Clinical Evidence of Accumulation of DEHP in Tissue Stimulates Regulatory Debate on Blood Contact Devices
On September 10, 2012, following a call for experts by the European Commission into DEHP in medical devices, Medical Plastics News hosted a conference call in which Prof Terry Gourlay of the University of Strathclyde, UK, presented evidence that DEHP accumulates in the tissues of rats—particularly the brain and the liver—and remains there for up to 28 days, increasing the risk of an inflammatory response. Prof Gourlay also said that the results can be extrapolated to human cells. The presentation was made to a number of experts in medical plastics with an interest in plasticised PVC and alternative technologies.
The issue about DEHP in the medical device industry is complex. When used with PVC, the chemical is a very good plasticiser in terms of mechanical performance and is generally inexpensive. For many years it has been—and in many countries still is—used by compounders, making PVC flexible and durable while maintaining transparency.
On a number of occasions over the past few years, the safety of DEHP has been brought into question. Because there is no covalent bond between molecules of DEHP and molecules of PVC, DEHP is free to migrate from a PVC compound and onto or into whatever that compound is in contact with. And tests of DEHP on animals have given adverse results, particularly on the reproductive systems of adult males.
For medical devices which come into contact with blood, the issue is complicated further because DEHP is lipophillic, which means it is attracted to lipids. So when in contact with blood, DEHP is attracted to the lipids in red blood cells where it binds to and stabilises the cell membrane.
In blood bags, this is a beneficial characteristic because the stabilisation of the red blood cells actually preserves the cells. It keeps them fresh by stopping them from rupturing and the releasing their contents—a process known as haemolysis—which would otherwise render them useless.
However, Prof Gourlay’s evidence raises a crucial new concern about DEHP plasticised PVC in extracorporeal applications like haemodialysis, haemofiltration, cardio pulmonary bypasses, and extra corporeal membrane oxygenation (ECMO). Like in blood bags, DEHP migrates from the PVC used in these devices and into the blood where it binds to red blood cells. Prof Gourlay says that pump-based systems which compress DEHP plasticised PVC increase the rate of migration as DEHP is “squeezed” out of the PVC and into the blood.
Prof Gourlay works closely with clinicians at a leading UK hospital who are investigating inflammatory responses in patients undergoing extracorporeal treatments. In addition to attempting to manage these responses with drugs, Prof Gourlay has looked at the materials used in the systems themselves, including DEHP-plasticised PVC.
Prof Gourlay is concerned that DEHP may be creating an inflammatory response in neonates and repeat dialysis patients. He believes that neonates are more at risk than adults because there is an extremely high ratio of surface area of DEHP plasticised PVC to the baby’s body mass, significantly increasing the dosage in relative terms compared with adults.
And because he has evidence that DEHP stays in the tissue for up to 28 days, repeat dialysis patients, who are typically treated once every two days, are exposed to a multiplied dosage of DEHP.
Prof Gourlay’s experiment involved radioactively tagging molecules of DEHP and using this DEHP to produce plasticised PVC and then exposing different surface areas of this material to rats via an extra corporeal circulatory system which is mimetic of clinical systems. The research follows existing work published by Prof Gourlay that shows that DEHP is proinflammatory in both humans and rodents.
When presented with Prof Gourlay’s evidence, medical PVC expert and former Baxter polymer engineer Len Czuba said: “Prof Gourlay’s evidence suggests that there may be regulatory gaps for certain devices which contain DEHP-plasticised PVC. However, it is crucial that any conclusions about DEHP are communicated clearly to manufacturers and consumers. In the past, people have carelessly lumped DEHP and PVC together and this has resulted in confusion about whether PVC is safe or not, especially in the USA. Regulators must make it clear that phthalate-free PVC is a suitable alternative for many applications at comparable prices. Phthalate-free PVC is particularly popular in Europe, where PVC in general has a good press.”
Current DEHP Regulations
In Europe, along with a handful of other phthalates, DEHP has been classified as a substance of very high concern (SVHC). It is banned in children’s toys and usage in other sectors is strictly by prior authorisation from the European chemical industry’s regulating body Reach. The explanation given for this is that at certain high doses there is evidence which suggests the chemical is a reprotoxin that disrupts the endocrine system of young males.
At the time of going to press, all medical device manufacturers in Europe are exempt from Reach’s regulative restrictions on DEHP usage. But under the Medical Device Directive (MDD) any devices containing DEHP must demonstrate the effect that migratory DEHP molecules have on the device’s performance. They must also bear labels stating that the device contains DEHP. On September 6, 2012, the Danish government banned the use of phthalates in shower curtains and oil cloths. There is pressure on the government in that country to extend the ban to more products including medical devices.
