ANNALS OF CLINICAL AND LABORATORY SCIENCE, Vol. 9, No. 1 Copyright © 1979, Institute for Clinical Science, Inc.

Efficacy of Sodium Diethyldithiocarbamate (Dithiocarb) in Acute Nickel Carbonyl Poisoning*

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

Institute for- Clinical Science, Hahnemann Medical College and Hospital,

Philadelphia, PA 19102

ABSTRACT

A brief historical resume is presented on the use of dithiocarbamates for the treatm ent of persons exposed to nickel carbonyl. The specificity of the treatm ent is dem onstrated in an industrial accident in which four m en were simultaneously exposed to nickel carbonyl vapors. Three of the men re­ceived dithiocarb w ithin 24 hours after exposure and the fourth was hos­pitalized by his family physician and treated for bronchopneum onia with antibiotics and without benefit of dithiocarb. The three workmen who re­ceived dithiocarb became symptomless and returned to work w ithin 72 hours after exposure. The fourth man who had not received dithiocarb died w ithin five days after exposure.

Introduction

Although poisoning from the inhalation of nickel carbonyl was recognized as early as 1903,2 nevertheless, the hazards from occupational exposure have been em ­phasized for only the past three or four decades. It may also be noted that specific therapy for acute nickel carbonyl poison­ing has been available on a lim ited basis for only two decades. In the United States, the specific antidote, dithiocarb, is still categorized as an investigational drug.

T his p resen ta tion is prim arily con­cerned with acute nickel carbonyl poison­ing and specifically with the developm ent o f sod ium d ie th y ld ith io c a rb a m a te (dithiocarb) as an antidote. For purposes of historical perspective, reference will be

* Presented at the Kristiansand Conference on Nickel Toxicology, Kristiansand, Norway, May 1978.

10091-7370/79/0100-0001 $01.50 ©

made to some of our early work on preven­tion, diagnosis and treatm ent of acute nic­kel carbonyl po ison ing since the d e ­velopm ent in our laboratory of dithiocarb as a chem otherapeutic agent was, in large m easure, dep en d en t upon these early studies.

In 1943 during World War II, it became apparent that exposure to nickel carbonyl presented a serious health hazard and a deterrent to research in atomic energy. As a co n seq u e n c e , acu te and chron ic* studies were initiated at that time (and have been continued to the present) (1) to provide safeguards for the prevention of acc id en ta l exposu re , (2) to d ev e lo p

* The studies on chronic toxicity led eventually to the demonstration for the first time that exposure to nickel carbonyl was capable of producing pulmonary cancer in the Wistar rat,—a species singularly resis­tant to spontaneous pulmonary cancer.

Institute for Clinical Science, Inc.

2 SUNDERM AN

methods for the early detection of poison­ing in persons who m ight have been un­knowingly exposed and (3) to establish therapeutic measures for the treatm ent of those exposed.

Prevention

The early efforts for prevention of acci­dental exposure to nickel carbonyl en ­tailed not only careful engineering and architectural design of working areas to ensure adequate ventillation and to guard against spillage and leakage, but also the developm ent of a monitoring system to make certain that the concentrations of nickel carbonyl in the working environ­m ent did not exceed the maximal allow­able limits for safety.

Obviously, the sim plest m ethod of de­term ining the presence of a noxious sub­stance in air is its detection by odor. How­ever, n ickel carbonyl, even in highly hazardous concentrations, has only a mild, non-penetrating odor, often described as “ sooty” or “musty.” Thus, its presence is likely to be unnoticed by those unfamiliar with it. For example, in an accident that occurred in an oil refinery 25 years ago in which more than 100 persons were ex­posed to nickel carbonyl, there was no suspicion of exposure until the workmen started to become acutely ill.

