Pervasive 'Forever Chemical' Linked to
Liver Cancer

Laird Harrison

August 22, 2022

People exposed to high levels of perfluorooctane sulfonic acid (PFOS) — a widely used synthetic chemical — run an increased risk of hepatocellular carcinoma, researchers say.

The correlation does not prove that PFOS causes this cancer, and more research is needed, but in the meantime people should limit their exposure to it and others in its class, said Jesse Goodrich, PhD, a post-doctoral scholar in environmental medicine at the University of Southern California in Los Angeles.

"If you're at risk for liver cancer because you have other risk factors, then these chemicals have the potential to kind of send you over the edge," he told Medscape Medical News.

Goodrich and colleagues published their research online this month in JHEP Reports.

Dubbed "forever chemicals" because they can take thousands of years to break down, polyfluoroalkyl substances (PFAS) figure in makeup, food packaging, waterproof clothing, nonstick cookware, firefighting foams, and groundwater. They have spread through the atmosphere into rain and can be found in the blood of most Americans. PFOS is one of the most widely used PFAS.

"You can't really escape them," Goodrich said.

Previous research has linked PFAS to infertility, pregnancy complications, learning and behavior problems in children, immune system issues, and higher cholesterol, as well as other cancers. Some experiments in animals suggested PFAS could cause liver cancer, and others showed a correlation between PFAS serum levels and biomarkers associated with liver cancer. But many of these health effects take a long time to develop.

"It wasn't until we started to get really highly exposed groups of people that we started as scientists to be able to figure out what was going on," said Goodrich.

High Exposure, Increased Incidence

To measure the relationship between PFAS exposure and the incidence of hepatocellular carcinoma more definitively, Goodrich and colleagues analyzed data from the Multiethnic Cohort Study, a cohort of more than 200,000 people of African, Latin, Native Hawaiian, Japanese, and European ancestry tracked since the early 1990s in California and Hawaii. About 67,000 participants provided blood samples from 2001 to 2007.

From this cohort, the researchers found 50 people who later developed hepatocellular carcinoma. The researchers matched these patients with 50 controls of similar age at blood collection, sex, race, ethnicity, and study area who did not develop the cancer.

They found that people with more than 54.9 μg/L of PFOS in their blood before any diagnosis of hepatocellular carcinoma were almost five times more likely to get the cancer (odds ratio [OR] 4.5; 95% CI, 1.2 - 16.0), which was statistically significant (P = .02).

This level of PFOS corresponds to the 90th percentile found in the US National Health and Nutrition Examination Survey (NHANES).

To get some idea of the mechanism by which PFOS might do its damage, the researchers also looked for linkage to levels of metabolites.

They found an overlap among high PFOS levels, hepatocellular carcinoma, and high levels of glucose, butyric acid (a short chain fatty acid), α-Ketoisovaleric acid (a branched-chain α-keto acid), and 7α-Hydroxy-3-oxo-4-cholestenoate (a bile acid). These metabolites have been associated in previous studies with metabolic disorders and liver disease.

Similarly, the researchers identified an association among the cancer, PFOS, and alterations in amino acid and glycan biosynthesis pathways.

Risk Mitigation

The half-life of PFAS in the human body is about 3-7 years, said Goodrich.

"There's not much you can do once they're in there," he said. "So, the focus needs to be on preventing the exposure in the first place."

People can limit exposure by avoiding water contaminated with PFAS or filtering it out, Goodrich said. He recommended avoiding fish from contaminated waterways and nonstick cookware. The Environmental Protection Agency has more detailed recommendations.

But giving patients individualized recommendations is difficult, said Vincent Chen, MD, MS, a clinical instructor in gastroenterology at the University of Michigan in Ann Arbor, who was not involved in the study. Most clinicians don't know their patients' PFOS levels.

"It's not that easy to get a test," Chen told Medscape Medical News.

People can also mitigate their risk factors for hepatocellular carcinoma, such as a poor diet, a lack of exercise, and smoking, said Goodrich.

The researchers found that patients with hepatocellular carcinoma were more likely to be overweight and have diabetes, and PFOS was associated with higher fasting glucose levels. This raises the possibility that PFOS increases the risk for hepatocellular carcinoma by causing diabetes and obesity.

Goodrich and his colleagues tried to address this question by adjusting for baseline body mass index (BMI) and diabetes diagnosis in their statistical analysis.

After adjusting for BMI, they found that the association between PFOS and hepatocellular carcinoma diminished to a threefold risk (OR, 2.90; 95% CI, 0.78 - 10.00) and was no longer statistically significant (P = .11).

On the other hand, adjusting for diabetes did not change the significance of the relationship between PFOS and the cancer (OR, 5.7; 95% CI, 1.10 - 30.00; P = .04).

The sample size was probably too small to adequately tease out this relationship, Chen said. Still, he said, "I thought it was a very, very important study."

The levels of PFOS found in the blood of Americans has been declining since the 1999-2000 NHANES, Chen pointed out. But that's not as reassuring as it sounds.

"The problem is that if you put a regulation limiting the use of one PFAS, what people can do is just substitute with another PFAS or another molecule, which for all we know could be equally harmful," Chen said.

Funding was provided by the Southern California Environmental Health Science Center supported by the National Institutes of Health. Goodrich and Chen report no relevant financial relationships.

JHEP Reports. Published online. August 8, 2022. Full text

Laird Harrison writes about science, health, and culture. His work has appeared in national magazines, in newspapers, on public radio and on websites. He is at work on a novel about alternate realities in physics. Harrison teaches writing at the Writers Grotto. Visit him at or follow him on Twitter: @LairdH

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