Nickel toxicology L.G. Morgan Inco Europe Ltd., Clydach, Swansea, SA6 5QR, Wales
The toxicological properties of nickel and its compounds are species dependent and it is, therefore, most important when considering them be very specific about the chemical form under discussion. The best recognised problems relate to acute poisoning by nickel carbonyl gas, the carcinogenicity of certain nickel compounds and the sensitizing action of nickel salts and the metal. Acute poisoning by nickel carbonyl was one of the earliest manifestations of nickel toxicology to be recognised. It was observed when a number of accidents occurred at the commencement of operations of Mond's Nickel Refinery in Wales in 1900. The poisoning is characterised by an acute phase of toxaemia followed by a symptom free period of a few hours, and then the onset of chemical pneumonitis. Treatment is by the administration of a chelating agent either diethyldithiocarbamate (DDC) or disulfiram (Antabuse). Jones et al. (1984) have shown that the DDC facilitates the transfer of nickel from intra to the extracellular space and Neiboer (1988) suggests that as it is a radical scavenger the time of administration may be crucial to its efficacy. Sunderman et al. (1983) showed that nickel carbonyl was an embryotoxic agent. While the gas was originally suspected of being a human carcinogen epidemiological studies have pointed to nickel-containing dusts as being the more probable agents. Doll (/ARC, 1984), reviewed the epidemiological data for nickel carcinogenicity and showed that a high risk of respiratory cancer has been encountered in those operations where there was exposure to the roasting of nickel subsulphide at high temperatures but no significant excess in refineries with other ores or different processes; reports on refinery workers from many countries include Wales (Peto et al., IARC 1984), Canada (Egedhal and Rice; Roberts et al., Shannon et al., I A R C , 1984) and Norway (Langard, IARC, 1984). Reports on user industries which have given consistently negative results include aero-engine manufacture (Bernacki et al., 1978), alloy manufacture (Cox et al., 1981; Redmond, IARC, 1984), nickel powder usage (Cragle et al., IARC, 1984) and stainless steel foundry workers (Cornell and Landis, IARC, 1984). In 1985 a nickel speciation workshop was set up with the purpose of finding out which nickel species were carcinogenic to man. The workshop involved nickel researchers throughout the world under the Chairmanship of Sir Richard Doll. They reviewed and updated nearly all the relevant epidemiology. The report of this working party is expected in June 1989. Preliminary reports are available, however, from the abstracts of papers presented at a conference on Nickel Toxicology held in Helsinki in
September 1988 where Anderson (1988) suggested that exposure to the soluble salts at the electrolytic refinery in Kristiansand in Norway does also have to be considered as carcinogenic. IARC reviewed nickel and a number of other substances in 1987 and classified nickel and nickel compounds as human carcinogens, and IARC will be holding a further assessment meeting in June 1989. In a review of animal studies, Sunderman (/ARC, 1984) demonstrated a graded response with nickel subsulphide and alpha-nickel sulphide producing local tumours in nearly 100% of animals, nickel oxide and beta-nickel sulphide and nickel dust producing a less dramatic response with around 50% of animals affected and amorphous nickel sulphide and nickel arsenide being almost negative. Intramuscular animal studies, while interesting, do not reflect very accurately the human situation since most occupational exposure is through the lungs. There are only two positive animal inhalation studies: that by Ottolenghi et al. (1975) where a 10% tumour rate in rats exposed to 1 mg Ni m 3 of nickel subsulphide is reported and that by Saknyn and Blokhin (1978)3 where a 20% tumour rate after exposure to 70 mg Ni m- of a mixture of Ni3S2, N i t and Ni is reported. A number of studies on inhalation of nickel compounds in rats have been reported (Bingham et al., 1972; Camner; Wehner et al., IARC, 1984) where no carcinogenic effects are recorded. Pott (1987) using intratracheal and intraperitoneal installations found nickel powder, nickel oxide and nickel subsulphide to be carcinogenic. In vitro studies have so far been of little value in predicting the carcinogenic potential of nickel-containing materials. One interesting area of new research has been the investigation of the carcinogenicity of different nickel oxides. Sunderman (1987) has shown that an increase in the haematocrit after intrarenal injection of a suspected material correlates with the potential of that material to produce tumours after intramuscular injection. Using this technique he has demonstrated that a variety of substances all with the same chemical formula N i t but prepared at different temperatures and varying in colour, have different activities. This may explain the difference in results o f some of the human and animal studies reported. Nickel allergy generally manifests itself as a cutaneous reaction to skin contact. This is well recognised and documented. Denmark has recently proposed the banning of those nickel materials worn next to the skin which fail a specific leachability test. Malt et al. (1982) have shown that respiratory allergy to nickel salts can occur and have demonstrated immunoglobulin IgE changes which resolved after cessation of exposure.