In the USA, there are no regulatory restrictions on the use of DEHP. But in a report published on the FDA website on August 28, 2012, by biologist Laura A Alonge, there are precautions about its usage in certain treatments. The warnings concern similar treatments to those raised by Prof Gourlay (see table 1).
The FDA’s recommendations are to “play it safe”. The report states: “Don’t avoid performing high-risk procedures simply because DEHP could pose a health risk. Forgoing a necessary procedure is far riskier. However, you can take some precautions.”
Its suggestion is: “For some procedures, you can use PVC devices that don’t contain DEHP or use devices made from other materials, such as ethylene vinyl acetate, silicone, polyethylene, or polyurethane. If you must use devices with DEHP, you can minimise exposure by using the freshest possible blood products stored at the lowest possible temperature or by using heparin coated ECMO circuits.”
The next stages of Prof Gourlay’s work will involve a specific investigation into inflammatory responses resulting from repeat DEHP exposure during two-day haemodialysis cycles on rats. There is also potential to take some human tissues from a tissue bank which have been exposed to DEHP through haemodialysis but this will require ethics approval.
A podcast of the conference call in which Prof Gourlay presented his evidence is available at www.bit.ly/QWxzwN.
DEHP Supply
According to Andrea Zanichelli, technical director at Italy-based medical PVC compounder Resilia KemOne, the European market for DEHP is shrinking fast. Already manufacturers of the chemical have exited the continent and just one producer of medical grade DEHP, Arkema, remains. Mr Zanichelli conceives that the use of the chemical will become more restricted going forward, which could push Arkema to exit or switch production to another chemical.
Should this happen, a European medical DEHP market would be wiped out completely forcing up the price of DEHP in Europe as importers face fees for registering the chemical with Reach. Mr Zanichelli argues that a higher price for DEHP removes one of its key advantages—it’s low price—encouraging the use of alternatives.
According to a statement from Eastman Chemical, one of the largest producers of DEHP, “the company does not produce or sell DEHP in Europe.” Eastman Chemical is a member of the PVC Medical Alliance, set up by the European Council of Vinyl Manufacturers (ECVM).
In the USA, the situation is far more fluid. As long as the FDA doesn’t regulate against DEHP, companies will be free to use it. Eastman Chemical supports the safe use of DEHP in FDA cleared medical devices. The company’s brand is Eastman DOP Plasticiser.
Eastman offers a wide range of DEHP alternatives including Eastman 168 non-phthalate plasticiser. The company is giving attention to this chemical’s potential use in a wide range of medical applications, including DEHP-free blood bags.
DEHP in Blood Bags
For most DEHP-plasticised medical devices, there are many alternative materials available, including phthalate-free plasticisers and alternative flexible polymer compounds like TPUs, TPEs and silicones.
There is one product, however, that is almost completely dependent on PVC plasticised with DEHP—blood bags.
The reason for this is that, as mentioned earlier, DEHP appears to be a natural preservative of blood. The chemical migrates from PVC and binds with membranes of the red blood cells, preventing haemolysis and keeping them fresh for up to 42 days.
A 42-day shelf life for blood bags is critical for blood banks to manage their supply chain and provide a continuous and reliable supply to clinicians. Because they rely on donations, supplies from donors can be uneven and feature peaks and troughs. Without the shelf life, these peaks and troughs would be unmanageable.
Medical Plastics News is only aware of one commercial blood bag system which does not contain DEHP—the Pearl BPU, a PVC blood bag plasticised with butyl trihexyl citrate (BTHC). The bag was developed in 1991 and is currently marketed by US infusion systems manufacturer Fenwal, formerly owned by Baxter Healthcare.
The hexanol in the BTHC is the chemical which preserves the blood and the level of leaching from the PVC is believed to be lower than with DEHP-plasticised PVC.
According to an investigation by the EC in 2008, BTHC does not accumulate in the tissues.
Strangely, dependence on DEHP was purely accidental. PVC blood bags were first used by the US army in the Korean war in the early 1950s. PVC was used to replace glass so that bags of blood could be thrown out of helicopters without them smashing to pieces. The fact that DEHP extended the shelf life of blood was an unexpected bonus.
Prof Gourlay’s new evidence about the accumulation of DEHP in tissues may open a debate as to whether there is a need in the industry for DEHP-free blood bags. However, Prof Gourlay says that because the majority of blood bags are used in serious trauma incidents involving adults where there has been a lot of blood loss, the risk of inflammation as a result of exposure to DEHP is minute compared to the reward of saving a person’s life. Furthermore, the percentage of DEHP which migrates into the blood is very small.
However, taking into account the treatment of neonates and small children, there is a much finer balance between risk and reward. The fact that the baby’s body mass is a fraction of the size of an adult’s means that any single dosage of DEHP is proportionately more significant.
