- Email: [email protected]
599. Toxicity of cyanoacrylates
PROCESSING AND PACKAGING CONTAMINANTS
421
pyrene, 1-methylpyrene, 2-methylpyrene and 4-methylpyrene while chrysene appears side by side with its 1-methyl and 6-methyl derivatives.
598. PTFE and high-density polyethylene implants in the body Charnley, J. (1963). Tissue reactions to polytetrafluorethylene. Lancet ii, 1379. In a letter by one of Britain's most prominent orthopaedic surgeons a warning is given concerning the introduction into the body of polytetrafluoroethylene (PTFE)--also known as Teflon and Fluon--in circumstances where it is likely to be abraded in situ. Particles of PTFE give rise to an intense foreign-body reaction, resulting in granulomatous masses, and quantities of sterile pus. The formation of large quantities of caseous material has been seen containing as much as 13 % dry weight of PTFE and causing insidious bone erosion. The reaction is thought to be partly due to persistent meebanical movement between the PTFE implant and the bone and partly a chemical reaction to the abraded particle. The author describes the effect of subcutaneous injection into his own thigh of finely divided specimens of PTFE and "high-density" polyethylene. The PTFE injection caused unpleasant subjective reactions and tenderness in the region of the implant. Nine months later the PTFE implant had swollen to twice its size and could be clearly felt. No such reaction occurred following injection of "high-density" polyethylene in a finely divided form. 599. Toxicity of cyanoacrylates Lewers, D. T., Just-Viera, J. O. & Yeager, (3. H. (1963). Lethal properties of a rapidly polymerizing adhesive. Product used in nonsuture surgery. Arch. Surg. 87, 627. Kline, D. G. & Hayes, (3. J. (1963). An experimental evaluation of the effect of a plastic adhesive, methyl 2-cyanoacrylate, on neural tissue. J. Neurosurg. 20, 647. A considerable advance in surgery could be achieved if it were possible to replace the use of sutures by an adhesive that would cause the edges of wounds or incisions to adhere together until healing takes place. Cyanoacrylates have been shown to be promising in this respect, but two papers recently published indicate that their toxicity may prevent their use in sutureless surgery. The monomer, methyl 2-cyanoacrylate, proved effective for the closure of incisions of the aorta in dogs, and since this product may be intended for use in man, acute toxicity tests were performed by Lewers et al. (cited above). The liquid monomer was injected in doses of 0-1-0.3 ml into the skin, into the peritoneal cavity and into the livers of rats and mice; the polymer was also implanted into mice. Control groups received normal saline. Mortality resulted in all the experimental groups. Mice receiving 0.2 ml of the monomer intrahepatically all died within 7 days, 66 % dying within 24 hr. Intraperitoneal injections killed 94 % of the mice within a week, whereas subcutaneous injections killed only 5.4 % of mice in the same period. Intraperitoneal administration to mice of the polymerized material proved uniformly fatal within 7 days. There was no apparent increase in peritoneal fluid nor obvious peritonitis, intestinal obstruction or distension. The cause of death was thus obscure, but the monomer itself appeared to be responsible. The same compound was used in the investigations of Kline & Hayes (cited above). These workers painted the compound on exposed peripheral nerves and brain tissue of dogs and the wounds closed. Twelve weeks after painting, all the nerves showed histological evidence of inflammation and increased adhesions around the experimental site. The stimulation threshold of the nerve was increased by 1-6 volts in 25 ~o of the animals, and about half the treated nerves were discoloured brown. Histological examination of the treated brains revealed extensive cortical necrosis, leucocyte and plasma cell infiltration, and widespread degeneration of myelin in the white matter. It is concluded that the use of neural tissue provides a useful test preparation for estimating the potential toxicity of implants;
422
PROCESSING AND PACKAGING CONTAMINANTS
and further, that methyl 2-cyanoacrylate is too dangerous to be used in contact with such tissue. 600. Prosthetics is the science of prostheses Arons, M. S. (1963). Plastics in plastic surgery: A review of the carcinogenic problem. Tex. Rep. Biol. Med. 21, 163. Simmers, M. H., Agnew, W. F. & Pudenz, R. H. (1963). Effects of plastic polymers within the rat's peritoneal cavity. Bol. Inst. Estud. m~d. biol., M~x. 21, 1. Plastics ale used fairly extensively in prostheses, particularly in breast reconstruction after surgery. How hazardous is the use of permanent plastics implants ? This Journal (Cited in F.C.T. 1964, 2, 269) has previously referred to the problem. Arons (cited above) examines this question, pointing out that the sarcomas which develop in rats and mice following implantation of a wide variety of synthetic polymers under the skin take up to 2 yr to develop. A survey reported in 1961 that of 16,000 breast implants followed up, although many different plastics had been used, not a single case of malignancy had ensued (Harris, Plast. reconstr. Surg. 1961, 28, 81). Yet might not these tumours develop over 15-20 yr? No such doubts exist in the mind of Heuper (Mod. Med., Minneap. 