(PPAR)
, that would seem to be present in humans in an inactive form. A Review
G. Latini
Division of Pediatrics, Ospedale A. Perrino, Brindisi, Italy
G.Latini, MD
Division of Pediatrics, Ospedale A.Perrino
Azienda Ospedaliera A.Di Summa, Piazza Di Summa
I -72100 Brindisi (Italy)
Tel.+39 0831 537471, Fax +39 0831 537861, E-Mail gilatini@tin.it
Accessible online at: www.karger.com/journals/bon
Key Words: Polyvinylchloride . Di-(2-ethylhexyl)-phthalate . Medical device . Pregnancy
Many plastic items are made of polyvinylchloride (PVC) blended with plasticizers. The most frequently used plasticizer is di-(2-ethylhexyl)-phthalate (DEHP). DEHP migrates at a constant rate from plastics to the environment: it has been detected in water, soil and food and is therefore considered as a widespread environmental contaminant. Over the past several years, a number of publications concerning toxic effects of DEHP on animals and humans have been reported. Although DEHP is suggested to be of low acute toxicity, long-term exposure, especially in human beings at risk such as pregnant women and children, requires more in-depth studies. If DEHP toxicity in humans were to be confirmed, it would be advisable in the future to replace current PVC plasticizers, especially if they come into contact with babies, with better-quality materials.
Phthalate esters are a class of water-insoluble organic chemicals which have been used as plasticizers for polyvinylchloride (PVC) formulations since about 1930.They are extensively produced and widely used (annual production being estimated at about 2 million tons) in many applications (e.g. medical devices, toys, food wraps, shoe soles, and interior building surfaces), as a result of their cost, convenience and adaptability.
In fact, PVC is a rigid material and these additives are added to the polymer to make the plastic flexible and appropriate for different uses. Di-(2-ethylhexyl)-phthalate (DEHP) is the most commonly used plasticizer. It is an odorless, oily liquid and its content in plastics varies from 40 to 50%of the final weight. But, plasticizers are not chemically bound to the polymer and, with time and use, have been shown to be released from PVC formulations into the external environment. Phthalates have been found everywhere in the environment, both in aquatic and ground mediums, indoor as well as outdoor environments, in animals and humans, in domestic wastes, in foods and in babymilk formulae, for example [1 -8] and therefore they have been considered as ubiquitous environmental contaminants.
DEHP action is dose, time and age dependent. Therefore, DEHP potential exposure risk will be presumably higher for infants, particularly infants at an early and more sensitive stage of their development, and pregnant women. In fact, Parke [9] showed that neonates are often more receptive than adults to the toxic effects of chemicals and Dostal et al. [10] confirmed younger rats were more sensitive than adult ones to DEHP toxic effects.
There are several PVC formulations with which babies may come into contact. For example, they may ingest up to 6 mg of DEHP/day, sucking on plastic toys; but it is likely that a similar or higher assumption of this substance could be reached sucking on pacifiers, teethers or plastic bottles or by skin contact with clothing or playpens [11 - 13]. Accordingly, in the follow-up to its recommendation dated July 1, 1998, on November 10, 1999, the European Union Commission proposed an emergency and permanent ban of phthalates in toys and articles for children under 3 years of age.
However, the most dangerous risk of exposure for infants is probably the release of DEHP from PVC medical devices because plasticized PVC is mostly used in these items.
The utilization of plastic medical devices has greatly reduced the use of glass, thus avoiding the risk of cross-contamination and infection and the need for resterilization [14]. But DEHP is lipid soluble, so when PVC medical devices are contiguous with lipid-containing body tissues (e.g. blood), this plasticizer leaks out, accumulating in blood and tissues, particularly in the liver, kidney and lung, especially if renal function is impaired [15]. Consequently, medical devices become more rigid [16]. DEHP is released from several medical devices (feeding tubes, infusion tubing systems, umbilical catheters, PVC blood bags, transfusion tubing systems, hemodialysis systems, cardiopulmonary bypass, continuous peritoneal dialysis, extracorporeal membrane oxygenation circuits (ECMO) or endotracheal tubes [15 -43] ).
The acute toxicity of DEHP on man is probably low, while the consequences of chronic exposure have not been investigated, but are presumably higher although the constant presence of this substance as an environmental contaminant complicates these evaluations. Presumably for these reasons, Jaeger and Rubin [44] described it as being of subtle toxicity.
Since the end of the 1960s, several studies have been performed to analyze the biological effects of such substances, and during these years an increasing number of reports have appeared in the literature on the adverse effects of DEHP and its major metabolite, mono(2-ethylhexyl) phthalate (MEHP) on animals and humans, especially those with poor renal function, e.g. in patients undergoing hemodialysis and newborn babies at risk. Presumably, DEHP is not as safe as originally thought.
