I want to say one word to you—just one word—“plastics”

Blood bags, blood administration sets, and medical devices are manufactured with the plastic polyvinylchloride (PVC). Phthalates are plasticizers that impart flexibility, strength, temperature resistance, compatibility, and gas exchange to PVC and hence are vitally important to PVC manufacture and the functionality of PVC products. Phthalates are aromatic diesters, noncovalently bound to PVC during manufacture, and can represent 20 to 40 percent of the finished weight of the plastic.1 Di(2-ethylhexyl) phthalate (DEHP) migrates out of the plastic and leaches into blood or other lipid-containing solutions. The rate of leaching increases with storage over time and varies by temperature. DEHP leaching has been studied extensively for stored whole blood,1 platelets,2 and plasma.3 The most well studied phthalate is DEHP and its toxic metabolite monoethlyhexyl phthalate (MEHP); these compounds have been reported to cause a wide range of adverse effects in animal models including hepatotoxicity, teratogenicity, hepatic and renal malignancies, and reproductive toxicity including testicular atrophy, chromosomal breakage, ovarian dysgenesis, and hypospermia. The developing male reproductive tract appears to be particularly susceptible to damage. A safety assessment of DEHP has been published by the FDA4 and adverse human health outcomes have been reviewed by Hill and colleagues,5 the American Council on Science and Health,6 and the Lowell Report.7 The National Health and Nutrition Examination Survey (NHANES) has documented measurable exposure to phthalates in the general population.8 Concerns over environmental, household, and oral exposure to phthalates have resulted in a series of expert panels with subsequent changes in manufacture and use. The European Commission on Health and Consumer Products,9 Health Canada,10, 11 and the Japanese Ministry of Health12 have spoken out against DEHP, and some manufacturers have voluntarily removed PVC from nipples, pacifiers, teethers and infant toys, housing stock, and many cosmetics. In the United States, the Public Health Service has recommended substitution of medical devices containing PVC by use of other plastics and minimizing exposure whenever possible. In August 2004, the Institute of Medicine (IOM) established a committee to evaluate postmarket surveillance of medical devices in pediatrics. The concerns of the IOM are several, but of significance is the fact that studies rarely continue long enough to evaluate the impact of medical devices and long-term exposures on a child's growth and development. The toxicology of phthalates will be covered in the IOM report (M. Fields, personal communication, January 2005). In 1989, Rubin and Ness13 published an editorial entitled "What price progress? An update on vinyl plastic bags" in TRANSFUSION. They reviewed some of the early toxicological data and embryopathies reported from in vitro and animal studies. They warned about potential human organotoxicity and theorized that the "collective inertia" of the blood bank community resulted from the inconclusive nature of the data, counterbalanced by the practical disadvantages of changing to alternative plastics. Much of that inertia was fostered by the lack of consensus on whether the extensive animal data, which has continued to grow over the past 16 years, have relevance to humans. Some argue that experimental animal exposures differ in terms of dose, timing, route, and species differences in metabolism and excretion, wherein the toxic metabolites, the cellular targets(s), and concomitant exposure cannot be equated to human exposure. Several studies published this year, however, now question whether DEHP and/or MEHP and other phthalate metabolites are truly nontoxic and have identified fetuses and neonates as high-risk populations that warrant careful study and challenge us out of that inertia. In 2003, the American Academy of Pediatrics' Committee on Environmental Health reviewed the current literature and recommended that medically exposed infants and older children were at highest risk for gonadotoxicity. They advised studies of several sensitive populations, especially women of childbearing age, premature infants, and others undergoing extensive medical procedures.14 Although many older studies have quantified plasma concentrations of DEHP in infants undergoing exchange transfusion,15 simple transfusion,16 open heart surgery,17 and extracorporeal membrane oxygenation,18 none quantified the toxic MEHP and other phthalate metabolites. Sophisticated tandem mass spectrometry had not yet been developed, and there were no comparative studies on the general US population. Methods have now been developed and documentation of urinary metabolites has since been published.19, 20 A flurry of recent studies have now focused the medical community again on phthalates; these include a study on long-term effects on pubertal development,21 concentrations of urinary oxidative metabolites in premature infants,22, 23 adverse effects of prenatal phthalate exposure on infant anogenital distance,24 and modulation of DEHP leaching from ECMO circuits.25 Of particular note are those studies detailed below. Urine samples were collected from six premature infants (23-26 weeks of gestation; birth weight, 440-880 g) and evaluated for urinary MEHP and other oxidative metabolites including mono(2-ethyl-5-hydroxyhexyl) phthalate (mEHHP) and mono-(2-ethyl-5 oxohexyl) phthalate (mEOHP). This was the first study to quantify levels of DEHP metabolites in tiny premature infants who underwent a wide variety of medical procedures (including blood transfusion). This study confirmed a 20-fold increase in urinary concentration of these metabolites as compared to a reference population of healthy US children age 6 or older.22 To further characterize the nature of DEHP exposure, a companion study was performed