Posted on February 28th, 2022

With the advent of revisions of ISO 10993-1 over the past 13 years, the evaluation of medical device biocompatibility has evolved from the evaluation of test results to the evaluation of all available information that could impact the risk of biological safety. Testing should be evaluated in conjunction with information obtained from other non-clinical assessments and post-market experiences, as long as the latter is relevant to biocompatibility evaluation.

Initial information gathering could include chemical information regarding materials and components. Each material can be evaluated regarding its hazard potential and an estimate of its exposure during intended use. The extractable compounds can then be used to form a "toxicological risk assessment" based on the expected biological response to the chemical compounds.

Bisphenol A (BPA) is an organic compound that is present as a constituent in many daily-use plastics such as epoxy resins and polycarbonate. It is one of the most vulnerable endocrine-disrupting chemicals. Food is the most common source of BPA exposure as evidenced by the many plastic drink containers labeled as BPA-free.

BPA interacts with many receptors such as estrogen, aryl hydrocarbon, androgen, and peroxisome proliferator-activated receptors, thus changing the function of leptin, insulin, adiponectin, thyroxin, and other hormones that are involved in maintaining the immune and nervous system (Fenichal, P et al. 1974).

Endocrine Disruptor

It is common for manufacturers to evaluate raw materials for biocompatibility assuming that they can then leverage the findings to the final device (Maak and Wylie, 2016).

However, the effects of the manufacturing process must be evaluated. One of the major reasons that materials are not considered interchangeable between devices is that the manufacturing process between the new device and the predicate device may differ significantly.

Changes in materials and/or components could present different types or amounts of residual chemicals, which could give off a toxic response even if the base material has a long history of safe use. FDA could allow for chemical characterization to eliminate the need for device biocompatibility testing in these circumstances.

BPA is considered a xenoestrogen substance, which mimics the action of estrogen in the pancreatic cells. BPA is responsible for the overproduction of insulin as 17-β estradiol by binding with estrogen receptors and activating extracellular signaling kinase (Irshad, K et al, 2021). BPA exposure cause fasting hyperglycemia, hyperinsulinemia, and intolerance of glucose in animals.

Many endocrine-disrupting chemicals can disturb the homeostasis of glucose in the various organs such as the liver, pancreas, adipocytes, and neuroendocrine cells. BPA influences glucose homeostasis in the liver, adipose tissues, skeletal muscles, pancreas, and central nervous system (Rotondo and Chiarelli, 2020).

BPA can disturb the functions of various kinds of hormones such as insulin, thyroxin, and leptin and be responsible for producing hepatotoxic, carcinogenic, immunotoxic, and mutagenic effects.

Metabolic Syndrome (MetS)

The major cause of metabolic syndrome lies in the same causes of obesity and type II diabetes Those being high-calorie diets, less exercise, and certain possible genetic predispositions.

Environmentally available chemicals could have an impact on the etiology of metabolic syndrome but with less significance than an increased body mass index (BMI).

BPA can interfere in the activity of aromatase, regulators of lipogenesis, lipoprotein lipase, and the level of hormones in fat tissues that are very crucial for balancing the weight of the body. There is a link between exposure to BPA and an increase in body weight, therefore BPA contributes to MetS (Irshad, K. et al, 2021).

BPA has the potential to exhibit its role as an obesogen and diabetogenic but this is certainly secondary to the impact of diet and lifestyle.

Recent studies show that exposure of BPA to pregnant mice and adult male offspring impairs both insulin and glucose tolerance via inhibiting the activation of the Akt signaling pathway. As a result, it decreases the sensitivity of peripheral insulin (Irshad, K. et al, 2021).

Exposure to a high concentration of BPA can cause metabolic dysfunction. Exposure of low concentration of BPA to human adipocytes in vitro causes dysregulation of the functions of adipocytes by impairing the utilization of glucose-stimulated by insulin and pathway of insulin signaling.

Because of the strong association between MetS and cardiovascular disease, BPA has the potential for an adverse impact of cardiovascular health.

Liver Issues

BPA has the ability to damage the liver via oxidative stress.

Oxidative stress is a phenomenon caused by an imbalance between the production and accumulation of oxygen reactive species (ROS) in cells and tissues and the ability of a biological system to detoxify these reactive products. BPA induces the production of oxidative stress, impairs the signaling of cells, and changes in DNA due to inhibition of methylation of DNA (Irshad, K. et al, 2021).

BPA has the ability to damage DNA in the eukaryotic cell. Can cause genotoxicity in human intestinal, hepatoma, and renal cells.

Immunology

BPA has an effect on the estrogenic receptors due to which it has the ability to induce modulation in the immune system functions. Due to exposure to BPA, the amount of T lymphocytes is increased and as a result, the level of interferon increases while interleukin level is decreased.

BPA produces lymphocytes with a higher concentration of immunoglobulin A and also immunoglobulin G 2a. Studies also show that female mice exposed to BPA have more susceptibility for infection caused by the influenza virus which causes a modulation in the immune system (Irshad, K. et al, 2021).

Discussion

BPA’s role as an endocrine disrupter is certainly of concern depending on the intended use of the chemical as a medical device constituent. While its identified hazard is not part of a typical biocompatibility test program, it certainly is serious enough to demand further study into the potential for harmful effects specific to its use as a medical device.

References:

Fenichel P, Chevalier N, Brucker-Davis F. Bisphenol A: an endocrine and metabolic disruptor. Ann Endocrinol (Paris). 2013 Jul;74(3):211-20. doi: 10.1016/j.ando.2013.04.002. Epub 2013 Jun 21. PMID: 23796010.

Irshad, Kanwal, Kanwal Rehman, Hina Sharif, and Muhammad Sajid Hamid Akash. 2021. “Bisphenol A as an EDC in Metabolic Disorders.” In Endocrine Disrupting Chemicals-Induced Metabolic Disorders and Treatment Strategies, 251–63. unknown.

Rotondo and Chiarelli (2020).  Endocrine-disrupting Chemicals and Insulin Resistance in Children.  Biomedicines 8(6): 137.

Travis G. Maak, James D. Wylie. (2016). Medical Device Regulation. Journal of the American Academy of Orthopaedic Surgeons 24:8, 537-543.).