a review of the metabolism and toxicology of nickel* f · a review of the metabolism and toxicology...

ANNALS OF CLINICAL AND LABORATORY SCIENCE, Vol. 7, No. 5Copyright © 1977, Institute for Clinical Science

A Review of the Metabolism and Toxicology of Nickel* fF. WILLIAM SUNDERMAN, JR., M.D.

Department of Laboratory Medicine, University of Connecticut School of Medicine,

Farmington, CT 06032

ABSTRACT

Although nickel is an essential element for animal nutrition, the physiological role of nickel is not yet established. Pathological alterations of nickel metabolism are recognized in several human diseases. The diverse clinical manifestations of nickel toxicology include: (1) acute pneumonitis from inhalation of nickel carbonyl, (2) chronic rhinitis and sinusitis from inhalation of nickel aerosols, (3) cancers of nasal cavities and lungs in nickel workers, and (4) dermatitis and other hypersensitive reactions from cutaneous and parenteral exposures to nickel alloys. The toxicity, carcinogenicity and embryotoxicity of nickel compounds in experimental animals are reviewed in this article, and consideration is given to the therapeutic use of chelating drugs in nickel poisoning.

Introduction

The objective of this paper is to summarize recent contributions to the metabolism and toxicology of nickel. This manuscript is intended to bring up-to-date the comprehensive monograph on medical and biologic effects of nickel that was published in 1975 by the Panel on Nickel ofthe National Academy of Sciences.144

* Supported by research grants from the Energy Research and Development Administration (#E(11-1)-3140) and the National Institute of Environmental Health Sciences (#ES 01337-01).

f Presented at the International Symposium on Clinical Chemistry and Chemical Toxicology of Metals, Monte Carlo, Monaco, March 4,1977. This paper will be included in modified form in the proceedings of that Symposium.

Metabolism and Pathophysiology of Nickel

N u t r it io n a l E s s e n t ia l it y

Studies from 1970 to 1974 by Nielsen et al,90,91 Sunderman et al,153 and Anke et al2 suggested, but did not conclusively demonstrate, that nickel might be an essential element for nutrition of experimental animals. The nutritional essentiality of nickel has recently been unequivocally revealed by investigations of Schnegg and Kir- chgessner.68,69,114-117 These investigators have produced a nickel deficiency in rats associated with retarded growth115 and reduction of blood hemoglobin concentrations, hematocrit values and erythrocyte counts.114 Schnegg and Kir- chgessner116,117 have shown that nickel

377

378 SUNDERMAN

deprivation profoundly impairs intestinal absorption of iron and thereby causes anemia. Moreover, Kirchgessner and Schnegg69 have found that nickel deficiency is attended by diminished activitie s of malate dehydrogenase and glucose-6- phosphate dehydrogenase in rat hepatocytes.

N i c k e l M e t a l l o p r o t e in s

In 1966, Himmelhoch et al46 fractionated human serum by column chromatography, and they isolated a metalloprotein which is rich in nickel and which does not contain detectable amounts of other trace metals. In 1971, Nomoto et al94 isolated a similar nickel-containing protein from rabbit serum which they named “nickeloplasmin.” Immunologic studies have indicated that rabbit serum nickeloplasmin reacts as an ax-macroglobulin.93 The nickel that is present in nickelplas- min is not readily exchangeable with 63Ni(II) in vivo or in vitro.23 Haupt et al42 have isolated a 9.5S-a1-glycoprotein which is present in human serum and which has strong binding for Ni(II). The relationship between the Ni-binding-9.5S-a!- glycoprotein42 and serum nickeloplas- min23,94,95 is obscure, but it is possible that nickeloplasmin may represent a complex of the 9.5S-ai-glycoprotein with serum ai-macroglobulin. Interest in nickel metalloproteins has been stimulated by the recent discovery of Dixon et al24 that jack bean urease is a nickel metalloenzyme. Several animal enzymes are currently under scrutiny as possible nickel metalloenzymes.25 One of these enzymes, formylglycineamidophosphoribosyl transferase (“FGAR transferase”), has been isolated by J. M. Buchanan at the Massachusetts Institute of Technology and has been subjected to nickel analyses in our laboratory. Our analyses have shown that the purified FGAR transferase does not contain a significant amount of nickel.

N ic k e l B in d in g t o A l b u m in s

Several investigations15,19,104,105,124 have shown that albumin is the principal Ni(II)-binding protein in human, bovine, rabbit and rat serums. Ni(II) competes with Cu(II) for binding within a square planar ring that is created by (1) the terminal amino group, (2) the first two peptide nitrogen atoms at the N-terminus of the albumin molecule and (3) the imidazole nitrogen of the histidine-residue which is located at the third position from the N-terminus.104 The presence ofhistidine at the third position of the albumin molecule appears to be a key feature of the binding site. Thus canine and porcine albumins contain tyrosine in lieu ofhistidine at the third position,104 and these albumins have less affinity for Ni(II) than do the albumins for other species15 (table I).

It is interesting to note that Lau et al74 synthesized diglycylhistidine-N- methylamide as a biochemical analog of the primary binding site of human albumin for Ni(II) and Cu(II), and they proposed that this tripeptide might serve as a drug for chelation of these metals. Horak et al54 tested the antidotal efficacy of diglycylhistidine-N-methylamide in rats which received parenteral injection of NiCl2, and they found that the tripeptide possessed the antidotal property for which it was specifically designed. However, the effectiveness of diglycylhistidine-N- methylamide as a chelating drug appeared to be limited by its rapid rate of catabolism.54

I n t r a c e l l u l a r N i c k e l -b in d in g

P r o t e in s

Little is known about intracellular Ni(ll)-binding proteins. Insofar as the authors can ascertain, there is no evidence that Ni(II) binds to metallothionein and related cysteine-rich proteins in the cytosol of mammalian liver and kidney. Thus, E. Sabbioni (personal communica

METABOLISM AND TOXOLOGY OF NICKEL 379

tion, 1975) did not observe in vivo binding of 63Ni(II) to metallothionein in rats after induction of the protein by an injection of Cd(II). According to Sabbioni and Marafante107 and Piotrowska and Szymenska,106 parenteral administration of Ni(II) to rats does not influence the concentrations of metallothionein-like proteins in liver and kidney. Attempts to isolate and to characterize Ni(II)-binding proteins in the ultracentrifugal supernatant fractions of liver and kidney homoge- nates from 63Ni(II)-treated rats are currently in progress in our laboratory.

U l t r a f il t r a b l e N ic k e l -b in d in g

Su b s t a n c e s

Ultrafiltrable Ni(II)-binding ligands play an important role in (1) extracellular transport of nickel,45,124 (2) intracellular binding of nickel149 and (3) excretion of nickel in urine and bile.6 Asato et al6 used autoradiography of thin layer chromatograms to demonstrate five distinct63 Ni- complexes in serum ultrafiltrates from rabbits that had received intravenous injection of 63N iCl2. The ultrafiltrable 63Ni(II)-complexes were rapidly cleared from the rabbit serum and eliminated in urine and bile. The identity of the ultrafiltrable Ni(II)-ligands in serum has not been established, but the ligands react with ninhydrin to yield purple- colored compounds. Preliminary experiments suggest that63Ni(II) may be com- plexed with cysteine, histidine and aspartic acid, either singly or as mixed-ligand species.6,124

N i c k e l M e t a b o l is m in H e a l t h y

P e r s o n s

According to Schroeder et al,119 the dietary intake of nickel by adults in the USA in 1962 ranged from approximately 300 to 600 fj,g per day. Most of the nickel that is ingested orally is excreted in the feces. Horak and Sunderman51 found that

TABLE I

Species Differences in N i(II)-B ind ing to Albuminí

Anima I Species

1st Assn. Constant For Ni (II)-Binding

Amino Acid Sequenc At N-Terminus

Man 6 x 1 0 5 NH 2 -Asp-Ala-His-Rat 4 x 105 m 2-Glu-Ala-His-

Pig 1 . 6 x 1 0 5 NH2-Asp-Thr-Tyr-Dog 0.5 x 105 HH2~Glu-Ala-Tyr-

the fecal excretion of nickel in 10 healthyadults averaged 259 (SD ± 126) fig perday. The normal fecal excretion of nickel is approximately 100 times greater than the normal urinary excretion of nickel. Reference values for nickel in body fluids and excreta from healthy adults who reside in the vicinity of Hartford, Connecticut are listed in table II, based upon measurements in the author’s laboratory 17-49>51'82-89>95

The mean concentration of nickel in sweat from healthy men is approximately 20 times greater than the mean concentration of nickel in urine.49 Under conditions of profuse sweating, appreciable amounts of nickel are excreted in sweat, which may be responsible for the diminished concentrations of serum nickel which have been reported by Szadkowski et al161 in workmen who were chronically exposed to extreme heat. Schroeder and Nason,121 Nechay and Sunderman,89 and Katz et al66 have performed measurements of nickel in hair samples from healthy subjects. Considerable disparities exist between the concentrations of nickel in hair that have been found by these workers, presumably as a result of differences in the techniques for collecting and washing the hair samples. Based upon animal experiments, Scheiner et al113 have recently concluded that hair is not a valid biopsy tissue for the assessment of nickel ingestion.

380 SUNDERMAN

Nickel Concentrations in Specimens from Healthy Residents o f Hartford

TABLE XI

Sample Number of Niekel Concentrations in Body Fluids and ExcretaSubjects Mean ± SD Range Units

Blood 17(10tf,7î) 4.8 + 1.3 2.9-7.0 y g / lite r

Serum 80(37^,43«) 2.6 ± 0.9 0.8-5.2 (Jg /lite r

Urine 50(24^,28?) 2 . 2 ± 1 . 2 0.7-5.2 y g / lite r

2.6 ± 1.4 0.5-6.4 yg/day

Saliva 20(14rf,6?i 2 . 2 ± 1 . 2 0.8-4.5 y g / lite r

Feces 14.2 ± 2.7 10.8-18.7 yg/g(dry)

258 ± 126 80-540 yg/day

Sweat 33* 52 ± 36 7-180 y g / lite r

Hair 20(13^,7?) 0 . 2 2 ± 0.08 0.13-0.51 yg/g

E n v ir o n m e n t a l E f f e c t s o f N ic k e l

M e t a b o l is m

McNeely et al82 compared nickel concentrations in serum and urine specimens from healthy adult inhabitants of Hartford, CT (a city with relatively low environmental concentrations of nickel) with nickel concentrations in specimens from a matched group of adult inhabitants of Sudbury, Ontario, Canada (a city which is the site of the largest nickel mines in North America). None of the subjects had occupational exposure to nickel. In contrast to the values for nickel in serum and urine of the Hartford inhabitants (table II), the inhabitants of Sudbury had mean concentrations of serum nickel of 4.6 ± 1.4 /¿g per liter (range = 2.0 to 7.3) and mean excretions of nickel in urine of 7.9 ± 3.7 /u-g per day (range = 2.3 to 15.7). These measurements provided the first direct evidence that analyses of nickel in serum and urine could serve as laboratory indices of environmental exposures to nickel.