1960, 28, 227) who condemns the use of plastics implants into any patient, unless his or her condition is so serious that a cancer risk is justified. Heuper is convinced that such implants will lead to malignancy within the normal lifespan of the individual. A less hysterical note has been introduced by Simmels et al. (cited above) who, after implanting plastics in different physical forms into the peritoneal cavities of rats, consider that there is little danger of carcinogenic effects from embedding these substances in man. They used silicone rubber, polytetrafluoroethylene, nylon and polyethylene, either as rods (10 × 2 × 2 mm) or as powder. Of 30 test animals surviving, only 6 showed tumours after 2.4 yr, and since the plastics was never found within any tumour, the authors conclude that the tumours were spontaneous. The authors believe that tumours resulting from implants are caused by physical means and they examine at some length the theory of carcinogenesis which postulates that tumours are caused by separation of a group of cells from their normal physical contacts with other cells, with resultant lack of either physical or chemical feedback. The restraint normally imposed on the cells is removed and uncontrolled growth can occur. The authors quote the support of Little (J. nat. Cancer Inst. 1958, 20, 441) and Crile (Perspect. Biol. Med. 1960, 3, 358) but do not go so far as to claim that carcinogenesis is the result of simple differentiation or that all cancers have identical aetiology. Simmers et al. (cited above) claim that the cancer hazard from plastics used in surgery is small. Their evidence for this statement is based on simple extrapolation from rats to man. Tumours of this type take 18 months to develop in rats, that is three-fifths of a rat's lifespan. The same proportion in man is 40 yr, so that cancer from plastics implantation would take 40 yr to develop. Since plastics are rarely implanted before the age of 30, say the authors, there is little need to worry since there is insufficient time for a tumour to develop. 601. A useful review on plastics
Autian, J. (1963). Plastics in pharmaceutical practice and related fields. Part I. J. pharm. Sci. 52, 1. Idem (1963). Plastics in pharmaceutical practice and related fields. Part II. ibid 52, 105. Many polymers are suitable for use as such, but others need to have added stabilizers, antioxidants, and plasticizers, while antistatic agents, slip agents, pigments, brighteners, and the like heighten the complexity. Up to 60 % of the total weight of the plastics composition may consist of additives. The chemical and physical properties of many common plastics are extensively discussed in this useful review. The use of plastics in pharmacy and
421
pyrene, 1-methylpyrene, 2-methylpyrene and 4-methylpyrene while chrysene appears side by side with its 1-methyl and 6-methyl derivatives.
598. PTFE and high-density polyethylene implants in the body Charnley, J. (1963). Tissue reactions to polytetrafluorethylene. Lancet ii, 1379. In a letter by one of Britain's most prominent orthopaedic surgeons a warning is given concerning the introduction into the body of polytetrafluoroethylene (PTFE)--also known as Teflon and Fluon--in circumstances where it is likely to be abraded in situ. Particles of PTFE give rise to an intense foreign-body reaction, resulting in granulomatous masses, and quantities of sterile pus. The formation of large quantities of caseous material has been seen containing as much as 13 % dry weight of PTFE and causing insidious bone erosion. The reaction is thought to be partly due to persistent meebanical movement between the PTFE implant and the bone and partly a chemical reaction to the abraded particle. The author describes the effect of subcutaneous injection into his own thigh of finely divided specimens of PTFE and "high-density" polyethylene. The PTFE injection caused unpleasant subjective reactions and tenderness in the region of the implant. Nine months later the PTFE implant had swollen to twice its size and could be clearly felt. No such reaction occurred following injection of "high-density" polyethylene in a finely divided form. 599. Toxicity of cyanoacrylates Lewers, D. T., Just-Viera, J. O. & Yeager, (3. H. (1963). Lethal properties of a rapidly polymerizing adhesive. Product used in nonsuture surgery. Arch. Surg. 87, 627. Kline, D. G. & Hayes, (3. J. (1963). An experimental evaluation of the effect of a plastic adhesive, methyl 2-cyanoacrylate, on neural tissue. J. Neurosurg. 20, 647. A considerable advance in surgery could be achieved if it were possible to replace the use of sutures by an adhesive that would cause the edges of wounds or incisions to adhere together until healing takes place. Cyanoacrylates have been shown to be promising in this respect, but two papers recently published indicate that their toxicity may prevent their use in sutureless surgery. The monomer, methyl 2-cyanoacrylate, proved effective for the closure of incisions of the aorta in dogs, and since this product may be intended for use in man, acute toxicity tests were performed by Lewers et al. (cited above). The liquid monomer was injected in doses of 0-1-0.3 ml into the skin, into the peritoneal cavity and into the livers of rats and mice; the polymer was also implanted into mice. Control groups received normal saline. Mortality resulted