The first monitoring system8 which was developed in our laboratories for the de­tection of nickel carbonyl in air was a sim­ple, manually operated rotameter and suc­tion pum p w hich perm itted air to be drawn into an absorber in which nickel carbonyl vapor was converted to a nickel halide by its reaction with brom ine or chlorine. The smoke formed was capable of scattering light, and the intensity of the scattered light could be related to the con­centration of nickel carbonyl in the con­tam inated air. This device, w hich we called “the snifter,” had a sensitivity of less than 1 ppm and was reasonably pre­cise. The system was later modified and

adapted for the continuous, autom atic monitoring of working areas. Eventually, the procedure was replaced by conduc- tim etric instrumentation.

Diagnosis

In our initial efforts to establish criteria for the early diagnosis of acute nickel car­bonyl poisoning, it was realized that in addition to monitoring the working areas, it became essential to develop a reliable chemical m ethod for the analysis of nickel w h ich w ou ld no t on ly d e te c t trace amounts in biological fluids bu t would also provide an estimate of the severity of exposure.8,9 Furtherm ore, it was desirable that such a m ethod be rapid, economical of m ateria ls , easy to m an ip u la te and adaptable for routine purposes. To m eet these criteria, the colorimetric m ethod of Alexander, Godar and L inde1 was mod­ified by Kincaid, Stanley, Beckworth and Sunderm an8 and became well adapted for the routine analysis of nickel in urine.

In our early studies of nickel metabo­lism in dogs,13 it had been found that under normal conditions, approximately 90 percent of ingested nickel was excreted in the feces and only 10 percent in the urine (figure 1). However, when balance studies were made on dogs exposed to nickel carbonyl, it was found that during the first three days after exposure more' than twice as much nickel was excreted in the urine as in the feces. This observation that there was a sharp increase in the nickel excretion in urine im m ediately after ex­posure to nickel carbonyl proved to be of major practical value and led to the de­velopm ent of procedures for detecting exposure in workers to m inimal amounts of n icke l carbonyl in con cen tra tio n s w hich were too low to produce acute symptoms. Simple m easurem ents of the nickel concentration in 100 ml of urine proved to be more satisfactory than the more laborious procedure of determ ining the total amount of nickel excreted in 24

D ITH IO C A R B IN ACU TE N IC K EL CARBONYL PO ISO N IN G 3

hours. Moreover, the time-saving factor proved to be im portant in critical cases.* In several industrial plants, procedures were set up by which workmen in nickel carbonyl areas would leave a specim en of urine for nickel analysis at the close of each working day. If the concentration of nickel exceeded set limits, the workman would be placed under observation and given medication if needed. Owing to cost factors, plant managers were at first reluc­tant to provide a urine testing service for employees in the nickel carbonyl areas; however, in the words of one manager, “ Experience over the years has shown that this service has paid off handsomely in sa feg u a rd in g th e h e a lth o f our em ployees.”10

Treatment

W hen we first undertook to treat pa­tients exposed to nickel carbonyl, the only available chelating drugs were BAL (di- mercaprol), d-penicillam ine and EDTA (calcium disodium ethylenediam inetetra- acetic acid). Our studies on experimental animals showed that (1) administration of d-penicillam ine9,16 had doubtful antidotal effectiveness and produced severe toxic side reactions; (2) EDTA provided no an­tidotal effects15; and (3) BAL was only par­tially effective.1 W ith BAL, the LD50 value in rats exposed to nickel carbonyl is in­creased by a factor of approximately two.

In an accident in 1954 in which 36 per­sons were exposed to nickel carbonyl,1132 received BAL. Two of the 36 persons died and one of those who died had received BAL. In the opin ion o f the attend ing physicians, the administration of BAL was beneficial in 31 of the patients receiving

* The concentration of nickel in urine samples ob­tained from 69 normal persons was 1.1 fxg per dl (S.D. ± 0.9). A statistical analysis o f these data led to the conclusion that only one specimen in 50 selected from a normal population will be found to exceed a value of 5 ¡jlg per dl. The value was therefore selected as the upper limit o f normal.