P a t h o p h y s io l o g y o f N ic k e l

M e t a b o l is m in M a n

Pathophysiological alterations of nickel metabolism have been observed in certain human diseases. D’Alonzo and Pell21

and Sunderman et al154 reported increased concentrations of nickel in serum from patients after acute myocardial infarction. Data for nickel concentrations in serum specimens obtained from a total of 73 patients at various intervals following onset of myocardial infarction are summarized in table III, based upon the reports of Sunderman et al,154 McNeely et al,83 and additional cases that have recently been studied by the author. Based upon unpublished studies in the author’s laboratory, it seems probable that the hypernickelemia in myocardial infarction is a secondary manifestation of leukocytosis and leukocytolysis. No correlation has been observed between serum nickel concentration and serum activity of creatine kinase or serum activity of the cardiac isoenzyme of lactate dehydrogenase. McNeely et al83 found hypernickelemia in patients with acute stroke and extensive thermal burns, and they observed hyponickelemia in patients with hepatic cirrhosis or uremia, as a consequence of marked hypoalbuminemia.

N ickel Carbonyl PoisoningC l in ic a l M a n if e s t a t io n s

Nickel carbonyl, Ni(CO)4, a volatile, colorless liquid was discovered in 1890


by Mond et al,87 and its extraordinary toxicity was quickly recognized by McKen- drick and Snodgrass.80 The first severe cases of nickel carbonyl poisoning in industrial workers occurred in 1902, soon after construction of the Mond nickel refinery in Clydach, Wales.3,55 The clinical manifestations of nickel carbonyl poisoning have been thoroughly described by Sunderman,133 von Ludewigs and Thiess172 and Vuopala et al173 and will be briefly summarized in this paper.

Accidental exposure of workers to inhalation of Ni(CO)4 usually produces mild, non-specific, immediate symptoms, including nausea, vertigo, headache, dyspnea and chest pain. These initial symptoms usually disappear within a few hours. After 12 to 36 hours, and occasionally as long as 5 days after exposure, severe pulmonary symptoms develop, with cough, dyspnea, tachycardia, cyanosis and profound weakness. Death has occurred from 4 to 13 days after the exposure to Ni(CO)4 and has usually been the result of diffuse interstitial pneumonitis and cerebral hemorrhage or edema.146 In addition to pathologic lesions in the lung and brain, lesions have been reported in

the liver, kidneys, adrenal glands and spleen of diseased workers.146 In patients who recover from acute Ni(CO)4 poisoning, there is usually a protracted convalescence, owing to pulmonary insufficiency.132, 133>170

P a t h o l o g ic a l R e a c t io n s t o Ni(CO)4

Studies of the pathologic reactions of experimental animals to Ni(CO)4 exposures have been performed by Sunderman et al136 and Hackett and Sunderman.37“39 The pulmonary parenchyma has consistently been found to be the principal target tissue of Ni(CO)4 toxicity, regardless of the route of administration. Type I alveolar cells (membranous pneumocytes) are primarily damaged by Ni(CO)4, but type II alveolar cells (granular pneumocytes) are also affected.38 The biochemical pathology of Ni(CO)4 injury of the lungs has recently been discussed by Witschi and Côté.171

M e t a b o l is m o f Ni(CO)4

Investigations of the metabolism of 63Ni(CO)4 and Ni(14CO)4 in rats, and gas chromatographic measurements of

TABLE I I I

Concentrations o f Nickel in Serum from Control Subjects and Patients with Acute Myocardial In farction

Subjects Number Serum Nickel Mean ± SD

( v-g/l) Range

Ni > 4.2 vg/l (% of Subjects)

Healthy Controls 80 2.6 ± 0.9 0.8-5.2 2.5

Myocardial In farction

0 - 1 2 hours 44 4.0 + 2 .111 0.2-8.9 5011

13-24 hours 46 3.9 ± 2.4V 0 . 2-1 0 . 8 48*

25-48 hours 64 3.5 ± 2 .3+ 0.2-11.4 33*

49-72 hours 57 3.1 ± 2.1 0.2-7.7 33*

72-96 hours 52 3.2 ± 1.8 0 . 2 -8 .7 351196-120 hours 23 2.5 ± 2.8 0.2-12.7

*13

P < 0.05 P < 0.005 P < 0.001 vs Healthy Controls

382 SUNDERMAN

Ni(CO)4 in blood and breath of rats have shown that Ni(CO)4 can cross the aveolar membranes in either direction without metabolic alteration.65,155,156 During 2 to 4 hours after exposure of rats or rabbits to Ni(CO)4, the lung is a major excretory organ for Ni(CO)4.85,156 Thereafter, Ni(CO)4 is progressively oxidized within erythrocytes and other cells to liberate (1) Ni(II) which is excreted in the urine and(2) carbon monoxide which is eliminated in the expired breath.65,85,155,156

I n d ic e s o f Se v e r it y o f Ni(CO)4 P o is o n in g

Mikheyev85 has reported that the severity of Ni(CO)4 poisoning can best be judged by the concentration of nickel in whole blood during the first minutes and hours after exposure. After a few hours, Mikheyev85 has reported that the concentration of nickel in urine serves as the best criterion of severity of Ni(CO)4 poisoning. Based upon observations of workers who were accidentally exposed to inhalation of Ni(CO)4, Sunderman and Sunderman137 classified human exposures as (1) mild if the initial-8-hour collection of urine has a nickel concentra

tion <100 fig per liter, (2) moderately severe if the nickel concentration in the initial 8-hour urine collection is >100 fig per liter but <500 fig per liter, and (3) severe if the nickel concentration is >500 fig per liter.

C h e l a t io n T h e r a p y o f Ni(CO)4 P o is o n in g

Sunderman and Sunderman137 recommended that patients in the moderately severe and severe categories of Ni(CO)4 exposure should be treated immediately by administration of a chelating drug, sodium diethyldithiocarbamate (“Di- thiocarb” ). Sodium diethyldithiocarbamate has been used successfully for therapy of numerous workers who have been poisoned by Ni(CO)4.130,133 Baselt et al8 have recently compared the antidotal efficacies of sodium diethyldithiocarbamate (DDC), d-penicillamine (d-Pen) and triethylenetetramine (TETA) as antidotes for acute poisoning of rats by inhalation of Ni(CO)4. The chelating drugs were each administered by im injection in dosages equivalent to 0.6 times their respective LD50 values. Illustrative data are given in table IV to demonstrate that

TABLE IV

Relative Efficacy of Chelating Drugs in Acute Ni(C0)^ Poisoning in Rats

Drug Interval(min)

Ni(C0)h* (mg Ni/1)

Dosage (mM/kg, i.p.)

Mortality^ Ratio

Vehicle 10 Before 3.0 _ 33/33 (100%)

DDC n u " 4.1 1/28 (4%)

d-Pen it it " 13.6 10/26 (38%)

Teta ii n " 1,4 22/26 (85%)

Vehicle 10 After 1.5 — 19/26 (73%)

DDC " " " 4.1 2/26 (8 %)

d-Pen " " " 13.6 4/26 (15%)

Teta II II II 1.4 6/26 (23%)

* Inha la tion o f NiCCO)^ in a ir for 15 min.t

M ortality w ith in 2 weeks

METABOLISM AND TOXOLOGY O F NICKEL 383

the antidotal efficacy of sodium diethyldithiocarbamate was greater than either of the other chelating drugs.

H y p e r g l y c e m ia I n d u c e d b y Ni(CO)4

Tseretili and Mandzhavidze170 reported hyperglycemia and glucosuria in patients with Ni(CO)4 poisoning. This finding has been confirmed by L. Morgan (personal communication, 1974). An investigation in the author’s laboratory163 has shown that exposure of rats to inhalation of Ni(CO)4 also induces transient hyperglycemia. The hyperglycemia is maximal at 0.5 and 1 hour after the onset of exposure to Ni(CO)4, and the magnitude of the hyperglycemia is directly related to the atmospheric concentration of Ni(CO)4 (table V). Although the pathogenesis of the acute hyperglycemia induced by Ni(CO)4 has not been established, it is presumably similar to the mechanism of hyperglycemia produced by inhalation or parenteral injection of Ni(II) compounds, as will be discussed subsequently.

M o l e c u l a r T o x ic o l o g y o f Ni(CO)4

The molecular mechanisms of Ni(CO)4 poisoning have been studied in several investigations.9,10,139~142-147>150 Sunderman

has proposed that (1) the immediate toxic effects of Ni(CO)4 may be mediated by acute inhibition of ATPase in target tissue,142 and (2) the delayed toxic effects of Ni(CO)4 may result from inhibition of RNA polymerase activity.10,147 Sunderman et al139-141, 150 have shown that Ni(CO)4 has an inhibitory effect on induction of several enzymes in livers of rats, including phenothiazine induction of arylhydrocarbon hydroxylase,139 phénobarbital induction of aminopyrine demethylase150 and cytochrome P-450,141 and cortisone induction of tryptophan pyrrolase.140 These findings may be a secondary manifestation of impaired synthesis of RNA (table VI). Administration of Ni(CO)4 to rats produces atypical segregation of the granular and fibrillar components of nucleoli in hepatocytes,39 which is consistent with a toxic effect of Ni(CO)4 upon nucleolar synthesis of RNA.

D e t e c t io n o f Ni(CO)4

Stedman and Tammaro126 have developed a novel apparatus for quantitative analysis of Ni(CO)4 in air by means of chemiluminescence. The chemiluminescent Ni(CO)4 detector is based upon the reaction between Ni(CO)4 and ozone, in the presence of excess carbon

TABLE V

Effects of Ni(CO)^ on Plasma Glucose in Rats

H(C0)h* (mg Ni/l)

No. of Rats Plasma Glucose Concentrations (mg/dl)̂ 0.5 hr11 1 hr ̂ 2 hr̂

Controls 20 111 + 15 110 ± 13 104 ± 14

0.45 19 141 ± 19* 130 ± 16* 107 ± 15

0.77 20 171 ± 28* 153 ± 32* 108 ± 211.25 20 162 ± 22* 189 ± 25* 126 ± 17

* Inha la tion o f Ni(C0)i, in a ir fo r 15 min; + Mean ± SD

In terva l a fte r in i t ia t io n o f inha la tion o f NiCCO)^; * p < 0.001 vs Controls

384 SUNDERMAN

TABLE VIAcute H epatic E ffe c ts o f i . v . Ni(C0)^ in Rats*

Experimental System % o f Controls(Mean ± SE)

Typtophan P y rro la se A c tiv i ty A fte r C ortisoneInduction 72 ± 7+Arylhydrocarbon Hydroxylase A c tiv ity A fte rPhenothiazine Induction 45 ± 8fCytochrome P450 A fte r P hénobarb ita l Induction 48 ± 5+1<4C-Leucine Uptake in to Microsomal P ro te in s 82 ± 6+^ C -O ro ta te Uptake in to RNA in vivo 25 ± 2+RNA Polymerase A c tiv ity in N uclei 40 ± 7tRNA S ynthesis by Chromatin-RNA Polymerase in v itr o 49 ± 6

Ni(C0 )i4, 2.2 mg/100g, i . v . 3 6 to 28 hours before s a c r i f ic e * P < 0.01 vs C ontro ls

monoxide, to yield an exicted molecule of nickel oxide. As the excited molecule of nickel oxide descends to the ground state, a photon (A.=:540 nm) is emitted, which can be detected by a photomultiplier detector. This instrument is specific for nickel carbonyl, and it furnishes a detection limit of approximately 10 parts per trillion in air. The recorder response of the Ni(CO)4 detector is linear from 20 parts per trillion to 100 parts per billion. By use of this apparatus, Stedman and Tammaro126 have shown that traces of Ni(CO)4 in air do not immediately decompose, as was previously believed. Instead, Stedman and Tammaro126 have found that Ni(CO)4 in air decays by first- order kinetics, with a half-life of approximately 0.5 hours. The chemiluminescent Ni(CO)4 detector may prove to be more convenient than gas chromatography155 as a means for rapid and definitive diagnosis of Ni(CO)4 poisoning by measurement of Ni(CO)4 in expired breath of exposed persons.

