Transfusion Medicine Reviews
Volume 26, Issue 1 , Pages 27-37, January 2012

Progress in the Removal of Di-[2-Ethylhexyl]-Phthalate as Plasticizer in Blood Bags

published online 08 August 2011.

Article Outline

Polyvinylchloride (PVC) is used in blood component containers as well as in many other medical devices because it shows optimal inertness, durability, and resistance to heat and chemicals. However, the polymer itself does not provide good handling characteristics or the necessary properties for red blood cell (RBC) survival. PVC thus needs to be plasticized, and di-(2-ethylhexyl)phthalate (DEHP) has been the most common plasticizer to produce the required flexibility to PVC. However, DEHP has been found to leach out from the containers, causing toxic effects, as demonstrated mainly in rodents. It is considered to be a possible carcinogen and suspected to also produce endocrine effects especially in young males. Although controversial, it is commonly accepted that in vulnerable patients such as newborns, trauma patients, or pregnant women, high exposure to DEHP should be avoided.

The replacement of the common PVC + DEHP blood bags poses technical challenges due to the positive influence of the DEHP molecules on the red blood cell (RBC) membrane, and thus it has been shown to affect RBC storage and survival after transfusion. Different approaches are thus being taken to find a suitable alternative to DEHP for blood components bags. Environmentalists even favor the substitution of the PVC to avoid not only the plasticizers but even the other residues contained in the polymer material. Consequently, whereas the simplest solution is the substitution of the DEHP by other plasticizers, alternative plasticizer-free materials are becoming explored. Even modifications of existing materials are being presented by some research groups, ranging from covering of the DEHP-containing materials to alloys or special additive solutions. Different strategies as well as the most promising approaches are presented in this review. In any case, the degree of stabilization of RBCs undergoing prolonged storage will dictate the final acceptance for such alternatives.

 

SINCE THE FIRST description of the use of transfused blood in the 17th century, enormous developments have taken place.1 Initially, only a few transfused subjects survived and even fewer procedures were really followed by examining the positive effects on the patient. Fortunately, the discovery of the properties of citrate as anticoagulant and the ABO groups allowed blood storage and the dawn of modern transfusion medicine.1 The use of clean and sterile needles and glass containers decreased the occurrence of bacterial infections, although they continue to be reported, even today, which remains a major threat for the safety of the recipient of a transfusion. Since the 1950s, plastic bags have been used for blood storage instead of glass containers.2 The low production cost of the plastic bags permitted a single use of such devices and provoked further advantages in the reduction of transfusion-transmitted disease occurrence. The main polymer used for this purpose has been polyvinylchloride (PVC), due to its inertness, durability, and resistance to heat/cold, chemicals, abrasion, and kinking. However, because of its brittleness, it requires the use of plasticizers.3

The definition for a plasticizer is given by the Active Standard ASTM D-883 as a material incorporated into a plastic to increase its flexibility.4 Although the effect of plasticizers is simple, their working principle is not yet fully understood but explained by several existent theories. Some theories propose that plasticizers act as an internal lubricant, either by weakening intermolecular forces or by increase of free volume. To increase PVC flexibility, the plasticizer is inserted between the PVC chains, enlarging the distances between the molecules without altering the microcrystalline structure of the polymer, which increases the mobility of the PVC molecules. This creates increased volume due to Brownian movement, making polymers more flexible and, in many cases, leads to a reduced glass transition temperature.3, 5

