ToxSci Advance Access originally published online on December 2, 2003
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Toxicological Sciences 77, 368-374 (2004)
Copyright © 2004 by the Society of Toxicology
SAFETY EVALUATION |
Comparative Study on Cardiotoxic Effect of Tinuvin 770: A Light Stabilizer of Medical Plastics in Rat Model
Járay*
* Department of Transplantation and Surgery, Semmelweis University, Budapest, Hungary, 1082;
Department of Cardiovascular Surgery, Semmelweis University, Budapest, Hungary, 1122;
Department of Forensic Pathology, Semmelweis University, Budapest, Hungary, 1091; and
National Institute of Forensic Toxicology, Budapest, Hungary, 1146
Received September 12, 2003; accepted October 29, 2003
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Tinuvin 770 [bis(2,2,6,6-tetramethyl-4-piperidinyl) sebacate], is a UV light stabilizer plastic additive used worldwide. It is a component of many plastic materials used in medical and food industries. Earlier studies demonstrated its in vitro L-type Ca2+ channel and nicotinic acetylcholine receptor blocking properties. Our previous experiments have proved the toxic effects of Tinuvin 770 on isolated rat cardiomyocytes. The present study investigates the cardiotoxic effects of Tinuvin 770 in vivo. Wistar rats were intraperitoneally injected with increasing doses of Tinuvin 770 (1, 10, 100 µg, and 1 mg) 15 times during a 5-week period. Myocardial samples were analyzed by light, electron, and fluorescent microscopy. The lead-acetate method was used to detect intracellular Ca2+, and glyoxylic acid technique to assess alteration in adrenergic innervation. Focal myocytolysis and hypercontraction necrosis could be observed in rats treated with higher doses of Tinuvin 770. In these groups, intracellular Ca2+ accumulation and increased catecholamine release were detected. Tinuvin 770 not only displays L-type Ca2+ channel blocking properties, but can also lead to catecholamine release, similar to effects of the first generation of L-type Ca2+ channel blockers. Morphological results correspond to catecholamine-induced myocardial damage. Current literature, as well as our study, indicates that more detailed toxicological analysis of Tinuvin 770 should be required, and current regulations in medical and food industries should adopt the new results.
Key Words: Tinuvin 770; cardiotoxicity; catecholamine; L-type Ca2+ channels, light-stabilizers; hemodialysis.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Photostabilizers are plastic additives that can prevent light-induced photodegradation of plastics. Hindered amines light stabilizers (HALS) represent one of the most important groups of additives (Gächter et al., 1990
). A member of this group, Tinuvin 770 [bis(2,2,6,6-tetramethyl-4-piperidinyl) sebacate] is used worldwide to stabilize polyethylene, polypropylene, polycarbonate, polyurethane, polystyrene, polyamide, polyacetyl, and acrylonitril polymer products (Wiles et al., 1983). These polymers are components of plastics used in medical and food industries (Glossmann et al., 1993; Marque et al., 1996; Papke et al., 1994; Sótonyi et al., in press). Depending on the actual use of plastic products, they can gain access to the body via the gastrointestinal system, transdermally, or through the bloodstream. In vitro experimental studies show that Tinuvin 770 has a benzothiazepine (+)-cis-diltiazem-like, extremely potent (IC50 values < 10 nM) L-type Ca2+ channel-blocking effect (Glossmann et al., 1993). Its action is mediated through binding to the phenylalkylamine and benzothiazepine-selective domain of the 
1 subunit of the receptor. This compound also diminishes the 1,4-dihydropyridine-sensitive Ca2+ uptake. Interestingly, its structure is not related to formerly known Ca2+ channel blockers. Beyond the above-mentioned effects, it is a more potent blocker (IC50 values 
200 nM) of the neuronal nicotinic acetylcholine receptors than the experimentally extensively used ganglion blocker Mecamylamine (IC 50 values 10 µM) (Papke et al., 1994). Tinuvin 770 binds to the 4,ß2 acetylcholine receptors with high affinity in the central nervous system (Flores et al., 1992).
