Looking Beyond Individual Chemicals: Why PFAS Risk Assessment Is Evolving

Growing evidence suggests that the greatest risks associated with PFAS may not simply depend on how much exposure occurs, but also when it occurs and which combinations of chemicals are involved. In a recent study published in Clinical Gastroenterology and Hepatology, researchers from the Icahn School of Medicine at Mount Sinai found that prenatal and early-life exposure to PFAS mixtures was associated with biomarkers of intestinal inflammation years later in childhood.

While the study does not establish that PFAS cause inflammatory bowel disease, it adds to a growing body of research suggesting that fetal development and early childhood represent uniquely vulnerable periods of exposure. It also reflects a broader shift in environmental health research toward evaluating PFAS as mixtures rather than as individual chemicals.

3E News spoke with two of the study authors to discuss why studying PFAS mixtures, developmental exposure, and long-term health outcomes may reshape how scientists - and eventually regulators - approach chemical risk assessment. While interviewing Dr. Manasi Agrawal, lead author and assistant professor of medicine (gastroenterology) and environmental medicine and public health, and Dr. Vishal Midya, assistant professor of environmental medicine and public health, for a recent series of articles about PFAS, it became clear that many of the insights shared by Agrawal and Midya extended well beyond the scope of a few quotes.

Rather than condense a wide-ranging discussion into a handful of excerpts, we are publishing this edited Q&A to allow readers to hear directly from the researchers - in their own words - about the science behind their study and what it may mean for the future of PFAS risk assessment.

The following interview has been edited for length and clarity.

Most PFAS studies examine individual chemicals. Why did your team choose to study PFAS as mixtures instead, and should risk assessment move in that direction?

Dr. Vishal Midya: We are simultaneously exposed to multiple chemicals, multiple PFAS. Studying each of them obviously is important. However, once we are looking at the synergistic effect of many of these chemicals simultaneously, we get a bigger picture because practically, we are exposed to all the chemicals all the time.

Studying them individually is easier to do and easier to understand, but how relevant is that when we’re really exposed to them simultaneously as a mixture? That’s what we wanted to address in this paper. We wanted to consider the mixture because of its practical relevance.

In terms of risk assessment, right now most assessments are done on an individual chemical basis. I think there should be movement toward a mixture-based approach where regulators look at PFAS simultaneously. It’s not going to be an easy process, but I think regulation should move in that direction because that’s what happens in the real world.

We’re talking about PFAS here, but the same principle applies to microplastics and many endocrine-disrupting chemicals. They should be considered using a mixture-based approach instead of only looking at individual chemicals.

Dr. Manasi Agrawal: I completely agree with what Vishal said. We want to understand human health outcomes, so we have to think about what an individual is exposed to in totality and the synergistic effects of all of these chemicals together.

The other aspect is that these chemicals are often correlated. A product doesn’t contain just one chemical; it contains other chemicals as well. Microplastics co-occur with specific PFAS, phthalates, and other compounds. That correlation makes it even more relevant to study them together.

At the same time, understanding the specific effects of individual PFAS - or specific subclasses - is also important. That’s more difficult because we’re dealing with thousands of different chemicals, but I think studying PFAS both ways is important. Looking at PFAS as a class provides valuable information, while understanding the roles of specific subclasses based on their side chains and individual chemistry is equally informative. These approaches complement one another.

Your study found that prenatal and early-life PFAS exposure was associated with biomarkers of intestinal inflammation years later. What does that tell us about critical windows of vulnerability during development?

Agrawal: I think that’s the key question: this window of susceptibility.

Increasingly, we’re recognizing that early life, which starts during pregnancy and extends through the first few years after birth, is a period of very high vulnerability to environmental exposures. These exposures can influence downstream events and inform later health and disease.

This concept is known as the Developmental Origins of Health and Disease (DOHaD) theory, and across many different health outcomes we’re increasingly recognizing the relevance of this early-life period. That’s what spurred this research. Vishal, many of our colleagues, and I wanted to understand whether PFAS are particularly relevant during early life.

We measured PFAS levels in maternal plasma during pregnancy, cord blood - which represents both maternal and fetal circulation - and newborn blood spots, which represent neonatal exposure. Years later, we found evidence of intestinal inflammation based on elevated levels of fecal calprotectin in stool samples from these children.

These findings tell us two things. First, mothers and babies are exposed to these chemicals during a very susceptible period, and those chemicals are biologically internalized. Second, it appears that these early-life exposures are associated with intestinal inflammation much later in childhood: up to four, five, six years of age, and in one cohort between nine and ten years of age.