The ability of polymers to induce platelet aggregates, platelet adhesion and thrombus formation during in vivo blood-material contact is well known and the lack of these undesirable effects is considered very important in order to assess biocompatibility of biomaterials [45]. It has been shown that DEHP can influence the biocompatibility of PVC medical devices and this might have detrimental effects on exposed subjects. In fact, since 1976 it has been known that DEHP might increase platelet adhesion and aggregation due to the greater adsorption of Á -globulin and fibrinogen [46].
In addition the presence of DEHP in the polymer may favor the extraction of toxic components from plastic matrix [47].
Moreover, in 1995 Kicheva et al. [48] reported that an increased amount of DEHP causes material deterioration in PVC drain tubes, inducing the formation of thrombi on the surface of material in vitro as well as in vivo and decreasing blood coagulation time and hemoglobin concentration in exposed dogs. Likewise, in 1999 Zhao and Courtney [49] observed that a reduction in the amount of surface plasticizer improves the blood compatibility of plasticized PVC. In addition, Webb et al. [50] showed that plasticization with DEHP increases adhesion of fungi to plasticized PVC and stimulates its biodegradation and we observed that DEHP leakage contributes significantly to material degradation in endotracheal tubes after application [43]. More recently, Lamba et al. [51] reported that when the DEHP-plasticized PVC comes into contact with the human blood it is a potent activator of complement.
Since DEHP is not chemically bound to the plastic matrix, it may leach out into the biological fluids which it comes into contact with. Increased leakage of the plasticizer may occur in relation to factors such as the duration of contact, elevated temperature or alkalinity of the extractant [17] , but lipophilicity of the solution in contact with the PVC item and the mechanical alteration of the material may also facilitate it. In most species, including man, DEHP is rapidly and extensively metabolized to its hydrolysis products MEHP, 2-ethylhexanoic acid and phthalic acid (PA). In healthy human beings they are rapidly (by 24 h) excreted by the kidney (90%), as conjugated (glucuronide) oxidation products of MEHP, and feces (10%) [52]. Hydrolysis of DEHP to its main metabolite MEHP occurs in the liver, intestine, and plasma during storage. The (ˆ-1)-hydroxylation of MEHP is catalyzed by a cytochrome P-450-dependent monooxygenase system and occurs, at least in rodents, in liver microsomes [53].
In healthy subjects, MEHP is the principal metabolite, while PA is the main metabolite in subjects with renal insufficiency. In these patients a large amount of PA can be found in urine which might be explained in part by the good water solubility of PA. On the other hand an active tubular secretion of PA can be suspected because the concentration in urine is much higher than that in the serum of the patients [54].
Different situations of exposure should be considered according to various pieces of medical equipment. In detail, it has been shown that:
(1) The leakage of DEHP from blood bags may be up to 11. 5 mg/100 ml. In adult patients who received blood transfusions, significant amounts of DEHP were found in the spleen, liver, lung and abdominal fat, in levels ranging from 0.025 to 0.270 mg/g dry weight [37, 44]. In neonatal tissues, this compound was detected in the heart and gastrointestinal tract, ranging from 0.66 B 0. 22 to 1.27 B 0.42 µg/g in the heart and from 0.10 B 0.02 to 0.41 B 0.13 µg/g in the gut tissues [30].
(2) Hemodialysis patients are exposed to considerable amounts of DEHP and its metabolites (up to 3.1 mg/kg body weight per day) with values ranging from 250 mg to 50 g per year [55].
(3) Newborn babies who underwent exchange transfusion were estimated to be exposed during a single exchange transfusion to amounts of DEHP and MEHP ranging from 0.8 -3.3 and 0.05 -0.20 mg kg -1 body weight, respectively. However, 4 -6 mg of DEHP/kg body weight were infused into an infant who had undergone three exchange transfusions within 16 h [19].
(4) In artificially ventilated preterm infants DEHP exposure ranged from 1 to 4, 200 µg/h [27]. In addition in the used endotracheal tubes we reported a loss of DEHP, ranging from 0.06 to 0.12 mg/mg of sample (6 -12%) on a time-related basis [43].
(5) Among patients placed on a cardiopulmonary bypass, the highest levels of DEHP and MEHP were found in infants (5.1 and 2.7 µg/ml, respectively). In most of them, DEHP and MEHP returned to preoperative levels within 24 h. In patients with low urinary output, both compounds were still measurable after 120 h [24].
