Chelation Therapy in Nickel Poisoning

F. WILLIAM SUNDERMAN Sr., M.D., Ph .D.

Hahnemann Medical College and Hospital, Philadelphia, PA 19102

ABSTRACT For the treatment of acute poisoning from the inhalation of nickel car bonyl, sodium diethyldithiocarbamate (Dithiocarb) has proved to be a specific antidote; tetraethylthiuram (Antabuse) is effective to a lesser de gree; d-penicillamine and dimercaprol (BAL) have limited therapeutic value. For the treatment of nickel eczema and dermatitis, favorable response has been obtained by placing patients on a diet of low nickel content together with the oral administration of Dithiocarb or Antabuse. No specific therapy has been advanced for the treatment of nickel cancer in humans. In experimental animals, Dithiocarb has an inhibitory effect on the production of rat rhabdomyosarcomas induced by the intramuscular implantation of nickel subsulfide, and N-methyl formamide inhibits the growth of transplantable nickel fibromas in rats. It is suggested that for the treatment of tumors arising from the implantations of nickel-containing prostheses in humans, chelation therapy be considered.

It is only within recent decades that the of sexual vice on the nervous system.” 11 hazards of exposure to nickel and nickel And now, since World War II, the uses of compounds have come to be recognized. nickel for medicinal purposes have been In an interesting review of “On the Uses completely abandoned, and it has become of Nickel Sulphate in Medicine,” recognized that in addition to nickel car Kolipinski19 in 1911 stated, “Nickel and bonyl, exposure to nickel and other nickel nickel salts, excepting for the very compounds may be deleterious to health. poisonous nickel carbonyl, have no place On the other hand, nickel is probably an or record in toxicology.” He dismissed the essential trace element for mammalian case of Emperor of Austria, Franz Josef, life. In 1936, Bertrand and Nakamura3 where an illness was attributed to nickel suggested that nickel may play a normal poisoning, as being doubtful. Kolipinski physiological role in metabolism. In 1974, elaborated on the exceptional medicinal Schwartz indicated that nickel is probably value of nickel salts for the treatment of an essential element for the life and health epilepsy, chorea, migraine, and neuralgia. of animals.35 He also noted that “nickel acts as a seda Before considerations of current tive and tonic of peculiar and elective therapy for nickel poisoning, it may be power in controlling the damaging effects informative to indicate the relative

0091-7370/81/0100-0001 $01.20 © Institute for Clinical Science, Inc. 2 SUNDERMAN TABLE I should also be mentioned that in previous Toxicity of Nickel and Its Compounds years, it had been believed that the inges tion of milligram quantities of nickel con Nickel (Colloidal and Powdered) tained in food and also derived from food Intravenous Dogs LD » 10 to 20 mg/kg Acute oral Dogs Tolerated: 1 to 3 g/kg cooked in stainless steel utensils was Nickel Salts (Cl, NOs, SO4 , 0) Intravenous Dogs LD = 10 to 20 mg/kg without detectable deleterious effects on Subcutaneous Rabbits LD = 1.3 g/kg the health of people. However, it now ap Acute oral Rats LD50 =2.0 g/kg Chronic oral Cats Tolerated: 25 mg/kg/day pears that in persons hypersensitive to for 200 days nickel, even minute quantities may be Skin application Human 1:10,000 evokes sensitivity reaction deleterious. Nickel Carbonyl - Ni(CO) 4 The most toxic of all of the compounds Inhalation Mice LC50 « 0.067 mg/liter for 30 minutes of nickel that are encountered in indus Inhalation Rats LC50 * 0.24 mg/liter for 30 minutes trial operations is nickel carbonyl Inhalation Cats LC50 = 1.9 mg/liter (Ni(CO)4). The LD50 values for a 30 min for 30 minutes Intravenous Rats LDso = 22 ± 1.1 mg/kg ute exposure to Ni(CO)4 for mice and rats Subcutaneous Rats LD50 = 21 ± 4.2 mg/kg are 0.067 and 0.24 milligram per liter, cor IntTaperitoneal Rats LD50 * ± mg A g responding to 10 and 33 parts per million, respectively.39