76
Nickel toxicology
Research into nickel toxicology has been increasing in recent years with particular emphasis on carcinogenesis. It is most important that manufacturers, users and legislators know which forms of nickel are carcinogenic to man and the results of the speciation working party are, therefore, awaited with interest. Lines of future research include the demonstration of hazards from nickel in welding, evaluation of cofactors in nickel carcinogeneses, methods of surveillance of nickel workers (and their relevance to the known situations), the role of nickel in dental and orthopaedic implants and the role of the nickel ion in the mechanisms of carcinogenicity. References Andersen, A. 1988. Recent follow-up of respiratory cancer in a Norwegian nickel refinery. Abstract, p.49. Fourth International ConfeEence on Nickel Metabolism and Toxicology, September, Finland. Bemacki, E.I., Parsons,G.E. and Sundemaan, F.W. Jr. 1978. Investigation of exposure to nickel and lung cancer mortality; case control study at aircraft engine factory. Ann. Clin. Lab. Sci., 8. 190-194. Bingham, E., Barkley, W., Zerwas, M., Stemmer, K. and Taylor, P. 1972. Response of alveolar macrophages to metals. I. Inhalation of lead and nickel. Arch. Environ. Health, 25, 406-414. Cox, J.E., Doll, R., Scott, W.A. and Smith, S. 1981. Mortality of nickel workers. Experience with men working with metallic nickel. Br. J. Ind. Med., 38, 235-239.
IARC, 1984. Sunderman F. W. (ed.), Nickel in the Human Environment, IARC Scientific Publications No. 53. Jones, D.C. May, P.M. and Williams, D.K. 1984. Antidotal efficacy of tetra-ethylpentamine for acute nickel carbonyl poisoning in rats. lnorg. Chem. Acta., 91, 151-153. Malo, J., Cartier, A., Doepner, M. and Neiboer, E. 1982. Occupational Asthma caused by Nickel Sulphate. J. Clin. Allergy, 69, 55-59. Neiboer, E., Epand, R.M., Menon, C.R. and Stafford, A. 1988. Implications of the Ability of Diethyldithiocarbamate (DDC) to act as an lonophore and Radical Scavenger in the Chelation Treatment of Nickel Carbonyl Poisoning. Ottolenghi, A.D., Haseman, J.K., Payne, W.W., Falk, H.L. and Macfadand, H.N. 1975. Inhalation studies of nickel sulfide in pulmonary carcinogenesis of rats. Cancer Inst., 54, 1165-1172. Pott, F., Ziem, U., Reiffer, F.J., Huth, F., Ernst, H. and Mohr, U. 1987. Carcinogenicity studies on fibres, metal compounds and some other dusts in rats. Exp. Pathol., 32, 129-152. Sunderman, F.W., Reid, M.C., Shen, S.K. and Kevorkian, C.B. 1963. Embryotoxicity and teratogenieity of nickel compounds. In: Clarkson, T.W., Nordberg, G.F, and Sager, P.R. (eds.), Reproductive and Development Toxicity of Metals. Plenum Publishing Corp., New York. Sunderman, F. W., Hopfer, S. M., Knight, J. A. et aL 1987. Physicochemical characteristics and biological effects of nickel oxides carcinogenesis, Vol. 8. No. 2, pp. 305-313. Saknyn, A.V. and Blokhin, V.A. 1978. Development of malignant tumours in rats exposed to nickel containing aerosols. Vopr. Onkol,, 24,44. (Manuscript No. 190: received July 3, and accepted for publication July 3, 1989.)
