PFAS and medicine

PFAS is the acronym for "per- and polyfluoroalkyl substances". PFAs represent a significant problem for our environment and for our health. Reliable measurement methods have been developed for the determination of PFASs and are widely available (liquid chromatography-mass spectrometry). PFASs are found in human biological samples of all kinds, including serum, skin and even hair (Piva E et al. 2021). American scientists suggest that over 98% of the U.S. population has one or more detectable PFAS chemicals in their blood. In addition to drinking water, inhalation of PFAS-contaminated indoor air and dust (from furnishings) are the main sources of exposure for the general population (Pitter G et al. 2020; Stubleski J et al. 2017). However, intake is also possible via fish, meat, milk, eggs, and vegetables from contaminated regions.

Some PFAS are readily absorbed by the body, bind to serum proteins, and have low to negligible renal clearance, allowing them to accumulate in organs such as the liver but also in the skin. They bioaccumulate. Bioaccumulation of PFCAs with more than four carbon atoms also occurs in cows, both in plasma and skin (Lupton SJ et al. 2022). The half-lives of commonly used PFASs are relatively long, ranging from 2 to 9 years depending on the compound (Cardenas A et al 2019, Li Y et al 2018). These figures illustrate that the public health impacts of PFAS exposures will continue for many years. There is a direct association between the distribution of contaminated drinking water and PASF- plasma levels in different exposure groups, resulting in increased concentrations over time, especially in the moderate and high exposure areas (Wilhelm M et al 2015; Li Y et al 2018).

PFAS an occupational problem? Examples of occupational groups particularly exposed to PFAS are the military and firefighters who use flame retardant foams. These firefighting foams contain high levels of PFASs (Tarapore P et al. 2021). Occupational exposure can also lead to high blood PFOA concentrations in factory workers, reaching up to 100 μg/ml serum in 3M factory workers. In 2007, Olsen et al. studied the serum of retired PFAS production workers and found mean serum levels of PFOS of 800 ng/ml (range 145-3490 ng/ml) and of PFOA of 691 ng/ml (range 72-5100 ng/ml) (Tarapore P et al. 2021).

PFAS the medical problem: Acute PFAS injury can occur with Teflon fumes rising from heated Teflon utensils. Polymer fume fever or Teflon fever they are called. They have been known for some time (Greenberg MI et al. 2015) and are likely caused by release of proinflammatory cytokines with consecutive activation of neutrophils and formation of oxygen radicals.

Remarkably, little is known to date about the dermal absorption potential of various PFAS. However, it can be assumed that they can be absorbed through the skin to a not insignificant extent (Ragnarsdóttir O et al. 2022). Ultimately, however, it is known that PFAS organ exposures are associated with a significantly higher risk of all-cause mortality. This statement relates to heart disease mortality and cancer mortality (Wen X et al. 2022). Several studies demonstrate quite clear associations between PFAS contamination and an increase in the incidences of breast and prostate cancers (Steenland K et al. 2021). Associations with renal and testicular cancer, pancreatic cancer, hepatocellular carcinoma, and thyroid tumors have also been demonstrated (Del Fiore P et al. 2022) . In melanoma, prolonged exposure to PFAS is associated with higher mitotic levels in the tumor parenchyma. A survival difference could not be elicited in this melanoma clientele so far (Del Fiore P et al. 2022).

PFAS and breastfeeding: Of immense biological importance is the observation that per- and polyfluoroalkyl substances (PFAS) are transferred from mother to infant via breastfeeding (LaKind JS et al. 2023; LaKind JS et al. 2023). There is a clear dependence between the extent of maternal exposure and the concentration of PASF in colostrum and breast milk (Blomberg AJ et al. 2023). This implies that infants are already exposed to PFAS through breastfeeding. (Blomberg AJ et al.2023).

For pregnancy, an association between exposure to perfluoroalkyl substances (PFAS) and the risk of hypertensive pregnancy disorders has been established (Liu B et al. 2022). Furthermore, there is strong evidence that concentrations of perfluorundecanoic acid and perfluorononanoic acid in the serum of pregnant women correlate positively with the extent of postpartum hemorrhage. In model studies, the risk of postpartum hemorrhage increases with increasing exposure to a PFAS mixture (Lin M et al. 2022).

PFAS and fertility: Perfluoroalkyl substances (PFAS) are endocrine disrupting chemicals. Evidence shows associations of PFOS and PFOA and lowered testosterone levels in infertile men. Thus, epidemiological studies demonstrate that PFOA and PFAS have effects on male reproductive parameters. Among workers at 3M, a company contaminated with PFOA, those with the highest serum levels of PFOA were found to have a 10% increase in mean estradiol levels. A cross-sectional study of 212 exposed men from the Veneto region of Italy found that elevated levels of PFOA (but not PFOS) in serum and seminal fluid resulted in decreased semen quality, testicular volume, and penile length. A cross-sectional study from Nanjing, China, of 664 adult men showed that PFOA and PFOS levels in semen were significantly associated with a lower percentage of progressive sperm and a higher percentage of DNA fragmentation. A follow-up study with the same population confirmed the association between serum and seminal fluid PFOA levels and showed a decrease in total testosterone and free testosterone.

