Document jBgOZwwz7dR2wop97qna10wOk

R&S 105946 BIOMEDICAL RESEARCH DOCUMENT DESCRIPTION FORM 63 68 69 <np*/KJ3676 Duplicate in all cards:--> year as-1961- File number [Right justify [Numeric only] Author(s), as Last Name FS (No Punctuation) and coden for journal as JAMA preceeded by. one blank space 1 '/EW/. F 'P. 20-21 40 41 77 78 Sub-Index Code 60 61 62 11 12 LO Title of P^eport; end with space-hyphen-hyphen-space. Follow with Index Terms. separated from each other with -comma-space. Avoid other punctuation; do`not abbreviate. 12 .' _ 61 62 Source (Journal, Vol., Number, Pages, Date) 12 /fk/gAu/ .............. ' ' <3- C$) bPf 74. 1----------------------- ---------------------1-- Brief Summary' 12 10 SUMMARY: 61 62. 31 32 61 62 61 62 63 64 4* ' 3KSHELF z below are now availLeonidas, Ml 490G6. Holmes,. -5 pages. prevention, IS, 1975. ) 375, TABOLISM vsky, S37.50 $39.50 $22.50 S49.50 $27.50 $49.50 $29.50 $47.50 $45.00 $29.50 $49.50 $24.50 $22.50 $24.95 $32.50 J3 nnw Bo W 0 01 (O -J ; I) M ( yQ." y Sri 0000036 r(l- ARfffiY"2t5):3S4-3SS (1976) -n EDITORIAL _ }\( 0 !_ `'n / POLYVINYLCHLORIDE PLASTICS - THE ENEMY WITHIN? The widespread use of plastic goods having medical and biological application arises partly from the generally held view that plastics are "inert" and "safe"* While this may be true of some plastics, there is both direct and indirect evidence that other plastics, particularly the flexible polyvinylchloride (PVC; plastics, can release chemical agents toxic to living systems* Despite warnings to this effect, the use of PVC plastics in medicine and research continues. If one examines the scattered reports of "plastics toxicity" that have emerged over the past 15 years, it becomes clear that we are long overdue in identifying the toxic agents and in de fining their toxicity. To emphasize this point, I would like to draw attention to studies that may be of interest to individuals working in the blood , cardiovascular, and cell or tissue culture areas. PVC plastics contain agents called "plasticizers" which determine the flexibility properties of the plastic product (1-3); esters of phthalic acid are commonly used for this purpose, particularly di-2-ethylhexyl phthalate (DEHP) (3,4). While the phthalates are generally viewed as having a low order of acute and chronic toxicity in animals by classical toxicological criteria (3,5-8), a number of important observations have been made recently which suggest that phthalates warrant closer examination. Chick embryo heart cells are particularly sensitive to DEHP; a con centration of 4 ug/ml in the culture medium can kill 97-98% of the cells in 24 hours (9). Phthalate toxicity extends to cultured mouse fibroblast L-cells (10) and neonatal rat cerebellar fibroblasts (11,12). DEHP has also T' 1 ^< R&S 105948 --- -------------------------- ij l-fTffBffi 5 * * been found to depress or stimulate reticuloendothelial function in rats, depending upon the schedule of administration (9). Evidence has also been presented that phthalates alter platelet adhesiveness (9) and alter the survival of platelets stored frozen in PVC bags (13). In our own studies ** 1 on the biochemical effects of DSiP in rats, we have found that the addition of DEHP to rat diets at a level of 0.15? results in a 25-455$ inhibition of l^C-palmitoyl CoA oxidation by heart mitochondria in vitro within 2 to 4 days (14). Additionally, we found that DEHP feeding to rats over a 10 day period resulted in a steady decrease in squalene and sterol biosynthesis from 14c-acetate and ^H-mevalonate in liver slices (l5)j 14c_acetate incorporation into other hepatic lipids was also significantly reduced with DEHP feeding t when examined after 10 or 18 days of treatment (16). \ } The observations cited above (9-16) give rise to concern in view of the i fact that the intake and accumulation of phthalates from plastic medical ; devices occurs in patients undergoing a variety of medical treatments such a as blood transfusion, haemodialysis, extracorporeal circulation, and umbilical 1 catheterization. DEHP leaches into human plasma from PVC haemodialysis tubing (17) and has been found to be extracted by human and dog blood from plastic bags used for blood storage (18,19). The levels of DEHP found in stored blood can be considerable. Jaeger and Rubin (18,0) reported levels of 5-7 mg/lOO ml in human blood stored 21 days in PVC bags and found the rate of DEHP accumulation to be linear with time at a rate of about 0,25 mg/lOO ml blood/day (21). These workers calculated (21) that a whole-oody exchange transfusion in a 70 kg man with 21-day old blood would average about 