on 54 infants in two Level III Neonatal Intensive Care Units.23 Three exposure categories were defined (low, medium, and high) through observation over time. Spot urine samples were collected at least once from each infant and analyzed for 10 phthalate monesters. Urinary MEHP levels in the high-exposure group were 5.1 times higher than those among infants in the low-DEHP-exposure group and were modestly higher among male than female infants. Differences in MEHP exposure between the two NICU's were ascribed to the use in one institution of unsiliconized PVC endotracheal tubes and hemodynamic monitoring umbilical venous catheters used for parenteral nutrition and as a source for intravenous (IV) access. The third article of significance to the debate on the potential adverse effects of phthalates was published in August 2005.24 This study's aims were to evaluate anogenital distance (AGD) in infants whose mothers participated in the multi-institutional pregnancy cohort Study for Future Families (SFFI). AGD is a sensitive measure of antiandrogenic effect, seen in rodents exposed to DEHP,26 and is part of a "phthalate syndrome," which includes testicular, epididymal, and gubernacular cord agenesis.27 Anthropomorphic measurements, including a standardized examination of the genitals, provided an anogenital index (AGI). Urinary phthalate metabolites were also measured. A total of 134 infants were evaluated at a mean age of 15.9 months. Mothers' urine samples were collected at a mean of 28 weeks' gestation. More than 90 percent of the 85 mothers tested had evidence of some phthalate exposure. Four metabolites including MEHP were significantly associated with short AGI, and short AGI was associated with incomplete descent of one or both testicles and small penile size. Of great concern is the fact that phthalate levels in the mothers with boys with short AGI were consistently higher than those of other mothers and US female patients tested in NHANES III. Although this study shows an association between maternal phthalate exposure and AGI in boys, it was not designed to show causation, but cumulatively with the two other recently published articles, raises concerns for pregnant women, the fetus, premature infants, and children heavily exposed through medical devices and, of course, transfusion. Why is the fetus and/or neonate at increased risk for phthalate toxicity? Toxicokinetics, how the fetus and/or infant metabolizes the toxicant, and toxicodynamics, how the toxicant affects the body, are dependent on the unique physiology and developmental stage of the infant. Both quantitative and qualitative differences can significantly affect absorption, distribution, metabolism, and excretion of DEHP. Glucuronidation is the major metabolic pathway that converts DEHP to its more toxic metabolite, MEHP, which is then excreted through urine. Glucuronidation pathways are not mature in the infant until 6 months of age. Thus, the neonate is at risk for longer intravascular circulation of DEHP. Urinary concentration mechanisms are poorly developed in the infant. Thus, there is less ability to excrete MEHP and its oxidative metabolites. Tubular secretion matures slowly in the infant with peak renal capacity reached by age 2 to 3 years. Blood–brain and, more critical for DEHP and/or MEHP, blood–testis barriers are attenuated in the infant, leading to greater exposure of DEHP and/or MEHP to the still developing gonads and central nervous system. Finally, gastric lipase hydrolyzes DEHP when administered orally; gastric lipase concentrations are low in neonates. Those infants exposed intravenously through blood and blood administration sets, exposed to respirators and other medical devices, receiving total parenteral nutrition intravenously or orally, who are housed in the plastic environment of the NICU, have multiple sources of exposure. If one adds exchange transfusion and blood product support during extracorporeal membrane oxygenation, their cumulative risk is 20-fold that approved as the tolerable human intake.28 Why should these recent human studies, the ever-expanding toxicological animal data, governmental tracks, or organizational recommendations affect how the blood banking community practices? The answer lies in the hypothesis of endocrine disruption and carcinogenicity. Environmental contaminants even at low doses can lead to adverse effects on the endocrine system. These so-called endocrine disrupters can influence the morphologic and physiologic development of the offspring of mothers exposed during pregnancy and also the reproductive behavior of those offspring when they reach adulthood.29 Endocrine disrupters can be estrogenic, antiestrogenic, androgenic, antiandrogenic, and thyroid depleting. Their ubiquitous presence may account for population-based trends including decreasing age at menarche, decreased semen quality, increasing rates of hypospadius, rising rates of both male and female infertility, and rates of testicular cancer. Furthermore, childhood hepatocellular carcinoma and leukemia have been correlated with a complex neonatal course and ascribed to hyperoxygenemia.30 Perhaps it is the carcinogenetic potential of phthalates, not oxygen, that should be more fully explored. If any adverse consequences, especially gonadotoxicities, are to be identified, then a population of infants, massively exposed by oral, IV, and environmental routes at the second most vulnerable time in their development, that is, in the neonatal period, should be studied. We must ascertain whether adequate pubertal development has occurred in these formerly medically fragile infants as they approach adolescence. If confirmed, the blood bank community should again explore alternative plastics to protect highly vulnerable populations of pregnant women, fetuses, neonates, and children heavily exposed to blood transfusion.

Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.