Per- and polyfluoroalkyl substances: toxicokinetics, exposure and health risks

Abstract

Per- and polyfluoroalkyl substances (PFAS) are a group of chemicals containing stable per- or polyfluoroalkyl groups. Recent epidemiological studies have shown that PFAS cause health risks even at low concentrations. This review outlines the toxicokinetics, exposure and health risks of PFAS, with a focus on perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), and long-chain perfluoroalkyl carboxylic acids (LC-PFCAs). These compounds are known to interact with various proteins in vivo, including the peroxisomal proliferator-activated receptor-α (PPARα). PFOA and PFOS have been identified as carcinogenic. It is known that PFOA and PFOS are transported by transporters such as organic anion transporter. Significant species differences in the behavior of these compounds exist, with much longer half-lives in humans than in mice and rats. One of the reasons that the half-lives of PFOA and PFOS are long in humans is that their renal clearance is low in humans. For animal toxicity experiments, it is essential that the doses in animal experiments are converted to equivalent doses in humans using pharmacokinetic models. Compared with PFOA, some LC-PFCAs have longer half-lives and accumulate more in the liver. Although tap water is a source of exposure to PFAS, the most common exposure source is food, with seafood being an important source for exposure to PFAS in Japan. PFOS and PFOA concentrations in human blood in Japan have been decreasing in recent years. However, according to clinical guidance published in 2022 by the United States National Academies, most Japanese residents are still in the medium risk group (PFAS concentration in plasma or serum is greater than 2 ng/mL and less than 20 ng/mL) or above. Further research is needed to help reduce exposure, and further risk assessments are required.

INTRODUCTION

Per- and polyfluoroalkyl substances (PFAS) are a group of chemicals containing stable per- or polyfluoroalkyl groups with fluorinated methyl or methylene groups. PFAS have been used since the 1950s in the production of water and oil repellents, foam fire extinguishing agents, and fluoropolymers. PFAS is the name for a group of thousands of chemicals, the most common of which are perfluoroalkyl carboxylic acids (PFCAs) and perfluoroalkyl sulfonic acids (PFSAs). PFCAs and PFSAs have various carbon number analogs (Table 1). Among these, the PFCA with eight carbon atoms is known as perfluorooctanoic acid (PFOA), and the PFSA with eight carbon atoms is known as perfluorooctane sulfonic acid (PFOS). PFCAs with more than eight carbon atoms are referred to as long-chain PFCAs (LC-PFCAs), and these compounds have been detected in the environment and biota in Japan and other countries.

Table 1. Per- and polyfluoroalkyl substances (PFAS) covered in this review.

TOXICITY

PPARα-dependent toxicity

PFOA and PFOS are chemically stable and have poor reactivity with biomolecules. However, because of their similarity to fatty acids (the hydrogen in the alkyl group of a fatty acid is replaced by fluorine), PFOA and PFOS are thought to interact with various proteins. One of these proteins is peroxisome proliferator-activated receptor-α (PPARα) (Takacs and Abbott, 2007). There are species differences in PPARα activation, with rats and mice being the most sensitive, and primates, including humans, being less sensitive. Thus, humans are not as responsive to PPARα agonists as other species such as rats and mice; however, the functionality of PPARα is thought to lead to PFOA and PFOS toxicity in humans too (Nakagawa et al., 2012). On the other hand, not all PFOA and PFOS toxicity seems to be PPARα-dependent. Reports suggest that independent mechanisms are also involved (Abbott et al., 2009).

Carcinogenicity

In 2014, the International Agency for Research on Cancer (IARC) stated that PFOA was classified into Group 2B (possibly carcinogenic to humans) (Benbrahim-Tallaa et al., 2014). In further meetings in 2023, PFOA was placed in Group 1 (carcinogenic to humans) (Zahm et al., 2024) . Group 1 compounds have highest evidence of carcinogenicity, and other members of this group are tobacco, asbestos, and coal tar. PFOA was placed in Group 1 based on evidence of its carcinogenicity in experimental animals and scientific evidence of the mechanism of carcinogenicity. On the other hand, epidemiological studies in humans have shown limited evidence of carcinogenicity for PFOA in renal cell carcinomas and testicular cancer. PFOS has been classified into Group 2B (possibly carcinogenic to humans) according to strong mechanistic evidence in various test systems. This includes in exposed humans, where epigenetic changes, immunosuppression, and several other key features of carcinogenicity have been observed. However, the evidence for carcinogenicity of PFOS is limited in experimental animals and insufficient in epidemiological studies.