Our previous study has indicated the time-dependent nature of Tinuvin 770 cytotoxicity on isolated rat cardiomyocytes caused by altered Ca2+ metabolism. The cardiomyocytes culture, suspended in 25 nM Tinuvin 770 solution for 60 min, showed hypercontraction in 53% of the cells, along with marked decrease in ATP and creatine-phosphate (CP) concentration. After 120 min, 60% of the suspended cardiomyocytes showed irreversible damage with further drastic fall in ATP and CP level (Sótonyi et al., 2001).
The significance of Tinuvin 770 content of medical industry products is underlined by fact that the molecule can come to direct contact with the circulation. During hemodialysis 250–300 ml/min blood flows trough a 1–1.8 m2 plastic dialysis membrane for 3–4 h. This treatment is usually repeated three times a week in patients with chronic renal failure. Our previous analytical study showed that Tinuvin 770 is extractable from four different types of hemodialysis membranes (Sótonyi et al., in press), underlining the significance of experimental toxicological analysis of this chemical.
The literature is extensive on the adverse effects of hemodialysis, caused by the method itself, and directly or indirectly by the plastic membranes. Some of the most important adverse effects include anaphylactic reaction to ethylene oxide (Bommer and Ritz, 1987) and formaldehyde (Kessler et al., 1988) used for sterilization, the reuse of the hemodialysis membranes (Sótonyi et al., 1996), intoxication of chloramine (Tipple et al., 1991) and fluorine (Arnow et al., 1994), pyrogenic reactions (Roth and Jarvis, 2000) caused by bacterial contamination, shock-syndrome (Tielemans et al., 2000) due to interaction of ACE inhibitors and AN-69 membrane, and other unexpected cardiopulmonary events (Tielemans et al., 1996) using different types of membranes and dialyzing solutions.
In 2001, several countries (Spain, Croatia, United States, Italy, Germany, Taiwan, and Columbia) reported separately cases of unexpected chest pain, dyspnea, and circulatory collapse followed by deaths, during or soon after hemodialysis. Subsequent toxicological studies showed the presence of perfluorohydrocarbon (PF5070) in pulmonary capillaries (Sass et al., 1976). PF5070 is a material used in premarket testing of membrane permeability. The investigation revealed remnants of this material, which was not removed completely during manufacturing and formed an emulsion with blood at a normal body temperature and low oxygen pressure. It is apparent that the interaction between plastics and the human organism can cause a wide range of unexpected reactions (Canaud, 2002).
Hypotension is the most common complication of hemodialysis, occurring in about 15–20% of patients (Sato et al., 2001). Clinical symptoms can develop subsequent to a drop in systolic blood pressure of a minimum 30–50 mm Hg. Most commonly observed symptoms are nausea, vomiting, dizziness, and sometimes loss of consciousness. Decreased blood volume, peripheral vasoconstriction, and cardiac factors can be held responsible for the development of hypotension (Daugirdas, 1991). Because Tinuvin 770 displays the L-type Ca2+ channel blocking effect on both the peripheral vessels and the myocardium, this molecule might potentially contribute to hypotension.
Based on our formerly published observations on myocardial cell cultures, we decided to study Tinuvin 770-induced morphologic changes of myocardium of rats.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Animals.
Fifty Wistar rats (25 males and 25 females), weighing 250–330 g, kept under standard laboratory circumstances with access to food ad libitum, were used in the study in accordance with the ethical regulations of animal care at Semmelweis University. This experimental study was approved by the Regional Ethical Committee of the Semmelweis University (No: 59/2001).
Animal exposure and tissue analysis.
