MORE COMMENTS: I certainly am not dismissing most structure-activity relationship (SAR) studies. Kepone binding to the estrogen receptor was simply a very memorable exception. 😊 As I recall, the main clinical effect of chlordecone was neurotoxicity — even small children exhibited neurological symptoms from being exposed to the contaminated boots of their fathers coming home after a day’s work in the Kepone factory. Chlordecone was not federally regulated until after the Hopewell disaster (along the James River in Virginia), in which 29 factory workers were hospitalized with various ailments, including neurological problems.
Linda, I certainly agree there are many epidemiological studies showing some association of PFAS toxicity in in-vitro and cell-culture studies. However, I’m always trying to look at the Big Picture. For example, new research (just reported 24 Aug 2023 in the peer-reviewed journal Environmental Science & Technology) [https://doi.org/10.1021/acs.est.3c00343] found that Asian-Americans have (on average) 88% more PFAS body burden (bioaccumulation) than White-Americans or Black-Americans (on average). [One possible explanation might be a higher consumption of fish and seafood (which, due to being at the end of the food chain, probably accumulate more PFAS than an animal at the top of the food chain) in Asian-Americans?]
Because extensive exposure of PFAS began in the 1950s — wouldn’t we expect to see (by now) “elevated cholesterol levels, increased kidney and testicular cancer rates, both immune suppression and autoimmunity, increased risk of preterm birth, hypertension during pregnancy, low birth-weight, increased risk of type-2 diabetes (T2D) and overweight/obesity” in Asians? But clearly — 70 years later — we do not see any of these ethnic effects in Asians in the Real World. ☹
MORE COMMENTS: I’ve spent most of three days, researching PFAS. One thought I had was that, if some PFAS is/are difficult to degrade and therefore bioaccumulative — it might be possible to overwhelm some receptor(s) with a dissociation constant (Kd) of 10-2, or 10-4, when the physiological ligand for that receptor might have a (Kd) of, say, 10-9.
However, whatever findings one can demonstrate in vitro (in a test tube), or in cell culture, very often cannot be replicated (under physiological conditions) in the intact lab animal or in clinical patients. This is what I can conclude for PFAS — seeing or realizing that worldwide PFAS exposures since the 1950s — have revealed no clear-cut evidence for cause-and-effect between one or more PFAS and clinical toxicity of some organ system.
As far as trying to relate a chemical structure to a particular receptor binding site, long ago Yours Truly concluded we should forget about that. ☹ In the late 1970s, recall that Richard Palmiter reported that the insecticide/fungicide Kepone (chlordecone) could be shown to bind to the estrogen receptor(!!) — although the chemical structures of Kepone and estrogen are wildly different…!! Kepone looks like a six-sided box with Cl atoms at every possible position except for the one C=O site…!!!
kepone chemical structure from webbook.nist.gov
[By the way, in 1975 Kepone was removed from the market — due to (experimentally-demonstrated) extreme toxicity to animals and humans. Contrast THAT chemical with the hand-waving & smoke-and-mirrors that the epidemiologists are doing with the PFAS…] ☹
To bring many of our GEITP-ers up-to-speed on this “PFAS discussion” — let me try to summarize. Perfluorooctane sulfonic acid (PFOS) is one of a group (i.e., a subset) of related chemicals known as per- and poly-fluorinated alkylated substances (PFAS); collectively, these are also called perfluorochemicals (PFCs). This group of synthetic chemicals (which number almost 15,000…!!) has been commonly used in a wide range of industrial processes since the 1950s and is found in many consumer products (e.g., firefighting foam, non-stick cookware, teflon, cosmetics, and materials that protect against grease, oil, and water — such as stain-resistant carpeting and fabrics, food packaging, and water-repellent clothing).