(6) In newborn infants on ECMO, plasma DEHP concentrations ranged from 18 to 98 µg/ml. DEHP levels of 3.3, 1.0 and 0.4 µg/g were found in liver, heart and testicular tissue, respectively, while traces of this compound were observed in the brain. The rate of DEHP extraction was directly correlated to the duration of exposure. Duration exposure in ECMO infants is much higher (71 -330 h) than in those undergoing a cardiopulmonary bypass (1 - 4 h), hemodialysis (3 -4 h) and exchange transfusion (2 - 3 h) [31, 41].
In animals, or at least in rodents, bronchial hyperreactivity, asthma, pulmonary constriction, pulmonary edema [21, 22] , carcinogenesis, teratogenesis, hepatotoxicity [29] and reproductive toxicity [56, 57] were observed. Lung damage with infiltration and degranulation of polymorphonuclear leukocytes, histologically similar to protease-induced lung lesions, increased release of lysosomal enzymes from alveolar macrophages in vitro [58] as well as inhibition of the rabbit alveolar macrophage killing [59] were also observed. Alveolar macrophages are known to produce and release reactive oxygen species, while containing antioxidative enzymes [60] and a wide variety of proteases, that can cause lung damage and emphysema [58].
In 1991 an interesting observation was made by Sjoberg et al. [61] who reported a competitive inhibition between MEHP and bilirubin for glucuronidation in the guinea pigs. Since both MEHP and bilirubin use the same glucuronyltransferase system(s), this might lead to a decreased elimination of MEHP and/or bilirubin with a consequent prolonged exposure to each of them. This might also explain high levels of MEHP found in hyperbilirubinemic babies undergoing exchange transfusions. In 1997 Peters et al. [62] reported teratogenesis and zinc deficiency during pregnancy and it is known that zinc deficiency leads to maternal and embryo-fetal toxicity. In addition, histological damage in testis, kidney and liver during pregnancy and suckling [63] , cryptorchidism after prenatal exposition [64] and persistent thyroid hyperactivity [65] were observed. Then, polycystic kidney disease and a decrease in kidney function [66, 67] as well as a dose-dependent decrease of cell viability in kidney epithelial cells [68] , hypotension and cardiac arrest [69] , decrease in the concentration of vitamin E in liver and testis [70] and finally peroxisome proliferation in liver, kidney and brain [71 -74] were also reported.
Although exposure to DEHP in babies is often significant, no evidence of toxicity has been reported to date. More precisely, higher levels of DEHP in plasma of newborn infants during exchange transfusions [18 -20] , as well as in the gastrointestinal tissue of 3 premature babies who died of necrotizing enterocolitis, were observed [30]. In ECMO infants, based on a statistically significant association between DEHP levels and degree of cholestasis, Shneider et al. [31] postulated that DEHP exposure could cause cholestasis. On the other hand, Karle et al. [41] did not observe any evidence, at least of short-term toxicity. Moreover, Roth et al. [27] reported pathological changes of lungs, corresponding to those observed in hyaline membrane disease, in preterm infants, while Øie et al. [75] suggested that plasticizers could cause asthma in children by stimulating production of prostaglandins and tromboxanes in lungs.
Finally, we observed DEHP leakage from used endotracheal tubes to ventilate very-low-birth-weight infants and hypothesized that it could play some role in causing bronchopulmonary dysplasia [43].
A different picture emerges in the case of human tissues and biological fluids, where a more consistent number of adverse effects have been reported. More exactly in 1988 Labow et al. [76] showed inhibition of human platelet phospholipase A2 and decreased platelet function in stored platelets. In 1990 Barry et al. [23 -25] reported arrhythmias, a decrease in strength of contraction and negative inotropic effect on human heart muscle and atropine inhibition of these effects, presumably due to the cholinergic receptors. In 1993 Fredricsson et al. [77] observed that long-term exposure to DEHP resulted in a 25%reduction of human sperm motility and Calo et al. [78] showed an increased secretion of interleukin-1 in DEHP-stimulated mononuclear human cells that could be, at least in part, responsible for peritoneal sclerosis in subjects undergoing peritoneal dialysis. In 1995 Smith et al. [47] observed acute toxicity in cultured human lung fibroblasts, probably subsequent to the synergistic action of plasticizer and stabilizer, while in 1998 Fischer et al. [79] showed a dose-dependent impairment in leukocyte oxidative metabolism in vitro. More recently, an increase in lipid peroxidation of erythrocytes and consequent hemolysis, presumably due to oxidative damage to the cell membrane, as well as a decrease in the concentration of vitamin E in blood stored in DEHP-plasticized bags have been reported [70, 80, 81].
