**4. Bisphenol A in hemodialyzers**

The largest scale studies with a consistently high number of enrolled participants (*n* = 2517 and 5476 individuals) spread over a broad range of age were carried out in the USA and

In these studies, the highest BPA levels detected in urine were 3.6 ng/mL for the US and 1.30 ng/mL for the Canadian ones in a subgroup of population within the age group of 6 and 11 years. On the contrary, the adult population had lower BPA urine concentration: 2.6 and 1.16 ng/mL, respectively. Zhang et al. show the same results in a recent study conducted on the

Mose et al. [8] studied the BPA trans-placental transfer rate in human placentas in ex vivo experiments. Results led the authors to conclude that free BPA can cross the placenta by passive diffusion with a trans-placental transfer rate of 1 (e.g., the concentration in the fetal blood was equal to the concentration in the blood of the mother), as previously demonstrated by

Searching in the literature an increasing number of studies are found containing data coming from epidemiological studies on the association between BPA exposure and healthy outcomes. Unfortunately, this number is still limited, and results are coming from cross-sectional trials that limit their interpretability for pathology with long latency periods like cardiovascular diseases or diabetes. An example of number of publication per year, found in PubMed,

Six cross-sectional analyses of data from the US National Health and Nutrition Examination Survey (NHANES) reported associations of BPA exposure with self-reported diagnosis of pre-existing cardiovascular disease, hypertension, obesity, diabetes, and liver-enzyme abnormalities [10–15]. Two other studies in the US [16] and China [17] reported an association between BPA exposure and coronary disease at the time of diagnosis and obesity and insulin resistance, respectively. In addition, a study found associations between urine BPA and immune function and allergy [18]. These cross-sectional analyses have the same weaknesses that limit their interpretation. One of the major limitations of these studies could be assigned to the problem relating to sampling procedure (single spot urine) reflecting only recent BPA exposure and not on a long period (months or years) much more useful to assess the exposure

Progressive exposure to BPA can affect adiposity, glucose or insulin regulation, lipid profiles

Finally, BPA could have a negative effect on the heart: stimulating estrogen concentration and modifying free calcium concentration control inside heart cells in women. Provoking an increase of Ca2+ release from sarcoplasmic reticule that could cause arrhythmias that in some

Canada, respectively [4–6].

78 Bisphenol A Exposure and Health Risks

Asian population [7].

Balakrishnan et al. [9].

is shown in **Figure 2**.

**3. Bisphenol A and human health**

effect on cardiovascular disease and diabetes pathologies.

case could degenerate into infarction [28].

or other end-points relating to diabetes or metabolic syndrome [19–27].

Several types of medical devices are produced using polycarbonate (PC) polymer. Industries utilize PC for its toughness and stability, optical clarity, and resistance to heat and electricity. Unfortunately, these medical devices produced using PC could contain and release BPA residual in routine use. Additional source of BPA is coming from other materials such as dental supplies manufactured using bisphenol derivatives like bisphenol A glycidyl methacrylate (Bis-GMA) and bisphenol A dimethacrylate (Bis-DMA). Bisphenol A is also used in the production of inks and adhesives, as well as in polysulphone (PS) membranes widely used in hemodialyzer production.

Recently, the Scientific Committee on Emerging and Newly Identified Health Risks (SCENIHR) published an opinion of the safety of bisphenol A use in medical devices [29].

In their report, the SCENIHR described the risk assessment of exposure to BPA via medical devices that are manufactured with materials that potentially leach BPA. This include oral (via dental material), subcutaneous, and intravenous (e.g., during hemodialysis) routes of exposure.

This group evaluated the different scenarios of exposition considering the type of materials used, frequency and duration of a single treatment as well as the information relating to BPA leaching, generating an accurate report on short- and long-term toxicological exposure.

As a conclusion, the SCENIHR group reports a possible existence of adverse events risk of BPA when this is directly available in the blood, and in a particular case, for neonates in intensive care units, infants undergoing prolonged medical procedures, and for dialysis patients. Although the use of medical device should be considered together with the benefit for the patient, a BPA-free device should be taken into consideration if available. What they also suggest is to consider the possibility of replacing BPA in medical device products against their efficiency in the treatment, as well as the toxicological profile of the alternative materials.

Several studies have reported the leaching of BPA from hemodialyzers. Haishima et al. [30] studied the amount of BPA released from different hemodialyzers composed of a combination of polycarbonate housing and cellulose acetate hollow-fibers, polycarbonate housing and polysulfone fibers, and polystyrene and polysulfone. Water and bovine serum were circulated at room temperature in the four different devices tested. The bovine serum was used as a stimulant for human blood circulating into hollow fibers during hemodialysis.

BPA recovered ranged from 3.78 to 141.8 ng/module using water circulation and from 140.7 to 2090 ng/module when bovine serum was used. The highest values of BPA released corresponded to hemodialyzers consisting of PC housing and PS.

Murakami et al. [31] reported a BPA concentration of 8.33 and 12.25 ng extracted from 10 mg of polysulfone and polyester polymer alloy (PEPA) hollow fibers. The fibers, taken from individual dialyzers, were crushed and dissolved in hexane.

Fink [32] investigated BPA leaching from five different types of dialyzers and polyvinylchloride blood tubing. All the dialyzers were composed of either polycarbonate or polysulfone: polycarbonate housing and polysulfone-polyvinylpyrrolidone (PVP) blend membranes, PC housing and polyamide-polysulfone blend membrane, and polypropylene housing, polysulfone-PVP blend membrane. Different surface area range was investigated (from 1.3 to 1.8 m<sup>2</sup> ). Dialysis was simulated using two different eluents: reverse osmotic water and 17.2% ethanol [32].

In agreement with the study of Haishima et al., the highest levels were measured when 17.2% ethanol was used, ranging from 54.8 to 4299 ng/dialyzer. Using osmotic water as eluent, the BPA levels measured span from 6.4 to 71.3 ng/dialyzer.

Additional factors influence the BPA released from dialyzers, like the type of dialyzer, surface area, and duration of dialysis session. Generally, large amount of BPA is released in long dialysis sessions or in dialyzer with high surface area.

The contribution of the PVC tubing to total BPA content in the eluates was negligible, and the levels found were below the limit of quantification.

Krieter et al. [33] also reported release of BPA from three different high and low flux dialyzers with different surface area (from 1.3 to 1.7 m<sup>2</sup> ) and with polycarbonate housing. BPAfree sterile water was circulated through the blood and dialysate compartments at 37°C, and BPA was measured by ELISA method. The amount of BPA eluted was significantly different between dialyzers evaluated, with average levels from 140.8 ± 38.7 to 6.2 ± 2.5 ng/dialyzer. These results are in the range with those reported in other studies when using water as eluent. The highest BPA levels were eluted from the low-flux dialyzer with polysulfone membrane, and the lowest from the dialyzer with polyethersulfone (PES) membrane. A summary of data available from the literature is presented in **Table 2**.

**Table 2** summarizes the levels of BPA released by dialyzers and measured in different fluids.


**Table 2.** Levels of BPA released by dialyzers and measured in different fluids reported in the literature.