Nickel Carcinogenesis

C a n c e r in N ic k e l R e f in e r y W o r k e r s

The carcinogenicity of nickel compounds in industrial workers has been comprehensively reviewed in several publications.4,30, 144-146 Increased inci

dences of cancers of the lung and nasal cavities have been documented by epidemiological investigations of nickel refinery workers in Wales,26,27 Canada,77, 159 Norway102 and Russia.109 The present authors maintains a tabulation of respiratory cancers that have occurred in workers who were exposed to nickel compounds in industrial operations. As of March, 1977, this tabulation included 447 cases of lung cancer and 143 cases of cancers of the nose and paranasal sinuses. In addition to increased risk of respiratory tract cancers, increased risk of laryngeal cancers has been found in Norwegian nickel refinery workers102 and increased risks of gastric carcinomas and soft tissue sarcomas have been reported in Russian nickel refinery workers.109

Three cases of renal cancer occurred among 225 Canadian workers who were involved in electrolytic refining of nickel.159 Since renal cancer is rare, it seems possible that the renal cancers in these refinery workers might have been related to occupational exposures to nickel compounds. The identity of the nickel compounds that induce cancers in nickel refinery workers remains uncertain, although principal attention has been focused upon (1) insoluble dusts of nickel

subsulfide(Ni3S2) and nickel oxides (NiO; Ni20 3), (2) the vapor of nickel carbonyl (Ni(CO)4) and (3) soluble aerosols of nickel sulfate, nitrate or chloride (NiS04; NiNOa; NiCl2).48,144,146

C a n c e r in O t h e r N ic k e l W o r k e r s

Tsuchiya171 reported a significant increase in lung cancer incidence among Japanese workers who were exposed to nickel in a variety of industrial operations, but he did not analyze the proportion of these cancers that occurred among refinery workers versus non-refinery workers. To date, there have not been any epidemiological studies of cancer


mortality among groups of workers who were not employed in nickel refineries, but who nevertheless were chronically exposed to inhalation of nickel com

pounds (e.g., welders, platers, grinders and chemical workers who employ nickel catalysts for hydrogenation reactions). There have been three previous case reports of cancers of the respiratory tract in workers who were exposed to inhalation of nickel in nickel-plating and grinding

operations.13, 143, 169 An additional patient has recently been examined by the author. This case will be described in detail since it provides additional justification for epidemiological investigations of cancer risks among nickel workers.

C a s e R e p o r t

The patient is a 36 year old Caucasian man. He was employed as a tractor driver from age 16 to 24 years. From age 25 (1965) until the present (1977), he has worked in a cutlery factory in Connecticut. From 1965 to 1970, the patient was engaged in a nickel-stripping process, in which he dipped small nickel-plated items (such as teapots) into hot HC1- H N 03 at approximately 85°C in order to strip off old nickel plating (e.g., from used hotel utensils) in order to expose the base of copper. The items were then brushed clean and were transported to another room of the factory where the items were replated with nickel. The patient never used a respirator, and he was continually exposed to hot acid fumes from the nickel-stripping tanks. It is notable that the patient had no exposure to chromium, although he was exposed to copper and silver, in addition to nickel. The patient stated that the most noxious aspect of this work was his weekly duty of cleaning out the nickel sludge in the nickel-stripping tanks.

After five years of work in the nickel-stripping process, the patient developed severe symptoms of nasal irritation, and he transferred to work in a hydraulic press room from 1970 to 1973. He returned to work in the nickel-stripping process from 1973 to1975. During 1975, he worked in a metal grinding room where stainless steel fabrication was performed. In December 1975, the patient developed an infection of the right nostril and sinusitis. These conditions did not respond to therapy, and in March1976, he was admitted to Middlesex Hospital in Middletown, CT, where a biopsy was performed on a polypoid lesion in the nose. The biopsy revealed an invasive epidermoid carcinoma (figures 1 and 2). The tumor was excised surgically, and there was no evidence of involvement of lymph nodes.

The patient was referred to Yale University Hospital in New Haven, Connecticut for radiation

F ig u r e 1. Low-power photomicrograph of squamous cell carcinoma of the nasal mucosa, showing the transition between normal epithelium and neoplastic epidermoid cells. (Hematoxylin-eosin stain, x 160)

F ig u r e 2. High-power photomicrograph of squamous cell carcinoma of nasal mucosa, showing strands of invasive epidermoid cells. (Hematoxylin-eosin stain, x 320)

386 SUNDERMAN

therapy. He received 6,000 rads by combination orthovoltage and electron therapy in April 1976. The patient developed nose bleeds, infection and a nasal septal defect during radiation therapy. In January 1977, the patient was referred to the University of Connecticut Hospital in Farmington, Connecticut for evaluation. At that time, the nasal lesions had healed, and there was no evidence of recurrent neoplasia. The concentration of nickel in the patient’s urine was 1.3 fig per liter, which is within the normal range. This normal concentration of nickel in urine was expected, since the patient had not any significant occupational exposure to nickel for several months. The patient smoked cigarettes (5 to 10 cigarettes per day) since age 14. He never consumed alcoholic beverages. He never had any serious illnesses prior to the present nasal cancer problem. There is no family history of cancer. In the author’s opinion, there is a strong likelihood that this patient’s nasal cancer was caused by occupational exposure to nickel. There is close resemblance between this case and another worker in a cutlery factory who developed cancer of

the nasal cavity, as previously reported by Bouras- set and Galland.13

N ic k e l C a r c in o g e n e s is in A n im a l s

Cancers have been induced in experimental animals by administration of several nickel compounds by a variety of routes, as summarized in table VII. Pulmonary carcinomas have developed in rats following inhalation of Ni(CO)4 and Ni3S298’131'134 and carcinomas of the cranial sinuses have developed in cats following implantation of Ni3S2 discs (J. P. W. Gilman, personal communication, 1970). In most of the studies that are

listed in table VII, the malignant neoplasms developed locally at the site of ex

TABLE V I I

Experimental Models o f Nickel Carcinogenesis

Authors Animats Compounds Routes Tumors

Heuper5 6 *57 Rats § Rabbits Ni dust Intraosseous § In trap leura l

Sarcomas

Heuper58 Guinea pigs Ni dust Inha lation Anaplastic S Adenocarcinomas (lungs)

Sunderman et aZ13]-> 134,135

Rats Ni(C0)i| Inha lation Epidermoid, Anaplastic § Adenocarcinomas (lung)

Gilman33 Rats & Mice NÌ3S2 dust NiO dust

Intramuscular Rhabdomyosarcomas

Heath et Rats Ni dust Intramuscular Rhabdomyosarcomas

Fürst et aZ3 2 »1*1 Rats § Hamsters Nickelocene Intramuscular Sarcomas

J.P.W . Gilman* Cats NÌ3S2 discs Sinus implants Epidermoid § Adenocarcinomas; Sarcomas

Lau et at73 Rats N i(CO) 4 Intravenous Carcinomas § Sarcomas

Fürst § Cassetta31 Rats Ni dust In tra thoracic & In traperitoneal

Mesotheliomas

Ottolenghi et Rats NÌ3S2 dust Inha lation Epidermoid § Adenocarcinomas (lung)

Sosinsk i125 Rats NÌ2O3 dust Intracerebral Sarcomas § Meningiomas

Stoner et at129 Mice Ni(C2H3Q2) In traperitoneal Adenocarcinomas (lung)

Jasmin § R iope lle 63 Rats NÌ3S2 dust In trarenal Adenocarc inomas

Sunderman et aZ152 Hamsters NÌ3S2 dust Intramuscular Sarcomas

Damjanov et al22 Rats NÌ3S2 dust In tra te s t ic u la r Sarcomas

* Personal Communication, 1970


posure, injection, or implantation. However, Stoner et a l129 have observed pulmonary carcinomas in mice that received repeated intraperitoneal injections of nickel acetate. Therefore, it appears likely that certain nickel compounds may induce tumors at sites that are distant from the point of primary contact. Payne,101 Gilman34 and Sunderman and Maenza151 have found that Ni3S2 is the most highly carcinogenic of the nickel compounds that have been evaluated in experimental animals.

M o l e c u l a r B io l o g y o f N ic k e l

C a r c in o g e n e s is

The experimental evidence that pertains to the molecular mechanisms of nickel carcinogenesis has been comprehensively reviewed by the author in several articles.143-146 In order to avoid repetition of this material in the present paper, readers are asked to consult the most recent of these reviews.144 Particular attention is directed to the notable discovery that manganese suppresses the carcinogenicity of Ni3S2 in rats.149 In vitro screening tests for malignant transformation in tissue culture cells or mutagenesis in bacteria have not yielded positive results for nickel compounds. However, Ni(II) has been shown by in vitro tests to decrease the fidelity of DNA transcription by DNA polymerase.122

Other Aspects of Nickel Toxicology

N i c k e l A n a l y s e s a s I n d ic e s o f

O c c u p a t io n a l E x p o s u r e s

Concerns about the carcinogenic hazards of nickel exposures have stimulated several investigators to perform measurements of nickel concentrations in body fluids of various groups of industrial workers.11,40,48,96,162 These studies demonstrated increased nickel concentrations in urine or serum of (1) chemical workers who use Ni(CO)4,40,132 (2) workers in the

electrolytic and roasting-smelting departments of a nickel refinery,48,96 (3) welders who use nickel-containing electrodes to weld stainless steel,96 (4) workers in plants that produce nickel- containing pigments162 and (5) workers in nickel-plating operations.11,162

Illustrative data for excretion of nickel in urine from nickel-plating workers are shown in table VIII, based upon a recent study in the author s laboratory.11 Also included in table VIII are data for excretion of nickel in urine from hydrogenation process workers in a pilot plant for coal gasification. These workers were engaged in use of nickel catalysts for hydrogenation of carbon monoxide and carbon dioxide to yield methane. The mean concentration of nickel in the urine of the coal-gasification workers was only slightly greater than in control workers who had no occupational exposures to nickel. On the other hand, a great increase in the mean concentration of nickel was found in urine of the nickel- plating workers. In the author’s opinion, measurements of nickel concentrations in urine provide a practical and reliable index of occupational exposures to nickel.