Speculations
As reported above, DEHP belongs to the class of peroxisome proliferators (PPs). Peroxisomes are subcellular organelles ubiquitous in mammalian cells, involved in the oxidation of long-chain fatty acids, in the production of hydroxyl and superoxide radicals and probably of the pulmonary surfactant [82, 83]. Peroxisome acyl-COA oxidases catalyze peroxisomal ß -oxidation and donate electrons directly to molecular oxygen, thereby producing H2O2. Antioxidant enzymes (catalase, superoxide dismutase and glutathione peroxidase) are present in peroxisomes and protect them from oxidative damage. The loss of peroxisomal function and inhibition of catalase activity following ischemia-reperfusion injury suggest that peroxisomes are implied in the pathophysiology of free radical injury and play an important role in diseases associated to free radical damage. In recent years, increasing experimental and clinical observations have shown that hyperoxia or ischemia-reperfusion injury and the consequent excess radical generation participate in the pathogenesis of the main four complications of prematurity (chronic lung disease, retinopathy of prematurity, intraventricular hemorrhage and necrotizing enterocolitis) [84 -89] , while the respiratory distress syndrome is the most important cause of death in premature babies.
Peroxisomes proliferate in response to several chemicals, which are indicated as PPs. PPs (such as DEHP) cause oxidative stress situations through sustained overexpression of H2O2-generating peroxisomal fatty acyl-COA oxidase and overproduction of other reactive oxygen species. PPs also decrease antioxidant enzyme production [82]. Considering that preterm babies are less protected against oxygen metabolite toxicity and are at higher health risk of DEHP, an intriguing hypothesis could be that DEHP leakage from medical devices could make an important contribution to this increased free radical formation and might therefore play some role in causing the above-reported diseases. Also, considering that DEHP is a lipid-soluble substance and that the major part of surfactant consists of lipids, another interesting hypothesis could be that DEHP, easily solubilized in the surfactant layer lining the alveolar wall, might interfere with the secretion and/or turnover of surfactant and get worse evolution of the respiratory distress syndrome.
Most of the observed toxic effects are not caused by DEHP itself but by its metabolites. Among these there is accumulating evidence that its primary metabolite MEHP is responsible for the chronic toxic effects that may occur after long-term exposure. As reported above, the exposure to them may occur in a number of situations. During the last several years, most of the toxic effects resulting from exposure to DEHP have been observed in animals, while the potential toxicity from DEHP in humans, and especially babies, has been poorly evaluated. However, potential hazards of exposure to DEHP observed in animals cannot be thoroughly applicable to humans, because metabolism and toxicity of phthalate esters have interspecies variability and species differences subsist also among human beings themselves.
On the other hand, there is general agreement that DEHP is of low acute toxicity, since median lethal dose (LD50) of standard laboratory animals administered this compound by most of the routes (oral, topical or intraperitoneal) ranges from 14 to 50 or more g/kg. But, it should be considered that, when DEHP is administered intravenously, the LD50 is much lower (200 mg/kg) [90]. For this reason long-term exposure risk, especially for hemodialyzed and multiply transfused patients, should be carefully evaluated. For example, the amount of DEHP migration might be insignificant in each hemodialysis, but when these patients undergo up to 100 -150 treatments a year, DEHP accumulation is likely to increase.
Moreover, since oxidation and glucuronide formation are impaired in preterm and newborn babies due to the immaturity of the liver, they probably have higher exposure risk than adults. Presumably, for these reasons Sjoberg et al. [19] observed that the elimination of MEHP in a preterm infant was slower than its formation and Plonait et al. [20] found significant amounts of DEHP in a preterm baby 4 days after an exchange transfusion.
Equally, considering that DEHP and its metabolites are prevalently eliminated by urine, in healthy subjects we commonly observe lack of toxicity, while patients with impaired renal function, again hemodialyzed patients and extremely-low-birth-weight infants, have increased exposure to plasticizers.
Further studies will be necessary in the near future to detect which of the toxic effects reported in animals are also present in humans. To date only cardiotoxic effects have been observed both in animals and in human tissues.
The presence of DEHP as a widespread environmental contaminant (low but
measurable levels of DEHP, <1 µg/ ml) found in the blood of healthy
volunteers) [55] has made these studies difficult. Furthermore, not all the
toxic effects reported in animals are present in humans. For example, liver PPs
are considered a class of rodent hepatocarcinogens, but humans differ from
rodents in their response to liver PPs. In fact, they are less or nonresponsive
to the hepato toxic effects of PPs. There are quantitative and qualitative
differences to explain this different response to PPs. In fact, on the one hand,
these effects are mediated by PP-activated receptor (PPAR)
, that would seem to be present in humans in an inactive form.