On PubMed, requesting “PFOS toxicity review,” there are 141 reviews posted (from 2008 to 2023). Requesting “PFAS toxicity review,” there are 211 reviews listed (from 2018 to the present). Some of these reviews (of course) are listed in both searches. The reviews include both clinical studies and studies of various species of animals. The C-F bond is very difficult to break; hence, degradation (in the environment or in the body of animals) is slow, which means that all of us (in most, if not all, organs) carry a load of those PFAS that are able to bioaccumulate.
The summaries of the two most thorough epidemiological reviews are posted below. Needless to say, I notice that “associations of PFAS with serious health disorders” always seem to be “weak or nil” and “further studies” always seem to be “warranted.” ☹
 Association between per- and polyfluoroalkyl substances exposure and risk of diabetes: a systematic review and meta-analysis.
Gui SY, Qiao JC, Xu KX, Li ZL, Chen YN, Wu KJ, Jiang ZX, Hu CY.J Expo Sci Environ Epidemiol. 2023 Jan; 33(1): 40-55.
Background: Emerging evidence suggests that per- and polyfluoroalkyl substances (PFAS) are endocrine disruptors and may contribute to the etiology of diabetes.
Objectives: This study aimed to systematically review the epidemiological evidence on the associations of PFAS with mortality and morbidity of diabetes and to quantitatively evaluate the summary effect estimates of the existing literature.
Methods: We searched three electronic databases for epidemiological studies concerning PFAS and diabetes published before April 1, 2022. Summary odds ratio (OR), hazard ratio (HR), or β and their 95% confidence intervals (CIs) were respectively calculated to evaluate the association between PFAS and diabetes using random-effects model by the exposure type, and dose-response meta-analyses were also performed when possible. We also assessed the risk of bias of the studies included and the confidence in the body of evidence.
Results: An initial literature search identified 1969 studies, of which eventually 22 studies were included. The meta-analyses indicated that the observed statistically significant PFAS-T2DM associations were consistent in cohort studies, while the associations were almost non-significant in case-control and cross-sectional studies. Dose-response meta-analysis showed a “parabolic-shaped” association between perfluorooctanoate acid (PFOA) exposure and T2DM risk. Available evidence was rated with “low” risk of bias, and the level of evidence for PFAS and incident T2DM was considered “moderate”.
Conclusions: Our findings suggest that PFAS exposure may increase the risk of incident T2DM, and that PFOA may exert a non-monotonic dose-response effect on T2DM risk. Considering the widespread exposure, persistence, and potential for adverse health effects of PFAS, further cohort studies with improvements in expanding the sample size, adjusting the covariates, and considering different types of PFAS exposure at various doses, are needed to elucidate the putative causal associations and potential mode of action of different PFAS on diabetes.
Impact statement: A growing body of evidence suggests that per- and polyfluoroalkyl substances (PFAS) are endocrine disruptors and may contribute to the development of diabetes. However, epidemiological evidence on the associations of PFAS and diabetes is inconsistent. We performed this comprehensive systematic review and meta-analysis to quantitatively synthesize the evidence. The findings of this study suggest that exposure to PFAS may increase diabetes risk among the general population. Decreased exposure to these “forever and everywhere chemicals” may be an important preventive approach to lowering the risk of diabetes across the population. [Or, deceased exposure to PFAS may not be important in lowering the risk of diabetes?]
 Early-Life Exposure to Per- and Poly-Fluorinated Alkyl Substances and Growth, Adiposity, and Puberty in Children: A Systematic Review.
Lee YJ, Jung HW, Kim HY, Choi YJ, Lee YA.Frontiers in Endocrinol (Lausanne). 2021 Sep 9; 12: 683297. Free PMC article.
Per- or polyfluoroalkyl substances (PFAS), a family of synthetic polyfluorinated compounds, are widely used in consumer products. Ubiquitous exposures to PFAS, in consideration of their persistence, bioaccumulation potential, and toxicities have led to concerns regarding possible harmful effects during critical periods of development in early-life and long-term consequences on health. The potential effects of PFAS depend on various factors including the type of PFAS and the timing and level of exposure.