Animals were randomly selected into five groups (I–V), with 10 animals in each (five males and five females). Group I served as control, receiving a mixture of equal amount of physiologic saline solution (Salsol solution, Human, Gödöll, Hungary) and 96% ethanol (Riedel de Haen, Seelze, Germany) intraperitoneally (ip) during the full length of the experiment. Groups II–V, were injected ip 15 times during a 5-week period (three times a week: Mondays, Wednesdays, and Fridays) with varying doses of Tinuvin 770 [bis(2,2,6,6-teramethyl-4-piperidinyl) sebacate, Ciba Geigy Co., Basel, Switzerland], in a 1-ml solution containing equal amount of physiologic saline and 96% ethyl alcohol. The applied Tinuvin 770 doses were calculated on the basis of parallel execution of an acute hemodynamic dog model, where the acute effective dose range (leading to hypotension and diminished ventricular contractility) was from 1 to 100 mg on dogs with 25 kg body weight (EC50 
0.137 mg/kg body weight, LD50 4 mg/kg body weight). The Tinuvin 770 doses were: 1 µg for group II, 10 µg for group III, 100 µg for group IV, and 1 mg for group V. Animals were decapitated following deep ether narcosis. Myocardial samples for morphologic studies were taken from the left ventricular myocardium, the interventricular septum, and the papillary muscles. Myocardial tissues were fixed in phosphate buffered 4% formaldehyde (pH 7.2). After routine histological processing, hematoxylin-eosin (H&E), azan, phosphotungstic acid-hematoxylin (PTAH), Van Gieson, and PAS stains were used. For transmission electron microscopic studies, the myocardial samples were fixed in 3% glutaraldehyde, buffered with 0.1 M Na-cacodylate, postfixed in 1% osmium tetroxide and embedded in araldite. Toluidine blue stained semithin sections were used to select areas for ultrastructural investigation. Following araldite removal, further semithin sections were stained with PTAH and Movat methods. Ultrathin sections were contrasted with uranyl acetate and lead citrate, coated with carbon, and examined with JEOL 100B electron microscope at 60 kV accelerating voltage.
For cytochemical detection of Ca2+ lead-acetate method was used (Carasso and Favard, 1966). Alterations in adrenergic innervation were followed by the glyoxylic acid technique (Shwalev and Zhuchkova, 1979; Zhuchkova et al., 1984). Evaluation was performed by using Jenalumar fluorescent microscope (VEB Carl Zeiss, Jena, Germany) with exciting filter VG1/3.5+BG52/2 and closing filter GG9+OG4.
Urinalysis.
Last urine samples were collected by direct urinary bladder puncture and analyzed for noradrenalin using high performance liquid chromatography (HPLC). Extraction was performed using Discovery C18 column; the mobile phase was a mixture of 3% acetonitrile, 96% potassium dihydrogen phosphate (pH 3, 25 mM), EDTA, octane-sulphophosphoric acid (0.05 mM). Noradrenalin was detected by dual electrochemical method (Coulochem 2 coulometer, 550 mV).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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No significant changes were observed in the behavior and feeding habits of the animals in groups I–III. There was no animal loss in these groups. The animals in groups IV–V gradually lost activity from the third week. They became apathetic, and their food consumption decreased. The resulting weight loss is demonstrated in Table 1
. They huddled up against each other in the cage and reacted very poorly to external stimuli. One animal was lost in group IV, and three in group V on the fourth week.
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Light and electron microscopic studies of the myocardium showed no pathological changes in group I. The myocardial structure was well preserved; no necrosis or focal lesions were observed. Slight Ca2+ reactions were present in the sarcoplasmic reticulum and mitochondria in left ventricular myocardium (Fig. 4A
). The glyoxylic acid reaction shows regular, longitudinal catecholamine depletion along the myofilaments (Fig. 5A).
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No significant morphologic changes were present in group II.
In group III, small disseminated hemorrhages were presented on the upper third of the interventricular septum at gross examination. On histology, slight, small, focal hypercontraction, interstitial edema, and myocytolysis were found (Fig. 2A). In groups II and III, catecholamine release did not increase at the adrenergic nerve terminals, and there were no differences in Ca2+ content compared to the control group.