TABLE VIII

Urine Nickel as an Index of Environmental and Occupational Exposures

Subjects Number Urine Ni Concentration*

ug / l vg/g Creatinine

Hospital Workers IS 2.7 ± 1.4 2.5 ± 1.3(0.7 - 4.0) (0 .7 - 5.7)

Non-exposed Industrial 10 2.8 ± 1.3 2.5 ± 1.0Workers (0.4 - 4.2) (0 .6 - 3.5)

Ni-Plating Workers 21 28 ± 21f 19 ± 15+(5 .3 - 65) (2.4 - 62)

Hydrogenation Process 9 4.2 ± 2.4 3.2 ± 1.6Workers (0 .4 - 7.9) (0.1 - 5.8)

Mean ± SD, and range in parentheses ^ P < 0.001 vs Hospital Workers

388 SUNDERMAN

E m b r y o t o x ic it y a n d T r a n s p l a c e n t a l

T r a n s p o r t o f N i c k e l

Recent changes in employment practices in North America and Europe have substantially increased the proportion of women among workers in the nickel industry. As a result, there is growing concern regarding possible embryotoxicity associated with exposures of pregnant women to nickel during early pregnancy. Relevant clinical data are not available, and the only evidence related to embryotoxicity of nickel is derived from animal studies.1,29,120,157 Schroeder and Mitchener120 studied three generations of rats that were continually given an unspecified nickel salt in the drinking water (5 ppm). Schroeder and Mitchener120 observed increased proportions of runts and enhanced neonatal mortality in each of the three generations, compared to control rats. Moreover, they noted a substantial reduction in the mean litter size and a reduced proportion of males in the third generation of the nickel-treated rats.

Ambrose et al1 administered nickel sulfide to rats for three generations. The nickel sulfate was added to the diet in amounts yielding dietary Ni concentrations of 0, 250, 500 and 1000 ppm. Increased incidence of stillbirths was observed in the first generation at all dietary levels of nickel. At the 1000 ppm level of nickel, decreased body weights of weanlings were observed in all generations. Ferm29 administered nickel acetate to pregnant hamsters by iv injection on day 8 of gestation at dosages ranging from 0.7 to 10 mg Ni per kg. Ferm29 found dose- related increases in the number of resorbed embryos, as well as a few unspecific malformations in surviving embryos.

Sunderman et al157 administered nickel chloride to pregnant rats by im injection on day 8 of gestation at dosages ranging from 8 to 10 mg Ni per kg. Sunderman et

al157 reported dose-related decreases in the mean weights of surviving pups. No congenital malformations were observed. The findings of Schroeder and Mitchener,120 Ambrose et al,1 Ferm29 and Sunderman et al157 indicate that administration of nickel to pregnant rodents produces fetal mortality and impairs intrauterine growth (table IX). Sunderman et al157 also showed that63Ni(II) can enter the products of conception after im administration to pregnant rats on the day 8 or 18 of gestation (table X). On the basis of the available data, it appears that the embryotoxic hazards of nickel may be comparable to those that have been recognized for certain other metals, including lead, cadmium and mercury.

C h e l a t in g A g e n t s a s A n t id o t e s f o r

Ni(II) T o x ic it y

As mentioned previously, Baselt et al8 reported that sodium diethyldithiocarbamate was more effective than d-penicillamine and triethylenetetramine as an antidote for acute Ni(CO)4 poisoning in rats. It is noteworthy that the converse relationship applies to the antidotal efficacy of these chelating agents in acute Ni(II) poisoning.54 Horak et al54 found that triethylenetetramine and d-penicillamine were very effective antidotes for Ni(II) toxicity in rats and that sodium diethyldithiocarbamate was much less effective. Sunderman et al148 administered triethylenetetramine im in rats immediately prior to ip injection of 63NiCl2 and found that triethylenetetramine greatly reduced the concentrations of 63Ni in hearts and lungs after 6 hours, compared to the concentrations of63Ni in hearts and lungs of rats that only received 63NiCl2.

H y p e r g l y c e m ia I n d u c e d b y N i ( I I )

Clary20 administered NiCl2 to rats by intraperitoneal and intratracheal injec


tions and observed a marked transient increase in serum glucose. This finding has been confirmed by Horak and Sunder- man,52,53 who have established the dose- response relationships for Ni-induced hyperglycemia. Clary20 and Horak and Sunderman52 observed that Ni-induced hyperglycemia is antagonized by exogenous insulin, and Horak and Sunderman52 reported that the hyperglycemic response to N i(II) is suppressed but not completely prevented by adrenalectomy or hypophysectomy. Horak and Sunderman53,148 measured concentrations of immunoreactive glucagon in plasmas from rats after ip injection of N iCl2, and they found parallel responses of plasma glucagon and glucose concentrations, suggesting that hyperglucagonemia may be responsible for the acute hyperglycemic response to Ni(II). In the studies of Horak and Sunderman,52,53 ip administration of Ni(II) was attended by hyperinsulinemia, presumably as an adaptive response to hyperglycemia. In contrast, Clary20 noted progressive diminutions in concentrations of plasma insulin following intratracheal administration of NiCl2. Interest in the mechanism of Ni(II)-induced hyperglycemia has been stimulated by the recent report of Saggerson et al108 that Ni(II) possesses an in vitro insulin-like activity on fat-cell mejnbranes in rats, with stimulation of glucose incorporation into fat-cell membranes in rats, with stimulation of glucose incorporation into fat-cell lipids and diminution of lipolysis. Unpublished studies of Horak and Sunderman demonstrate that Ni-induced hyperglycemia in rats is not prevented by current administration of somatostatin.

R e n a l A c c u m u l a t io n a n d

N e p h r o t o x ic it y o f Ni(II)

Following parenteral administration of 63Ni(II) to rodents, the highest concentrations o f63 Ni are consistently found in

TABLE IX

Embryotoxicity of NiC^ in Rats*

Group

NiClo ^ *

Dosage (mg Ni/kg)

No.

o fDams

Live Fetuses Per Dam *

R atio o f Dead

Fetuses/ Conoeptuses

A 0 13 9.7 ± 1.1 2/128 (1.6%)B 8 12 8.9 ± 2.0 6/113 (5.Si)”C 12 11 7.7 ± 1.9* 8/93 (8. 3%) 11D 16 12 7.0 ± 3.9* 19/103 (18.5%)*

Injection i.m . on the 8th day of gestation.Dams were killed on the 20th day of gestation;Mean ± SD

P < 0.01 vs Controls (Group A)

the kidneys.20,100,123,176 Renal excretion is the principal route for elimination of injected 63Ni(II).18,47,97 In view of the renal accumulation and excretion of nickel, Gitlitz et al36 suspected that administration of soluble nickel compounds to rats might produce renal toxicity. Gitlitz et al36 found that ip administration of NiCl2 to rats in dosages of 2 to 5 mg Ni per kg body weight caused proteinuria, aminoaciduria (figure 3) and reduction of urea clearance, associated with morphological lesions in the renal glomeruli and tubules. Ni(II)-induced nephrotoxicity in

TABLE X

63Ni Concentrations in Rat Tissues*t

Cone. (vg/g wet wt

Non-Pregnant Pregnant Bats^Tissue Rats 9th Day 19th Day

Kidney 16.4 ± 3.1 12.2 ± 2.7 9.6 ±1. 7

Lung 2.3 ± 0.7 2.0 ± 0.3 2.0 ± 0.3Spleen 0.8 ± 0.2 0.6 ± 0.3 0.7 + 0.2.iver 0.6 ± 0.3 0.6 ± 0.2 0.4 ± 0.1.nne Contents - - 2.0 ± 0.4 —

Placenta ___ 2.6 ± 0.7Fetuses 1.1 ± 0.4Amniotic Fluid — — 0.6 ± 0.2*

N = 12 (4 rats/group)^ 63NiCl2 (12 mg Ni/kg) injected i .m . 24 hr before

death; Mean ± SD ̂Rats were killed on the specified day of gestation

390 SUNDERMAN

Days after ip N i (II)

FIGURE 3. Urinary excretion of amino acids (solid lines) and protein (dashed-line) in rats after a single ip injection of NiCl2 (5 mg Ni per kg).

rats was prevented by concurrent administration of triethylenetetramine.148 To date, there have been no clinical evaluations of renal function in workers who are chronically exposed to inhalation of soluble nickel compounds (e.g., nickel electroplaters). Proteinuria has been noted in a few workers who were accidentally exposed to inhalation of nickel car

bonyl.14’16

E r y t h r o c y t o s is I n d u c e d b y

I n t r a r e n a l I n j e c t io n o f Ni3S2

Jasmin and Solymoss64 discovered that administration of nickel subsulfide,

Ni3S2, to rats by intrarenal injection produces pronounced erythrocytosis. They observed 1.5 fold increase in blood erythrocyte count and 2.4 fold increase in body erythrocyte mass at 5 months after an intrarenal injection of 10 mg of Ni3S2. These findings have been confirmed by Morse et al,88 and they elucidated the dose-response and time-response relationships for N i3S2-induced erythrocytosis in rats.

Hopfer et al50 showed that induction of erythrocytosis by intrarenal injection is not specific for Ni3S2, but also occurs (to a lesser degee) after intrarenal injection of other nickel compounds. They observed strain-differences in susceptibility of rats to Ni3S2-induced erythrocytosis, and they noted that erythrocytosis did not occur in mice or rabbits after intrarenal injection of Ni3S2. The physiological mechanism of Ni3S2-induced erythrocytosis has not been established, but it is presumed to be related to increased renal production and release of erythropoietin.64,88

R e s p ir a t o r y T r a c t T o x ic it y o f

N ic k e l

Tatarskaya,164 Kucharin71 and Sushenko and Rafukova138 have described chronic rhinitis and nasal sinusitis in workers in electrolytic nickel refineries who were chronically exposed to inhalation of nickel aerosols (e.g., NiS04). Many of these workers developed anosmia and severe damage to the nasal mucosa, including perforations of the nasal septum. The histological findings in the nasal mucosa of workers in an electrolytic nickel refinery have been reviewed by Toijussen and Solberg.168 They found precancerous nasal lesions (atypical epithelial metaplasia) in 16 percent of 92 nickel-exposed workers. No such lesions were observed in a control group of workers. Tolot et al167 and McConnell et al78 have published reports of asthmatic lung disease in workers in nickel plating operations.


Cases of Loeffler’s syndrome with nickel hypersensitivity have been described by Arvidsson and Bogg5 and Sunderman and Sunderman.138 Bingham et al12 exposed rats to inhalation of soluble (NiCl2) and insoluble (NiO) aerosols of nickel at atmospheric concentrations near or below the levels that were considered to be acceptable for occupational exposures of workers. They observed hyperplasia of bronchiolar and bronchial epithelium with peribronchial lymphocytic infiltrates, and a marked increase in mucus production. Bingham et al12 concluded that the current threshold limit value of 1 mg per m3 for atmospheric concentrations of nickel may be too high.

