Women with relatively greater exposure to common disinfection byproducts in drinking water — even at levels below federal limits — may be at an increased risk for uterine cancer, a large prospective study suggests.

Among over 53,000 California women followed for two decades, those exposed to the highest levels of disinfection byproducts called trihalomethanes (THMs) had an 18% higher risk for uterine cancer vs women with the lowest exposure levels. They also had a 23% higher risk for endometrioid tumors, specifically.

The researchers were quick to point out that the findings, published in JAMA Network Open, do not prove causation.

Instead, they represent a “credible but still preliminary association,” study author Rena R. Jones, PhD, of the National Cancer Institute, Rockville, Maryland, told Medscape Medical News.

She also noted that an 18%-23% relative increase in risk may not be significant to individuals — though it could be important at the population level because exposure to drinking water disinfection byproducts is widespread.

For now, the findings are not enough to spur changes in drinking-water regulations or personal habits, according to Jones.

“The findings do not warrant advising women to avoid disinfected tap water altogether, given the important role of water disinfection in preventing infectious disease,” she said.

The Search for Environmental Culprits

Uterine cancer is the most common gynecologic malignancy in the US. Endometrial cancer accounts for more than 95% of uterine cancers, and both incidence and mortality rates have increased in recent years. Geographic variation in incidence and continuing increases in cases suggest that environmental exposures may be playing a role.

Drinking water has gained interest, in part because 90% of the US population receives drinking water from community water systems. Chlorine and other disinfectants are essential for controlling waterborne infections, but they can react with naturally occurring organic material to form disinfection byproducts, including THMs and haloacetic acids (HAAs).

There’s evidence that certain THMs and HAAs may interact with estrogen receptors or disrupt hormone signaling, while others may promote oxidative stress, cellular injury, or DNA damage.

And a 2022 study offered the first signal that exposure to those chemicals is linked to endometrial cancer. Those findings, from the Iowa Women’s Health Study, showed that postmenopausal women with greater exposure to THMs and HAAs had an elevated risk of developing endometrial cancer over two decades.

Building on that work, the new analysis included 53,100 women in the California Teachers Study, a prospective cohort of public-school teachers and administrators. At enrollment in 1995-1996, the women (median age, 50 years) were cancer-free, had not undergone hysterectomy, had lived at their current address for at least 10 years, and had an address linked to a community water system.

Participants were followed for a mean of 19 years, during which 1038 uterine cancers were diagnosed.

The researchers linked participants’ residential addresses to state monitoring data for community water systems. They calculated 15-year mean concentrations, from 1990 through 2005, of total and individual THMs, nitrate, arsenic, and uranium. Because historical HAA data were more limited, HAA exposure was assessed using mean concentrations through 2013, with cancer follow-up for those analyses beginning in 2010.

A Link That’s Now ‘Harder to Dismiss’

In multivariable analyses, women in the highest tertile of total THM exposure, beginning at approximately 16 μg/L, had an 18% higher risk for uterine cancer than those in the lowest tertile (hazard ratio [HR], 1.18; P for trend =.06). The association was somewhat stronger for endometrioid tumors (HR, 1.23; P for trend =.01), with no association observed for nonendometrioid tumors.

Among the individual THMs, chloroform produced the clearest signal. Women in the highest exposure tertile had an 18% higher risk for uterine cancer overall and a 27% higher risk for endometrioid tumors than those in the lowest tertile.

As for HAA exposure, women in the highest tertile of total exposure had an 86% higher risk for nonendometrioid tumors than those in the lowest tertile (HR, 1.86) — but that finding was based on fewer cancer cases and limited historical exposure data.

Finally, in an analysis of contaminant mixtures, each IQR increase in combined exposure to individual THMs, nitrate, arsenic, and uranium was associated with a 34% higher risk for endometrioid tumors. Chloroform and dibromochloromethane were the principal contributors.

Associations generally persisted in sensitivity analyses, including analyses restricted to women whose average contaminant concentrations were below current federal maximum contaminant levels. Nor did the results differ significantly according to menopausal status, smoking, hormone therapy use, or most BMI categories.

The findings, together with those from the Iowa cohort, make the association between drinking water disinfection byproducts and uterine cancer “substantially harder to dismiss,” according to an accompanying editorial.

Important Caveats

Opinions varied on the implications of the study. Susan Richardson, PhD, professor of chemistry at the University of South Carolina in Columbia, said the findings add to concerns about disinfection byproducts and support action.

“This is a very important study because millions of people in the US, and billions worldwide, are exposed to disinfection byproducts every day in their drinking water,” Richardson, who was not involved in the research, told Medscape Medical News.

“We need to strive to minimize [disinfection byproducts] in our drinking water,” she said.

Jones had a more cautious take. She said her team’s findings provide “some evidence that current standards may not be sufficiently protective.”

But she stressed that this study alone cannot establish a new regulatory threshold — which requires replication across populations, mechanistic support, and consideration of geographic differences in contaminant levels and mixtures.

That point was echoed by Lauren McCullough, PhD, MSPH, associate professor of epidemiology at Emory University Rollins School of Public Health in Atlanta.

“Regulatory decisions should be based on the totality of evidence across multiple studies, exposure settings, populations, and study designs,” McCullough, who was not involved in the new research, told Medscape Medical News.

She also pointed to some key limitations of the study, including a lack of information on women’s personal water-drinking habits or use of filtration.

In addition, McCullough said, people are rarely exposed to a single chemical in isolation. “Drinking water contaminants often co-occur with other environmental and social exposures, making it difficult to disentangle the effects of any one compound,” she noted.

In her view, the findings should not change how clinicians counsel individual patients.

“The absolute risk of endometrial cancer remains relatively low, and most established risk factors — such as obesity, reproductive characteristics, and hormone exposure — continue to have much stronger evidence supporting their role,” McCullough said.

Still, from a research standpoint, this study broadens the discussion to include other environmental exposures that may influence risk over the life course.

“This paper provides one critical piece of evidence and highlights an area where additional research is needed,” McCullough said.

For anyone concerned about their drinking water exposures, Jones said that using a filter specifically certified to reduce total THMs or volatile organic compounds may be a reasonable, low-risk precaution. She noted, though, that a drinking-water filter would not address exposure during bathing, where disinfection byproducts can potentially be inhaled or absorbed via skin contact.

The study was supported by the National Institutes of Health. Jones, Richardson, and McCullough reported having no relevant disclosures.