Should DEHP be eliminated in blood bags?

Abstract

Whole blood for transfusion was initially collected in glass bottles, but these are fragile, heavy to transport and prone to bacterial contamination. After the Second World War, Carl Walter experimented with plastics for collection and storage of blood, and found that di-ethylhexyl phthalate (DEHP) as plasticizer for polyvinyl chloride (PVC) had the most favourable properties [1, 2]. The breakage rate of frozen plasma in DEHP PVC is low, and the better storage properties of red cell concentrates in DEHP PVC are explained by leaching of plasticizer into the lipid bilayer of these cells, thereby improving membrane stability resulting in lower haemolysis rates [3]. However, ever since the 1970s, scientific and public concern has been raised on the toxicity of DEHP for transfused patients [4, 5]. DEHP and its metabolite mono ethylhexyl phthalate (MEHP) are associated with impairment of reproduction in animal models, resulting in testicular dysgenesis syndrome in (male) rodents, as reviewed in depth elsewhere [6], and particularly, neonates are susceptible to the risks of high exposure to DEHP. Due to the omnipresence of phthalates (not only DEHP), and some important differences in DEHP metabolism between animal models and humans [6], it is difficult to estimate the effect of DEHP toxicity in humans. A study of 234 young men showed no effect of MEHP in urine on their reproductive function [7], but others showed that DNA damage in sperm was associated with the MEHP concentration (after adjustment for other DEHP oxidative metabolites) [8]. In vitro human testis explants incubated with DEHP or MEHP showed that both significantly inhibited testosterone production [9], and a study of 881 men showed a 9% lower free androgen index between the lowest and the highest quartile of the proportion DEHP excreted as MEHP (P = 0.02) [10]. Also, an association was found between urinary MEHP concentrations and lower free T4 and lower total T3 thyroid hormones in adult men [11]. In addition to these effects on hormonal level in adult males, DEHP and its metabolites can have an effect on fetal development, with a shorter anogenital distance associated with higher metabolite concentrations in urine samples collected during pregnancy [12]. Others found no difference in T4 and testosterone levels, as well as no effect on phallic length in 13 male adolescents 14– 16 years of age that had underwent ECMO treatment in their neonatal period, as compared to ageand sexmatched controls [13]. Also, DEHP/MEHP exposure (as detected in cord blood) was significantly associated with a shorter pregnancy duration [14]. Despite these associations, they should be interpreted with care. DEHP is not the only phthalate that may cause these effects; studies that showed no association may not have been published; DEHP administered through the intestinal tract is converted to MEHP in a higher degree as by intravenously [15]; and because phthalates are everywhere in our environment, comparisons are less versus more, rather than absent versus present. DEHP-plasticized PVC has long been used as standard material for a wide range of applications, like packing foil (including food), building material, toys and plastic devices. DEHP is considered to be a ubiquitous environmental contaminant and is present in air, dust, water, soil and food. The latter is considered to be the main source of DEHP intake for the general population. The current daily intake is estimated to be between 2 and 5 lg/kg for adults and between 4 to 8 lg/kg for children [16, 17]. Various measures to reduce the use of DEHP-plasticized PVC have indeed resulted in a 2-times lower exposure to DEHP in the general population over the last two decades [18]. DEHP is applied in many medical devices, and depending on the procedure, patients can be exposed to high (peak) concentrations of DEHP, in the order of 1 mg per kg of bodyweight. One of the sources of DEHP exposure is the leaching from the blood bags into the content of the container, particularly into lipophilic solutions such as plasma [19], but also red cells. Therefore some patient groups, including pregnant or nursing women and children, are considered to be most at risk of possible harmful effects attributable to DEHP exposure by medical treatments. DEHP is broken down into various metabolites. First, it is hydrolysed to MEHP and then further oxidized to mono-(2-ethyl-5-hydroxyhexyl) phthalate (5OH-MEHP),