300 mg of DEHP j intravenously, representing a dose of 4-5 yg/g body weight. In fact, in 13 patients previously transfused with blood delivering from 14-600 mg DEHP, i levels of DEHP in spleen, liver, lung and adipose tissue ranged from 25-270 ug/g (dry weight) with the highest level being found in adipose, while % 385 _ial function in rats, Evidence has also been ass (9) and alter the _), In our own studies a found that the addition 3 25-453J inhibition of tn vitro within 2 to 4 to rats over a 10 day .a sterol biosynthesis from lj}C-acetate incorporation zinced with DEHP feeding ~o concern in view of the . from plastic medical medical treatments such . circulation, and umbilical za PVC haemodialysis cmsan and dog blood from =vels of DEHP found -rin (18,20) reported vs in PVC bags and found = at a rate of about y exchange transfusion about 300 mg of DEKP weight. In fact, in ring from 14-600 mg DEHP, zssue ranged from 25-270 3 in adipose, while 37 flo C/) o U1 CO 7 of 12 lung samples contained 13,4 - 91.4 ig/g. The DEHP extracted by whole blood from plastics is found associated with the platelets (22,23), plasma lipoproteins (18,21), and the erythrocytes (18,21). Although it is not known what effect phthalates may have on plasma lipoprotein or.blood cell metabolism _in vivo, phthalates do appear to modify some aspects of erythrocyte metabolismj the exposure of human erythrocytes to phthalates has been reported to result in a 2-to 3-fold increase in the incorporation of l,<*C-linoleic acid into erythrocyte lipids .in vitro (24). DEKP has also been found to contaminate platelet concentrates stored in plastic blood bags (22,23). The platelets appear to preferentially accumulate DEHP since, after only 2 days of storage, DEHP concentration in platelets has been reported at 37.7 mg/lCO ml (packed volume), while the platelet-poor plasma fraction contained 16.7 rng/lOO ml (22). . A recent study by Hillman et ah (25) further emphasizes the extent and seriousness of phthalate exposure during medical treatment. These investi gators studied DEHP levels in neonatal heart and gastrointestinal tissue from 17 infants after umbilical catheterization alone or in combination with bicod products administration. They observed a rapid accumulation of DEKP in heart tissue that, in general, reflected the combined dosages of the number of catheters and amount of blood products; DEKP levels reached S pg/g of heart tissue (wet weight). Of possible significance as well was their observation that in gastrointestinal tissue from 3 infants whose death was attributed to necrotizing enterocolitis, DEHP levels were ca. 10-12 times higher than in infants without the disease (25). It was suggested that DEKP may act as a vascular or gastrointestinal toxin, A similar explanation v/as offered for the development of intestinal perforation following exchangetransfusion in neonates in which PVC tubing v/as employed (26). A toxic effect of phthalates on vasculature may be the explanation for the loss of vascular response to physiological stimuli observed iji vitro in perfused 386 'T " w human umbilical arteries and perfused feline lungs in systems employing PVC tubings (26,28). In addition to plasticizers, flexible PVC plastics frequently contain other additives, called "stabilizers" (l), such as organotin compounds} other organometallic agents are used as well (27,28). Unfortunately, like plasticizers, the stabilizers are not without biological effects. Meyler et a_l. (27) traced the early deterioration of cardiac performance in isolated per fused rat hearts to an organotin leached from PVC tubing into the perfusion medium. Subsequent studies by Guess and Stetson (29) demonstrated that the addition of pieces of PVC endotracheal tubing to tissue cultures of mouse fibroblasts or chick embryo cells resulted in cell death. Toxicity was, again, attributed to the migration of organotin from the plastic pieces. The material presented here, while by no means a comprehensive review of the literature, points out a variety of biological effects attributable to agents present in PVC plastics currently used in medicine and research. The message seems clear} until chemical additives to PVC plastics are iden tified and their biochemical and pharmacological effects evaluated, users of such products should be advised to consider alternatives, such as glass, where possible. j 1 -- *i Department of Pathology McMaster University Hamilton, Ontario Canada R&S 105950 REFERENCES 1. little, K. and J. Parkhouse. 1962. Tissue reactions to polymers. Lancet 2i857-861. 