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Di-(2-Ethylhexyl)Phthalate 

In PVC blood bags, di-(2-ethylhexyl)phthalate (DEHP) has been used for more than 50 years as the plasticizer, resulting in a functional polymer with excellent characteristics such as inertness, flexibility, transparency, and high resistance to heat and chemicals. Additionally, the processing characteristics of this material such as moldability, sterilization by steam or radiation, and its sealability by high-frequency radiation lead to a low-cost product that clearly dominated the market. It was just in the late eighties of the last century that scientists realized the migration characteristics of DEHP especially into organic liquids or into protein-containing solutions. The intake by the body of DEHP can take place in many different ways due to its lipophilic nature, which enables the plasticizer to pass natural barriers such as skin, pulmonary tissues, and the intestine without major difficulties.6 The more important routes of intake are oral or intravenous.7 Once inside of the body, most of the tissues contain enzymes that have the ability to hydrolyze the diester to its monoester, mono-(2-ethylhexyl)phthalate (MEHP), whereas complete hydrolysis seems to require enzymes present mainly in the liver.8 Such phase I metabolism leads to other metabolites as mono(2-ethyl-5-hydroxyhexyl)phthalate, mono(2-ethyl-5-oxohexyl)phthalate, mono(2-ethyl-5-carboxypentyl)phthalate, and mono(2-carboxymethylhexyl)phthalate. To facilitate elimination of the metabolites from the body, glucuronidation is performed, and so the bulk of the DEHP absorbed by the body is excreted within 24 hours and no tissue accumulation could be demonstrated.6 The exposure of children undergoing equal medical treatments is proportionally higher.9 Since the metabolism in childhood, especially in neonates, is not yet mature, the excretion level is lower due to lower levels of glucuronidation that takes place, even though hydrolysis to MEHP is higher.7 The latter situation is especially problematic because part of the toxicity of DEHP is due to its monoester MEHP.

In rats and mice, both DEHP and MEHP were shown to produce toxic effects in liver, kidney, and testes. Hints on carcinogenicity, as well as reproductive toxicity, have also been reported.10, 11 Most theories assume that the observed toxicity is mediated via peroxisome proliferation, which would explain the differences seen in laboratory animals such as rats or mice and higher species as chimpanzees and humans. As the mechanism behind carcinogenicity is specific for rats and mice, it is at present considered not to be relevant in the human liver. DEHP is therefore considered not to be carcinogenic for humans.12 The endocrine effects in young male mice that lead to highly reduced testicle activity were irreversible and occurred at far lower doses than that seen in adult rats given the same concentrations of DEHP without changes being observed.13

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Substitution of DEHP to Other Plasticizers 

PVC plasticized with DEHP has been used for more than 50 years as material for applications as different as blood bags, toys, or floor coverings. The appearance of hazard warnings on the latter products was unexpected and sometimes shocking and has led to a general decrease in DEHP exposure,12 while awareness of the blood bag problem in the population is unfortunately quite low. Because transfusions do not represent day-to-day contact with plasticizers for most people, the population at large is not as concerned as in the discussions about toys, where huge public protests have drastically changed the market situation. Moreover, the medical plastic industry may also be quite interested in maintaining the situation unchanged to keep their development costs low and to avoid the effort of changing production methods. Transfusion medicine hospital personnel seem mostly unaware of the topic. Indeed, the beneficial effects of DEHP on RBC storage may very well have precluded its substitution at the current time. However, since the risk of exposure to DEHP is acknowledged, the question remains—how to change a status quo?

The driving force has to be legislation. For instance, in the European Union, free trade of products drives the market to be harmonized by general rules. To capture scientific data on the problem, the Scientific Committee on Medicinal Products and Medical Devices (SCMPMD) authored a literature survey “Opinion on DEHP in Medical Devices.” This report concluded in 2002 that the advantages of DEHP preponderate, and just in the final version in 2008,14 a risk was found to be mainly dependent on (a) background exposure, (b) exposure dose, via leaching from medical devices, and (c) vulnerability of patients. Even other plasticizers had been considered, but due to a lack of toxicity data, a full risk assessment could not be performed.