H a z a r d s f r o m I n t e r n a l E x p o s u r e

t o N ic k e l

Nickel dermatitis from external (cutaneous) exposure to nickel alloys was comprehensively reviewed in the report of the Panel on Nickel146 and, hence, will not be considered in detail in this paper. However, numerous recent papers have drawn attention to the problem of allergy and dermatitis from internal exposures to nickel, owing to the presence of nickel in alloys used for orthopedic prostheses,7,70,81,103,160 cardiac pacemaker electrodes,110 cardiac valve replacements,75 surgical instruments,72,166 steel sutures118 and intravenous cannulae.128 The cutaneous reactions to internal exposures to nickel have included urticarial,81,118,160,166 eczematous7,72,103 and pemphigoid70 lesions.

These allergic reactions to nickel have often been sufficiently severe to necessitate removal of nickel-containing prostheses. It may be noted that Dube and Fisher28 reported a patient with hemangioendothelioma of the tibia at the site of a nickel-containing implant that had been retained for 20 years, and

McDougall79 reported a patient who developed a sarcoma of soft tissue of an arm at 30 years after implantation of a steel plate. These reports have aroused concern about allergic hazards and possible long-term neoplastic sequellae of internal exposure to nickel alloys.

L y m p h o c y t e B l a s t T r a n s f o r m a t io n

T e s t f o r Ni Se n s it iz a t io n

In 1970, Pappas et al" reported that nickel acetate is a potent stimulant for in vitro blast transformation of human peripheral blood lymphocytes. Pappas et al99 did not note any differences in the response of lymphocytes from nickel hypersensitive and non-sensitive patients. Subsequent studies by Hutchinson et al,61 Millikan et al,84 Gimenez- Camarassa et al,35 and Kim and Schoepf®7 have shown that lymphocyte blast transformation, as evidenced by increased thymidine uptake ratios, is enhanced in cells from nickel-sensitive subjects. Millikan et al84 found good correlation between the in vitro response of lymphocytes and the results of in vivo patch testing for nickel sensitivity, and they recommended use of blast transformation of lymphocytes as an in vitro test for nickel allergy.

A study of Hutchinson et al60 demonstrated direct binding of 63Ni to the cell surface of lymphocytes from sensitive and non-sensitive subjects, and they concluded that Ni-binding to the cells is not per se the stimulus for transformation. Several investigators76,86,165 have recently attempted to employ the leukocyte migration inhibition test to differentiate nickel sensitive and non-sensitive subjects; but the results have been negative or equivocal. Therefore, the lymphocyte blast transformation test remains the only practical in vitro procedure for diagnosis of nickel sensitivity.

392 SUNDERMAN

N ic k e l Se n s it iz a t io n in E x p e r im e n t a l

A n im a l s

Experimental sensitization of guinea pigs to nickel has been reported by some investigators,92,127’175 but these findings could not be confirmed by other workers.59,62'111,112 Recently, Wahlberg174 has succeeded unequivocally in sensitizing guinea pigs to nickel by two different schedules of intradermal injection of NiS04. This accomplishment will greatly facilitate experimental study of nickel allergy. Wahlberg174 predicts that it may soon be feasible to perform passive transfer of nickel allergy in experimental animals.

Summary and Conclusions

Nickel is an essential trace metal for animal nutrition, although the physiological role of nickel has not been established. Pathological alterations of nickel metabolism occur in several common diseases of man, such as acute myocardial infarction and stroke. Clinical concerns about nickel toxicology are focused primarily on (1) acute poisoning from inhalation of nickel carbonyl, (2) chronic rhinitis and sinusitis with anosmia and septal perforations from occupational exposures to aerosols of nickel compounds,(3) cancers of the nasal cavities and lungs in nickel-exposed workers, (4) dermatitis and other hypersensitive reactions to nickel, especially following implantation of nickel-containing prostheses and devices and (5) potential embryotoxicity of nickel in pregnant women who have occupational exposures to nickel compounds.

Measurements of nickel concentrations in urine and serum provide laboratory indices of occupational and environmental exposures to nickel compounds. Sensitive gas chromatographic and chemiluminescent techniques are available for detection and quantitation of nickel car

bonyl in exhaled breath, for the specific diagnosis of acute nickel carbonyl poisoning. Human hypersensitivity to nickel can be detected in vitro by the lymphocyte blast transformation test.

Studies in experimental animals have shown that parenteral injections of Ni(II) produce (1) acute transient hyperglycemia and hyperglucagonemia in rats, (2) nephrotoxicity with proteinuria, aminoaciduria and diminished urea clearance in rats, and (3) allergic hypersensitivity in guinea pigs. In addition, (4) intrarenal injection of nickel subsulfide induces marked erythrocytosis with bone marrow hyperplasia in rats. Abundant experimental evidence exists for carcinogenicity in laboratory animals of certain nickel compounds, such as nickel subsulfide and nickel carbonyl. In vitro screening tests for malignant transformation in tissue culture cells or for mutagenesis in bacteria have not yielded positive results for nickel compounds. However, Ni(II) has been shown by in vitro tests to decrease the fidelity of DNA transcription by DNA polymerase.

Sodium diethyldithiocarbamate is the most effective antidote for acute nickel carbonyl poisoning in man and experimental animals. Triethylenetetramine and d-penicillamine are effective as antidotes for acute toxicity of Ni(II) after parenteral administration of nickel chloride to rats.

References

1. A m b r o s e , A. M., L a r s o n , P. S., B o r z e l -

LECA, J. F., and H e n n ig a r , G . R., J r .: Long term toxicologic assessment of nickel in rats and dogs. J. Food Sei. Technol. 13:181-187,1976.

2. A n k e , M., G r u n , M., D i t t r ic h , G .,

G r o p e l l , B., and H e n n ig , A.: Low nickel rations for growth and reproduction in pigs. Trace Element Metabolism in Animals-2. Hoekstra, W. G., et al, eds. Baltimore, University Park Press, pp. 715-718, 1974.

3. ANON.: Nickel carbonyl poisoning. Lancet 1 :268-269, 1903.


4. A n o n .: Nickel and nickel compounds. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Lyon, Internat. Agency for Research in Cancer 11:75-112, 1976.

5. ARVIDSSON, H. and BOGG, A.: Transitory pulmonary infiltrations—(Loeffler’s Syndrome) in acute generalized dermatitis. Acta Derm. Venereol. 39:30-34, 1959.

6. A sa t o , N., So e s t b e r g e n , M . Va n , and Su n -

DERMAN, F. W., Jr.: Binding of 63Ni(II) to ultrafiltrable constituents of rabbit serum in vivo and in vitro. Clin. Chem. 21:521-527,1975.

7. BARRANCO, V. P. and SOLOMAN, H.: Eczematous dermatitis from nickel. J. Amer. Med. Assoc. 220:1244, 1972.

8 . Ba s e l t , R., M it c h e l l , J., H o r a k , E., and SUNDERMAN, F. W., Jr.: Comparisons of the antidotal efficacies of chelating drugs in acute nickel carbonyl poisoning in rats. Proc. New Eng. Soc. Pharmacol., in press.

9. B e a c h , D. J. and Su n d e r m a n , F. W., Jr .:

Nickel carbonyl inhibition of I4C-orotic acid incorporation into rat liver RNA. Proc. Soc. Exp. Biol. Med. 131:321-322, 1969.

10. Be a c h , D. J. and Su n d e r m a n , F. W., J r .:

Nickel carbonyl inhibition of RNA synthesis by a chromatin-RNA polymerase complex from hepatic nuclei. Cancer Res. 30:48-50, 1970.

11. Be r n a c k i , E. J., Su n d e r m a n , F. W., J r ., and M ik a c -De v ic , M .: Nickel excretion in urine of workers in nickel-plating and coal gasification operations. Ann. Clin. Lab. Sci., in press,1977.

12. B in g h a m , E., Ba r k l e y , W., Z e r w a s , M., St e m m e r , K., and Ta y l o r , P.: Responses of alveolar macrophages to metals. I. Inhalation of lead and nickel. Arch. Environ. Health 25:406-414, 1972.

13. Bo u r a s s e t , A. and G a l l a n d , G .: Cancer des voies respiratoires et exposition aux sels de nickel. Arch. Malad. Prof. 27:227-229, 1966.

14. BRANDES, W. W.: Nickel carbonyl poisoning. Report of a case. J. Amer. Med. Assoc. 102:1204-1206, 1934.

15. C a l l a n , W. M. and Su n d e r m a n , F. W., J r .:

Species variations in binding of 63 N iCl2 by serum albumin. Res. Commun. Chem. Pathol. Pharmacol. 5:459-472, 1973.

16. C a r m ic h a e l , J. L.: Nickel carbonyl poisoning. Report of a case. A.M.A. Arch. Ind. Hyg. Occup. Med. 8:143-148, 1953.

17. C a t a l a n a t t o , F. A., Su n d e r m a n , F. W., J r .,

and MACINTOSH, T. R.: Nickel concentrations in human parotid saliva. Ann. Clin. Lab. Sci. 7:146-151, 1977.

18. CHAUSMER, A. B.: Measurement of exchangeable nickel in the rat. Nutr. Rep. Intern. 14:323-336, 1976.

19. C h e n , J. K. M., H a r o , R. T., and F u r s t , A.:

Excretion of nickel compounds by the rat: Blood and urine levels. Wasmann J. Biol. 29:1-15, 1971.

20. C l a r y , J. J.: Nickel chloride-induced metabolic changes in the rat and guinea-pig. Toxicol. Appl. Pharmacol. 31:55-56, 1975.

21. D ’Al o n z o , C. A. and Pe l l , S.: A study o f

trace metals in myocardial infarction. Arch.

Env iron . H ea lth 6:381-385, 1963.22. D a m ja n o v , I., M it c h e l l , J. M ., Al l p a s s , P.

R., B i g a z z i , P., and Su n d e r m a n , F. W., Jr .:

Induction of rhabdomyosarcomas and fibrosarcomas by intratesticular injection of nickel subsulfide in Fischer rats. Proc. Amer. Assoc. Cancer Res., in press, 1977.

23. D e c s y , M. I. and Su n d e r m a n , F. W., Jr.: Binding of 63Ni to rabbit serum a t- macroglobulin in vivo and in vitro. Bioinorgan. Chem. 3:95-105, 1974.

24. D ix o n , N. E., G a z z o l a , C., Bl a k e l e y , R. L., and Z e r n e r , B .: Jack bean urease (EC 3.5.1.5) is a metalloenzyme. A simple biological role for nickel? J. Amer. Chem. Soc. 97:4131-4133, 1975.

25. D ix o n , N. E., G a z z o l a , C ., Bl a k e l e y , R. L., and ZERNER, B.: Metal ions in enzymes using ammonia or amides. Science 191:1144-1150,1976.

26. D o l l , R., M a t h e w s , J. D ., and M o r g a n , L.G.: Cancers of the lung and nasal sinuses in nickel workers. Brit. J. Indust. Med., in press,1977.

