer (IARC) concluded that perfluorooctanoic acid (PFOA) is possibly carcinogenic to humans (Group 2B) and the United States Environmental Protection Agency indicated that there was suggestive evidence of cancer causing potential of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS) in humans 105, 106, 107, 108. Increases in testicular and kidney cancer were noted in highly exposed humans 109, 110, 111.
Forever Chemicals in Kidney disease, uric acid, and kidney cancer
Extended human half-lives of long-chain forever chemicals are attributed to active renal tubular reabsorption. Legacy forever chemicals such as PFOA and PFOS are concentrated in renal tissues, and histopathologic, molecular, oxidative stress, and epigenetic studies provide evidence of potential nephrotoxicity 237, 238, 239, 240. In addition, the strong influence of kidney reabsorption on the extended half-lives of long-chain forever chemicals is consistent with both human protein binding and experimental forever chemicals excretion data.
Human studies have associated legacy forever chemicals exposure to diminished glomerular filtration and/or defined chronic kidney disease in adults and children 241, 242, 243, 244. However, this outcome may be due to reverse causation 245, 242. Some reviews of the available epidemiologic and toxicologic evidence suggest causative links between forever chemicals and diminished kidney function and chronic kidney disease 239, 246; these authors also note several knowledge gaps and uncertainty about which proposed mechanisms of action are most important. A propensity score approach to NHANES data 247, 248 and a study with repeated forever chemicals and health measures over an 18-yr period 244 recently concluded that forever chemicals exposure likely causes diminished renal glomerular filtration.
Uric acid, a biomarker of increased risk for renal disease 249, is also consistently associated with forever chemicals exposure in adults and children 250, 118, 183, 243, 251, 252, including a visible dose-response curve that begins at or near historic background levels in human populations 250, 252. Serum forever chemicals concentrations exhibit an inverted U-shaped pattern related to glomerular filtration, initially exhibiting a modest accumulation as glomerular filtration begins to decrease and then decreasing in advancing renal disease, likely due to failure of normal strong reabsorption mechanisms in moderate to severe kidney disease 247. This finding is more dramatic across stages of glomerular filtration when there is also albuminuria 253. Studies suggest that the association of forever chemicals to uric acid is not due to reverse causation and is underestimated because the failing kidney excretes long-chain forever chemicals but retains uric acid. An implication is that population outcomes that occur in the presence of either albuminuria or moderate to severe renal disease such as hypertension 254 increasing presence of and uric acid (a biomarker of renal disease) 255, 252 can be underestimated in cross-sectional studies; in other words, the link between these health outcomes and forever chemicals exposure is obscured in these studies because of enhanced forever chemicals excretion patterns in the presence of either albuminuria or moderate to severe kidney disease. Furthermore, the strong influence of renal reabsorption on the long half-lives of long chain forever chemicals is consistent with both human protein binding of forever chemicals and experimental forever chemicals excretion rates in high-dose rodent studies 256.
Kidney cancer diagnoses have been increasing since 1975, a finding that is partially independent of improved detection, with 5-year cancer-specific survival of approximately 80% 257. The C8 Health studies noted longitudinal (n = 32 254) increases of kidney cancer (hazard ratio = 1.10) and kidney cancer mortality 258, 200, 201. A review of 6 published studies found long-chain forever chemicals exposure associated with kidney cancer or kidney cancer mortality, with risks ranging from 1.07 to 12.8 239. Subsequent preliminary data from the heavily exposed Veneto, Italy, population also suggest a significant increase in kidney cancer mortality with forever chemicals exposure 259. Evidence is accumulating for forever chemicals as a cause of chronic disease and kidney cancer.
Forever Chemicals Thyroid effect
The C8 Science Panel concluded that there is a “probable link” of PFOA exposure to thyroid disease, with sex-specific outcomes in women (for hyperthyroid disease) versus men (hypothyroid disease) 260. Subsequent reviews drew attention to hypothyroid outcomes in women and children and to the possibility that populations with a priori circulating antithyroid peroxidase antibodies may be at additional risk 261. A broad childhood disease review noted “some evidence” that forever chemicals cause childhood hypothyroidism and characterized the number of studies as “limited” for childhood disease conclusions 262. A meta-analysis of 12 child and adult studies that excluded populations with higher exposures noted that forever chemicals exposure is negatively associated with serum total thyroxine levels and that “PFAS could induce thyroid dysfunction and disease” 263.