Those rules, which are mandated through European Directives, are adopted by each single country's legal systems. With respect to the medical device market, there are some directives as listed in Table 1. Changes to these directives were made in September 2007, particularly in directive 2007/47/EG, which had to be implemented from March 2010 onward. The labeling of products containing DEHP as the plasticizer is now mandatory, and those include the listing of the risks that are associated with DEHP, especially for more vulnerable patient groups. Compliance with the directives has to be proven for both new and previously used devices. In the United States, concerns are mainly addressed to special groups of patients such as long-term transfusion recipients, male newborns, and pregnant women.9

Table 1. Main European Directives Regarding the Use of DEHP in Medical Devices
DirectiveSummary of contents
90/385/EWGActive implantable medical devices
93/42/EWGMedical devices (general); PVC-free materials should be used preferably
98/79/EGIn vitro diagnostics
2007/47/EG(a) The manufacturer has to prove that the use does not cause any form of danger.
(b) One-way products have to be labeled as such.
(c) Software for medical use is treated as a medical device to avoid misuse.
(d) Paperwork has to be stored for at least 15 years.
(e) Quality management systems of subcontractors have to be controlled.
(f) Medical devices containing phthalates that could access the human body have to be labeled as such.

The process of finding alternative materials for blood bags gets even more complicated by the fact that there are various medical procedures using blood transfusions often requiring different types of processing of the blood product. Blood can be used as whole blood or as components. Obtainable by centrifugation at the blood centers are RBCs, white blood cells, plasma, and platelets, but more specific compounds can be separated from plasma, using further techniques at the manufacturing level.1 Once the desired compounds are fractionated, there are even several storage possibilities (eg, refrigerated storage, cryopreservation, freeze-drying). Obviously, each application has special properties for the blood bags used. Considerations will mainly be based on the hypothermic storage of RBCs or whole blood, but further considerations may be needed based on other storage considerations.15

For toys, food packaging, and several kinds of medical devices, approaches have been taken to eliminate or at least reduce the use of DEHP. For example, in medical tubing or bags used for parenteral infusions, this plasticizer has been almost completely substituted. For platelet bags, alternatives have demonstrated even better characteristics with respect to permeability, and their use is widespread. For RBCs, however, few manufacturers make DEHP-free products accessible.16

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DEHP and RBC Storage 

There is one fundamental difficulty for the elimination of DEHP in RBC containers. The main reason is that RBCs have improved survival rates when they are stored in DEHP. These findings can be confirmed adding DEHP to RBC concentrates stored in DEHP-free containers, where longer in vivo survival rates can be observed as well.17

RBCs make up about 45% of the volume of the human blood. They are produced in the bone marrow, and their common life span is normally between 90 and 120 days. As RBCs lack a nucleus and organelles, glycolysis is their main metabolic pathway to produce ATP and gain energy. Several studies have shown that ATP production is the main factor influencing the in vivo recovery of RBCs.18 Senescent RBCs are removed from the circulation by the mononuclear phagocyte system, mainly in the spleen but also in the liver and bone marrow.

The most important factors influencing the viability of RBCs are the content of ATP, 2,3-diphosphoglycerate, hemoglobin, the integrity of RBC membrane lipids and proteins, and the flexibility of the RBC membrane in the microcirculation. Metabolic changes and oxidative damage depend strongly on the storage medium, its pH, and the temperature. Such changes when they occur are usually followed by changes in O2 affinity and delivery. AuBuchon et al17 did not observe changes in the ATP levels, the values of free plasma hemoglobin, or the osmotic fragility in their DEHP addition trial to alternative blood bags, which led to the conclusion that DEHP does not strongly affect the metabolism of RBCs.

During the RBC aging process that occurs during RBC storage, the characteristic shape of RBCs may change from biconcave disks to echinocytes. This process is reversible by rejuvenation (ie, treatment with a nutrient solution). In a next step, the echinocytes may traverse an irreversible shape loss, which transforms the disks with spicules into bumpy spheres. This progress usually advances by blebbing of microvescicles, leading to a loss of membrane area that is bigger than the loss of volume.19 Those irreversible changes result in a severe decrease in membrane deformability. Coupled with the observation that 5% to 10% of the DEHP found in blood is incorporated into the cell walls of RBCs, it can be concluded that DEHP affects the membrane flexibility as do other membrane stabilizers such as mannitol. A flexible RBC membrane maintains the adaptability of the cell at different circulatory conditions and so assures RBC integrity and the flow characteristics of blood.20

Another assumed mechanism for DEHP action is based on the observation that, during normal RBC aging, some of the deformability is lost due to the altered cholesterol/lipid ratio. The DEHP molecule might occupy the vacated space and thus maintains RBC membrane flexibility; alternatively, DEHP might help by bridging its asymmetric bilayer. A suitable replacement for DEHP would be expected to have a similar effect, but most alternative plasticizers are not incorporated into the RBC membrane.