2. Graham, P.R. 1973. Phthalate ester plasticizers - why and how they are used. Environ. Health Perspect.. 3t 3-12. 387 1m (sm*t Afsiaa rn systems employing PVC nics frequently contain -anotin compounds; other zortunately, like plas_ effects. Meyler et al. rrmance in isolated perjoing into the perfusion demonstrated that the isue cultures of mouse reath. Toxicity was, again, _astic pieces, a comprehensive review :i effects attributable medicine and research. PVC plastics are idenects evaluated, users of -ives, such as glass, .-rank P. Bell, Ph.D. Department of Pathology McMaster University Hamilton, Ontario Canada iions to polymers. s - why and how they are I 1 3. Autian, J. 1973. Toxicity and health threats of phthalate esters; Review of the literature. Environ. Health Perspect. 4; 3-26. 4. Marx, J.L. 1972. Phthallc acid estersi Biological Impact uncertain. Science 178; 46-47. 5. Hodge, H.C. 1943. Acute toxicity for rats and mice of 2-ethyl hexanol and 2-ethylhexyl phthalate. Proc. Soc. Exp. Biol. Med. 53; 20-23. 6. Shaffer,-C.B., C.P. Carpenter and H.F. Smyth, Jr. 1945. Acute and subacute toxicity of di-2-ethylhexyl phthalate with note upon its metabolism. J. Ind. Hyg. Toxicol. 27; 130-135. 7. Carpenter, C.P., C.S. Weil and H.F. Smyth, Jr. 1953. Chronic oral toxicity of di-2-ethylhexyl phthalate for rats, guinea pigs and dogs. Arch, Ind. Hyg. Occup. Med. J3; 219-226. S. Harris, R.S., H.C. Hodge, E.A. Maynard and H.J. Blanchet. 1956. Chronic oral toxicity of 2-ethylhexyl phthalate in rats and dogs. A.M.A. Arch. Ind. Health 13; 259-264. 9. Rubin, R.J. and R.J. Jaeger. 1973, Some pharmacologic and toxicologic effects of di-2-ethylhex/l phthalate (DEHP) and other plasticizers. Environ. Health Perspect. 3; 53-59. 10. Dillingham, E.O. and J. Autian. 1973. Teratogenicity, mutagenicity and cellular toxicity of phthalate esters. Environ. Health Perspect. 3t 81-89. 11. Kasuya, M. 1973. Cytotoxicity of phthalate esters. Jap. J. Hyg. 28: 248-252. 12. Kasuya, M. 1974. Toxicity of phthalate esters to nervous tissue in culture. Bull. Environ. Contain. Toxicol. 1_2: 167-172. 13. Kim, B.K. and M.G. Baldini. 1973, Preservation of viable platelets by freezing. Effect of plastic containers. Proc. Soc. Exp. Biol. Med. 142; 345-350. 14. Bell, F.P. Unpublished results. 15. Bell, F.P. 1976, Di-2-ethylhexyl phthalate; An inhibitor of hepatic sterol and squalene biosynthesis in the rat. J.A.O.C.S. 53: A463. 16. Bell, F.P. and D.J. Nazir. 1976. Effect of dietary di-2-ethylhexyl phthalate on lipid biosynthesis in selected tissues from the rat, in vitro. Lipids 11: 216-221. 17. Easterling, R.E., E. Johnson and E.A. Napier, Jr. 1974, Plasma extrac tion of plasticizers from "medical grade" polyvinylchloride tubing. Proc. Soc. Exp. Biol. Med. 147: 572-574. 18. Jaeger, R.J. and R.J. Rubin. 1970. Plasticizers from plastic devices: Extraction, metabolism, and accumulation by biological systems. Science 170; 460-461. ?88 DO * 1 Ull T fiP </> o U1 (0 tn 19- Marcel, Y.L. and S.P. Noel. 1970. A plasticizer in lipid extracts of human blood. Chem. Phys. Lipids 4i 417-418. 20. Jaeger, R.J. and FUJ. Rubin. 1970. Contamination of blood stored In plastic packs. Lancet 2i 151. 21. Jaeger, R.J. and R.J. Rubin. 1972. Migration of a phthalate ester plasticizer from polyvinylchloride blood bags into stored human blood and its localization in human tissues. N. Engl. J, Med. 237i 1114-1118. 22. Jaeger, R.J. and R.J. Rubin. 1973. Oi-2-ethylhexyl phthalate, a plasticizer contaminant of platelet concentrates. Transfusion 13i 107-108. 23. Contreras, T.J., R.H. Sheibley and C.R. Valeri. 1974. Accumulation of di-2-ethylhexyl phthalate (DEHP) in whole blooo, platelet concentrates, and platelet-poor plasma. Transfusion _14t 34-46. 24. Shastri, K. and D. Rubinstein. 1969, The metabolism of the erythrocyte. XIX. Factors affecting esterification of linoleate by human erythrocytes. Can. J. Biochem. 47i 967-975. 25. Hillman, L.S., S.L. Goodwin and W.R. Sherman. 1975, Identification and measurement of plasticizer in neonatal tissues after umbilical catheters and blood products. N. Engl. J. Med. 292i 381-366. 26. Rogers, A.F. and P.M. Dunn. 1969. Intestinal perforation, exchange transfusion and PVC. Lancet 2i 1246. 27. Meyler, F.L., A.F. Willebrands and D. Durrer. 1960. The influence of polyvinylchloride (PVC) tubing on the isolated perfused rat's heart. Cir. Res. 8: 44-46. 28. IXike, H.N. and J.R. Vane. 1966. An adverse effect of polyvinylchloride tubing used in extracorporeal circulation. Lancet 2i 21-23. 29. Guess, W.L. and J.3. Stetson. 1968. Tissue reactions to organotinstabilized polyvinylchloride (PVC) catheters, J. Amer. Med. Assoc. 204 580-584. 389 R&S 105952