We performed a systematic review of the epidemiologic literature to assess the effects of early-life PFAS exposure on prenatal and postnatal growth, adiposity, and puberty in children and adolescents. For birth size, most studies indicated that prenatal PFAS exposure, in particular long-chain PFAS, may impair fetal growth, albeit there are some reports of null associations with maternal PFAS.
For growth within the first 2 years of age, prenatal PFAS exposure showed no associations with height and either null or negative associations with weight. However, postnatal PFAS exposures were inversely related to height and weight at 2 years in a cross-sectional study.
For postnatal adiposity, prenatal PFAS may mostly have negative associations with body mass index in the first 2 years of life, but positive relationships with adiposity in childhood and adolescence, although some studies showed null associations.
For time of onset of puberty, the evidence for associations between early-life PFAS exposure and pubertal development or sex hormone levels were limited and inconclusive.
From experimental studies, plausible mechanisms through which PFAS may affect early-life growth and puberty include PFAS-induced activation of peroxisome proliferator-activated receptor, alterations of thyroid or steroid hormone synthesis and metabolism, and their weak estrogenic or anti-androgenic properties.
Although the published literature suggests possible effects of PFAS exposures on early-life growth, adiposity, and puberty, current human evidence is limited in establishing PFAS-induced effects on early-life physical development. Further investigation is warranted to clarify PFAS-induced effects on growth and physical development in consideration of the critical time-window of exposure, concomitant exposure to chemical mixtures including various PFAS types, and possible non-monotonic dose-response relationship for growth and adiposity trajectories.
What is the difference between a “monotonic” and a “non-monotonic” dose-response curve? Well — they say that “a picture is worth a thousand words.” The following dose-response curves are reproduced from ResearchGate.com:
In summary, a “monotonic” dose-response curve — is a boring linear relationship between dose and response. A “non-monotonic” dose-response curve — is anything else that is not linear. ☹ Below is an excellent review:
Toxicol Appl Pharmacol 15 Jan 2018; 339: 10-23:
This study aims to evaluate the evidence for the existence of non-monotonic dose-responses (NMDRs) of substances in the area of food safety. This review was performed following the systematic review methodology with the aim to identify in vivo studies published between January 2002 and February 2015 containing evidence for potential NMDRs. Inclusion and reliability criteria were defined and used to select relevant and reliable studies. A set of six checkpoints was developed to establish the likelihood that the data retrieved contained evidence for NMDR.
In this review, 49 in vivo studies were identified as relevant and reliable, of which 42 were used for dose-response analysis. These studies contained 179 in vivo dose-response datasets with at least five dose groups (and a control group), because fewer doses cannot provide evidence for NMDR. These datasets were extracted and analyzed using the PROAST software package. The resulting dose-response relationships were evaluated for possible evidence of NMDRs by applying the six checkpoints. In total, 10 out of the 179 in vivo datasets fulfilled all six checkpoints. Whereas these datasets could be considered as providing evidence for NMDR, replicated studies would still be needed to check if the results can be reproduced to rule out that the non-monotonicity was caused by incidental anomalies in that specific study. This approach, combining a systematic review with a set of checkpoints, is new and appears useful for future evaluations of the dose response datasets regarding evidence of non-monotonicity.
Overall, humans have been eating and exposed to PFOS and PFAS through all portals of entry — since the 1950s — yet very few (if any) serious health problems can be identified and/or quantified. As Shakespeare once said, along with hand-waving and smoke-and mirrors, “It appears that there may be ‘Much Ado About Nothing’.” ☹
This topic is reminiscent of the Linear Non-Threshold (LNT) Model controversy — which assumes that every increment of ionizing radiation dose, or environmental chemical dose, no matter how small — constitutes an increased cancer risk or toxicity risk for humans. ☹
Looking at this again more thoroughly, the statement (that these fluoride compounds are toxic at parts-per-quadrillion (ppq) levels) seems hard to believe — without additional information. How are they toxic? Toxic to humans and/or animals? What is(are) the target organ(s)? What toxicology studies support this?