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Alternatives to the Use of DEHP 

Necessary requirements for a blood bag material are resistance to heat and chemicals, especially during the sterilization, and permeability of gases to assure that the pH and the oxygen level are kept constant. There are 3 strategies to develop “low-risk blood bags” that do not contain the stated carcinogen and leaching plasticizer, DEHP. Manufacturers, however, must pay attention not to introduce further risks due to changes in material (weaker weldings, more fragile, etc).12

Substitution of the Plasticizer 

In this situation, PVC is usually kept as the polymer used to create the blood bags. In recent years, a huge range of plasticizers has been developed. These include various chemical structures from esters, epoxides, and ionic liquids, which have been used for this purpose. A selection of plasticizers (see Fig 1) has been used in the manufacture of bags used for transfusion.

Tri-(2-ethylhexyl)trimellitate (TEHTM) is a plasticizer similar to DEHP. This compound has also been referred to as trioctyltrimellitate (known as TOTM). As is the case for most plasticizers, it exhibits a high boiling point, a low melting temperature, and it is readily soluble in most organic solvents. Compared with DEHP, it is less efficient as a plasticizer; thus, the polymer used requires a higher plasticizer content to reach a fixed flexibility when it is plasticized with TEHTM. On the other hand, it is less likely to leach from the plastic, most likely due to its higher molecular weight. The additional side chain also causes a lower solubility in water with low bioavailability and biodegradability as logical consequences. Biodegradation is likely to occur, similarly to DEHP, by hydrolysis of the esters. Its metabolites, di- and mono-(2-ethylhexyl)trimellitate, are found only in amounts of 6% and 1%, respectively, compared with nearly 50% of MEHP for DEHP. Oral acute toxicity is low (2 g/kg), and no aquatic toxicity has been demonstrated, neither for fish daphnia nor for algae.21, 22 Bags with TEHTM as the plasticizer demonstrate sufficient gas permeability for O2 as well as for CO2, but improved significant positive effects on RBCs have not been detected.23

Platelets are extremely sensitive to changes in the pH of the medium in which they are suspended, so sufficient gas permeability to O2 and CO2 has to be assured in the containers devoted to their storage. For this reason, DEHP has been almost fully replaced with TEHTM because a better gas exchange has been found in bags plasticized with TEHTM or polyolefins. This potentially will allow the storage of platelet concentrates for up to 7 days, if measures to prevent bacterial contamination can be safely implemented.

Butyryl-tri-n-hexylcitrate (BTHC) was developed especially for use for RBC containers. Neither the plasticizer itself nor its metabolites show toxicity, especially because the metabolites are found to be citrate, hexanol, and butyric acid. Draper et al24 state that even the side chain metabolite hexanol plays a role in RBC preservation. The technical properties of BTHC are equal or superior to those of DEHP, and even at extremely low temperatures, required for frozen storage, BTHC-plasticized PVC demonstrates a higher resistance to cold stress, which can be explained by a lower glass transition temperature.25 BTHC reduces RBC lysis to a lesser extent than does DEHP.26 Still, this permits the storage of RBC concentrates at 4°C for 35 days. Some authors describe an unpleasant odor, but currently, the main drawbacks of this plasticizer are its elevated price and the lack of the possibility of steam sterilization. Of lower importance is another citrate plasticizer acetyl-tri-n-butylcitrate (ATBC), which is used mainly in the United States and shows characteristics that are very similar to those of BTHC.

