Bisphenol A (BPA) is a kind of environmental phenols utilized in baby bottles, food containers, and dentistry (1). The exposure of humans to BPA is pervasive, originating from various sources such as consumer products, food, water, and dust (2). National biological monitoring data in the United States reveals that BPA is detectable in more than 90% of urine samples in the general population (3). Currently, 12 states have enforced regulations to restrict the use of BPA in the United States. While BPA is known to undergo rapid metabolism and is primarily eliminated through urine, its cumulative exposure in everyday items could lead to concerns regarding potential long-term health consequences (4). The potential pathways underlying BPA-induced adverse health outcomes include endocrine disruption (5), oxidative stress (6) and inflammation (7).

Exposure to bisphenol A starts very early in life, causing adverse health outcomes not only in children but also later in life (8, 9). The BPA exposure has been linked to disruptions in endocrine function and metabolism (10), which can contribute to the development of metabolic disorders (11). Some studies showed that BPA exacerbated inflammation by regulating gut physiology (12) and was involved in the development of type 2 diabetes mellitus (13), obesity (14), hypertension (15) and cardiovascular disease (16). Despite mounting evidence indicating potential toxic effects of BPA on various human cancers (17, 18), the relationship between BPA exposure and mortality remains unclear.

A study reported that BPA exposure was positively related to all-cause mortality in adults. However, nonsignificant association between BPA exposure and cancer mortality was found (19). Even so, the previous study had a lower number of sample and lacked a nonlinear analysis. Therefore, we conducted a study utilizing a comprehensive database to examine the correlation between urinary BPA levels and mortality rates related to all causes and cancer.

The study included a sizable cohort of 8,035 individuals, predominantly middle-aged, with a slight majority being male. According to Table 1, 137 cases of cancer mortality were documented over a 7.5-year follow-up period. The measurement of urinary bisphenol A (BPA) levels revealed a median concentration of 2.0 ng/mL. Notably, individuals who succumbed to cancer during the follow-up period tended to be older (p = 0.001), male (p = 0.035), and had higher incidences of diabetes (p = 0.001) and cardiovascular disease (p < 0.001). These observations underline the importance of considering demographic and health-related factors when assessing mortality risk.

Kaplan–Meier analysis indicated significant associations between urinary BPA levels and both all-cause mortality and cancer mortality. The analysis suggests that lower urinary BPA levels are associated with an increased risk of all-cause mortality (log-rank p = 0.01) and cancer mortality (log-rank p = 0.007) (Figure 1). However, compared with the lowest quartile of BPA, no association of all-cause mortality was observed in any quartiles across models, which suggested that BPA was not independently associated with all-cause mortality (Table 2).

On the contrary with expectations, the risk of cancer mortality was reduced with the increase of BPA levels both in the unadjusted model and adjusted models (Table 3). Most importantly, the second quartile’s multivariable-adjusted hazards ratio (HR) was 0.51 (95% CI: 0.30 to 0.86; p = 0.011) compared to the lowest quartile of BPA. However, these associations were not consistent across all quartiles of BPA levels, indicating a more nonlinear relationship. In order to confirm the nonlinear relationship, we used restricted cubic splines (Figure 2). We found that urinary BPA was U-shaped associated with cancer mortality (p for nonlinearity = 0.028). This suggests that the relationship is not purely linear, but rather exhibits a threshold effect. Specifically, lower levels of BPA (below approximately 1.99 ng/mL) were associated with an increased risk of cancer mortality. Beyond this threshold, higher BPA levels appeared to confer protection against cancer mortality. This nonlinear relationship highlights the complexity of BPA’s impact on health outcomes and underscores the need for careful consideration of dose–response relationships. Future research should focus on elucidating the mechanisms underlying these observed associations and conducting longitudinal studies to validate these findings across diverse populations and settings.

In this study, we found that urinary BPA was U-shaped associated with the risk of cancer mortality and a lower level less than 1.99 ng/mL increasing the risk of cancer mortality. This study provides valuable insights into the complex relationship between urinary BPA levels and cancer mortality, emphasizing the need for a nuanced understanding of dose–response dynamics and the consideration of confounding factors in epidemiological research.

BPA is a widely used raw material and is involved in the initiation and development of hormone-dependent cancers. A comparable study discovered that higher exposure to BPA was independently related with an elevated risk of all-cause mortality but with no significant association with cancer mortality (19). They divided BPA into tertiles and did not explore the nonlinear relationship. A recent study showed that the highest tertile of urinary BPA levels corresponded to a 36% increase in all-cause mortality and a 62% increase in CVD mortality compared to the lowest tertile (21). Different from previous study, we demonstrated a U-shaped association between BPA exposure and cancer mortality using dose–response analysis and adjusting for more variables. A study also found that BPA was not significantly associated with all-cause mortality in overall population, but in the obesity, diabetes, and hypertension subgroups (22). Variations in the characteristics of the study populations, especially comorbidity, may account for the discrepancy.

BPA is an endocrine disruptor with multiple effects. BPA exhibits estrogenic properties by binding to estrogen receptors and interfering with the regular functioning of the endocrine system (23). Additionally, BPA has the potential to influence biological processes, including cell signaling, gene expression, and apoptosis, which can contribute to a range of health issues affecting the reproductive, immune, metabolic, and nervous systems (24, 25). Several studies found a U-shaped association between BPA levels and the risk of diabetes (26) and obesity (27). A higher level of BPA impacted the production of ROS (6), cancer metabolites (28), and tumoral immune microenvironment (29), contributing to the migration and invasion of cancer cells. Conversely, a lower level may be the reflection of an imbalance of endocrine-related pathways. BPA could inhibit DNA replication and cell proliferation in tumor cells (30) by modulating cell cycle-and apoptosis-related proteins and genes in cancerous cells (31). Therefore, a lower and higher level of BPA both influenced the cancer mortality. More studies are warranted to explain the dose-repose relationship.

There may be various underlying mechanisms driving the positive correlation between BPA and all-cause mortality (Figure 3). Firstly, BPA caused endocrine disruption through agonistic or antagonistic behavior at various nuclear receptors such as estrogen (ER), androgen (AR) and glucocorticoid (GR) (32). Besides, BPA exposure resulted in a strong induction of oxidative stress and inflammatory response (33, 34). However, more research is necessary to elucidate the biological mechanisms underlying this association.

This study boasts several notable strengths, including its use of a nationally representative cohort from the United States and rigorous quality control measures. Nonetheless, this study does come with certain constraints. To begin with, BPA levels were assessed solely through spot urine samples at the baseline, offering no insight into long-term BPA exposure or fluctuations in BPA concentrations within the body. Lastly, it’s important to note that the generalizability of this study could be limited due to the exclusion of participants with incomplete covariate data, potentially introducing selection bias. BPA exposure is more related to hormone-associated cancers such as breast, prostate and ovarian cancers. However, the number of specific cancer type was few in the original database, which need to be verified by further large-scale cancer epidemiological investigations.

In conclusion, we found BPA exposure was U-shaped associated with the risk of cancer mortality, and a lower level of BPA less than 1.99 ng/mL was associated with a higher risk of cancer mortality. Our results can serve as valuable information for guiding policies related to enhanced monitoring of chemical exposures and risk assessment in cancer prevention field.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving humans were approved by National Center of Health Statistics. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

YY: Writing – original draft. QC: Data curation, Writing – original draft. XD: Supervision, Writing – original draft. QZ: Project administration, Writing – review & editing. XZ: Project administration, Writing – review & editing.