Epidemiology

In epidemiology, health effects of PFOA and PFOS have been observed even in populations in non-contaminated areas with low PFOA/PFOS concentrations, which suggests that humans are highly susceptible to these compounds. A series of studies by Grandjean et al. of PFAS and diphtheria and tetanus antibody levels in children after diphtheria and tetanus vaccination have been often used for risk assessment of PFAS. These studies found that diphtheria antibody levels at age 7 and 13 years were negatively associated with serum PFOA concentrations at age 5 and 7 years, respectively, and also negatively associated with serum PFOA concentrations at age 13 years (Grandjean et al., 2012, 2017; Mogensen et al., 2015). They also found an association between the serum PFOS concentration and tetanus antibody levels at age 5 years (Grandjean et al., 2012). In a study of children who did not have booster vaccinations, an association was found between the serum PFOS concentrations and tetanus antibody levels at age 7 years (Grandjean and Budtz-Jørgensen, 2013).

Fetal growth inhibition has been identified as a developmental effect of PFAS in animal studies, and this is found to occur at a lower concentration than other toxicological outcomes. The concentration that causes fetal growth inhibition has been adopted as the reference dose in many risk assessments (Dong et al., 2017). Epidemiological studies have reported negative correlations of varying degrees between maternal blood PFOA/PFOS concentrations and birth weight, and these correlations have also been observed in meta-analyses (Verner et al., 2015). A 2015 systematic review assessed the association between PFOA exposure and fetal growth in the general population and found that a 1 ng/mL increase in serum PFOA was associated with a decrease in birth weight (−18.9 g, 95% CI: −29.8 to −7.9 g) (Johnson et al., 2014). However, the authors stated that the magnitude of this decrease was influenced by the timing in the pregnancy of the maternal blood collection. Further research is needed, particularly on confounding factors related to renal function during pregnancy, as PFOA and PFOS are excreted from the kidneys.

Epidemiological studies in Japanese populations have been preceded by birth cohort studies. Notably, the Japan Environment and Children’s Study (JECS) reported an association between chromosomal abnormalities at birth and maternal PFAS levels. Among PFAS types, the strongest effects were seen in the order PFOS, C9 PFCA (PFNA), C11 PFCA (PFUnDA) and PFOA (Hasegawa et al., 2024).

TOXICOKINETICS

Clearance of PFOA and PFOS in humans and laboratory animals

PFOA and PFOS are thought to be well absorbed when taken orally in both humans and animals. Thus, the toxicity to laboratory animals can be evaluated by oral administration. However, it is difficult to compare their toxicities between species because of variations in clearance and other toxicokinetics and differences in toxicity mechanisms. PFOS and PFOA are excreted mainly from the kidneys into the urine (renal clearance) in rats and mice (Kudo et al., 2002; Kim et al., 2016), but renal clearance of PFOS and PFOA is extremely low in humans (Harada et al., 2007b; Fujii et al., 2015b) (Table 2). Biliary excretion does not show large differences between rats and humans, in both cases, absorption in the intestinal tract is high and enterohepatic circulation may occur. In conclusion, one of the reasons that the half-lives of PFOA and PFOS are long in humans is that their renal clearance is low in humans (Harada et al., 2007b). Therefore, it is essential that the doses in animal toxicity experiments are converted to equivalent doses in humans using pharmacokinetic models.

Table 2. Blood half-life and clearance of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS) in humans and rats.

It is known that PFOA and PFOS are transported by transporters such as Organic anion transporter (OAT), urate transporter (URAT), OAT polypeptides (OATPs) and multidrug resistant (MDR). OAT1 and OAT3 exhibit similar PFOA transport activity in rats and humans (Nakagawa et al., 2008). Reabsorption of PFOA and PFOS in the proximal tubule of the kidney must also be considered, because human OAT4 and URAT1 are also active for PFOA and PFOS (Nakagawa et al., 2009; Yang et al., 2010). Additionally, in vitro studies using Caco2 cells, which have properties similar to human small intestine columnar epithelial cells, have indicated that PFOA uptake is mediated by OATPs (Kimura et al., 2017; Kimura et al., 2020). ABC transporters have also been investigated, and altered bile efflux and renal clearance have been observed in multidrug resistant (MDR) 1- and 2-deficient mice (Furukawa et al., 2024).