Diethylhexyladipate and Diisononylester of Cyclohexanedicarboxylic Acid 

Two more plasticizers are currently being discussed for potential use in blood bags. These are diethylhexyladipate (DEHA) and a diisononylester of cyclohexanedicarboxylic acid (DINCH). DEHA is less compatible with PVC than DEHP, so that exudation (migration of the plasticizer toward the surface, forming separated drops there) has to be considered. Toxicity is only slightly lower than DEHP. That is the main reason why its use will probably stay limited to low-temperature applications and thus the widespread use for the liquid storage of RBCs will not occur. DINCH, also known by its trademark Hexamoll from BASF, have structural and technical characteristics very similar to DEHP. This makes processing with already existing equipment potentially feasible. Some of DEHP drawbacks are, however, somewhat reduced with DINCH. It is said to have almost no migration tendency and toxicity tests have been promising. DINCH has the Food and Drug Administration approval, and RBCs appear to be stable for 42 days in a Hexamoll-based blood bag.27

Use of Other Polymers 

Some of the stabilizers used during the production of PVC such as cadmium or lead have been replaced by calcium, boron, or zinc, which have fewer toxic effects.28 However, one of the main problems associated with PVC is that chlorine-related substances can be discharged to the environment especially during their incineration or combustion. Most of the PVC containing medical products are designed for their single use, so that PVC degradation is usually obtained through incineration, slowly liberating free chlorine, chlorine species (including phosgene), and even dioxins.29 Also, vinyl chloride monomers (VCMs) have been associated with carcinogenicity and other potential toxicities. Thus, reducing the production of PVC would result in a major reduction of the environmental exposure to VCMs. Environmental protective groups advocate the use of materials for single-use medical products that burn without objectionable effluents. However, since the production of most plastics requires other additives such as antioxidants or stabilizers, the issue might bring additional risks that should not be readily disregarded.30

Most alternative polymers commonly used as PVC/DEHP substitutes are ethylvinylacetate (EVA), polyolefins [such as polyethylene (PE), polypropylene (PP)], but even polyurethanes (PU), fluoropolymers as well as the so-called thermoplastic elastomers (TPE) are gaining importance in this regard (Fig 2).

Ethylvinylacetate 

Blood bags made from EVA are commercially available. EVA is a copolymer blend consisting of ethyl and vinyl acetate (VA) with attributes such as high toughness, good flexibility, good sealing properties, and high resistance to external influences and adhesion. As a polyolefin, EVA has a lower density than PVC, leading to an economic yield improvement (thus, more plastic foil is obtained per kilogram of polymer). Changing the percentage of VA can affect parameters such as melting point, film strength, and tackiness. The normal range is approximately 20% to 32% VA,31 and at low temperatures, the material shows high stress resistance and low rate of breakage. The material is already approved for most blood storage containers, and no adverse effects are expected for the storage of frozen RBCs.

Polyolefins are typical polymers, consisting of a single monomer type, which are chemically repeating molecules forming either chains or networks. The most common types of polyolefins are PE and PP, but PEs have better characteristics such as a high gas permeability, good heat stability, and high resistance. Being a nonpolar polymer, PE is neither weldable nor sealable by high frequency. It has a midrange of platelet reactivity, whereas PP implicates a high platelet reactivity with high platelet adhesion and thus a subsequent decrease in the platelet content. Mechanical properties of PE are strongly dependent on the way polymerization is performed, which includes temperature conditions, pressure, and used catalysts. Being 30% lighter than PVC, it is a financially competitive alternative.

PU and TPE 

Two other groups of polymers are partially overlapping. These are the PU and TPE (see Fig 2). Due to their chemical structure, built up by the addition of a polydiol component and a polyisocyanate, PUs are available in a huge structural variety. Both of the monomers can be either aliphatic or aromatic, and branching is possible when using polyol instead of a diol. Choosing various components, the characteristics of the obtained plastic can be varied from hard and tacky to flexible and soft. Often, the low-temperature performance of PUs is better than PVC, making the material sterilizable by either ethyleneoxide or γ-radiation, and at the same time, PU is accessible for high-frequency radiation treatment, which leads to good welding properties.32, 33 In addition to good strength and toughness, it has better biodegradability than PVC and exhibits the lowest degree of thrombogenicity among the considered plastic materials.34 Although isocyanate monomers are highly toxic, which leads to quite a high hazard, the level of residues is mostly undetectable, resulting in a low risk of toxicity.35 A potential drawback to their widespread use is their high price.

