This is the first study demonstrating that patients suffering from ESRD and treated by OL-HDF have a risk of overexposure to both BPA and to ClxBPA provided by intravenous infusion of replacement fluid.
4.3. Dialysate and Replacement Fluid are Sources of Exposure to BPA and ClxBPA
Ultrapure dialysate is obtained after ultrafiltration of purified water, followed by mixing with dialysis concentrates and by a second ultrafiltration. At the beginning of its production, dialysate fluid was five times more contaminated by BPA than incoming dialysis water. These results suggest that BPA could be continuously released by the machine’s internal fluid pass and/or dialysis concentrates and at a higher rate by ultrafilters. These ultrafilters are made of polycarbonate housing and a Polyamix™ membrane (a blend of polyarylethersulfone, polyvinylpyrrolidone, and polyamide) just like the Polyflux® dialyzer leaching large amounts of BPA.
In the dialysis system studied, replacement fluid is prepared by ultrafiltration of ultrapure dialysate. At the beginning of its production, replacement fluid was fifty times more contaminated by BPA than ultrapure dialysate. This contamination decreased during replacement fluid production but remained higher than contamination of ultrapure dialysate, suggesting that flushing the ultrafilter integrated in the sterile line provides BPA. The filter is a single-use device also composed of a polycarbonate housing and a polysulfone membrane. Thus, in practice, flushing the sterile replacement fluid with ultrapure dialysate when including an ultrafilter could be an appropriate precaution before beginning a treatment session to reduce BPA exposure by OL-HDF.
In addition to BPA, ClxBPA was detected in water contributing to the water purification process, after each treatment step and, finally, in dialysis water. These results suggest that none of the water treatment steps are as means of reducingClxBPA in dialysis water. The same amounts of ClxBPA were detected in dialysis water, in ultrapure dialysate and in replacement fluid. In the ClxBPA detected in fluids, DCBPA was determined at much higher concentrations than MCBPA, TCBPA, and TTCBPA. Previous in vitro studies have demonstrated that this chlorinated derivative has the strongest estrogenic activity: 38- to 105-fold higher than BPA [15
]. During OL-HDF, DCBPA, as well as other ClxBPAs, are directly and widely available for systemic exposure due to contamination of infused replacement fluid.
After oral route, BPA is rapidly and fully absorbed in the gastrointestinal tract, widely conjugated in bowel and liver (sulfo and glucuroconjugates) and is then rapidly eliminated, leading to blood half-life in less than 2 h [34
]. BPA is excreted in urine as BPA glucuronide for the most part, and to a much lesser extent in unchanged form. Therefore, in ESRD patients, decline in kidney function leads to the accumulation of BPA, yielding higher blood levels [28
]. Moreover, during dialysis, the contact of blood with polymeric medical devices, such as dialyzers made of polycarbonate, polysulfone, or polyester, may expose ESRD patients to BPA [23
]. In addition to dialyzers, BPA present in dialysate fluid is a source of exposure [23
]. To make matters worse, that removal of BPA from blood using dialysis methods is a challenge given the degree of protein-bound fraction of BPA in plasma [37
]. In 2015, the Scientific Committee on Emerging and Newly Identified Health Risks (SCENHIR) concluded that the risk of adverse effects due to BPA may exist in patients undergoing dialysis treatment [22
]. Cardiovascular risk [38
], blood pressure increase [39
], and monocyte cytotoxicity [40
] are potentially negative effects of BPA in this population. However, long-term follow-up of hemodialyzed patients is required in order to explore long-term negative impact of BPA.
We have demonstrated in a previous work that BPA exposure could reach an estimated 140 ng/kg b.w./day for HD patients. Concerning OL-HDF, infusion of 20 L of replacement fluid provides additional 7840 ng of BPA during a session, corresponding to an additional dose of 112 ng/kg b.w./day compared to HD. The European Food Safety Authority (EFSA) experts have established an oral temporary tolerable daily intake (t-TDI) of 4 µg/kg b.w./day [41
]. However, regarding hemodialysis and especially OL-HDF treatment, BPA is directly available for systemic exposure leading to a 100-fold higher oral equivalent dose of exposure. Last but not least, OL-HDF also leads to higher exposure to ClxBPA, yielded by dialysate (up to 3072 ng per session) and, in addition, by replacement fluid infusion (up to 1340 ng per session). Compared to BPA, no pharmacokinetic and toxicodynamic data are available for ClxBPA either in animals or humans. Hence, the metabolism, tissue distribution, and elimination from the body remains unclear and no-TDI has been established for these compounds. Recent studies affirm that OL-HDF could reduce BPA blood levels in dialyzed patients [42
]. However, the methodology used raises some questions since the number of patients was low, and some issues regarding the analytical method used. Indeed, enzyme-linked immunosorbent assay (ELISA) was performed to determine BPA concentration while this analytical method has been evidenced as non-specific due to cross-reactivity of the anti-BPA [44
]. Further studies using an appropriate biomarker of exposure should be performed in order to clarify the role of the replacement therapy on BPA blood levels.