Estimation of human clearance of PFCAs

Low renal clearance of PFAS can be explained by their high protein-binding affinity. It has been suggested that LC-PFCAs, which have longer carbon chains than PFOA, may have lower urinary clearance and longer half-lives than PFOA in humans. Therefore, to estimate the clearance of C8 to C14 PFCAs, human biological samples (blood, urine, and bile) were analysed (Fujii et al., 2015b). A one-compartment model was used to estimate the clearance of PFCAs, and showed a decreasing trend with increasing chain length for renal clearance (urinary excretion) (Fujii et al., 2015b). By contrast, biliary excretion showed an increasing trend with increasing chain length (Fujii et al., 2015b).

We recalculated the total clearance of LC-PFCAs using data from our previous studies (Fujii et al., 2015b) (Table 3A). In the previous study (Fujii et al., 2015b), assuming a volume distribution of 200 mL/kg, a serum half-life of 3.8 years, and that C8 could only be excreted into the urine and feces via the bile, the reabsorption rate of bile excreting C8 was calculated as 0.98. And the C8 value (0.98) was applied to the C9 to C14 PFCAs C9. This time, as there is thought to be no difference in the absorption ratio of PFCAs between mice and human, the values of absorption ratio in mice experiment (0.960 to 0.996, varies with carbon chain length) were extrapolated to humans (Table 3A). The absorption rate of PFCAs in the intestinal tract was calculated from data for oral and intravenous administration to mice (Fujii et al., 2015b). The fecal clearance was calculated using the absorption rates and PFCA values previously measured in human bile and serum. The renal clearance was also calculated by PFCA values in human urine, and serum (Fujii et al., 2015b) (Table 3A). As a result, the renal clearance was higher for C8–C10 PFCAs, while fecal clearance was higher for C11–C14 PFCAs. The renal and fecal clearances were summed to calculate the total clearance (Table 3A). The highest total clearance (0.45 mL/day/kg) was observed for C14 PFCA, followed by C13 and C8 PFCA, and C11 PFCA had the lowest total clearance rate (0.017 mL/day/kg).

Table 3. Clearance and estimated daily exposure dose of perfluoroalkyl carboxylic acids (PFCAs) in humans.

Assuming that the concentration of PFCAs in the blood is at a steady state, the exposure amount (daily exposure dose) of PFCAs was calculated from the blood concentrations of PFCAs in Kyoto of 2011 (Fujii et al., 2017) and compared with the actual measured values for dietary intake from 24-hr duplicate diet (all food and drink consumed in a 24-hr period) in Kyoto of 2011 (Fujii et al., 2017) (Table 3B). The estimated values for daily exposure dose from serum concentration were much lower than the actual measured values of daily dietary intake from 24-hr duplicate diet, except for PFOA (C8) (Table 3B). This is because, although blood concentrations of LC-PFCAs were increasing at this time (Okada et al., 2013), the blood concentrations were calculated as in a steady state, and the exposure estimates were at lower levels.

PFCA distribution in vivo: High accumulation in the liver

The distribution of PFCAs in vivo has been assessed in mice by equimolar dose administration of C6 to C14 PFCAs (Fujii et al., 2015b) (Fig. 1). Twenty-four hours after administration of PFCAs, PFOA (C8) showed the highest blood concentrations. Short-chain PFCAs (C6 and C7) were largely excreted in the urine, while LC-PFCAs (C9–C14), which had lower blood concentrations than PFOA, accumulated in the liver. This result suggests LC-PFCAs have higher transferability to tissues (a larger volume of distribution) than PFOA. In fact, many long-chain PFCAs reportedly accumulate in the liver of large marine mammals (Fujii et al., 2018a, 2018b).

Fig. 1

In vivo distribution and excretion of perfluoroalkyl carboxylic acids (PFCAs) (C6 to C14) 24 hr after intravenous administration (0.313 μmol/kg) in male mice (Fujii et al., 2015b)

HUMAN BLOOD CONCENTRATIONS AND EXPOSURE

Temporal changes in blood concentrations

Until the year 2000, PFOS and PFOA were detected in the Japanese population in several regions. Particularly in the Kansai region, blood concentrations of PFOA were two to three times those in the general population in the United States (US), whereas PFOS concentrations were approximately half those in the US (Harada et al., 2007a). Over time, the trend was consistent with the amount of fluoropolymer production, with a significant 4.4-fold increase in PFOA in the blood of Kyoto residents between the 1980s and the year 2000. Subsequently, there was a decrease in blood PFOS and PFOA concentrations because of the discontinuation of manufacturing by major companies, as well as other factors (Harada et al., 2011; Soleman et al., 2023; Harada et al., 2007a). However, high concentrations of PFAS have been reported in recent years in the blood of residents in Okinawa Prefecture, Settsu of Osaka Prefecture, the Tama area of Tokyo, and other areas (Lyu et al., 2024a). These results indicate that contamination from past PFAS use still affects humans.