Most probably, TPEs are the next generation of polymers likely to be used in the manufacture of blood containers. At room temperature, TPEs exhibit classical elastomer characteristics, and with increasing temperature, they get more pliable. TPEs usually consist of mixtures of polymers in a way that positive characteristics get enhanced and negative ones are reduced.36 The main problem with TPEs is the current high price.

Fluoropolymers 

The last important group is made up by the fluoropolymers, which offer a high degree of lubricity, exceptional chemical resistance, and almost no surface adhesion. The latter leads to a very low platelet reactivity and a high tensile strength (the maximum amount of stress that it can be subjected until failure).37 Fluoropolymers, as its widest known exponent polytetrafluorethylene (PTFE), are used for implantations, because their toxicity is low enough so that even in long-term applications, they are physically unobjectionable. They are characterized by an inherent strength of the material, permitting the manufacturing of very thin bags, reducing the material cost. However, their high price limits the use in blood bags. Also, their flouride content leads to critical environmental aspects of production and degradation. In the high-throughput environment of single-time-use items such as blood bags, such aspects have to be considered as important.

There have been attempts to use latex and silicones to produce blood bags, but as in most fields, those materials are being replaced due to their allergenic properties. It is thus likely that they will never be one of the main substitutes for blood bags.

Modifications of Already Existing Materials 

This third approach consists mainly of the modification of the already existing blood bags, material formulations, or storage conditions. It has to be considered that more sophisticated technologies usually lead to higher production costs38 and that most of the presented approaches are not yet technically realities, but current proposals of several research groups.

Being completely free of plasticizers is possible with the use of PVC alloys, mostly with PE, PP, or polystyrol. When 2 polymers are blended together, it should be realized that in the initial mixture they might not be compatible with each other. Then, the interfacial energy is reduced by adding a compatibilizer to obtain a better dispersion and more favorable characteristics of the material.30 In many cases, compatibilizers are copolymer or terpolymers consisting of 2 or 3 distinctive monomers.39 High-molecular-weight PVC, which is suitable for applications requiring soft materials, needs no plasticizer due to its higher degree of crystallinity and its improved mechanical strength.40

It has been recognized that good biocompatibility of medical devices is often due to their hydrophilic surfaces. Such hydrophilic materials reduce adsorption of proteins, cellular components (such as platelets, leukocytes, erythrocytes, and fibroblasts), diminished blood clotting pathways activation, as well as reduced leaching of plasticizers. Presumably, such a surface acts as a barrier to the DEHP diffusion.3 Recently, the addition of polyethylene oxide (PEO), both as additive or copolymer, has been shown to produce the favorable characteristics of the flexibility of PVC, its transparency, lubricity, and its surface activity.41 A number of US Patents disclose PEO monomers grafted on PVC as copolymer or terpolymer.

Messori et al42 proposed the coating with PEO and an inorganic silicium alkanoxide. PEO was chosen because of its intermolecular association complexes with PVC and its low cost and its availability. The coating was performed by a wet chemical sol-gel process, and the results obtained indicate that the leaching of the plasticizer can be significantly reduced by choosing the right composition of the coating.

It is also worth noting that plasticized PVC is used as the basic material for the production of cross-linked PVC, which is characterized by modifications in the chemical structure initiated by radiation or chemical agents.43 A reaction with a cross-linker creates further connections in the polymer that inhibits the migration of plasticizers; the main drawback is the high viscosity of the melt, leading to engineering problems.

Navarro et al44 presented a polymer with covalently bound mercaptophthalate plasticizer, which leads to plasticizer loss approaching zero. In case of the blood bags, however, the conservative effect of DEHP on RBCs might not be found if there is negligible migration of plasticizer leaching.