Alternative Materials for Blood Bags
The reliance of blood bags on DEHP makes them an interesting case study. Indeed, there are a number of scientists who are attempting to develop PVC free alternatives, primarily for neonates.
For these researchers, the main challenge is how to keep blood fresh for a shelf life of 42 days, as required by the blood bank sector.
The closest product is a prototype multilayered polyolefin solution, developed in the USA but not yet commercialised. The bag can preserve blood for the 42 days but is does not meet standards required for physical properties related to welding, flexibility, transparency, durability, centrifuging and handling.
Lubrizol, the USA-based speciality chemicals company, claims that its thermoplastic polyurethanes (TPUs) are theoretically suitable for the replacement of DEHP-plasticised PVC, although there is still a fair way to go on their research and TPUs are generally more expensive than most polyolefins and PVC.
Their approach is also a multi-layer approach. It aims to apply a similar technology to that used in its monolithic breathable films, currently in medical garments. They hope to incorporate a preservative into the inner TPU layer of the bag and allow the preservative to leach into the blood over time. The release rate of the preservative can be controlled in the TPU structure.
The advantage of a TPU layer, according to Lubrizol, is that it exhibits similar physical properties to PVC, including being easily weldable.
Weaning Neonates off DEHP
A broad consortium of healthcare suppliers and clinicians in Scandinavia, known as PVC Free Blood Bags, are targeting development towards serving a high risk group of transfusion therapies—neonatal babies. Their goal is to develop a blood bag which avoids PVC entirely.
The consortium has no commercial ties to the blood bag manufacturing industry and can therefore operate independently. It consists of a leading Swedish hospital—the Karolinska University Hospital—as well as Swedish green chemistry research institute Jegrelius, Finnish medical packaging films extruder Wipak, medical tubing maker Totax and polyolefin compounder Melitek, both based in Denmark, and Italian blood bag and tubing contract manufacturer Haemotronic.
According to project manager Lena Stigh, the consortium’s goal is to demonstrate to industry that it is possible to make a PVC free blood bag that meets the technical and regulatory requirements in an attempt to fuel demand from European healthcare companies.
They aim to remove PVC from blood bags altogether, arguing that even with newer plasticisers, no one can be sure they are safe until it is too late.
In terms of progress, the group has secured conditional orders via signed letters of intent from seven Swedish county councils. The councils say they will buy PVC Free blood bags if they can meet the specific requirements of the industry.
The group has stated that the mass production of competitively priced 100% PVC free blood bags is theoretically possible. Since its formation in September 2011, it has gathered information about what is required by the industry and has developed the technical specifications needed for their first prototype—based on the multilayer polyolefin system created in the USA and mentioned earlier, which is their starting point.
In parallel to this Melitek, the polymer compounder in the group, is working on a Eurostar-funded project called SafeBlood. In this research, Melitek is looking to impart an alternative stabiliser into a polymer material which could then be used to extend shelf life.
The consortium believes that there may be instances when a blood bag system does not need to remain fresh for the full 42 days. In these cases, there would be many more DEHP-free options to utilise for the blood bag system, but it would require a change of culture.
There is still a long way to go for the PVC Free Blood Bag consortium. They hope to demonstrate two key issues. First that there is a demand for a PVC free product in blood transfusions for neonates, chronically sick children and other high risk patients—including those with sickle cell disease, thrombotic thrombocytopenic purpura and haemolytic disease of the newborn. Second, it is theoretically possible to produce a PVC free product.
Table 1: Treatments whereby the FDA suggests precaution when using devices containing DEHP, published on August 28, 2012
Transfusion (especially multiple transfusions in neonates, trauma victims, and adults undergoing extracorporeal membrane oxygenation (ECMO)
ECMO in neonates
Multiple procedures in neonates
Haemodialysis in peripubertal boys and pregnant or lactating women
Enteral nutrition in neonates and adults, particularly total parenteral nutrition (with lipids in a PVC bag)
Heart transplantation or coronary artery bypass graft surgery
Article Credits:
John Cahill, Eastman Chemical Company
Len Czuba, SPE Medical Plastics Division and Czuba Enterprises
Brigitte Dero, European Council of Vinyl Manufacturers (ECVM)
Terry Gourlay, Bioengineering Unit, University of Strathclyde
Ole Grondahl Hansen, PVC Information Council, Denmark
Ralf Huther, Lubrizol
Jesper Laursen, Melitek and PVC Free Blood Bag
Sherry MacDonald, Practise Greenhealth
Rainer Otter, BASF
Craig Sandford, Fenwal
Ted Schettler, Healthcare Without Harm
Lena Stigh, PVC Free Blood Bag
Andrea Zanichelli, Resilia KemOne