27. D o l l , R., M o r g a n , L. G., and Sp e iz e r , F.E.: Cancers of the lungs and nasal sinuses in nickel workers. Brit. J. Cancer 24:623-632,1970.

28. D u b e , V. E. and F is h e r , D . E.: Hemangioendothelioma of the leg following metallic- fixation of the tibia. Cancer 30:1260-1266, 1972.

29. F e r m , V. H.: The teratogenic effects of metals on mammalian embryos. Adv. Teratol. 5:51-75, 1972.

30. FlSHBEIN, L.: Environmental metallic carcinogens: An overview of exposure levels. J. Toxicol. Environ. Health 2:77-109, 1976.

31. FuRST, A. and CASSETTA, D.: Carcinogenicity of nickel by different routes. Proc. Amer. Assoc. Cancer Res. 14:31, 1973.

32. F u r s t , A. and Sc h l a u d e r , M. C.: The hamster as a model for metal carcinogenesis. Proc. West. Pharmacol. Soc. 14:68-71, 1971.

33. G il m a n , J. P. W.: Metal carcinogenesis. II. A study on the carcinogenic activity of cobalt, copper, iron, and nickel compounds. Cancer Res. 22:158-162, 1962.

34. G il m a n , J. P. W.: Muscle tumorigenesis. Proceedings of the Sixth Canadian Cancer Research Conference, Honey Harbor, Ontario. Oxford, Pergamon Press, vol. 6 , pp. 209-223,1966.

35. G i m e n e z -Ca m a r a s s a , J. M ., G a r c ia -

C a l d e r o n , P., A s e n s io , J., and M o r a y a s , J. M . de.: Lymphocyte transformation test in allergic contact nickel dermatitis. Brit. J. Dermatol. 92:9-15, 1975.

36. G it l it z , P. H., Su n d e r m a n , F. W., Jr ., and G o l d b l a t t , P. J.: Aminoaciduria and pro

394 SUNDERMAN

teinuria in rats after a single intraperitoneal injection of Ni(II). Toxicol. Appl. Pharmacol. 34:430-440, 1975.

37. H a c k e t t , R. L. and Su n d e r m a n , F . W., J r .:

Acute pathological reactions to administration of nickel carbonyl. Arch. Environ. Health 14:604-613, 1967.

38. H a c k e t t , R. L. and Su n d e r m a n , F. W„ J r .:

Pulmonary alveolar reaction to nickel carbonyl. Ultrastructural and histochemical studies. Arch. Environ. Health 16:349-362, 1968.

39. H a c k e t t , R. L. and Su n d e r m a n , F. W., J r .:

Nickel carbonyl. Effects upon the ultrastructure of hepatic parenchymal cells. Arch. Environ. Health 19:337-343, 1969.

40. H a g e d o r n -Go t z , H. and Ku p p e r s , G .: On some problems in the supervision of nickel workers. Proc. International Conference on Heavy Metals in the Environment. Hutchinson, T. C., ed. Toronto, Canada, National Research Council, pp. B127-129, 1975.

41. H a r o , R. T., F u r s t , A., Pa y n e , W. W., and Fa l k , H . L.: A new nickel carcinogen. Proc. Amer. Assoc. Cancer Res. 9:28, 1968.

42. H a u p t , H ., H e im b u r g e r , N., Kr a n z , T., and Ba u d n e r , S.: Human serum proteins with a high affinity for carboxymethyl cellulose. III. Physical-chemical and immunological characterization of a metal-binding 9.55-ai- glycoprotein (CM-Protein III). Z. Physiol. Chem. 353:1841-1849, 1972.

43. H e a t h , J. C. and W e b b , M .: Content and intracellular distribution of the inducing metal in the primary rhabdomyosarcomata induced in the rat by cobalt, nickel and cadmium. Brit. J. Cancer 21 .-768-779, 1967.

44. H e a t h , J. C. and D a n ie l , M . R.: The production of malignant tumors by nickel in the rat. Brit. J. Cancer 18:261-264, 1964.

45. H e n d e l , R. C. and Su n d e r m a n , F. W., J r .:

Species variations in the proportions of ultrafiltrable and protein-bound serum nickel. Res. Comm. Chem. Pathol. Pharmacol. 4:141-146, 1972.

46. H im m e l h o c h , S. R., So b e r , H . A., Va l l e e , B. L., Pe t e r s o n , E. A., and F u w a , K.: Spectro- graphic and chromatographic resolution of metalloproteins in human serum. Biochemistry 5:2523-2530, 1966.

47. Ho, W. and F u r s t , A.: Nickel excretion by rats following a single treatment. Proc. West, Pharmacol. Soc. J 6:245-248, 1973.

48. H0GETVEIT, A. C. and Ba r t o n , R. T.: Preventive health program for nickel workers. J. Oc- cup. Med. 18:805-808, 1976.

49. H o h n a d e l , D. C., Su n d e r m a n , F. W„ J r .,

N e CHAY, M. W., and M cNEELY, M. D.: Atomic absorption spectrometry ofnickel, copper, zinc and lead in sweat collected from healthy subjects during sauna bathing. C lin . Chem. 19:1288-1292, 1973.

50. H o p f e r , S. M ., Su n d e r m a n , F . W .,J r ., F r e d

r ic k s o n , T. N., and M o r s e , E. E.: Compari

sons of the efficacies of nickel compounds for induction of erythrocytosis following intrarenal injection in rats. Proceedings of the American Society of Hematology, Boston, MA, December 1976, p. 109.

51. H o r a k , E. and Su n d e r m a n , F. W ., J r .: Fecal nickel excretion by healthy adults. Clin. Chem. 19:429-430, 1973.

52. H o r a k , E. and Su n d e r m a n , F. W ., J r .: Effects of Ni(II), other divalent metal ions, and glucagon upon plasma glucose concentrations in normal, adrenalectomized and hypophysec- tomized rats. Toxicol. Appl. Pharmacol. 32:316-329, 1975.

53. H o r a k , E. and Su n d e r m a n , F. W ., J r .: Effects of Ni(II) upon plasma glucagon and glucose in rats. Toxicol. Appl. Pharmacol. 33:388-395,1975.

54. H o r a k , E., Su n d e r m a n , F. W ., J r ., and Sa r -

k a r , B.: Comparisons of antidotal efficacies of chelating drugs upon acute toxicity of N i(II) in rats. Res. Comm. Chem. Pathol. Pharmacol. 14:153-165, 1976.

55. H o w a r d -Wh it e , F. B.: Nickel. An Historical Review. New York, D. Van Nostrand Company, Inc., 1963.

56. H u e p e r , W . C.: Experimental studies in metal carcinogenesis. I. Nickel cancer in rats. Texas Rep. Biol. Med. 70:167-186, 1952.

57. H u e p e r , W . C.: Experimental studies in metal carcinogenesis. IV. Cancer produced by par- enterally induced metallic nickel. J. Nat. Cancer Inst. 16:55-67, 1955.

58. H u e p e r , W . C.: Experimental studies in metal carcinogenesis. IV. Pulmonary lesions in guinea-pigs and rats exposed to prolonged inhalation of powdered metallic nickel. A.M.A. Arch. Path. 65:600-607, 1958.

59. H u n z ik e r , N.: De l’eczema experimental. Dermatologica 121:307-312, 1960.

60. H u t c h in s o n , R., M a c L e o d , T. M., and Ra f

f l e , E. J.: Nickel hypersensitivity. Nickel binding to amino acids and lymphocytes. Brit. J. Dermatol. 93:557-561, 1975.

61. H u t c h in s o n , R., Ra f f l e , E. J., and M a c L e o d , T. M.: The specificity of lymphocyte transformation in vitro by nickel salts in nickel sensitive subjects. J. Invest. Derm.58:362-365,

1972.

62. Ja d a s s o h n , W . and Sh a a f , F.: Über die Haut- figkeit des Vorkommens von Nickel-ekzemen. Arch. Derm. Syph. 157:572-577, 1929.

63. Ja s m in , G. and RiOPELLE, J. L.: Renal carcinomas and erythrocytosis in rats following intrarenal injection of nickel subsulfide. Lab. Invest. 35:71-78, 1976.

64. Ja s m in , G. and So l y m o s s , B.: Polycythemia induced in rats by intrarenal injection of nickel sulfide, Ni3S2. Proc. Soc. Exper. Biol. Med. 148:774-776, 1975.

65. Ka s p r z a k , K. S. and Su n d e r m a n , F . W ., J r .:

The metabolism of nickel carbonyl-14C. Toxicol. Appl. Pharmacol. 15:295-303, 1969.


66. Ka t z , S. A., B o w e n , H . J. M ., C o m a is h , J. S., 83.

and Sa m it z , M . H .: Tissue nickel levels and nickel dermatitis. I. Nickel in hair. Brit. J. Dermatol. 92:187-190, 1975.

67. Kim , C. W . and SCHOEPF, E . A.: Comparativestudy of nickel hypersensitivity by the lymphocyte transformation test in atopic and non- 84.atopic dermatitis. Arch. Dermatol. Res. 257:57-65, 1976.

6 8 . Kir c h g e s s n e r , M. and Sc h n e g g , A.: Nickelcontent of milk from lactating rats fed varying 85.nickel levels. Archiv, für Tierernahrung2 i :774-776, 1976.

69. K ir c h g e s s n e r , M. and Sc h n e g g , A.: Malate 8 6 .dehydrogenase and glucose-6 -phosphate dehydrogenase activity in livers of Ni-deficientrats. Bioinorgan. Chem., in press, 1977. 87.

70. Ku b b a , R. and C h a m p io n , R. H .: Nickel sensitivity resembling bullous pemphigus. Brit. J. Dermatol. 93:(Suppl 11)41-43, 1975. 8 8 .

71. KuCHARIN, G. M.: Occupational disorders of the nose and nasal sinuses in workers in an electrolytic nickel refining plant. Gig. Trud.Prof. Zabol. 14:38-40, 1970.

72. KVORNING, S.A.: Post-operative dermatitis fol- 89.lowing non-epidermal metal contact. Contact Dermatitis 1:327, 1975.

73. L a u , T. J., H a c k e t t , R. L., and Su n d e r m a n , F.

W., Jr .: The carcinogenicity of intravenous 90.nickel carbonyl in rats. Cancer Res. 32:2253- 2258, 1972.

74. L a u , S. J., Kr u k , T. P. A., and Sa r k a r , B.: A 91.peptide molecule mimicking the copper-II transport site of human serum albumin. J. Biol.Chem. 249:5878-5884, 1974.

75. L y e l l , A. and Ba in , W. H.: Nickel allergy and 92.valve replacement. Lancet 1 :408-409, 1974.

76. M a c L e o d , T. M ., H u t c h in s o n , F., and R a f

f l e , E . J.: The leukocyte migration inhibitiontest in allergin nickel contact dermatitis. Brit. J. 9 3 .Dermatol. 94:63-64, 1976.

77. M a s t r o m a t t e o , E.: N ickel: A review of its

occupational health aspects. J. Occup. Med.

