In a recent review published in the journal Science of The Total Environment, researchers collate and discuss available literature on per- and polyfluoroalkyl substances (PFAS). They highlight PFAS sources in the environment, compare PFAS exposure risk amongst different age groups, and elucidate epidemiological studies on these substances' hepatotoxicity in vitro and in vivo. They finally point out the current gaps in PFAS research and provide suggestions for bridging these gaps in future studies.
Study: Dietary exposure to per- and polyfluoroalkyl substances: Potential health impacts on human liver. Image Credit: Created with the assistance of DALL·E 3
What are PFAS and where do we find them?
Per- and polyfluoroalkyl substances (PFAS) are highly persistent synthetic chemicals comprising more than 4,700 fluorinated substances. PFAS are durable, heat-resistant, and grease- and water-repellent, resulting in their extensive application in the consumer sector.
The global footprint of PFAS
Despite being artificial and not found naturally in the environment, their near-ubiquitous incorporation in food packaging, fire-repellent foam, waterproofing material, paints, pesticides, and even cosmetics has resulted in PFAS being found from the peak of Mount Everest to the bottom of ocean trenches. Global studies have found PFAS in the tropics, the Arctic and Antarctic Poles, and everywhere in between.
The biological impact of PFAS
Alarmingly, PFAS have also been found in the bodies of virtually all plants and animals, including humans. Research has demonstrated the bioaccumulation and biomagnification of these substances across terrestrial and aquatic ecosystems, exposing humans to PFAS ingestion via inhalation, dermal contact, and dietary intake. Oral dietary intake predominates, with epidemiological studies linking increased serum PFAS concentrations with fish and shellfish consumption.
How do we consume PFAS?
PFAS have further been identified in fruits and vegetables, livestock, and processed foods, and given their use as food packaging, have been observed to contaminate food to direct migration from the packaging onto the food itself. PFAS have a strong affinity for proteins and bioaccumulate in protein-rich tissue. Research has identified high concentrations of PFAS in the human liver, where it has been associated with chronic diseases, including nonalcoholic fatty liver (NAFLD), hepatic fibrosis, and liver cancer.
PFAS and liver health
The present review aims to elucidate the sources and fates of PFAS in the environment, with a special focus on human exposure and PFAS-induced hepatotoxicity studies evaluating in vitro and in vivo murine models. The review is intended to raise public awareness about the demerits of PFAS contamination and its impacts on human liver health.
From production to pollution: The lifecycle of PFAS
PFAS, since their discovery and introduction in the 1980s, have been used extensively in consumer and industrial applications due to their durability and surfactant-like properties. After concerns about their environmental impacts came to the forefront in the early 2000s, PFAS manufacturers began phasing out long-chain PFAS (called 'legacy PFAS') and replacing them with short-chain variants ('emerging PFAS').
While additional research is required to confirm claims that short-chain PFAS are environmentally and medically safe, these emerging PFAS allow manufacturers to bypass legacy PFAS restrictions imposed during the Stockholm Convention and other global conferences.
How do PFAS get into our food and water?
Studies have identified industry wastewater and exhaust, wastewater treatment plants (WWTPs), untreated domestic wastewater, and aqueous film-forming foams (AFFFs) as the primary environmental PFAS pollutant sources. Uptake and use of this water by plants, aquatic organisms, and livestock results in bioaccumulation and biomagnification. This process, termed 'trophic transfer,' forms humans' main dietary source of PFAS.
Food packaging and nonstick cookware are rich in PFAS, especially polyfluoroalkyl phosphate esters (PAP) and fluorotelomer alcohols (FTOH). Studies have revealed that PFAS can migrate from packaging material and cookware to the food itself, with the degree and rate of migration dependent on PFAS characteristics (chain length) and the food matrix (pH, fat content, temperature, salt content). Migration is the primary source of PFAS in processed foods.
Effects of PFAS exposure in humans
Studies have identified PFASS in multiple human tissues, including the blood, brain, kidneys, cerebrospinal fluid, liver, placenta, and lungs. Exposure levels vary based on profession and age. Firefighters and fluorine-chemical industrial park workers are at much higher exposure risk than the general public due to their close contact with PFAS-secreting substances. For most humans, dietary habit is the critical determinant of PFAS exposure, with seafood diets generally resulting in higher PFAS concentrations than fruits and vegetables.
While some studies have identified reductions in serum PFAS levels in lactating women and loss of PFAS during menstruation, others have revealed that mother-to-child PFAS transmission can occur via direct umbilical cord blood and breastfeeding. Research has identified high concentrations of PFAS in dairy milk and infant formula, suggesting that infant exposure to PFAS is significantly higher than that of adults.
Following restrictions imposed by the Stockholm Convention and other international agreements, legacy PFAS in human serum shows an encouraging downward trend. Long-term studies in Sweden and the United States have revealed legacy PFAS serum reductions between 61% and 88%. However, while the overall PFAS concentrations in human serum seem to be in decline, legacy PFAS are being replaced by emerging short-chain PFAS such as chlorinated polyfluoroalkyl ether sulfonic acid (Cl-PFESA). These emerging PFAS have been linked to adverse pregnancy outcomes in Chinese studies.
Biological pathways of PFAS toxicity
In vivo, murine models have revealed PFAS absorption patterns in mammals. PFAS have a strong affinity for fatty-acid binding proteins found in the liver, resulting in the liver tissue usually having the highest PFAS concentrations in most humans. Most PFAS have chemically robust carbon‑fluorine bonds, preventing their biochemical metabolisms and resulting in bioaccumulation in human tissue.
"Several reports have shown that PFAS initially crosses the intestinal barrier and is distributed in the blood, binds to albumin and low-density lipoprotein in the blood, and then disperses into extraintestinal organ following blood circulation."
What do we know about PFAS-induced liver damage?
Epidemiological studies have elucidated extensive liver damage brought about by PFAS toxicity. PFAS has been associated with numerous liver-damage biomarkers, including alanine transaminase (ALT), Gamma-glutamyltransferase (GGT), and aspartate transaminase (AST). Studies have shown strong evidence for legacy PFAS being responsible for liver fibrosis and cancer, especially in women and older adults.
In vitro liver models have found that the cytotoxicity of PFAS depends on exposure duration, PFAS concentration, and carbon chain length. Alarmingly, some studies have found synergistic effects between multiple PFAS, causing more significant damage than the sum of individual PFAS.
In vivo studies have identified PFAS as being responsible for higher cholesterol levels and obesity in humans.
"A recent study showed that exposure to five PFAS mixtures (PFOS, PFHxS, PFOA, PFNA, and HFPO-DA) caused cholestasis in the liver and increased cholesterol and bile acid levels in the mice."
Conclusion
The present review elucidates the sources and environmental transmission of PFAS, a family of nearly 5,000 man-made substances with remarkable persistence. It provides an overview of the exposure routes for PFAS assimilation by humans and the adverse effects of PFAS toxicity in vitro and in vivo. Particular focus is paid to liver cytotoxicity, revealing that PFAS can result in chronic liver conditions, including cancer.
"This review aims to raise public awareness about food PFAS contamination and its potential risks to human liver health."
New drug approach shows promise in treating metabolic liver diseases