toxicities of nickel and its compounds in Routes of Exposure to Nickel experimental animals. A summarization of toxicity values of nickel is given in Any considerations of treatment of table I.28 nickel poisoning require a knowledge of It will be seen that solutions of colloidal the physical and chemical characteristics nickel or nickel salts have a high degree of of the nickel compound to which the sub toxicity when given either intravenously ject has been exposed, the concentration, or subcutaneously. On the other hand, the length and type of exposure as well as the ingestion of nickel or nickel salts has a sensitivity of the host, idiosyncracy, and relatively low degree of toxicity. When presence of disease. The physiologic re given orally, it will be seen that dogs are sponses depend in large measure upon able to tolerate doses of metallic nickel the route by which these compounds and nickel compounds as high as three enter the body and are distributed in the grams per kilogram of body weight. It tissues. A wide variety of distribution oc curs and nonhomogeneity of distribution appears to be the rule rather than the ex TABLE II ception. The routes to which nickel may Types of Nickel Poisoning enter the body are given in table II.

Inhalation (Ni(C0)4 , Ni, ^138 2, NiO, ^ 203) Inhalation Acute Pneumonitis with adrenal cortical insufficiency; hyaline membrane formation; pulmonary edema and That nickel carbonyl is highly toxic by hemorrhage; hepatic degeneration; brain and inhalation is well known from both clini renal congestion Chronic cal experience and studies on experimen Cancer of respiratory tract; pulmonary eosinophilia (Loeffler's syndrome); asthma tal animals. To a lesser known degree, the Skin Contact inhalation of finely divided nickel, nickel Primary irritant dermatitis; allergic dermatitis; eczema oxides and certain nickel-sulfur contain Parenteral (Prosthetic Implantations) ing compounds are also toxic, although Allergenic reactions; osteomyelitis; osteonecrosis; malignant tumors the symptoms may not be as well defined Oral Food and beverage; drugs as those of nickel carbonyl. The symptoms which follow acute exposure to the vapors CHELATION THERAPY IN NICKEL POISONING 3 of nickel carbonyl are of two types,— tact of the skin with nickel-containing de initial and delayed. The initial symptoms tergents,21 by working in stainless steel are generally mild and disappear quickly American-style kitchens,22 from costume when the subject is brought into uncon jewelry, garter buckles, watches, metal taminated air. In some cases, the patient straps, spectacle frames, pins, hair clips, may feel well for as long as several days scissors and coins.10,21,22,30,49 Although after the initial symptoms disappear and most of the investigators have directed at before the onset of the more serious de tention to the dermatologic manifesta layed reactions. In other cases, the two tions of nickel sensitivity, nevertheless, it stages may merge. In any event, the slow is noteworthy that other allergic ness of the development of symptoms is phenomena may also be encountered.2,45 such that the victim will usually be aware of exposure only after the inhalation of a Parenterally Induced Toxicity dosage sufficient to cause serious delayed effects.17 The most frequent toxic reactions of The most significant pathologic nickel via the parenteral route result from changes in acute poisoning from the inha surgical use of nickel alloys as implant lation of nickel carbonyl are found in the materials, such as total hip replacement or lungs. The lungs show a severe degree of nailing and fixation of fractures. Nickel congestion, pulmonary edema, hemor sensitized patients with implanted rhage, and interstitial pneumonia with prostheses containing nickel may develop hyaline membrane formation.18,28’38,41 Con loosening of the prostheses, osteo comitant hepatic and adrenal cortical de myelitis, osteonecrosis, hemangioendo generation and brain and renal congestion thelioma, and malignant tumors.6,9,24,27,32 are also usually observed. The carcinogenic effect of nickel im In addition to the acute effects, chronic planted in bone has been demonstrated in exposure to the vapors of nickel carbonyl rats in which sarcomas developed after and nickel dusts are attended by a high the injection of powdered nickel into the incidence of carcinoma of the respira femurs.13,14 Thus, it seems probable that tory passages as well as pulmonary the reported malignancies in humans eosinophilia (Loeffler’s syndrome)2,45 and have been caused by the metal implants. asthma.23 Ingestion of Nickel