Also, as an analytical chemist — “analysis at the ppq level” is unknown to me, albeit I have been out of the profession for a decade. There was mention of “hundreds of epi studies.” “Hundreds?” Really? Even so, mountains of studies (based on retro-collected data for other purposes) can only be used to support a hypothesis; that is Science 101. I imagine that I am exposed to PFOA levels greater than ppq levels every time I eat anything cooked in a Teflon-coated pot or pan. Maybe that’s what gave me prostate cancer?
Thanks, Linda, that is helpful. Many years ago, I did a ‘deep dive’ into all the occupational-exposure and worker-monitoring programs for perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) workers, who had enormous exposure and blood levels — relative to what is seen today. In spite of pretty decent medical records, there wasn’t anything anyone could really see. But these negative data may be a combination of “healthy worker” effects, and insensitive and/or inadequate biomedical follow-up, etc. And, there also were not any early-life-exposure-effects observed. But the dose difference (based on blood values) from what people see today is enormous; hence, my reference to a non-monotonic dose-response (NMDR) effect.
Sorry friends. But I don’t agree.
While some of the PFAS concerns may involve “non-monotonic dose-response” (NMDR), most are related to hundreds of clinical epidemiology studies — backed by even more animal (rodents, birds, fish, monkeys, wildlife, domestic animals) and mechanistic data. The National Academies of Sciences, Engineering, and Medicine (NASEM) issued a consensus report, recommending medical follow up when clinical blood-levels were at, or above, two parts-per-billion (2 ppb). And they recommended intensive biomedical monitoring at 20 ppb for the sum of only seven of the more than 14 thousand (>14,000) PFAS synthetic chemicals.
All PFAS are environmentally persistent and some are biologically persistent and bioaccumulative. Hope this helps.
COMMENT: Based on my many years in drug discovery and development prior to retirement, and as a chemist — I agree completely with Fred.
I completely agree with Fred. There may be some legitimate concerns over PFAS, but there is also a whole lot of hype that lacks any scientific credibility, mostly around so-called ‘non-monotonic dose-response curves,’ and endocrine disruption. As with most things, we often see elements of legitimate science — interspersed with lots of hysteria based on unsupported hypotheses.
The article below states “PFAS are also toxic at extremely low levels (i.e., parts per quadrillion), posing significant risks to our health.” One part per quadrillion = picomolar concentrations.
I have not worked on PFAS myself, but I think they are rather inert (due to the C-F bonds). That is why they stick around forever. A good example is Teflon, etc. I don’t think they are generally activated to reactive intermediates, nor are they potent ligands for any receptors. Therefore, pM (10-to-the-minus-12 molar) toxicity is pretty uncommon in Toxicology.
I understand that flouride atoms are present in about 40% of new drugs and, because of the strong carbon-fluoride bond, these new drugs are usually not a problem, with a couple of exceptions… Fred
This report summarizes a promising approach to bioremediation of per- and polyfluoroalkyl substances (PFAS) — which comprise a group of “forever chemicals” which are almost impossible to break down in our environment. 😊
woman doing science
Modified Iron Particles Could Improve Bioremediation of PFAS
A class of manmade chemicals known as PFAS — which stands for per- and polyfluoroalkyl substances — is part of what makes these consumer goods water-, stain-, and grease-resistant. PFAS are also toxic at extremely low levels (i.e., parts per quadrillion), posing significant risks to our health. If you’re wondering why they’re called “forever chemicals,” it’s because they are nearly indestructible.
Iron particles coated in a nontoxic material may enhance PFAS degradation by a certain bacterium, according to researchers funded by the NIEHS Superfund Research Program. The study could help in bioremediation efforts that harness the microbe, known as Acidimicrobium Strain A6, for cleaning up contaminated soil, sediments, and aquifers.
Distinctive PFAS properties, such as high heat tolerance and oil resistance, stem from exceptionally stable bonds between carbon and fluorine atoms. Because PFAS resist breakdown, they can accumulate in exposed organisms and ecosystems — posing as a risk to human and environmental health.