On the other hand, PPAR
levels in human liver are lower than in rodents [91, 92]. Therefore, according
to the Environmental Protection Agency, DEHP should be classified as an unlikely
human carcinogen [93]. Instead, DEHP and MEHP might lead to bronchial
hyperreactivity in man as well as in animals, since prostaglandins and
tromboxanes, which are considered inflammatory mediators of asthma, have
configurations resembling DEHP and MEHP, with regard to the molecular size and
ring structure [75]. Similarly, polycystic kidney disease in long-term
hemodialysis patients and renal cysts in DEHP- treated rodents have been
observed since the end of the 1970s. Therefore, although a causal relationship
between the two phenomena was not found, DEHP long-term exposure is likely to
result in renal cysts both in animals and in humans [66, 67]. Finally, it is
more complex to establish if testicular and ovarian damage and consequently
reproductive toxicity, that are rodent specific, might also be present in
humans. In fact, on the one hand Dostal et al. [94] reported that the loss of
Sertoli cells due to DEHP exposure in neonatal rats did not affect fertility as
adults, and on the other hand Arcadi et al. [63] noted the persistence of
testicular damage up to 8 weeks of age and then postulated its irreversibility.
Furthermore, Oishi [95] noted that the testicular injury could be partially
reversed if DEHP administration ceased.
Moreover, it should be kept in mind that perinatal exposure to environmental chemicals would seem responsible, at least in part, for the reported decline in sperm count in men [96] and prolonged exposure to DEHP resulted in significant reduction of human sperm motility [77]. Therefore, it would not seem improbable that long-term exposure to DEHP may play some role in causing, at least in males, reproductive disorders.
Hence, is DEHP as safe as originally thought? Presumably, it is not. In fact, to correlate toxic effects in animals and acceptable levels of exposure for humans a margin of safety is chosen. Acceptable margins of safety are commonly 100-to 1, 000-fold greater than those causing the toxic effect. In several studies MEHP levels causing toxic effects are only 15-to 50-fold greater than MEHP levels found in several clinical situations [23, 26, 76].
In addition to the above, a number of other points also emerge:
(1) The acute toxicological effects of DEHP on humans are likely to be low, while effects of long-term exposure are not well known and necessitate more in-depth studies, especially in high-risk human beings.
(2) Hemodialyzed, multiply transfused, extremely-low-birth-weight infants, especially those having a severely compromised cardiovascular or renal function, should be considered at higher risk of potential toxicity from DEHP, due to regular exposure to the plasticizer over prolonged periods of time.
(3) Several investigators have reported the material biodegradation in DEHP-plasticized PVC medical devices.
(4) There is increasing evidence of toxicity in animals, but these effects cannot be simply transferred to humans.
(5) No evidence of toxicity in children has been detected, but an increasing number of reports on adverse effects in human tissues and biological fluids have appeared in literature.
Considering the above-cited observations, further studies on this topic will be necessary to improve our knowledge; in the meantime, we could conclude asserting:
(1) According to the European Union Recommendations, we should change the materials in those PVC items such as toys, pacifiers or teethers, for example, where safer alternatives can be identified.
(2) Many investigators have proposed to discontinue the use of plastic medical devices containing extractable materials, which could be even slightly harmful [19, 25 - 30, 33, 35 -40, 42, 61] and to make every effort to detect improved additives in PVC medical devices. In the future, if DEHP toxicity in humans is confirmed, even if only in part, it would be appropriate to eliminate the use of DEHP in medical devices, especially when they are used in children, particularly if at an early and more susceptible stage of their development, and pregnant women. Preliminary studies have confirmed the possibility to detect improved materials [97].
(3) In the meantime, it will be necessary to study the DEHP kinetics from plastics and thereby establish the timing for replacing PVC medical devices in order to reduce exposure risk.
(4) Finally, considering that DEHP is an environmental contaminant, the introduction of new materials on the market could contribute to a safer environment and a better health status for all and particularly of babies.
The author expresses his gratitude to Gordon B. Avery, MD, PhD, Emeritus Professor of the Children's National Medical Center, Washington, D.C., USA, Robert D. Christensen, MD, Division of Neonatology, University of Florida, Gainesville, Fla., USA, and Thomas Mettang, MD, 'Abteilung Nephrologie Zentrum für Innere Medizin, Robert-Bosch-Krankenhaus ', Stuttgart, Germany, for their precious suggestions during the preparation of this paper.
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