PFAS and thyroid function: Several experimental studies revealed that PFAS are able to affect thyroid hormone-binding proteins. The combined results showed a positive association between changes in TSH and exposure to perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), and perfluorodecanoic acid (PFDA) (Zhang L et al. 2023). In women in early pregnancy, a doubling of PFOS, PFOA, and PFNA concentrations was associated with an increase in FT4 levels. Exposure to PFOS, PFOA, and PFNA was associated with higher FT4 concentrations in women in early pregnancy (Jensen RC et al. 2022)

PFAS and association with gout: Several studies have found a positive association between perfluoroalkyl acids (PFAA), including perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS), and hyperuricemia. Evidence suggests a positive association between serum uric acid levels and elevated levels of PFOA, PFNA, PFOS, PFHxS, and PFDA (Scinicariello F et al. 2020; Ward-Caviness CK et al. 2022). Exposure to PFAAs is likely to be a risk factor for hyperuricemia and gout.

PFAS and serum lipids: Several studies demonstrate an association between serum lipid levels and exposure to perfluoroalkyl substances (PFAS). The associations with perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) and perfluorohexane sulfonic acid (PFHxS) have been demonstrated several times. In the studies, serum PFAS levels were 5 to 100 times higher in the exposed groups than in the controls. In this population with mixed PFAS exposure, predominantly PFOS and PFHxS, the extent of PFAS exposure was positively associated with serum lipid levels (Li Y et al. 2020).

PFASand diabetes: PFAS are structurally similar to fatty acids and appear to upregulate fatty acid oxidation pathways, increasing oxidative stress and possibly leading to insulin resistance (Cardenas A et al 2019; Duan X et al 2011). Evidence suggests a link between PFAS and type 2 diabetes (Zhu Y et al 2022). Thus, circulating PFAS are associated with weight gain in adults and obesity in adolescents. Doubling the baseline concentration of branched perfluorooctanoic acid is associated with a 14% increase in diabetes risk compared with placebo, and doubling N-ethylperfluorooctanesulfonamidoacetic acid is associated with a 17% higher likelihood of microvascular disease. A similar association was observed for perfluorodimethylhexanesulfonic acid (Cardenas A et al 2019).

Inflammatory markers and PFAS: Serum levels of perfluorononanoic acid (PFNA), perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), and perfluorodecanoic acid (PFDA) are significantly associated with a percentage increase in lymphocyte count, as well as a percentage increase in serum iron and serum albumin. Furthermore, serum levels of PFHxS, PFNA, PFOA, and PFOS were found to be associated with a percent increase in total bilirubin (Omoike OE et al. 2021). It is not yet definitively clear how ultimately the inflammatory cascade is set in motion. However, this much is already known: that the double-stranded DNA receptor AIM2 is able to recognize perfluorooctane sulfonate (PFOS) and trigger IL-1β secretion and pyroptosis (Wang LQ et al. 2022).

Chronic spontaneous urticaria: In adults, an association between serum PFAS level and the occurrence of chronic spontaneous urticaria (CSU) has been presented. Interleukin-4 serum level was significantly higher in this clientele at baseline and was positively related to PFHpA level (Shen M et al 2022).

PASF and immune functions: A number of studies indicate an association between immunotoxicity and perfluoroalkyl substances (PFAS). Serious evidence exists in both humans (and animals/Guillette TC et al. 2022) that PFAS exposures to the organism lead to suppression of the immune system. This may be associated with an increased risk of infections, allergies, and asthma (von Holst H et al. 2021). To date, little information is available on the mechanisms underlying the toxicity of PFAS. Evidence suggests negative effects of PFASs on antibody prodution, suggesting that PFASs may impair B-cell function as well as immunological signal transduction, among other effects. For example, PFOA decrease the expression of RAG1 and RAG2, genes involved in immunoglobulin and T cell receptor V(D)J recombination (Janssen AWF et al. 2022). Direct clinical evidence of PFAS-induced immune dysfunction was provided for the highly PFAS-exposed population in Veneto, Italy. For this population, Italian immunologists had to detect a higher mortality risk for COVID-19 compared to non-contaminated individuals. This is also evidence that the population directly paid a price for a PFAS environmental scandal that occurred years ago (Catelan D et al. 2021). Evidence of immunosuppression with reduced antibody response to childhood vaccination was found with PFOA, PFOS, and PFHxS exposures (von Holst H et al. 2021).

PFAS and atopic dermatitis/ bronchial asthma: In 2020, an American research group demonstrated that early childhood exposure to perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorononanoic acid (PFNA), and perfluorohexanesulfonic acid (PFHxS) increased the risk of allergic and respiratory diseases. The authors suggest that serum PFAS concentrations are associated with increased asthma prevalence in US children (Jackson-Browne MS et al 2020). Similarly, for bronchial asthma, higher concentrations of the five PFASs at age 5 years were associated with increased risk of asthma at ages 5 and 13 years in children not vaccinated against MMR (Timmermann CA et al 2017). A larger study (n= 687 children) with a 2-year follow-up demonstrated that prenatal exposure to PFOA, PFDA, PFDoA, and PFHxS significantly increased the risk of atopic dermatitis (Chen Q et al. 2018).

PFAS: common representatives of this group of substances with the assigned acronyms.

• Perfluorohexane sulfonic acid (PFHxS)
• Perfluorooctane sulfonic acid (PFOS)
• Perfluorooctanoic acid (PFOA)
• Perfluorononanoic acid (PFNA)
• Perfluorodecanoic acid (PFDA)

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• Perfluorohexanesulfonic acid (PFHxS)
• Perfluorooctanesulfonic acid (PFOS)
• Perfluorooctanoic acid (PFOA)
• Perfluorononanoic acid (PFNA)
• Perfluorodecanoic acid (PFDA )

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