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1.4 1.2

1.0

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0.6 0.4

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PRE-EXPOSURE PERIOD I PERIOD H

THREE DAY METABOLIC PERIODS

F igure 1. N ickel balance studies in dogs before and after exposure to nickel carbonyl.

BAL and may have been life-saving in several.

In the early 1950’s, our attention was attracted to the metabolic studies on di- thiocarbamates that were appearing in the literature at that tim e. These studies were of especial interest to us since sodium di- e thy ld ith iocarbam ate is the chem ical used as the nickel-binding reagent in our routine m ethod for measuring nickel in urine. In 1949, Domar and coworkers3 re­ported d iethyldith iocarbam ate to be a metabolic reduction product of Antabuse (disulfiram). After the administration of Antabuse to man and experimental ani­mals, these investigators dem onstrated that dithiocarb was present in the blood, tissues, urine, bile and feces. The m eta­bolic pathway of Antabuse, and presum a­bly d ith iocarb , is show n in figure 2. D ith io ca rb is p a rtia lly ex c re te d u n ­changed in urine and bile. A portion undergoes oxidation to form free and ethereal sulfates as w ell as metal com­plexes. The structure of the nickel chelate

4 SUNDERM AN

ANTABUSE DITHIOCARB METABOLITES

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F igure 2. Metabolism o f disulfiram and sodium diethyldithiocarbamate.

of diethyldithiocarbam ate is depicted in figure 3 .14 E xcep tin g for th e m ethy l groups, the nickel in the complex is a square coplanar hybrid.

Hald, Jacobsen and Larsen in 1948 and 19526-7 showed that the diethyldithiocar- bam ates w ere rela tively non-toxic for mice and rats,—the LD50 value for the sodium salt being approximately 1.5 gper kg of body weight. Goth and Robinson5 noted that the dithiocarbamates displayed antidotal activity by showing that the bis­muth salt protected mice against Type I pneum ococcal infections. In addition, Garattini and Leonard4 found dithiocarb to be an effective in vitro inhibitor for the growth of Mycobacterium, tuberculosis.

Recognition of the nickel binding and biologic properties of the dith iocarba­mates as well as their low toxicity promp­

ted us to initiate studies to determ ine their possible chem otherapeutic properties as an an tido te to acu te n ickel carbonyl poisoning.

The th erap eu tic effectiveness o f 13 alkyl dithiocarbamates was studied in ex­perim ental animals receiving lethal inha­lations of nickel carbonyl.16 Of the various derivatives tested, sodium diethyldithio­carbamate proved to be the least toxic and one of the most effective.

Antidotal Activity of Dithiocarb in Mice and Rats

The antidotal activity of dithiocarb in mice exposed to nickel carbonyl is given in table I. O f 30 mice exposed to nickel carbonyl vapors in a concentration of 6 ppm for 30 minutes, only six survived a

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F igure 3. Chelation of nickel by dithiocarb.

D ITH IO C A R B IN A CU TE N ICK EL CARBONYL PO ISO N IN G 5

period of five days following exposure. In concentrations of 8 ppm and above, prac­tically all of the exposed mice failed to survive. It will be seen in the table that of 30 mice exposed to nickel carbonyl in a concentration amounting to several times the LD 10o dose and receiving dithiocarb parenterally in dosages of 50 and 100 mg per kg of body weight im m ediately after exposure, all of the animals survived. It will also be seen that of 390 mice exposed to nickel carbonyl at 10 ppm, all bu t two died w ithin five days. On the other hand, of mice exposed to th is same concentra­tio n o f n ick e l carbony l and g iven dithiocarb parenterally, all survived for five days and were in good health.