Human thyroid disease is mostly the result of an autoimmune response and is 5 to 10 times more prevalent in women than men 264. Concerning forever chemicals and clinically diagnosed outcomes, women in the highest quartile of PFOA exposure (>5.7 ng/mL) reported clinical hypothyroid disease (odds ratio 2.2) over 3 cycles of National Health and Nutrition Examination Survey (NHANES) data (1999–2006, n = 3974 adults), with similar findings in men 265. The C8 Science Panel studies (median serum PFOA 26.1 ng/mL) found thyroid disease hazard ratios of 1.00, 1.24, 1.27, 1.36, and 1.37 across cumulative exposure quintiles in women 266, with parallel hypothyroid findings in children aged 1 to 17 years 267. The Ronneby, Sweden, population experienced excess risk of thyroid disease in a discrete time period (1984–2005) among women (hazard ratio 1.29) that did not persist over time despite higher cumulative forever chemicals exposure 268. The authors did not link exposure to hypothyroid outcome, noting a nonmonotonic dose-response relationship 268.
Human population studies augment experimental data that forever chemicals interact with thyroid hormone binding proteins, one of several mechanisms by which forever chemicals can perturb feedback relationships between free thyroid hormone and the hypothalamic-pituitary-thyroid axis 269, 270, 271. Exposures to forever chemicals also interfere with thyroid peroxidase (TPO) enzyme activity in vitro 272. Several forever chemicals studies have pursued this putative mechanism, finding that maternal and neonatal thyroid hormone outcomes were more readily detected in those with a priori abnormally high circulating anti-TPO antibodies 273. One case-control study investigated congenital hypothyroidism, a rare condition 274. Serum concentrations of PFOA (5.40 vs 2.12 ng/mL), perfluorononanoic acid (PFNA; 1.93 vs 0.63 ng/mL), perfluorodecanoic acid (PFDA; 0.52 vs 0.30 ng/mL), and perfluoroundecanoic acid (0.98 vs 0.44 ng/mL) were higher in the newborns with congenital hypothyroidism; and levels of several forever chemicals, including PFOA and PFHxS, were correlated with thyroid autoantibodies 274.
Thyroid disease is not the only concern. Doctors are concerned about subclinically elevated thyroid-stimulating hormone (TSH) in early pregnancy because it may be associated with several possible adverse maternal and fetal outcomes 275. This general concern has prompted numerous forever chemicals-exposure evaluations of corresponding TSH in maternal serum, cord blood, and newborns. A review of maternal and child biomarkers with forever chemicals exposure noted that higher TSH has been reported in 4 second-trimester studies 276, but there are also conflicting findings. Studies measuring forever chemicals in the first trimester have also found associations between forever chemicals exposure and altered TSH levels in newborns, including nonmonotonic patterns of dose response that mirror the marked alterations of thyroid hormone levels during pregnancy 277.
From the available studies, forever chemicals definitively alter human thyroid hormones and potentially contribute to thyroid auto-immunity but do not so far appear to be a cause of thyroid cancer 200, 201. Also, thyroid cancer is usually survived; thus, morbidity rather than mortality studies are useful.
Forever Chemicals Reproductive and Developmental effects
Exposure to PFOA impairs human sperm motility and sperm penetration into viscous media 278, 279 and is longitudinally associated with lower sperm concentration and count and higher adjusted levels of luteinizing and follicle-stimulating hormones in young men 280, 281, 282. Serum concentrations of forever chemicals are also cross-sectionally associated with deleterious markers of semen quality 283, 284.
Legacy and emerging forever chemicals have been found in follicular fluid 285. They appear to alter endometrial regulation such as progesterone activity in young women 286 and possibly menstrual cycle length 287. Associations with menarche and menopause may be substantially due to reverse causation because menstruation is a route by which women eliminate forever chemicals 245, partially explaining why men have higher forever chemicals levels than women in the same communities. Women on birth control and who do not menstruate or with poor cyclicity because of age, activity level, or disease may have elevated forever chemicals levels in comparison with menstruating women. Exposure to forever chemicals has been associated with endometriosis in the United States and in China 288, 289, but the specific forever chemicals associated with this effect vary among studies.