Skin Contact As previously mentioned, nickel in gested from foods is believed to be rela The most commonly observed toxic tively non-toxic.8 The ordinary adult diet, reactions to nickel and nickel compounds according to Kent and McCance,4,16 are nickel dermatitis and skin hypersensi supplies 0.3 to 0.5 milligram of nickel tivity. The increasing prevalence of nickel daily. It may be noted that acidic foods dermatitis and skin sensitivity has been extract nickel from cooking and storage emphasized by many investigators. It has utensils and processing equipment.20 The been estimated that five percent of all extent and the amount of nickel extracted cases of eczema are caused by contact from this source has not been adequately with nickel or nickel compounds.30 Ap studied. proximately two-thirds of patients with Nickel present in drinking water is not nickel dermatitis are female. This pre regarded as a health hazard. On the basis ponderance is believed to be related to of analyses of nickel concentrations of 969 the greater exposure to nickel by females. water supplies in the United States during Nickel dermatitis arises from direct con 1969-1970,28 the average concentration of 4 SUNDERMAN nickel in water samples taken at the con properties as an antidote to acute nickel sumer’s tap was 4.8 micrograms per liter. carbonyl poisoning. With an estimated daily intake of two li The therapeutic effectiveness of 13 ters of water, an adult would consume ap alkyl dithiocarbamates was studied in ex proximately 10 micrograms of nickel per perimental animals receiving lethal in day in drinking water.28 halations of nickel carbonyl.50 A list of the dithiocarbamate compounds that proved Antidotal Activity of Chelating Agents to be effective is given in table III. Of the in Nickel Carbonyl Poisoning three dithiocarbamate derivatives that gave complete protection in experimental For a number of years, our laboratory animals in a dosage of 50 milligrams per has studied the hazards of acute and kilogram of body weight, sodium diethyl- chronic exposure to nickel carbonyl. dithiocarbamate (Dithiocarb) was the When we first undertook to treat patients least toxic,—the LD50 dosage in mice acutely exposed to nickel carbonyl, the being 1,500 milligrams per kilogram. It is only available chelating drugs were BAL our opinion that the undesirable side ef (Dimercaprol), d-penicillamine, and EDTA fects and the large dosage required to give (calcium disodium ethylenediaminetetra- complete protection precluded the use of acetic acid). Our studies on experimental penicillamine in humans. Attention is di animals showed that (1) administration of rected to the partial protection afforded by d-penicillamine18,50 had doubtful anti tetraethylthiuram disulfide (Antabuse), dotal effectiveness and produced severe since this drug is readily available and, toxic side reactions; (2) EDTA provided unlike Dithiocarb, is no longer cate no antidotal effects40; and (3) BAL was gorized as an investigational new drug. only partially effective.1 With BAL, the The dramatic effectiveness of Dithio LD50 value in rats exposed to nickel car carb in counteracting the lethal effects of bonyl was found to be increased by a fac nickel carbonyl in experimental animals tor of approximately two.37 led us to use this chemical in humans who Recognition of the nickel binding and were accidentally exposed to nickel car biologic properties of the dithiocar- bonyl. These exposures occurred in con bamates as well as their low toxicity junction with a variety of applications of prompted us to initiate studies to deter nickel carbonyl in several types of indus mine their possible chemotherapeutic try. To date, more than 350 workmen ex posed to nickel carbonyl have received TABLE III Dithiocarb. To our knowledge, no ex Antidotal Activity for Nickel Carbonyl* Poisoning in Mice posed workman died who received

Percent Dithiocarb within the first five days after I.P. Parenteral Protection exposure. The efficacy of Dithiocarb as a Dithiocarbamate l d5o Dosage Against Compound mgA g mg/kg Ni(C0)/i specific antidote for acute nickel poison