in all the experimental groups. Mice receiving 0.2 ml of the monomer intrahepatically all died within 7 days, 66 % dying within 24 hr. Intraperitoneal injections killed 94 % of the mice within a week, whereas subcutaneous injections killed only 5.4 % of mice in the same period. Intraperitoneal administration to mice of the polymerized material proved uniformly fatal within 7 days. There was no apparent increase in peritoneal fluid nor obvious peritonitis, intestinal obstruction or distension. The cause of death was thus obscure, but the monomer itself appeared to be responsible. The same compound was used in the investigations of Kline & Hayes (cited above). These workers painted the compound on exposed peripheral nerves and brain tissue of dogs and the wounds closed. Twelve weeks after painting, all the nerves showed histological evidence of inflammation and increased adhesions around the experimental site. The stimulation threshold of the nerve was increased by 1-6 volts in 25 ~o of the animals, and about half the treated nerves were discoloured brown. Histological examination of the treated brains revealed extensive cortical necrosis, leucocyte and plasma cell infiltration, and widespread degeneration of myelin in the white matter. It is concluded that the use of neural tissue provides a useful test preparation for estimating the potential toxicity of implants;
422
PROCESSING AND PACKAGING CONTAMINANTS
and further, that methyl 2-cyanoacrylate is too dangerous to be used in contact with such tissue. 600. Prosthetics is the science of prostheses Arons, M. S. (1963). Plastics in plastic surgery: A review of the carcinogenic problem. Tex. Rep. Biol. Med. 21, 163. Simmers, M. H., Agnew, W. F. & Pudenz, R. H. (1963). Effects of plastic polymers within the rat's peritoneal cavity. Bol. Inst. Estud. m~d. biol., M~x. 21, 1. Plastics ale used fairly extensively in prostheses, particularly in breast reconstruction after surgery. How hazardous is the use of permanent plastics implants ? This Journal (Cited in F.C.T. 1964, 2, 269) has previously referred to the problem. Arons (cited above) examines this question, pointing out that the sarcomas which develop in rats and mice following implantation of a wide variety of synthetic polymers under the skin take up to 2 yr to develop. A survey reported in 1961 that of 16,000 breast implants followed up, although many different plastics had been used, not a single case of malignancy had ensued (Harris, Plast. reconstr. Surg. 1961, 28, 81). Yet might not these tumours develop over 15-20 yr? No such doubts exist in the mind of Heuper (Mod. Med., Minneap. 1960, 28, 227) who condemns the use of plastics implants into any patient, unless his or her condition is so serious that a cancer risk is justified. Heuper is convinced that such implants will lead to malignancy within the normal lifespan of the individual. A less hysterical note has been introduced by Simmels et al. (cited above) who, after implanting plastics in different physical forms into the peritoneal cavities of rats, consider that there is little danger of carcinogenic effects from embedding these substances in man. They used silicone rubber, polytetrafluoroethylene, nylon and polyethylene, either as rods (10 × 2 × 2 mm) or as powder. Of 30 test animals surviving, only 6 showed tumours after 2.4 yr, and since the plastics was never found within any tumour, the authors conclude that the tumours were spontaneous. The authors believe that tumours resulting from implants are caused by physical means and they examine at some length the theory of carcinogenesis which postulates that tumours are caused by separation of a group of cells from their normal physical contacts with other cells, with resultant lack of either physical or chemical feedback. The restraint normally imposed on the cells is removed and uncontrolled growth can occur. The authors quote the support of Little (J. nat. Cancer Inst. 1958, 20, 441) and Crile (Perspect. Biol. Med. 1960, 3, 358) but do not go so far as to claim that carcinogenesis is the result of simple differentiation or that all cancers have identical aetiology. Simmers et al. (cited above) claim that the cancer hazard from plastics used in surgery is small. Their evidence for this statement is based on simple extrapolation from rats to man. Tumours of this type take 18 months to develop in rats, that is three-fifths of a rat's lifespan. The same proportion in man is 40 yr, so that cancer from plastics implantation would take 40 yr to develop. Since plastics are rarely implanted before the age of 30, say the authors, there is little need to worry since there is insufficient time for a tumour to develop. 601. A useful review on plastics
Autian, J. (1963). Plastics in pharmaceutical practice and related fields. Part I. J. pharm. Sci. 52, 1. Idem (1963). Plastics in pharmaceutical practice and related fields. Part II. ibid 52, 105. Many polymers are suitable for use as such, but others need to have added stabilizers, antioxidants, and plasticizers, while antistatic agents, slip agents, pigments, brighteners, and the like heighten the complexity. Up to 60 % of the total weight of the plastics composition may consist of additives. The chemical and physical properties of many common plastics are extensively discussed in this useful review. The use of plastics in pharmacy and