Time-to-pregnancy (fecundity) studies provide indirect evidence of changes in fertility. Methodologic considerations include maternal and paternal age, parity (which in turn affects serum forever chemicals), and health status. Among 1240 women in the Danish National Birth Cohort, PFOS exposure was associated with decreased fecundity (median serum PFOS 35.5 ng/mL) 290. Reverse causation may explain this finding because it is duplicated in parous, but not among nonparous, women 291, 292. Prospective odds of actual infertility in the Maternal-Infant Research on Environmental Chemicals cohort (n = 1743) at low-dose exposures were associated with PFOA (geometric mean 1.66 ng/mL; odds ratio = 1.31) and PFHxS (odds ratio = 1.27) 293. The reported fertility rate improved following water filtration in a forever chemical-contaminated community along with measures of birth weight 294.
Per- and polyfluoroalkyl substances (PFAS) reliably move across the placenta and enter breast milk 295, 296; serum forever chemicals levels in young children generally exceed maternal serum concentrations 297, 298, 299. Population studies provide evidence that breastfeeding duration and milk quantity are adversely affected by forever chemicals exposure 300, 301, 302.
A systematic review reported that PFOA exposure was associated with a small decrease in infant birthweight; the meta-analysis estimated that a 1-ng/mL increase in PFOA was associated with an approximately 19-g reduction in birth weight 303. The authors noted similarities in experimental studies 304, 305 and concluded that there was “sufficient” human and corroborative toxicology evidence of a detrimental effect of PFOA on birth weight 304, 305, 303. However, another meta-subpopulation analysis, focused on early pregnancy or the time shortly before conception, detected only a small and nonsignificant association, which was less subject to bias 306. Different approaches to the possible confounding role of shifting glomerular filtration rates in pregnancy can affect interpretations; evidence suggests this consideration can, at most, only partially explain associations of forever chemicals exposure to decreased birth weight 307, 308. A recent review of mostly prospective cohort studies (n = 24 studies) noted forever chemicals associated with altered fetal and postnatal growth measures, such as lower birth weight. Many (n = 22) of the relevant studies suggest developmental and childhood immunomodulatory effects, whereas 21 studies concerning neurodevelopment were inconclusive 210. The authors of the review noted methodologic challenges of developmental and newborn epidemiology, including consideration of critical exposure windows for developmental effects, the effects of breastfeeding and parity on maternal forever chemicals levels, and the variety of possible mechanistic explanations for growth outcomes, such as disruption of glucocorticoid and thyroid hormone metabolism in utero 210. Recent Faroe Island studies report that prenatal forever chemicals effects on thyroid hormone status do not support a causal relationship 309.
Review articles suggest that prenatal exposure to PFOA may increase risk of subsequent childhood adiposity, noting that steroid hormones, retinoid X receptor, and other pathways may be contributing to this effect 310, 311. Prospective evidence supports this relationship in adults with a high risk of diabetes 155. However, some well-performed community studies do not support this outcome in adults or children 312, 313.
Based on several preliminary findings, supported by longitudinal follow-up studies 314, 315, 316, 317, 318, the C8 Science Panel concluded that PFOA is probably linked to pregnancy-induced hypertension or preeclampsia. Population-level evidence implicating additional forever chemicals having pregnancy-induced hypertension (preeclampsia) has included studies with longitudinal designs 319, 320, 321. Experimental support includes forever chemicals effects on human trophoblast migration in vitro 322 and recent evidence of PFOA and GenX (or hexafluoropropylene oxide dimer acid) effects on mouse placenta, as well as excessive gestational weight gain 323. However, a recent longitudinal study did not find an association of forever chemicals with pregnancy-associated hypertension (preeclampsia) 324.
The possibility that circulating forever chemicals may reduce bone mineral density (BMD) has been investigated. Cross-sectional and practical trial associations have been found in adults 325, 326, 327 and there is emerging longitudinal evidence from a mother and child pair study indicating that children may also be affected 328.
Testicular cancer diagnoses are increasing steadily, a trend unrelated to improved detection 329, 330. Most patients diagnosed (>90%) will be cured and die of other causes; mortality studies therefore provide little help in understanding disease risk factors. The C8 Science Panel detected longitudinal evidence for increased testicular cancer risk (1.35, 95% CI 1.00–1.79) for cumulative PFOA exposure 200. There are ample supportive data of testicular damage following forever chemicals exposure, including strong evidence of endocrine disruption; but the cell-specific associations are different in humans (germ cell) than the outcomes in rodents (stromal) 2.
Per- and polyfluoroalkyl substances have deleterious effects on conception, pregnancy, and infant development 2. The underlying birth weight data are mostly supportive, although the subsequent growth and adiposity literature is mixed 2. The most sensitive reproductive and developmental outcomes are a topic of ongoing discussion.References
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