9:127-136, 1967. 94.78. M cC o n n e l l , L. H., F in k , J. N., Sc h l u e t e r ,

D. P., and SCHMIDT, M. G., JR.: Asthmacaused by nickel sensitivity. Ann. Intern. Med.78:888-890, 1973. 95,

79. M c D o u GALL, A.: Malignant tumor at site of bone plating. J. Bone Joint Surg. 38B:709-713,1956.

80. M cKe n d r ic k , J. C. and Sn o d g r a s s , W.: On 96.the physiological action of carbon monoxide of nickel. Proc. Phil. Soc. Glasgow. 22:204-216, 1890-1891.

81. M c K e n z ie , A. W., A it k e n , L . V. E ., and

R id s d e l l -Sm it h , R.: Urticaria after insertion 97.of Smith-Peterson vitallium nail. Brit. M ed. J.4:36, 1967.

82. M cN e e l y , M. D., N e c h a y , M. W., and Su n

d e r m a n , F. W., Jr.: Measurements of nickel in

serum and urine as indices of environmental 98.exposure to nickel. Clin. Chem. 28:992-995,1972.

M c N e e l y , M . D ., Su n d e r m a n , F. W., J r .,

N e c h a y , M . W., and L e v in e , H.: Abnormal concentrations of nickel in serum in cases of myocardial infarction, stroke bums, hepatic cirrhosis and uremia. Clin. Chem. 27:1123- 1128, 1971.M il l ik a n , L. E., C o n w a y , F ., and F o o t e , J.

E.: In vitro studies of contact hypersensitivity: Lymphocyte transformation in nickel sensitivity. J. Invest. Dermatol. 60:88-90, 1973. MlKEHYE V, M . I .: Distribution and excretion of nickel carbonyl. Gig. Trud. Prof. Zabol. 15:35-38, 1971.M ir z a , M., Pe r e r a , M. G., and Be r n s t e in , I. L.: Leukocyte migration inhibition test in nickel dermatitis. Fed. Proc. 33:728, 1974. M o n d , L., L a n g e r , C., and Q u in c k e , F.: Action of carbon monoxide on nickel. J. Chem. Soc. 67:749-753, 1890.M o r s e , E. E., L e e , T. Y., R e is s , R . F., and Su n d e r m a n , F. W., J r .: Dose-response and time-response study of erythrocytosis in rats after intrarenal injection of nickel subsulfide. Ann. Clin. Lab. Sci. 7:17-24, 1977.N e c h a y , M. W. and Su n d e r m a n , F. W., J r .:

Measurements of nickel in hair by atomic absorption spectrometry. Ann. Clin. Lab. Sci. 3:30-35, 1973.N ie l s e n , F. H. and O l l e r ic h , D. A.: Nickel: A new essential trace element. Fed. Proc. 33:1767-1774, 1974.N ie l s e n , F. H. and Sa u b e r l ic h , H. E.: Evidence for a possible requirement for nickel by the chick. Proc. Soc. Exp. Biol. Med. 134:845-849, 1970.N i l z e n , A. and W ik s t r o m , K.: The influence of lauryl sulphate on the sensitization of guinea-pigs to chrome and nickel. Acta Derm. Venereol. 35:292-299, 1955.N o m o t o , S., D e c s y , M . I., M u r p h y , J. R.,

and Su n d e r m a n , F. W., J r .: Isolation of63Ni- labelled nickeloplasmin from rabbit serum. Biochem. Med. 8:171-181, 1973.N o m o t o , S., M c N e e l y , M . D., and Su n d e r

m a n , F. W., J r .: Isolation of nickel a2- macroglobulin from rabbit serum. Biochemistry 20:1647-1651, 1971.N o m o t o , S. and Su n d e r m a n , F. W., J r .:

Measurements of nickel in serum and other biological materials by atomic absorption spectrometry. Clin. Chem. 16:477-485, 1970. NORSETH, T.: Urinary excretion of nickel as an index of nickel exposure in welders and nickel refinery workers. Proc. Cold Spring Harbor Colloquium on Occupational Carcinogenesis, in press, 1977.O n k e l in x , C., Be c k e r , J., and Su n d e r m a n ,

F. W., Jr.: Compartmental analysis of the metabolism of 63Ni(II) in rats and rabbits. Res. Commun. Chem. Path. Pharmacol. 6:664-676,1973.O t t o l e n g h i , A. D ., H a s e m a n , J. K., Pa y n e ,

W. W., Fa l k , H . L ., and M a c F a r l a n d , H . N.:

Inhalation studies of nickel sulfide in

396 SUNDERMAN

pulmonary carcinogenesis of rats. J. Nat. Cancer Inst. 54:1165-1172.

99. Pa p p a s , A., O r f a n o s , C . E ., and Be r t r a m ,

R.: Non-specific lymphocyte transformation in vitro by nickel acetate. A possible source of errors in lymphocyte transformation test (LTT). J. Invest. Deim. 55:198-200, 1970.

100. Pa r k e r , K. and Su n d e r m a n , F. W., J r .: Distribution of63Ni in rabbit tissues following intravenous injections o f 63NiC l2. Res. Com- mun. Chem. Path. Pharmacol. 7:755-762, 1974.

101. Pa y n e , W. W.: Carcinogenicity of nickel compounds in experimental animals. Proc. Amer. Assoc. Cancer Res. 50:50, 1964.

102. Pe d e r s e n , E., Hj6g e t v e it , A. C., and A n

d e r s e n , A.: Cancer of respiratory organs among workers at a nickel refinery in Norway. Int. J. Cancer 22:32-41, 1973.

103. Pe g u m , J. S.: Nickel allergy. Lancet 2:674,1974.

104. Pe t e r s , T., J r .: Serum albumin: Recent progress in the understanding of its structure and biosynthesis. Clin. Chem. 23:5-12, 1977.

105. Pe t e r s , T., J r . and B l u m e n s t o c k , F. A.: Copper binding properties of bovine serum albumin and its amino-terminal peptide fragment. J. Biol. Chem. 242:1574-1578, 1967.

106. PlOTROWSKA, J. K. and SZYMENSKA, J. A.: Influence of certain metals on the level of metallothionein-like proteins in the liver and kidneys of rats. J. Toxicol. Environ. Health 2:991-1002, 1976.

107. Sa b b io n i , E. and MARAFANTE, E.: Heavy metals in rat liver cadmium binding protein. Environ. Physiol. Biochem. 5:132-141, 1975.

108. Sa g g e r s o n , E . D., So o r a n n a , S. R., and E v a n s , C . J.: Insulin-like actions of nickel and other transition-metal ions in rat fat-cells. Biochem. J. 184:349-357, 1976.

109. Sa k n y n , A. V. and SHABYNINA, N. K.: Epidemiology of malignant neoplasms in nickel plants. Gig. Trud. Prof. Zabol. 17:25-28,1973.

110. Sa m it z , M. H. and Ka t z , S. A.: Nickel dermatitis hazards from prostheses. In vivo and in vitro solubilization studies. Brit. J. Dermatol. 92:287-290, 1975.

111. Sa m it z , M. H., Ka t z , S. A., Sc h e in e r , D. M., and LEWIS, J. E.: Attempts to induce sensitization in guinea-pigs with nickel complexes. Acta Dermatovener 55:475-480, 1975.

112. Sa m it z , M. H. and Po m e r a n t z , H.: Studies of the effects on the skin of nickel and chromium salts. A.M.A. Arch. Ind. Health 18:473-479, 1958.

113. Sc h e in e r , D. M., Ka t z , S. A., and Sa m it z ,

M. H.: Nickel levels in hair and nickel ingestion in guinea-pigs. Environ. Res. 22:355-357,1976.

114. SCHNEGG, A. and KlRCHGESSNER, M.: Changes in the hemoglobin content, erythrocyte count and hematocrit in nickel deficiency. Nutr. Metab. 19:268-278, 1975.

115. SCHNEGG, A. and KlRCHGESSNER, M.: Essentiality of nickel for the growth of animals. Z.

Tierphysiol. Tieremah. Futtermittelkunde, 36:63-74, 1975.

116. Sc h n e g g , A. and KlRCHGESSNER, M.: Absorption and metabolic efficiency of iron during nickel deficiency. Intern. J. Vitamin Nutr. Res. 46:96-99, 1976.

117. Sc h n e g g , A. and K ir c h g e s s n e r , M.: Interaction of nickel with iron, copper and zinc. Archiv. fur Tieremahrung 26:543-549, 1976.

118. Sc h r ir e r , W. R., Sh e r e f f , R. H., D o m n it z ,

J. M., Sw in t a k , E. F., andC lv jA N , S.: Allergic response to stainless steel wire. Oral. Surg. 42:578-581, 1976.

119. Sc h r o e d e r , H. A., Ba l a s s a , J. J., and T ip

t o n , I. H.: Abnormal tract elements in man-

nickel. J. Chronic Dis. 25:51-65, 1962.120. Sc h r o e d e r , H. A. and M it c h e n e r , M .:

Toxic effects of trace elements on the reproduction of mice and rats. Arch. Environ. Health 23:102-106, 1971.

121. Sc h r o e d e r , H. A. and N a s o n , A. P.: Trace metals in human hair. J. Invest. Dermatol. 53:71-78, 1969.

122. SlROVER, M. A. and LOEB, L . A.: Infidelity of DNA synthesis in vitro: Screening for potential metal mutagens or carcinogens. Science 294:1434-1436, 1976.

123. Sm it h , J. C. and HACKLEY, B.: Distribution and excretion of nickel-63 administered intravenously to rats. J. Nutr. 95:541-546, 1968.

124. SOESTBERGEN, M. VAN and SUNDERMAN, F. W., JR.: 63Ni-Complexes in rabbit serum and urine after injection of “ NiClj. Clin. Chem. 28:1478-1484, 1972.

125. SOSINSKI, E.: Morphological changes in rat brain and skeletal muscle in the region of nickel oxide implantation. Neuropat. Pol. 23:479-483, 1975.

126. STEDMAN, D. H. and T a m m a r o , D. A.: Chemiluminescent measurement of parts- per-billion levels of nickel carbonyl in air. Anal. Lett. 9:81-89, 1976.

127. St e w a r t , S. G. and C r o m ia , F. E.: Experimental nickel dermatitis. J. Allergy 5:575- 582, 1934.

128. STODDART, J. C.: Nickel sensitivity as a cause of infusion reactions. Lancet2:741-742, 1960.

129. St o n e r , G. D., Sh im k in , M. B., Tr o x e l l , M. C., T h o m p s o n , T. L., and Te r r y , L. S.: Test for carcinogenicity of metallic compounds by the pulmonary tumor responses in strain A mice. Cancer Res. 36:1744-1747, 1976.

130. Su n d e r m a n , F. W.: Nickel and copper m obilization by sodium diethyldithiocarbamate. J. New Drugs 4.154-161, 1964.