Na diethyl 1500 50 100 ing has been reported previously by Na dimethyl <1000 SO 100 u s 37,39,41 Na diisopropyl >1000 50 100 Na morpholine-1 1000 100 100 Na N,N'-ethylene-bis >500 250 50 Oskarsson and Tjalve31 have recently Na 2-(2-oxo-l-imidazo- lidyl) ethyl <1500 100 50 studied the effects of Dithiocarb and Na N,N'-dimethyl-N,N*- penicillamine on the tissue distribution of ethylene-bis >1500 100 40 Tetraethylthiuram di 63NiCl2 in mice. They indicated that sulfide (Antabuse) >500 250 70 B,6-dimethylcysteine nickel diethyldithiocarbamate is lipophilic, (Penicillamine) 259 200 100 (250 fatal) whereas nickel-DL-penicillamine complex is hydrophilic and that these differences *Ni(C0)^ concentration = 0.09 mg per L. in chemical properties may determine the CHELATION THERAPY IN NICKEL POISONING 5 effects that the chelating agents have on TABLE IV the fate of nickel in the tissues. Treatment of Acute Nickel Carbonyl Poisoning A detailed procedure for the administra Mild or doubtful exposure ÇUrine Ni <10 yg/dl) tion of Dithiocarb in persons known or Give 2 gm Dithiocarb orally in divided doses (4 hour suspected of having been exposed to period) Moderately severe to severe exposure (Urine Ni >10 yg/dl) hazardous concentrations of nickel car Give Dithiocarb orally as follows: bonyl have been published.17'42 In table /2.0 gm (10 - 0.2 g capsules) 0 hours . ll.0gm(5-0.2g capsules) 4 hours IV is given a synopsis of this procedure. In day jo.6gm(3-0.2g capsules) 8 hours (o.4 gm ( 2 - 0.2 g capsules) 16 hours addition to the administration of Dithio Subsequent days: 0.4 gm every 8 hours carb, -our group and others48 have found Maintenance of adequate oxygenation that maintenance of adequate oxygena Cortisol administration for adrenal cortical insufficiency tion and the administration of Cortisol to be valuable adjuncts to therapy. treated with Dithiocarb administered parenterally; 25 were untreated. Of the Nickel Cancer untreated rats, 84 percent developed Excepting for isolated reports, no spe rhabdomyosarcomas whereas only 50 cific type of chemotherapy has been ad percent of the treated rats developed vanced for the treatment of nickel cancer tumors. In Gilman’s studies,12 the inci in man. For example, the administration dence of sarcomas from nickel subsulfide of 5-fluorouracil to a subject with cancer implantations was 80 percent. Although due to nickel was reported by Rybnikov the number of rats in our study was small, and Volkova34 to have increased the the studies suggest that the induction of elimination of nickel from the body and to rhabdomyosarcoma in rats from intra have lowered the nickel concentration in muscular implantations of nickel subsul the blood and some of the organs.47 For fide may be partially inhibited by the ad practical purposes, chemotherapy for ministration of Dithiocarb. On the basis of nickel carcinogenesis has been limited to these observations, consideration might studies in experimental animals. Furst thus be given to the administration of and his colleagues11 induced fibrosar Dithiocarb periodically in patients with comas in Fischer-344 rats by intramuscu prostheses who develop a hypersensi lar implantations of nickel powder. The tivity to nickel and have the potential to fibrosarcomas that developed were trans develop malignant tumors. planted to host rats of the same strain. After the growth pattern was estab Treatment of Nickel Dermatitis lished, the rats were treated with a and Eczema number of diverse chemotherapeutic During the past five years, noteworthy agents. Of the agents studied, only advances have been made in the treat- N-methylformamide exhibited antitumorigenic activity. Recent studies have been undertaken TABLE V in our laboratory in which nickel subsul Experimental Chemotherapy in Nickel Carcinogenesis fide was implanted in the thigh muscles of four-month old Fischer rats with the pur N-methylformamide - Antitumorigenic activities pose of inducing sarcomas and ascertain exhibited to nickel-induced transplanted ing the possible antitumorigenic effec fibrosarcomas in rats tiveness of Dithiocarb. Forty-nine rats Sodium diethyldithiocarbaroate - Partial inhibition of rhabdomyosarcoma induction from i.m. were implanted according to Gilman’s implantation of NijS2 in rats procedure12 and 24 of the group were 6 SUNDERMAN T A B L E VI tetraethylthiuramdisulfide (Antabuse) in Treatment of Nickel Dermatitis its place. Antabuse is a reasonable substi tute since in the metabolism of Antabuse, Domar and associates7 have shown that Ingestion of diet of low nickel content. Oral administration of Dithiocarb (DDC) or two molecules of Dithiocarb are formed as Oral administration of Antabuse. a reduction product.38 As shown in table V, Topical applications of corticosteroid and/or Dithiocarb preparations. Antabuse is also a chelating agent that is partially effective in the treatment of acute nickel carbonyl poisoning. Based on the observations of the Danish workers, ment of skin lesions that result from con the suggested treatment for nickel der tact with nickel. Christensen and Moller5 matitis is outlined in table VI. In addition in 1975 showed that the ingestion of to the ingestion of a diet of low nickel nickel in amounts present in the normal content, it is our suggestion that courses of diet caused an exacerbation of dermatitis Dithiocarb or Antabuse be given over a in nickel-sensitive patients. This observa seven day period, followed by a week tion obviously suggested that patients suf without medication. It is believed that fering from nickel dermatitis be placed on this intermittent type of administration of a diet of low nickel content and be given a Dithiocarb might diminish any side ef nickel chelating agent. By using a low fects and aid in the evaluation of the nickel diet, Kaaber, Veien, and Tjell15 ob therapeutic response. It should be noted, tained improvement in hand eczema in however, that continuous administration nine out of 17 nickel-sensitive patients. of Dithiocarb for a period of 90 days in rats Menne and Kaaber25 also treated a patient and dogs failed to elicit any noteworthy with pompholyx due to nickel allergy with side effects and that the concentrations of Dithiocarb and Antabuse and obtained serum calcium, magnesium, and iron re improvement. Spruit et al36 used dithio- mained within the normal ranges of val carbamate therapy in one patient. More ues.44 In addition, topical applications of recently, Menne, Kaaber, and Tjell26 corticosteroids and Dithiocarb prepara treated 11 patients with chronic nickel tions are believed to be therapeutically hand dermatitis with Antabuse and ob helpful. served a clearing of the dermatitis in eight In table VII is given a list of foods and of them. Since Dithiocarb is categorized beverages with nickel concentrations as an experimental drug and was un over one part per million. Tea and cocoa obtainable in Denmark, the authors used are beverages with high nickel content. In general, the foods with the highest nickel