That fits with the DOHaD theory: early-life exposures may influence later health outcomes. I think this is one of the few studies demonstrating both that PFAS are relevant during this critical developmental window and that those exposures are associated with intestinal inflammation years later.

Should emerging evidence about prenatal and early-life PFAS exposure lead regulators to place greater emphasis on these vulnerable life stages when developing health-based standards?

Agrawal: Absolutely. I think it’s very important to have research across the spectrum - not just across sexes, but also across age groups and the entire lifespan - because we’re exposed to these chemicals from birth until the end of life, and different periods of life are susceptible to different degrees.

Early life is a particularly vulnerable period for all kinds of environmental exposures. Studies during this period are especially challenging because they require collecting biological samples during pregnancy, monitoring women throughout pregnancy, following mother-baby pairs over time, and then waiting years [or] sometimes decades for health outcomes to emerge.

These cohorts are particularly precious because they allow us to understand exposures during periods of vulnerability. You make a really good point that we need to study these exposures across the spectrum and pay particular attention to these highly susceptible periods of development.

Your study identified biological changes rather than clinical disease. How should regulators and public health officials interpret biomarkers like these when evaluating chemical risk?

Agrawal: That’s also a key question, and it’s something we highlight in our study.

Because this is a birth cohort, the children have been followed for what is, from a research perspective, a long period of time, but not long enough for diseases such as inflammatory bowel disease to develop. What we measured was a biomarker outcome. We found elevated levels of fecal calprotectin in stool samples from children with higher PFAS exposure, which is indicative of subclinical intestinal inflammation.

Whether that means these children will eventually develop inflammatory bowel disease, we don’t know. Other studies have shown that higher calprotectin levels are associated with an increased risk of inflammatory bowel disease later in life, but that does not mean these children will develop the disease.

We have to be cautious in interpreting these findings. This study represents an important piece of evidence showing what may be happening biologically with greater PFAS exposure, but the clinical significance still needs to be understood through longer-term follow-up and studies in additional cohorts.

Monitoring these children for decades is challenging, but it’s necessary. This is one piece of the puzzle, and we have to be careful not to overinterpret its clinical implications until we have more evidence.

What additional research is needed before findings like these can be translated into clinical practice or influence future chemical risk assessments?

Midya: One of the directions we’d like to move toward is bringing this type of research into a clinical setting.

Imagine going to your physician for routine blood work. We already measure things like cholesterol, metabolic panels, or hemoglobin A1C. At some point, it may be possible to include PFAS measurements as well.

I’m not saying PFAS levels would tell us that someone is definitely going to develop a disease. It’s more like what hemoglobin A1C does for diabetes. A higher A1C doesn’t mean you’ll develop Type 2 diabetes, but it helps stratify risk.

Perhaps PFAS measurements could eventually serve a similar purpose by identifying people who may have a greater likelihood of inflammation or other adverse outcomes. We’re still far from that point, but that’s one direction we’re thinking about. Instead of simply telling someone they have PFAS exposure, the goal would be to determine whether there are meaningful ways to help reduce their future health risks.

Looking ahead 10 or 20 years, how do you think PFAS research - and the way scientists assess health risks - will evolve?

Agrawal: I think it will be exactly what you described. Environmental medicine will become much more integrated into clinical medicine.

I envision developing environmental risk scores that estimate an individual’s cumulative exposure to environmental chemicals and use that information to assess the likelihood of future health outcomes. Based on those risk scores, physicians could counsel patients about reducing future exposures.

I also anticipate that interventions will become available to help reverse some of the effects of these chemicals. There’s already research exploring ways to lower systemic PFAS levels through medications or other interventions. If someone has very high PFAS levels, they may eventually become a candidate for treatments designed to reduce those levels.

In inflammatory bowel disease, we’re already moving toward prevention. Similar to what’s happening in diseases like Type 1 diabetes and rheumatoid arthritis, researchers are beginning to identify individuals at high risk and intervene before disease develops or delay its onset.

I think we’ll eventually see a similar concept applied here: precision prevention based on environmental risk scores. As we better understand the relationship between chemical exposures and health outcomes, we’ll be better positioned to identify individuals at higher risk and intervene before disease occurs.

This is Part 4 of a four-part series. Read the other articles in the series: The Next Frontier in PFAS Regulation: Measuring What Matters (Part 1), PFAS: Detection Is Becoming the New Bottleneck (Part 2), and PFAS: Thinking Beyond the Dose (Part 3).