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In group IV, uneven distribution of blood was grossly evident in the left ventricle. Flat, sheetlike large hemorrhages were present in the subendocardial region of the ventricular septum. Histology showed large amount of red blood cells in the interstice (Fig. 1A
). The myofibrils precipitated in various degrees, forming aggregates in the edematous sarcoplasm. With destruction of myofibrils, several different-sized vacuoles appeared in the sarcoplasm, focally forming even larger-sized vacuoles by fusion (Fig. 1B). The remaining sarcoplasm lined the sarcolemma in an annular fashion (Fig. 1C). Two other alterations were also observed: emptied tubules of sarcoplasm, caused by complete lysis of the myofilaments, leading to myocytolysis (Fig. 3A); and in some microscopic fields, cellular damage with intensively stained hypercontraction bands. Electron microscopic studies proved impairment of filaments in areas of Z and I bands. Loss of continuity of actin and myosin filaments could also be observed, along with partial or full lysis. In the close vicinity of damaged filaments, the electron dispersive properties of Z bands were decreased. The remaining filaments of the I bands showed bundle-like precipitation with the splitting of cross-bridges. In the surrounding areas of the injured actin and myosin filaments, marked intracellular accumulation of Ca2+ was noticed. Opposed to the control group, fluorescent microscopy detected an increased amount of stored catecholamine in the nerve terminals in the subendocardial areas of the septum.
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In group V, gross examination of the heart showed extensive hemorrhages underneath the endocardial layer of both ventricles, extending slightly into the myocardial layer. In the swollen, longitudinally arranged myocytes, contraction bands were observed (Fig. 1D
). Due to disruptions of fibrils, the filaments were diverged, with overstretched sarcomeres. The described histological alterations represent hypercontraction necrosis (Fig. 2B). Electron microscopy, in addition to different levels of hypercontraction necrosis (Fig. 3B), showed damage in the inner mitochondrial membrane and a reduced number of glycoprotein granules. Myocyte Ca2+ intake was substantially increased, with calcium particles present in the mitochondria (Fig. 4B). Fluorescent microscopy demonstrated massive, irregular catecholamine release in the nerve terminals of the subendocardial regions (Fig. 5B). The results are semiquantitatively summarized in Table 2.
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Animals lost before the end of the study showed similar alterations in all aspects to those observed in the animals of group V.
Histological examination of other organs (lungs, spleen, brain, kidneys, blood vessels) did not result any significant changes, except the livers in groups IV and V, where mild unspecific intracellular vacuolization was observed in hepatocytes.
Noradrenalin urine level was approximately 10 times higher in the treated groups (although without substantial differences between them) compared to the control one. Results are demonstrated in Table 3.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Ca2+ channel blockers are widely used medications in cardiovascular diseases. They selectively inhibit Ca2+ influx into the cells on voltage-dependent cell membrane Ca2+ channels. All clinically used Ca2+ channel blockers (phenylalkylamines, dihydropyridines, benzothiazepines) develop their action on the
1 subunit of the L-type Ca2+ channel (Epstein, 1998). L-type Ca2+ channels are found in the myocardium, in the vascular smooth muscles, and in a smaller amount in the skeletal muscles (McDonald et al., 1994). Blocking L-type Ca2+ channels causes negative ino-, chrono- and dromotropic effects and vasodilatation. Ca2+ channel blockers belong to a diverse group of medications based on their cardiac and vascular selectivity (Pelzer et al., 1992). Phenylalkylamines are more selective on the myocardium, and dihydropyridines on the vasculature (Gong et al., 1996; Pitt, 1997). The selectivity of benzothiazepines are between them. Tinuvin 770—based on in vitro experimental studies—cannot be classified as a member of any previously known group of Ca2+channel blockers; even its chemical structure is completely different. Tinuvin 770 can not only bind with high affinity to the region of the Ca2+channels, where phenylalkylamines and benzothiazepines are bound, but can also inhibit Ca2+influx by acting on the dihydropyridine site (Glossmann et al., 1993). This combined action of Tinuvin 770 explains its complex effect. In vitro studies have suggested that Tinuvin 770 may antagonize neuronal nicotinic acetylcholine receptors (Papke et al., 1994). Vasodilatation, typical of ganglion blockers, leads to further drop in blood pressure. No significant structural myocardial changes were seen in group II, where low dose (1 µg), of Tinuvin 770 was given. At the dose of 10 µg (group III), only slight alterations were observed. In groups IV and V, where higher doses of Tinuvin 770 (100 µg, 1 mg) were applied, an intense effect occurred. The L-type Ca2+ channel blockage may be counterbalanced and suspended by reflex sympathetic adrenergic activation. In support of this finding, our results demonstrated increased catecholamine activity by fluorescence microscopy and marked intracellular Ca2+ accumulation in the myocardium, showing myocytolysis and hypercontraction necrosis. Our experiments elegantly demonstrate the dose-dependent nature of this process.
