Associations between exposure to brominated flame retardants and gallstones risk in U.S. adults

Gallstones, affecting 6-13.9 % of adults worldwide, have been associated with metabolic disturbances and environmental pollutants. Brominated flame retardants (BFRs), a class of persistent organic pollutants with hepatotoxic potential, have been hypothesized to contribute to gallstone pathogenesis; however, the extant epidemiological evidence remains inconclusive. This study aims to investigate the association between serum BFRs and gallstone risk, exploring nonlinear relationships, mixed exposures, and mediating mechanisms.

From 15,560 participants in NHANES (2017-2020), 2026 individuals were included after applying exclusion criteria. Gallstone status was self-reported, and five serum BFRs with detection rates exceeding 75 % were analyzed. The analysis incorporated a range of covariates, including demographics, socioeconomic factors, and health-related variables. Statistical methods included weighted quantile sum (WQS) regression, quantitative g-computation (QGC), restricted cubic spline (RCS) models, and mediation analysis to assess nonlinearity, cumulative effects, and the role of the neutrophil-to-albumin ratio (NAR).

Among the 2026 participants, 92 % reported alcohol consumption. Restricted cubic spline models revealed positive associations between gallstone risk and four BFRs: bis(1-chloro-2-propyl) phosphate, bis-2-chloroethyl phosphate, dibutyl phosphate, and diphenyl phosphate (P < 0.05). WQS and QGC analyses indicated that mixed BFR exposure was positively associated with gallstones, with dibutyl phosphate contributing most strongly (weight = 0.55). Mediation analysis showed that NAR mediated 18.3 % of the effect of dibutyl phosphate on gallstones (P < 0.001), but did not mediate associations for other BFRs.

Among the evaluated BFRs, dibutyl phosphate was most strongly associated with gallstone prevalence, potentially involving pathways related to neuromodulation and activation. Although these findings do not establish causality, they suggest that BFR exposure may increase the risk of gallstones.