Please note: Dr. Simon used the health advisory levels (0.004 ppt for PFOSA and 0.020 ppt for PFOS) that were proposed in a draft released by EPA in July of 2022. EPA’s March, 2023 announcement of their proposed enforceable drinking water standards for PFAS contain MCL’s (Maximum Containment Levels) of 4 ppt for both PFOA and PFOS, which are the lowest levels that can be detected by most laboratories. The MCGL’s (which are goals and not enforceable) however, remain the same at 0, and indicate that this is the direction the EPA would like to see in cleaning up drinking water.

EPA just published an enforceable drinking water standard, known as a maximum contaminant level (MCL), of 0.004 ppt (yes, parts per trillion) and 0.02 ppt for PFOA and PFOS, respectively. 

After working at EPA for 13 years, and later, as a private citizen, serving on the Chemical Assessment Advisory Committee of EPA’s Science Advisory Board, I have a number of concerns with this decision.

To begin, no existing technology can measure such low concentrations. These vanishingly tiny concentrations also differ dramatically from the limits imposed by other governments. Susan Goldhaber, MPH, expanded on this point in a blog for the American Council for Science and Health regarding the stringency of EPA’s toxicity estimates of these two PFAS types, and how they differ from those used by other nations.1 As she points out: 

“Most countries and agencies have used other health endpoints to calculate safe levels for PFOA/PFOS. The EPA’s Health Advisory numbers are significantly lower than most—more than 100,000-fold differences between the safe levels from different countries. This is unprecedented; typically, there are only minor disagreements between countries on safe levels.”

She also highlights the questionable disparity between EPA’s limits for PFOA and PFOS, and the far more lenient limits set for known toxic substances such as cyanide:

“For comparison purposes, the MCL for cyanide, which everybody recognizes is an extremely toxic chemical, is 0.2 parts per million (ppm) – equivalent to 200,000 ppt. Since the MCLs are based on health, this translates to PFOA/PFOS being 50,000 times more toxic than cyanide, which should strike any scientist as somewhat absurd.”    

Perhaps most importantly, there are significant evidence gaps regarding the human health effects of PFOA and PFOS. The results of human studies have been inconsistent, and therefore a critical effect for people drinking water with PFOA and PFOS has yet to be established.

These gaps in evidence were highlighted in the findings of an independent critical review published in Environmental Research, which found that most PFAS studies have insufficient evidence to associate PFAS with any specific disease. The review was performed by the Center of Environmental Food and Toxicological Technology at the University of Rovira i Virgili in Spain, and was funded by the Center.

Many of the studies on PFOA and PFOS have involved high-dose animal studies, which cannot be translated to human health outcomes. Animals may react very differently from humans when it comes to chemical exposure, and many effects of PFAS compounds observed in animals do not occur in humans.

Thus, we cannot use the critical effect from animal data when making policies governing human exposure to PFAS compounds. For those interested in understanding exactly why, we can take a look at human biology and evolution. 

How PFAS moves through the human body

Two aspects of human biology greatly affect the kinetics and human half-lives of all PFAS compounds: plasma protein binding and renal reabsorption. 

PFAS are tightly bound to plasma proteins.2–4 Plasma proteins are not filtered by the kidney, and any bound substances will not be excreted. Unbound substances will pass through the glomerulus and into the kidney tubules. 

From there, PFAS compounds tend to be reabsorbed back into the blood. The reabsorption of PFAS compounds by the proximal tubular cells in the kidney is much more efficient in humans than in other primates or rodents.5, 6 

The persistence of PFAS in humans, compared to animals, is due to two specific evolutionary events related to uric acid handling by the kidneys.5, 7–9

PFAS persists in humans, thanks to two mutations

In many animals, but not in humans, ascorbate is the primary free radical scavenger in blood. 

About 45 million years ago, our pre-human ancestors lost the ability to synthesize ascorbic acid due to a mutation. Around that same time, another mutation in early humans resulted in the loss of the uricase gene that coded for the enzyme that metabolizes uric acid.10, 11

As a result of these two mutations, uric acid replaced ascorbate as our internal scavenger of free radicals. Our early hominid ancestors likely adapted to this change with sharply decreased production and renal excretion of uric acid. The resulting sensitivity to uric acid in humans has many consequences today, including gout, obesity, hypertension, and metabolic syndrome.12–19

The antioxidant activity of uric acid in the brain could be another mechanism for the evolution of human intelligence. Also, the chemical similarity between uric acid and the brain stimulants caffeine and theobromine suggests the possibility that the adoption of uric acid as the free radical scavenger contributed to the growth of the intellectual capacity of early man. 

The much longer lifespan humans enjoy in comparison to other primates may also be a result of this new role for uric acid. Indirect support of the hypothesized role of uric acid in the evolution of intelligence is provided by observed associations between higher levels of uric acid and intelligence in children and young adults. Hence, these two mutations may account for the characteristics that are uniquely human.20–24

The irony of PFAS and human evolution 

PFAS compounds were first shown to be commercially useful years before the physiologic role of uric acid emerged. Conventional wisdom suggests that toxic chemicals are highly reactive—think cyanide or the genotoxins used to damage DNA in initiation-promotion studies. PFOA and PFOS, however, possess very low reactivity, and are sufficiently inert to ensure their ubiquity and persistence in the natural environment and in humans. 

Ironically, the evolutionary changes made in humans to scavenge and dispose of highly reactive free radicals—the ones that largely account for what we call “human nature”—have resulted in the increased persistence of PFAS in our bodies! 

Animal studies aren’t enough—EPA needs stronger evidence

PFAS is no doubt ubiquitous in our modern world, but as Susan Goldhaber, MPH, points out in her blog post, the question of PFOS and PFOA toxicity in humans remains unanswered. “There is no clear evidence that PFOA/PFOS causes cancer,” she writes. 

Human studies have failed to show a causal relationship between PFOA and PFOS and adverse health outcomes in people in any kind of clear and consistent way, so EPA used animal studies to inform their health advisories instead.

Without a doubt, EPA has planted its flag in the ground on the issue of PFAS in drinking water. But whether or not its maximum contaminant levels are rooted in strong science is a different animal entirely.

by Ted W. Simon, Ph.D., D.A.B.T. 

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