The toxicological properties of nickel and its compounds are species dependent and it is, therefore, most important when considering them be very specific about the chemical form under discussion. The best recognised problems relate to acute poisoning by nickel carbonyl gas, the carcinogenicity of certain nickel compounds and the sensitizing action of nickel salts and the metal. Acute poisoning by nickel carbonyl was one of the earliest manifestations of nickel toxicology to be recognised. It was observed when a number of accidents occurred at the commencement of operations of Mond's Nickel Refinery in Wales in 1900. The poisoning is characterised by an acute phase of toxaemia followed by a symptom free period of a few hours, and then the onset of chemical pneumonitis. Treatment is by the administration of a chelating agent either diethyldithiocarbamate (DDC) or disulfiram (Antabuse). Jones et al. (1984) have shown that the DDC facilitates the transfer of nickel from intra to the extracellular space and Neiboer (1988) suggests that as it is a radical scavenger the time of administration may be crucial to its efficacy. Sunderman et al. (1983) showed that nickel carbonyl was an embryotoxic agent. While the gas was originally suspected of being a human carcinogen epidemiological studies have pointed to nickel-containing dusts as being the more probable agents. Doll (/ARC, 1984), reviewed the epidemiological data for nickel carcinogenicity and showed that a high risk of respiratory cancer has been encountered in those operations where there was exposure to the roasting of nickel subsulphide at high temperatures but no significant excess in refineries with other ores or different processes; reports on refinery workers from many countries include Wales (Peto et al., IARC 1984), Canada (Egedhal and Rice; Roberts et al., Shannon et al., I A R C , 1984) and Norway (Langard, IARC, 1984). Reports on user industries which have given consistently negative results include aero-engine manufacture (Bernacki et al., 1978), alloy manufacture (Cox et al., 1981; Redmond, IARC, 1984), nickel powder usage (Cragle et al., IARC, 1984) and stainless steel foundry workers (Cornell and Landis, IARC, 1984). In 1985 a nickel speciation workshop was set up with the purpose of finding out which nickel species were carcinogenic to man. The workshop involved nickel researchers throughout the world under the Chairmanship of Sir Richard Doll. They reviewed and updated nearly all the relevant epidemiology. The report of this working party is expected in June 1989. Preliminary reports are available, however, from the abstracts of papers presented at a conference on Nickel Toxicology held in Helsinki in
September 1988 where Anderson (1988) suggested that exposure to the soluble salts at the electrolytic refinery in Kristiansand in Norway does also have to be considered as carcinogenic. IARC reviewed nickel and a number of other substances in 1987 and classified nickel and nickel compounds as human carcinogens, and IARC will be holding a further assessment meeting in June 1989. In a review of animal studies, Sunderman (/ARC, 1984) demonstrated a graded response with nickel subsulphide and alpha-nickel sulphide producing local tumours in nearly 100% of animals, nickel oxide and beta-nickel sulphide and nickel dust producing a less dramatic response with around 50% of animals affected and amorphous nickel sulphide and nickel arsenide being almost negative. Intramuscular animal studies, while interesting, do not reflect very accurately the human situation since most occupational exposure is through the lungs. There are only two positive animal inhalation studies: that by Ottolenghi et al. (1975) where a 10% tumour rate in rats exposed to 1 mg Ni m 3 of nickel subsulphide is reported and that by Saknyn and Blokhin (1978)3 where a 20% tumour rate after exposure to 70 mg Ni m- of a mixture of Ni3S2, N i t and Ni is reported. A number of studies on inhalation of nickel compounds in rats have been reported (Bingham et al., 1972; Camner; Wehner et al., IARC, 1984) where no carcinogenic effects are recorded. Pott (1987) using intratracheal and intraperitoneal installations found nickel powder, nickel oxide and nickel subsulphide to be carcinogenic. In vitro studies have so far been of little value in predicting the carcinogenic potential of nickel-containing materials. One interesting area of new research has been the investigation of the carcinogenicity of different nickel oxides. Sunderman (1987) has shown that an increase in the haematocrit after intrarenal injection of a suspected material correlates with the potential of that material to produce tumours after intramuscular injection. Using this technique he has demonstrated that a variety of substances all with the same chemical formula N i t but prepared at different temperatures and varying in colour, have different activities. This may explain the difference in results o f some of the human and animal studies reported. Nickel allergy generally manifests itself as a cutaneous reaction to skin contact. This is well recognised and documented. Denmark has recently proposed the banning of those nickel materials worn next to the skin which fail a specific leachability test. Malt et al. (1982) have shown that respiratory allergy to nickel salts can occur and have demonstrated immunoglobulin IgE changes which resolved after cessation of exposure.
