Next-generation PFAS substitute shows low toxicity risk in long-term study

A new study has found that a substance used to replace per- and polyfluoroalkyl substances (PFAS) — the so-called "forever chemicals" that resist natural decomposition for hundreds of years — poses a low risk of serious toxic effects on the human body.

A research team led by Dr. Lee Byeong-seok and Dr. Han Ji-seok of the Biodiagnostics Research Center at the National Institute of Toxicological Research (KIT) conducted a 26-week repeated-dose toxicity study on perfluoroheptanoic acid (PFHpA), one of the alternative PFAS compounds. The team announced Monday that while some clinical and histopathological changes were observed in rat test subjects, no serious toxicological effects posing a significant risk to human health were identified.

PFHpA is a short-chain PFAS compound whose use has grown as a replacement for conventional long-chain PFAS. However, most previous studies were limited to short-term exposures of a few weeks, leaving gaps in the assessment of safety under long-term repeated exposure.

Following OECD test guidelines and Good Laboratory Practice (GLP) standards, the research team orally administered PFHpA to male and female rats over 26 weeks and comprehensively analyzed body weight, blood tests, neurobehavioral responses, organ weight, clinical pathology, histopathology and thyroid hormone levels.

The results showed hepatocyte hypertrophy, changes in thyroid follicular cells, decreased thyroid hormone levels and localized irritation of the gastric mucosa in the high-dose group. However, no toxicologically significant abnormalities were observed, including weight loss, death, marked neurobehavioral impairment or serious organ damage.

"Overall systemic toxicity was limited in the animal study, and the risk of serious toxicological concern for human health appears to be low," said Dr. Han. "However, these results should not be interpreted as directly indicating a risk — or lack thereof — to humans."

The study also found that blood concentrations of PFHpA were higher in male rats than in females, and that some tissue changes were more pronounced in males, underscoring the need to account for sex-based differences in toxicity assessments of the compound.

The research is significant for systematically generating long-term toxicity data on PFHpA through 26 weeks of repeated exposure. The key changes observed were interpreted as species-specific responses in rodents, suggesting that species differences between humans and rodents must be considered in risk assessments. The differing exposure characteristics and toxic responses between male and female subjects also confirmed the importance of incorporating sex differences into toxicity evaluations. The team plans to conduct follow-up studies that factor in actual human exposure levels, as well as reproductive toxicity and various exposure routes including inhalation and dermal contact.

"The use of alternative substances is growing as PFAS regulations tighten, but long-term safety data remain scarce," said Dr. Lee. "We hope this research will serve as a scientific basis for risk assessment and the development of regulatory policy."

The findings were published in Environment International, an international journal in the field of environmental toxicology.