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Diethylhexylphthalate (DEHP) is suspected of having a toxicity on reproduction and development in human populations. So it is important to find DEHP-free alternatives for infusion medical devices
G Montpied Hospital
bClinical Pharmacy and
Faculty of Pharmacy
University of Clermont 1
Polyvinylchloride (PVC) is a plastic widely used in medical applications. Because of its excellent and varied properties, this inexpensive material is used in a number of medical devices that often come into direct or indirect contact with critically ill patients. PVC is a relatively stiff polymer that needs added plasticisers to increase its flexibility, with diethylheyxylphthalate (DEHP) especially being used for this. As DEHP is not covalently bound to the plastic matrix, it can diffuse throughout the PVC and leach out into its environment, resulting in exposure to body tissues and fluids. DEHP has been suspected of having a certain toxicity in humans, particularly young children.
Risks related to DEHP and populations exposed
Risk assessments regarding DEHP have been carried out by various expert panels in Europe and the USA.[1-5] Rodent studies identified adverse effects on the liver, kidney, thyroid gland tissues and testes. But it is difficult to extrapolate these data to humans, and there are only a few studies concerning human toxicity. However, specialists appear to agree that DEHP has the potential to cause adverse effects on reproduction and development in human populations. It turns out that DEHP is the phthalate that has the highest toxicity, resulting in the definition of specific risk groups such as children under one year of age, critically ill children and pregnant women undergoing therapies or medical treatments using medical devices with DEHP.
The European Chemicals Bureau (ECB) has defined tolerable daily intake values for DEHP at 20 Î¼g/kg bw/ day for newborns less than three months old and for women of childbearing age, 25 g/kg bw/day for newborns 3-12 months old and 48 g/kg bw/day for the rest of population.
Sources of medical exposure to DEHP
Various clinical situations can provide exposure to high levels of DEHP, including blood transfusion, extracorporeal membrane oxygenation, artificial ventilation, enteral feeding, haemodialysis and lipophilic infusions.[6-11] Regarding infusions, DEHP can be released not only from PVC bags but also from infusors and tubings during contact with lipid emulsions, such as parenteral nutrition solutions and drug solutions containing polysorbate 80 or castor oil. It has been known for several years that high quantities of DEHP are released from PVC bags into infusion lipid emulsions. Consequently, manufacturers have also produced a range of PVC-free containers, such as ethylene-vinyl acetate (EVA) bags for parenteral nutrition, multilayer bags, or low-density polyethylene containers for drug solutions.
However, infusion systems include not only containers but also infusors and tubing. For a long time it has been thought that no substantial amounts of DEHP were released from these PVC lines because of the way the solution flowed along the lines. However, it now turns out that considerable leaching of DEHP from these tubings does occur, from the beginning of the infusion.[12,13] The quantity of released DEHP increases with length of tubing, concentrations of lipids, polysorbate or castor oil in emulsions, and temperature.[13,14] A neonate in an incubator at 37°C who is infused with a lipid emulsion is exposed to high levels of DEHP, especially when several metres of PVC infusion lines are needed. Thus, the effective dose of
DEHP for a typical 2 kg newborn through the nutrition itself (aminoacid/glucose/lipids) is at least 13 mg – 300 times higher than the tolerable daily intake defined by the ECB.[3,15] And this level of DEHP is reached only with PVC infusion lines. We also know that the extraction rate of DEHP is significant during the first 24 hours of infusion and dies down afterwards. Consequently, the more often infusion lines are changed, the more the patients are exposed to DEHP.
It has long been thought that coextruded PVC and polyethylene (PE) and triple-layered PVC, EVA and PE intravenous extension tubings could be used as alternatives to PVC in tubing. These alternatives are of interest because they limit the adsorption and absorption of drugs but do not prevent the release of DEHP. It has even been established that the amount of DEHP extracted from multilayer tubing is as high as the amount released from PVC tubing.
Today, only lines made of PE do not release DEHP, but these are expensive and present practical drawbacks, especially in terms of stiffness and opacity. The most interesting possible solution is replacing DEHP with a different plasticiser in PVC materials. Such a plasticiser would need to be nontoxic for humans and allow no or negligible amounts of release from PVC devices. There are certain plasticisers that do seem to fit these requirements: diethyhexyladipate (DEHA), trioctyltrimellitate (TOTM) and, particularly, di-(isononyl)- cyclohexane-1,2-dicarboxylate (DINCH).17-18 Some manufacturers already include these components in medical devices, including nasogastric tubes (TOTM), haemodialysis lines (DEHA), feeding sets (DINCH) and infusors (TOTM). However, at present it’s quite difficult to find PVC infusion tubings free of DEHP.
It is very important that medical and pharmaceutical teams adapt their practices to the present situation concerning DEHP. Food-handling institutions have a maximum defined quantity of DEHP in food packaging. The use of DEHP in toys intended for consumers younger than three years old was prohibited in the EU in 1999. Hospital pharmacists have a major role to play in integrating this notion in the choice of medical devices. Morever, since March 2009 an official recommendation requires French hospital pharmacists to use DEHP-free medical devices in situations with high risks of exposure.
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