76
Nickel toxicology
Research into nickel toxicology has been increasing in recent years with particular emphasis on carcinogenesis. It is most important that manufacturers, users and legislators know which forms of nickel are carcinogenic to man and the results of the speciation working party are, therefore, awaited with interest. Lines of future research include the demonstration of hazards from nickel in welding, evaluation of cofactors in nickel carcinogeneses, methods of surveillance of nickel workers (and their relevance to the known situations), the role of nickel in dental and orthopaedic implants and the role of the nickel ion in the mechanisms of carcinogenicity. References Andersen, A. 1988. Recent follow-up of respiratory cancer in a Norwegian nickel refinery. Abstract, p.49. Fourth International ConfeEence on Nickel Metabolism and Toxicology, September, Finland. Bemacki, E.I., Parsons,G.E. and Sundemaan, F.W. Jr. 1978. Investigation of exposure to nickel and lung cancer mortality; case control study at aircraft engine factory. Ann. Clin. Lab. Sci., 8. 190-194. Bingham, E., Barkley, W., Zerwas, M., Stemmer, K. and Taylor, P. 1972. Response of alveolar macrophages to metals. I. Inhalation of lead and nickel. Arch. Environ. Health, 25, 406-414. Cox, J.E., Doll, R., Scott, W.A. and Smith, S. 1981. Mortality of nickel workers. Experience with men working with metallic nickel. Br. J. Ind. Med., 38, 235-239.
IARC, 1984. Sunderman F. W. (ed.), Nickel in the Human Environment, IARC Scientific Publications No. 53. Jones, D.C. May, P.M. and Williams, D.K. 1984. Antidotal efficacy of tetra-ethylpentamine for acute nickel carbonyl poisoning in rats. lnorg. Chem. Acta., 91, 151-153. Malo, J., Cartier, A., Doepner, M. and Neiboer, E. 1982. Occupational Asthma caused by Nickel Sulphate. J. Clin. Allergy, 69, 55-59. Neiboer, E., Epand, R.M., Menon, C.R. and Stafford, A. 1988. Implications of the Ability of Diethyldithiocarbamate (DDC) to act as an lonophore and Radical Scavenger in the Chelation Treatment of Nickel Carbonyl Poisoning. Ottolenghi, A.D., Haseman, J.K., Payne, W.W., Falk, H.L. and Macfadand, H.N. 1975. Inhalation studies of nickel sulfide in pulmonary carcinogenesis of rats. Cancer Inst., 54, 1165-1172. Pott, F., Ziem, U., Reiffer, F.J., Huth, F., Ernst, H. and Mohr, U. 1987. Carcinogenicity studies on fibres, metal compounds and some other dusts in rats. Exp. Pathol., 32, 129-152. Sunderman, F.W., Reid, M.C., Shen, S.K. and Kevorkian, C.B. 1963. Embryotoxicity and teratogenieity of nickel compounds. In: Clarkson, T.W., Nordberg, G.F, and Sager, P.R. (eds.), Reproductive and Development Toxicity of Metals. Plenum Publishing Corp., New York. Sunderman, F. W., Hopfer, S. M., Knight, J. A. et aL 1987. Physicochemical characteristics and biological effects of nickel oxides carcinogenesis, Vol. 8. No. 2, pp. 305-313. Saknyn, A.V. and Blokhin, V.A. 1978. Development of malignant tumours in rats exposed to nickel containing aerosols. Vopr. Onkol,, 24,44. (Manuscript No. 190: received July 3, and accepted for publication July 3, 1989.)