TABLE VII content are cereals and green, leafy vege tables. It is suggested that patients with Foods and Beverages with Nickel Content Above 1 PPM nickel dermatitis curtail the ingestion of the listed foods and beverages. Fresh Wt. Dry Wt. Baking powder 13.4 Squash 4.6 Tea (orange pekoe) 7.6 Mushrooms 3.5 Buckwheat 6.5 Cabbage 3.3 Summary Cocoa S.O Spinach 2.4 Gelatin 4.5 Peas 2.3 Pepper (black) 3.9 Watercress 1.8 Earlier in this century, the opinion was Wheaties 3.0 Lentils 1.6 held that excepting for nickel carbonyl, Rye 2.7 Lettuce 1.5 Oats 1.'7-2.6 Figs 1 .2 nickel and nickel salts were not harmful to Rice (unpolished) 1 .8 ' humans. In fact, until World War II, nickel Salmon 1.7 Oysters 1.5 salts were extensively used medicinally for the treatment of a variety of disorders. CHELATION THERAPY IN NICKEL POISONING 7

During the past two or three decades, 12. G il m a n , J. P. W.: Metal carcinogenesis. II. A study on the carcinogenic activity of cobalt, however, it has gradually become evident copper, iron and nickel compounds. Cancer that, in addition to nickel carbonyl, expo Res. 22:158-162, 1962. sure to other nickel compounds may be 13. H e a t h , J. C. and D a n ie l , M. R.: The produc tion of malignant tumors by nickel in the rat. deleterious to health. Brit. J. Cancer 18:161-164, 1964. Dithiocarb (sodium diethyl dithiocar- 14. H u e p e R, W. C.: A quest into the environmental bamate) has proved to be a specific anti causes of cancer of the lung. Public Health dote for acute poisoning from the inhala Monograph No. 36, Public Health Service Pub lication No. 452. Washington, U.S. Government tion of nickel carbonyl. For the treatment Printing Office, 1955. of skin lesions caused by contact with 15. Ka a b e r , K., Ve ie n , N., and Tje l l , J. C.: Low nickel, favorable response has been ob nickel diet in the treatment of patients with chronic nickel dermatitis. Brit. J. Derm. 98:197, served by the ingestion of Dithiocarb 1978. combined with a low-nickel diet. Experi 16. Ke n t , N. L. and M c C a n c e , R. A.: Absorption mental studies suggest that chelation and excretion of ‘minor’ elements by man. therapy with Dithiocarb should be con Biochem. J. 35:877, 1941. 17. Kin c a id , J. F., St a n l e y , E. L., Be c k w o r t h , sidered for the treatment of tumors arising ■ C. H., and Sunderm an, F. W.: Nickel poisoning. from implantation of metallic prostheses. III. Procedure for detection, prevention, and treatment of nickel carbonyl exposure includ ing a method for the determination of nickel in References biologic materials. Amer. J. Clin. Path. 26:107-119, 1956. 1. Alexander, O. R., G o d a r , E. M., and L in d e , 18. Kin c a id , J. F., St r o n g , J. S., and Su n d erm a n , N. J.: Spectrophotometric determination of F. W.: Nickel poisoning. I. Experimental study traces of nickel. Indust. Eng. Chem. (Anal. Ed.) of the effects of acute and subacute exposure to J 8:206, 1946. vapors of nickel carbonyl. J. Amer. Med. Assoc. 