Sources of PFAS exposure

Although tap water is a source of exposure to PFAS, the largest source of exposure to PFAS in uncontaminated areas is likely to be food (Gebbink et al., 2015; Fujii et al., 2012). Higher concentrations of LC-PFCAs in blood have been reported in the Japanese population than in the European and US populations (Fujii et al., 2017). The proportion of C11 and C13 PFCAs is particularly high, and their sources and contaminated sites need to be identified. Edible clams contained high concentrations of PFOA (C8) in Japan (Fujii et al., 2020). On the other hand, LC-PFCAs are found in high concentrations in edible cod (Fujii et al., 2015a, 2019) and shrimp (Fujii et al., 2024) in the waters around Japan. A positive correlation between PFAS and eicosapentaenoic acid, which is a biomarker of fish consumption, has also been reported for human blood samples from Japan (Soleman et al., 2023; Lyu et al., 2024b). These studies indicate that edible fish and shellfish are potential sources of PFAS exposure.

Comparison of blood PFAS concentrations in the Japanese population with the clinical guidance by the US National Academies and HBM-II values

In 2019, the German Environment Agency announced the human biomonitoring (HBM)-II values are 20 ng/mL for PFOS and 10 ng/mL for PFOA in plasma or serum (Schümann et al., 2021). The doses for women of childbearing age are half the above values (Schümann et al., 2021). The committee states “The HBM-II-value represents the concentration of a substance in a human biological material above which – according to the knowledge and judgement of the HBM Commission – there is an increased risk for adverse health effects and, consequently, an acute need for exposure reduction measures and the provision of biomedical advice. The HBM-II-value should thus be regarded as an intervention or action level.” (UBA, 2023). If the HBM-II values are exceeded, it is necessary to reduce exposure. Clinical guidance on PFAS published by the US National Academies in August 2022 (National Academies of Sciences, 2022) recommends even stricter. If the sum of seven PFAS (PFOS, PFHxS, PFOA, three LC-PFCAs (PFNA (C9), PFDA (C10), PFUnDA (C11)), and MeFOSAA) in serum or plasma are “greater than 2 ng/mL and less than 20 ng/mL” (medium risk group) or “greater than 20 ng/mL” (high risk group), they are advising special clinical care.

Although it is considered rare for PFOS plasma concentrations to exceed 20 ng/mL in the Japanese population (Lyu et al., 2024a), this clinical guidance should be taken into consideration because it’s not only for PFOS, but also the sum of seven PFAS compounds. Notably, PFOA and LC-PFCAs, which are found at higher concentrations in blood from Japanese residents than in other countries (Harada et al., 2011; Fujii et al., 2017), are included in the US guidance. In fact, the total concentration of six PFAS (PFOS, PFHxS, PFOA, and three LC-PFCAs (PFNA (C9), PFDA (C10), PFUnDA (C11))) in the plasma of Japanese residents was reported to average 10 ng/mL (median 8.8 ng/mL) in the year 2023 (MOE, 2024). Therefore, the medium risk group (plasma concentrations of more than 2 ng/mL and less than 20 ng/mL) apply to most Japanese residents.

CONCLUSIONS

PFAS have concerning health effects, but the mechanism of action of their toxic effects still needs to be elucidated. A good understanding of exposure routes is important for regulation. Concerningly, according to the US National Academies’ clinical guidance from August 2022, many Japanese residents are currently at medium- or high-risk levels to these compounds. Further research is required for accurate risk assessment.

ACKNOWLEDGMENTS

This study was supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (JSPS) (grant number 21K12262) and the Uehara Memorial Foundation. The funders had no role in writing of this review or the decision to submit the work for publication. We thank Helen Jeays, BDSc, and Gabrielle David, PhD, from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.

Conflict of interest

The authors declare that there is no conflict of interest.

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