In view of the above, our observation is seemingly contradictory, because—as opposed to Ca2+channel blockers—Tinuvin 770 causes a dose-dependent myocardial damage (myocytolysis, hypercontraction necrosis). Tinuvin 770 can induce hypotension followed by reflex-induced increased sympathetic tone (data from our unpublished dog experiment), similar to effects caused by dihydropyridines. The cascade of events can lead to diminished oxygen supply, myocardial ischemia, and damaged myocardial contraction.
Myocytolysis and hypercontraction necrosis can be a final common pathway for many different events, including hypoxia, direct toxic effects, and left ventricular pressure overload. The described morphology is characteristic for catecholamine-induced myocardial damage. Elevated urine noradrenalin levels could be a marker for stress condition of the treated animals. Sudden increase in catecholamine blood level can induce hypermetabolism and forced myocardial contractility with increased work capacity and oxygen demand (Burniston et al., 2003). Catecholamines, in physiologic concentrations, can increase the contractility function of the myocardium by intensifying the consumption of high-energy phosphates. Using catecholamines in a higher than physiologic concentration, causes a dramatic increase in Ca2+influx, leading to the collapse of cellular energy and ionic homeostasis, and subsequent functional and structural cellular damage (Bristow, 1995; Lehr, 1981; Shinay et al., 2000; Zimmer, 1997). Catecholamine-induced myocardial damage is primarily a metabolic event. The aerobic oxidation will gradually shift toward anaerobic and fatty acid oxidation. ATP production in anaerobic glycolysis will be insufficient, because myocytes will be unable to maintain the ionic gradients, and the decreased amount of ATP is inadequate to maintain intracellular Ca2+ balance (Dhalla, 2001). In the case of decreased intracellular ATP level, relaxation of myocardium is suffered (Van der Velden, 1998). As a consequence, a rise in intracellular Ca2+ accumulation and decreased diastolic outflow develop. An increased intracellular Ca2+ accumulation will also appear in the mitochondria, affecting their structure and function.
The observed phenomenon is fully supported by the earlier in vitro studies on cardiomyocyte cultures (Sótonyi et al., 2001), that the cell membrane of myocytes lost their integrity, leading to irreversible damage of the isolated cells.
Summarizing the results of our morphological study, we can conclude that the toxic effects of Tinuvin 770 on the myocardium emerge when 100 µg or higher doses are administered long-term.
The above-described phenomenon should attract special attention, because Tinuvin 770 is a widely used industrial plastic additive, due to its excellent attribute as a UV light stabilizer, and due to its cost effectiveness. Long-term hemodialysis treatment could serve as a basis for contamination with Tinuvin 770, because of the long-lasting, direct interaction between blood and plastic surface. The likelihood emerges that Tinuvin 770 may play a role in the development of certain adverse events in chronic hemodialysis treatment. Our results aim to attract attention to the fact that any plastic device containing Tinuvin 770 can harbor the chance of contamination when it comes into contact with the human body.
We would like to call attention to the emerging latent problem of using Tinuvin 770 and initiate further interdisciplinary investigations. Development of systematized and extensive regular toxicological monitoring should also be obligatory for the safety of medical plastics.
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ACKNOWLEDGMENTS |
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The authors wish to thank Ilona Seffer and Albert Werglesz for their technical assistance. This work was supported by Hungarian National Research Foundation (OTKA T 030153).
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NOTES |
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1 To whom correspondence should be addressed at Semmelweis University, Department of Transplantation and Surgery, 23–25. Baross str., Budapest, Hungary H-1082. Fax: 00-36-1-3170-964. E-mail: sotonyi{at}hotmail.com.
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