2. ARVIDSSON, H. and BOGG, A.: T ransitory 155:889-894, 1954. pulmonary infiltration: Loeffler’s syndrome in 19. Kolipinski, L.: On the uses of nickel sulphate acute generalized dermatitis. Acta Derm.- in medicine. Monthly Cyclop. Med. Bull. Venereol. 39:30-34, 1959. 4:348-355, 1911. 3. B ertrand, G. and N a k a m u ra , H.: Recherches 20. L e h m a n n , K. B.: Hygienische Studien uber sur l’importance physiologique du nickel et du Nickel. Arch. Hyg. (Berl.) 68:421, 1908. cobalt. Bull. Soc. Sci. Hyg. Aliment. 24:338- 343, 1936. 21. M a l t e n , K. E., Sc h u t t e r , K., Van Se n d e n , K. 4. B ro w n in g , E.: Toxicity of Industrial Metals. G., and S p r u it, D.: Nickel sensitization and London, Butterworths, 1961, p. 218. detergents. Acta Derm.-Venereol. 49:10-13, 1969. 5. Christensen, O. B. and M o l l e r , H.: External and internal exposure to the antigen in the hand 22. Ma l t e n , K. E. and Sp r u it , D.: The relative eczema of nickel allergy. Contact Derm. 1 :136, importance of various environmental exposures 1975. to nickel in causing contact hypersensitivity. 6. D e u tm a n , R., M u ld e r , Th. J., B ria n , R., and Acta Derm.-Venereol. 49:14-19, 1969. N a t e r , J. P.: Metal sensitivity before and after 23. M cConnell, L. H., Fink, J. N., Schlueter, total hip arthroplasty. J. Bone Joint Surg. D. P., and SCHMIDT, M G., Jr.: Asthma caused 59:862-865, 1977. by nickel sensitivity. Ann. Intern. Med. 7. D om ar, G., F r e d GA, A., and LlNDERHOLM, H.: 78:888-890, 1973. The determination of tetraethyl-thiuramdisulfide 24. M c D o u g a l l , A.: Malignant tum our at site of (Antabuse, Abstinyl) and its reduced form, bone plating. J. Bone Joint Surg. 38B :709-713, diethyldithiocarbamic acid, as found in excreta. 1956. Acta Chem. Scand. 3:1441, 1949. 25. M e n n e , T. and Ka a b e r , K.: Treatm ent of pom- 8. D rinker, K. R., F airhall, L. T., Ray, G. B., pholyx due to nickel allergy with chelating and D r in k e r , C. K.: Hygiene and significance agents. Contact Derm. 4:289-290, 1978. of nickel. J. Industr. Hyg. 6:307, 1924. 26. M e n n e , T., Ka a b e r , K., an d Tj e l l , J. C.: 9. D u b e , V. E. and FISHER, D. E.: Hemangio Treatment of nickel dermatitis. The influence of endothelioma of the leg following metallic fixa tetraethylthiuramdisulfide (Antabuse) on nickel tion of the tibia. Cancer 30:1260-1266, 1972. metabolism. Ann. Clin. Lab. Sci. 10:160-164, 10. F is h e r , A. A. and Sh a p ir o , A.: Allergic ec 1980. zematous contact dermatitis due to metallic 27. N a t e r , J. P., Br ia n , R. G., D e u t m a n , R., and nickel. J. Amer. Med. Assoc. 161:717-721, MULDER, T. J.: The development of hyper 1956. sensitivity in patients with metal-to-plastic hip 11. F u r s t , A., H a r o , R. T., and Schlauder, M.: arthroplasties. Contact Derm. 2:259-261, 1976. Experimental chemotherapy of nickel-induced 28. N ational Research Council. Committee on fibrosarcomas. Oncology 26:422-426, 1972. Medical and Biologic Effects of Environmental 8 SUNDERMAN