131. Su n d e r m a n , F. W.: Metastasizing pulmonary tumors in rats induced by the inhalation of nickel carbonyl. Lung Tumors in Animals. Severi, L., ed. Proceedings of the Third Quadrennial Conference on Cancer, June 24 to June 29, 1966. University of Perugia, Perugia, Italy: Division of Cancer Research, pp. 551-564, 1966.

132. SUNDERMAN, F. W.: Nickel poisoning. Laboratory Diagnosis of Diseases Caused by Toxic


Agents. Sunderman, F. W. and Sunderman, F. W., Jr., eds. St. Louis, Warren H. Green, Inc., pp . 387-396, 1970.

133. Su n d e r m a n , F. W.: The treatment of acute nickel carbonyl poisoning by sodium diethyldithiocarbamate. Ann. Clin. Res. 3:182-185,1971.

134. Su n d e r m a n , F. W. and D o n n e l l y , A. J.: Studies of nickel carcinogenesis. Metastasizing pulmonary tumors in rats induced by the inhalation of nickel carbonyl. Amer. J. Path. 46:1027-1042, 1965.

135. Su n d e r m a n , F. W ., D o n n e l l y , A. J., W e s t ,

B., and Kin c a id , J. F.: Nickel poisoning. IX. Carcinogenesis in rats exposed to nickel carbonyl. A.M.A. Arch. Ind. Health 20:36-41,1959.

136. Su n d e r m a n , F. W., Ra n g e , C. L., Su n d e r

m a n , F. W., J r ., D o n n e l l y , A. J ., and LUCYSZYN, G. W.: Nickel poisoning. X III. Metabolic and pathologic changes in acute pneumonitis from nickel carbonyl. Amer. J. Clin. Path. 36:477-491, 1961.

137. Su n d e r m a n , F. W. and Su n d e r m a n , F. W., Jr.: Nickel poisoning. V III. Dithiocarb: A new therapeutic agent for persons exposed to nickel carbonyl. Amer. J. Med. Sci. 236:26-31, 1958.

138. Su n d e r m a n , F. W. and Su n d e r m a n , F. W., Jr.: Loeffler’s syndrome associated with nickel sensitivity. Arch. Int. Med. i07:405-408, 1961.

139. SUNDERMAN, F. W., Jr.: Inhibition of induction of benzpyrene hydrolase by nickel carbonyl. Cancer Res. 27:950-955, 1967.

140. Su n d e r m a n , F. W., J r .: Nickel carbonyl inhibition of cortisone induction of hepatic tryptophan pyrrolase. Cancer Res. 27:1595-1599,1967.

141. Su n d e r m a n , F. W., Jr.: Nickel carbonyl inhibition of phenobarbital induction of hepatic cytochrome P-450. Cancer Res. 28:465-470,1968.

142. Su n d e r m a n , F. W., J r .: Effect of nickel carbonyl upon hepatic concentrations of adenosine triphosphate. Res. Commun. Chem. Path. Pharmacol. 2:545-551, 1971.

143. Su n d e r m a n , F. W., J r .: The current status of nickel carcinogenesis. Ann. Clin. Lab. Sci. 3:156-180, 1973.

144. S u n d e r m a n , F. W., J r .: A review of the carcinogenicities of nickel, chromium, and arsenic compounds in man and animals. Prev. Med. 5:279-294, 1976.

145. S u n d e r m a n , F. W., J r .: Metal carcinogenesis. Advances in Modem Toxicology. Goyer, R. A. and Mehlman, M. A., eds. Washington, Hemisphere Publishing Corporation, pp. 257-295, 1977.

146. S u n d e r m a n , F . W., J r ., C o u l s t o n , F .,

E i c h o r n , G . L ., F e l l o w s , J. A ., M a s -

t r o m a t t e o , E ., R e n o , H. T., and Sa m it z , M.H.: Nickel. A Report of the Committee on Medical and Biologic Effects of Environmen

tal Pollutants. National Academy of Sciences, Washington, 277 pp., 1975.

147. Su n d e r m a n , F. W., J r . and E s f a h a n i, M .:

Nickel carbonyl inh ib ition of RNA polymerase activity in hepatic nuclei. Cancer Res. 28:2565-2567, 1968.

148. Su n d e r m a n , F. W., J r ., K a s p r z a k , K .,

H o r a k , E., G it l it z , P., and O n k e l in x , C.: Effects of triethylenetetramine upon the metabolism and toxicity of 63NiCl2 in rats. Toxicol. Appl. Pharmacol. 38:177-188, 1976.

149. Su n d e r m a n , F. W., Jr ., Ka s p r z a k , K. S.,

L a u , T. J., M in g h e t t i , P. P., M a e n z a , R. M.,

Be c k e r , N., O n k e l in x , C., and G o l d b l a t t ,

P. J.: Effects of manganese on carcinogenicity and metabolism of nickel subsulfide. Cancer Res. 36:1790-1800, 1976.

150. Su n d e r m a n , F. W., J r . and L e ib m a n , K. C.: Nickel carbonyl inhibition of induction of aminopyrine demethylase activity in liver and lung. Cancer Res. 30:1645-1650, 1970.

151. Su n d e r m a n , F. W., Jr . and M a e n z a , R. M .:

Comparisons of carcinogenicities of nickel compounds in rats. Res. Comm. Chem. Path. Pharmacol. 14:319-330, 1976.

152. Su n d e r m a n , F. W., J r ., M a e n z a , R. M .,

A l l p a s s , P. R., M it c h e l l , J. M ., D a m ja n o v ,

I., and G o l d b l a t t , P. J.: Carcinogenicity of nickel subsulfide in Fischer rats and Syrian hamsters after administration by various routes. Proc. Intemat. Symposium on Inorganic and Nutritional Aspects of Cancer. Schrauzer, G. ed. La Jolla, California, Jan. 2-5, in press, 1977.

153. S u n d e r m a n , F. W., J r ., N o m o t o , S.,

M o r a n g , R., N e c h a y , M . W., B u r k e , C. N.,

and N ie l s e n , S. W.: Nickel deprivation in chicks. J. Nutr. 102:259-267, 1972.

154. S u n d e r m a n , F. W., J r ., N o m o t o , S.,

P r a d h a n , A. M., L e v in e , H ., Be r n s t e in , S.

H., and H ir s c h , R.: Increased concentrations of serum nickel after acute myocardial infarction. N ew Eng. J. Med. 283:896-899, 1970.

155. Su n d e r m a n , F. W., J r ., R o s z e l , N. O., and C l a r k , R . J.: Gas chromatography of nickel carbonyl in blood and breath. Arch Environ. Health 16:836-843, 1968.

156. Su n d e r m a n , F. W., J r . and Se l in , C. E.: The metabolism of nickel-63 carbonyl. Toxicol. Appl. Pharmacol. 12:207-218, 1968.

157. Su n d e r m a n , F. W., J r ., Sh e n , S., M it c h e l l ,

J., Al l p a s s , P. R., and D a m ja n o v , I.: Fetal toxicity and transplacental transport of Ni(II) in rats. Toxicol. Appl. Pharmacol., in press,1977.

158. Su s c h e n k o , A. V. and R a f ik o v a , K. E .:

Questions of work hygiene in hydrometallurgy of copper, nickel and cobalt in a sulfide ore. Gig. Tr. Prof. Zabol. J 6:42-45, 1972.

159. Su t h e r l a n d , R. B.: Summary report on respiratory cancer mortality at the INCO Port Colbome Refinery. Dept, of Health, Toronto, Ontario, pp. 153, 1959.

160. Sy m e o n id e s , P. P., Pa s c h a l o g l o u , C., and PAGAGEORGIOU, S.: An allergic reaction after

398 SUNDERMAN

internal fixation of a fracture using a vitallium plate. J. Allergy Clin. Immunol. 4:251-252,1973.

161. Sz a d k o w s k i , D., Ko h l e r , G., and L e h n e r t ,

G.: Serum electrolyte und elektrischmechanische Herzaction unter chronischer industrieller Hitzebelastung. Arztl. Forsch. 23:271-284, 1969.

162. Ta n d o n , S. K., M a t h u r , A. K., and G a u r , J.S.: Urinary excretion of chromium and nickel among electroplaters and pigment industry workers. Ann. Occup. Hyg., in press, 1977.

163. Ta r a b is h i , R., H o r a k , E., and Su n d e r m a n ,

F. W., Jr .: Dose-response relationships of hyperglycemia induced in rats by inhalation of nickel carbonyl. Res. Commun. Chem. Pathol. Pharmacol., Submitted.

164. Ta t a r s k a y a , A. A.: Occupational diseases of upper respiratory tract in persons employed in electrolytic nickel refining departments. Gig. Trud. Prof. Zabol. 6:35-38, 1960.

165. T h u l in , H.: The leukocyte m igration test in

n ickel contact dermatitis. Acta Dermatovener

56:371-380, 1976.166. TlNCKLER, L. F.: Nickel sensitivity to surgical

skin clips. Brit. J. Surg. 59:745-747, 1972.167. TOLOT, F., BRODEM, P., and N e u l a t , G.: As

thmatic forms of lung disease in workers exposed to chromium, nickel and aniline inhalation. Arch. Mai. Prof. Med. Trav. Secur. Soc. 28:288-293, 1956.

168. To r ju s s e n , W. and So l b e r g , L . A.: Histological findings in the nasal mucosa of nickel workers. Acta Otolaryngol 82:266-267, 1976.

169. To u r a in e , R . and Ra m b a u d , G.: Les cancers bronchique primitifs a localization double unilatérale. J. Franc. Med. Chiurg. Thorac. 22:757-767, 1968.

170. T s e r e t il i , M . N. and M a n d z h a v id z e , R. P.: Clinical observations of acute carbonyl nickel poisoning. Gig. Tr. Prof. Zabol. 23:46-47,1969.

171. Ts u c h iy a , K.: The relation o f occupation to

cancer, especially cancer o f the lung . Cancer

28:136-144, 1965.

172. VON L u d e w iGS, H-J. and T h ie s s , A. M.: Arbeits medizinische Erkenntnisse bei der Nickelcarbonylvergiftung. Zentralbl. Ar- beitsmed. 20:329-339, 1970.

173. Vu o p a l a , U ., H u h t i , E., Ta k k u n e n , J., and HuiKKO, M.: Nickel carbonyl poisoning. Report of 25 cases. Ann. Clin. Res. 2:214-222,1970.

174. W a h l b e r g , J. E.: Sensitization and testing of guinea-pigs with nickel sulfate. Der- matologica 252:321-330, 1976.

175. WALTHAND, B.: Die Erzeugung experimenteller Nickelidiosynkrasie bei Laboratoriumstieren. Schweiz. Med. Wochenschr. 7:603- 604, 1926.

176. W ase , A. W ., Goss, D. M., and B o yd , M. J.: The metabolism of nickel. I. Spatial and temporal distribution of Ni63 in the mouse. Arch. Biochem. Biophys. 25:1-4, 1954.

177. W it s c h i , H . P. and C o t e , M. G.: Biochemical pathology of lung damage produced by chemicals. Fed. Proc. 35:89-94, 1976.

a review of the metabolism and toxicology of nickel* f · a review of the metabolism and toxicology...

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