Some PFAS, such as perfluorooctanoic acid (PFOA) — implicated in immune and kidney problems, among other disorders — are particularly recalcitrant to degradation. However, prior research by Princeton University’s Peter Jaffé, Ph.D., and colleagues found that Acidimicrobium Strain A6 (or A6 for short), can break down PFOA in contaminated wastewater.
This microorganism thrives in iron-rich, acidic environments, using inorganic material as an energy source. For the present study, Jaffé’s team sought to improve PFOA breakdown by stimulating A6 activity with iron.
Priming the Process
In nature, A6 generates energy by converting the nitrogen-based compound ammonium into nitrite. During the reaction, known as Feammox, electrons are released.
Most of those electrons are transferred to iron, such as a form called ferrihydrite. In PFOA’s presence, electrons can also latch on to fluorine atoms, effectively breaking their strong bonds with carbon.
Split image showing soil colloids in ground water attached to plain ferrihydrite and PAA-coated ferrihydrite not adhering to soil colloids.
Left: Colloids, or mixtures, of negatively charged soil or sediment can trap positively charged ferrihydrite particles. Right: Ferrihydrite coated with polyacrylic acid can move easily through soil. These modified iron particles appear to stimulate A6 conversion of ammonium (NH4+) to nitrite (NO2-). Electrons generated in the process can strip fluorine from surrounding PFAS. (Image courtesy of Park et al, 2023)
Adding ferrihydrite to wastewater can stimulate bacterial breakdown of PFOA, according to laboratory studies by the team. But polluted field sites present a hurdle: negatively-charged sediment can trap the iron particles — preventing their distribution and hindering Feammox reactions from occurring.
In earlier work, the researchers found that ferrihydrite particles coated with polyacrylic acid — a biodegradable synthetic chemical — can move better through sediment samples. Based on that finding, they wondered: Could these coated iron particles promote A6 breakdown of PFOA?
To investigate, the team mixed ferrihydrite with polyacrylic acid of four different molecular weights, ranging from 2,100 to 450,000 grams per mole. The samples also contained an ammonium-based medium to encourage A6 growth. In a related experiment, they added PFOA to the mixtures.
After the samples were incubated for several weeks under acidic conditions, the researchers analyzed their contents. Samples containing coated iron showed higher total bacteria populations compared to a control with bare ferrihydrite, suggesting that polyacrylic acid may stimulate bacterial growth, according to the authors. In addition, DNA sequencing indicated that A6 was the dominant group across all samples.
The team also found significantly less ammonium in the mixtures with coated iron compared to the control. Using a powerful imaging technique, they observed that electrons were more easily transferred to coated iron than to bare iron. Their findings suggested that the coated iron facilitated Feammox reactions.
Lowering PFOA Levels
Three sets of bar charts measuring PFOA concentrations measuring controls, 2,100, 6,000, 240,000, and 450,000 per mole across 0, 30, and 40 days.
Over a 40-day period, PFOA (measured in micromoles, or mM) significantly declined in samples containing ferrihydrite coated with polyacrylic acid of 6,000 grams per mole and 450,000 grams per mole, compared to other treated samples and a control containing bare ferrihydrite. (Image courtesy of Park et al, 2023)
In two of the samples containing coated iron, the team found significant declines in PFOA concentrations, as well as significantly more free-floating fluoride — signs that PFOA was decomposing.
The team was curious whether declining PFOA levels meant that the chemical had entirely degraded or simply had broken up into smaller PFAS molecules. They found only minor levels of PFAS intermediates appearing sporadically, suggesting that in most cases, PFOA was fully breaking down.
Together, the results demonstrated that polyacrylic-coated ferrihydrite boosted A6 growth and PFOA degradation, according to the authors. However, more research is needed to thoroughly explain the underlying mechanisms, they added. Further research should also explore how to optimize coated iron for use in more complex bioremediation settings, where different water chemistries and microbial communities may affect success.