Pollutants. Nickel. Washington, National ethylenediaminetetraacetic acid). A.M.A. Arch. Academy of Sciences, 1975. Ind. Health 18:480-482, 1958. 29. N ic Au d , P., L a d it t e , A., and G ro s, A.: Les 41. Su n d e r m a n , F. W.: Perspectives on Legion troubles de 1’intoxication chronique par le naires’ disease in relation to acute nickel car cadmium. Arch. Mai Prof. 4:193-303, 1942. bonyl poisoning. The Henry M. Scharf Lecture 30. O’DriSCOLL, B. J.: Allergy to nickel: A common on Current Affairs. Ann. Clin. Lab. Sci. 7:187- cause of eczema. J. Irish Med. Assoc. 56:162- 200, 1977. 163, 1965. 42. Su n d e r m a n , F. W.: The Treatment of acute 31. OSKARSSON, A. and T ja lv e , H.: Effects of nickel carbonyl poisoning with sodium diethyl diethyldithiocarbamate and penicillamine on dithiocarbamate. Ann. Clin. Res. 3:182-185, the tissue distribution of 6SNiCI2 in mice. Arch. 1971. Tox. 45:45-52, 1980. 43. Su n d e r m a n , F. W. and Kin c a id , J. F.: Nickel 32. Ro e d -P e t e r s e n , B., Ro e d -Pe t e r s e n , J., and poisoning. II. Studies on patients suffering from JORGENSEN, K. D.: Nickel allergy and osteo acute exposure to vapors of nickel carbonyl. J. myelitis in a patient with metal osteosynthesis Amer. Med. Assoc. 155:889-894, 1954. of a jaw fracture. Contact Derm. 5:108-112, 44. Su n d e r m a n , F. W ., P a y n t e r , O. E., and 1979. G e o r g e , R. B.: The effects of the protracted 33. Ro w e l l , N. R.: Contact dermatitis. Practitioner administration of the chelating agent, sodium 204:674-682, 1970. diethyldithiocarbamate (Dithiocarb). Amer. J. 34. Ry bnik o v, V. I. and Vo lk ov a , L. A.: Effect of Med. Sci. 254:46-55, 1967. radiation and drug therapy on blood and tissue 45. Sund erm a n , F. W. and Sund erm a n , F. W., Jr .: nickel levels in cancer of the uterus. Med. Nickel poisoning. X. Loeffler’s syndrome as Radiol. (Russia) 15:52-58, 1970. sociated with nickel sensitivity. A.M.A. Arch. 35. Sc h w a r t z , K.: Elements newly identified as Intern. Med. 107:405-408, 1961. essential for animals. Ann. Clin. Lab. Sci.4:130, 46. Su n d e r m a n , F. W. and W e s t , B.: Dithio- 1974. carbamates for treatment of nickel poisoning. 36. Sp r u it , D., Bo n g a a r t s, J. M., and d e J o n g h , U.S. Patent Office #2,876,159, March 3, 1959. G. J.: Dithiocarbamate therapy for nickel der 47. Ta n d o n , S. K. and MATHUR, A. K.: Chelation in matitis. Contact Derm. 4:350-358, 1978. metal intoxication. III. Lowering of nickel con 37. SUNDERMAN, F. W.: Efficacy of sodium diethyl tent in poisoned rat organs. Acta Pharmacol. dithiocarbamate (Dithiocarb) in acute nickel Toxicol. 38:401-408, 1976. carbonyl poisoning. Ann. Clin. Lab. Sci.9:l-10, 48. Vu o pa l a , U., H u h t i, E., T a k k u n e n , J., and 1979. H u ik k o , M.: Nickel carbonyl poisoning. Report 38. Su n d e r m a n , F. W.: Nickel and copper mobil of 25 cases. Ann. Clin. Res. 2:214-222, 1970. ization by sodium diethyldithiocarbamate. J. 49. Wa h l b e r g , J. E. and Sk o g , E.: Nickel allergy New Drugs 4:154-161, 1964. and atopy. Threshold of nickel sensitivity and 39. Su n d e r m a n , F. W.: Nickel pneum onitis and immunoglobulin E determinations. Brit. J. pulmonary carcinogenesis. XVI. International Derm. 85:97-104, 1971. Congress on Occupational Health. Tokyo, 50. W e s t , B. and Su n d e r m a n , F. W .: N ickel Japan, Septem ber 22-27, 1969. poisoning. VII. The therapeutic effectiveness 40. Su n d er m a n , F. W.: Nickel poisoning. VI. A of alkyldithiocarbamates in experimental ani note concerning the ineffectiveness of edath- mals exposed to nickel carbonyl. Amer. J. Med. amil calcium-disodium (calcium disodium Sci. 236:15-25, 1958.