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How to Overcome the Gap to be Left by DEHP 

Very few of the various alternatives to DEHP plasticized PVC discussed provide for the storage characteristics of DEHP. The substitution of an alternate plasticizer or material could thus lead to shorter RBC storage times, which could cause serious problems for blood banking. To overcome those problems, several research groups have proposed an optimized composition of additive solutions present in blood bags in combination with preliminary leukoreduction.45, 46 Leukoreduction is already frequently used in the routine preparation of blood products for transfusions, and it reduces RBC hemolysis. The separation of the components is usually obtained by a filter system removing the leukocytes. The removal of leukocytes has been shown to improve hypothermic storage of RBCs. This fact can be explained by minimized glucose consumption and waste production and no release of leukocyte enzymes that favor RBC hemolysis.

The normal composition of anticlotting solutions present in blood bags usually contain variable amounts of specific agents such as citrate/citric acid, monobasic phosphate, dextrose, adenine, and others. The basic idea in modifying those classical additive solutions is to decrease the morphologic, membranous, and metabolic deterioration that usually affects oxygen affinity and RBC deformability, which is important to enable RBCs to pass quickly through capillaries. Conditions that have been shown to improve RBC storage are washing, anaerobic conditions, and addition of carbohydrates such as sorbitol or mannitol. Hill et al44 obtained a significant reduction of hemolysis in polyolefin bags using an additive solution that contains monobasic sodium phosphate, adenine, and sodium chloride. Additionally, the solution contained mannitol, as metabolic enhancer, and glucose.43 Although hemolysis was significantly reduced using those polyolefin bags, both analyzed parameters (hemolysis and ATP levels) were still better in DEHP-plasticized PVC bags. Meryman et al,47 as well as Greenwalt et al,48 achieved a significantly longer RBC storage time using hypotonic solution with basic buffer capacity to neutralize the ammonia present that precludes clinical use. The additive approach is promising and, in combination with some of the previously mentioned materials, might open ways toward either a longer conservation or shorter but less degradative one using alternative products for the production of blood bags.

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Conclusions 

A short overview is shown in Table 2, which lists the various possibilities to replace DEHP as the plasticizer for blood bags. It can be concluded that there are many approaches and many practical alternatives available, and numerous research groups are tackling this topic for platelets and plasma. For RBCs, however, there are few convincing alternatives offering RBC the same protecting qualities of DEHP and allowing their long-term storage with equal qualities.16

Table 2. Summary of Possibilities for Alternatives to DEHP in Blood Bags
AdvantagesDisadvantages
• Substitute plasticizer
PVC is inert, durable, cheap, resists heat and cold, and binds readily with other plasticsContains chlorine (energy consuming during production), may lead to dioxin formation, phthalates increase smoke formation. Other plasticizers not fully risk-free
• Change polymer
No plasticizers neededNo positive effects on RBCs. Biocompatibility characteristics are not clear
Possibility that further stabilizers present can have a negative impact
• Technical improvements
Variable characteristics, high adaptability to client requirementsHigh technical effort may lead to elevated costs
Use of new materials can produce unexpected impact

As soon as research progress will allow the use of alternatives with similar quality as those in current DEHP-containing bags, the remaining question is whether it is possible to replace a hazard by a safer alternative. Even with the current unavoidable resistance to change in part based on the risk/cost ratio, this possibility should not be discarded. Instead, research should be continued to try to identify the best safe alternative.

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Acknowledgments 

The authors thank Dr. Otter of BASF for helpful information on the legislative status and Dr. L. Puig of the Banc de Sang i Teixits for providing some interesting insights. J Simmchen thanks the European Commission for a Leonardo da Vinci fellowship. The IMIM Foundation and the DIUE Generalitat de Catalunya (2009 SGR 492) partially supported the publication of this article.

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PII: S0887-7963(11)00056-3

doi:10.1016/j.tmrv.2011.06.001

Transfusion Medicine Reviews
Volume 26, Issue 1 , Pages 27-37, January 2012

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