The antidotal activity of dithiocarb in rats exposed to nickel carbonyl is shown in table II. It will be seen that of 30 rats exposed to nickel carbonyl in a concentra­tion of 67 ppm for 30 m inutes, only 11 survived for five days. In concentrations of 168 ppm and above, none survived. However, rats exposed to lethal concen­trations of n ickel carbonyl and given dithiocarb parenterally in doses of 50 and 100 mg per kg of body weight, all sur­vived. W hen a d m in is te re d o rally by stomach tube in dosages of 10 and 100 mg per kg of body weight imm ediately after nickel carbonyl exposure, dithiocarb pro­vided moderate protection. It would seem reasonable that even b e tte r protection might have been afforded if sodium bicar­bonate had been adm inistered w ith the dithiocarb. Similar studies, not tabulated here , on rabbits and dogs exposed to n ickel carbonyl and given d ith iocarb intravenously resu lted in com plete re­covery from nickel carbonyl poisoning.

Nickel Balance Studies in Rats

The results of the nickel balance studies in 12 normal rats and in 24 rats exposed to nickel carbonyl at a concentration of 33 ppm for 30 m inutes are shown in figure 4. At this concentration, all rats survived for

TABLE I

Antidotal Activity of Dithiocarb in Mice

N i(C O )4*con­

centration

No. o f mice surviving 5 days

Un-Treated with

dithiocarb i.p.(p.p.m.) treated 50 m g./kg. 100 m g./kg.

6 6/30 30/30 30/308 0/30 30/30 30/30

10 2/390 390/390 30/3016 0/30 30/30 30/3024 0/30 30/30 30/30

* Nickel carbonyl was administered by inhala-tion for 30 minutes.

at least three days. Twelve of the exposed rats were left untreated; the rem aining 12 received dithiocarb in a dosage of 30 mg per kg of body weight intraperitoneally immediately after exposure. In figure 4 are portrayed the average am ounts of nickel ingested in the food and excreted in the stool and urine in each of the three groups during the three-day metabolic pe­riod. In the control rats, approximately 80 percent of the ingested nickel was ex­creted in the stool and 20 percent in the urine. The rats exposed to nickel carbonyl

TABLE II

Antidotal Activity of Dithiocarb in Rats

N i(C O )4*con­

centration(p.p.m.)

No. o f rats surviving 5 days Treated with

dithiocarbUn­treated 50 m g./kg. 100 m g./kg.

i.p.67 11/30 30/30 30/30

105- 6/30 30/30 30/30168 0/30 30/30 30/30266 0/30 30/30 30/30

oral67 1/10 7/10 9/10

266 0/10 1/10 4 /10

* Nickel carbonyl was administered by inhalation for 30 minutes.

6 SUNDERM AN

F igure 4. Nickel balance studies in rats. Each group consisted of 12 rats. Nickel carbonyl inhala­tion was administered at a concentration of 33 ppm for 30 minutes after which 12 rats were given 30 mg per kg dithiocarb intraperitoneally.

and left untreated developed a positive nickel balance averaging 45 fig per rat during the metabolic period. It may be noted that the food consumption was ex­ceedingly low in these rats since most of them were too sick to eat. On the other hand, in the rats exposed to nickel car­bonyl and treated w ith dithiocarb, the

food consumption was essentially normal. The urinary excretion of nickel in the treated rats was more than twice that of the control rats and approximately twice that of the untreated exposed rats. Likewise, there was a marked increase in the fecal excretion of nickel in the treated rats. It will be observed that dithiocarb increased the excretion of nickel to the extent that a normal nickel balance was achieved.

In 1957 our first patient, who was se­verely exposed to nickel carbonyl, was trea ted w ith d ith iocarb .12 After I had served as the first control subject by taking a test dose of dithiocarb without ill effects, dithiocarb was adm inistered to a work­man who had been accidentally sprayed with nickel carbonyl. This man (PatientD) had to be resuscitated by oxygen inha­la tio n . P a tie n t D re c e iv e d one g of dithiocarb twice daily for 10 days after exposure. He became asymptomatic after the second day of hospitalization and de­veloped no delayed reactions. The nickel concentrations in Patient D ’s urine during the 16 days after exposure are shown in figure 5. It will be noted that the initial

PATIENT ” D". ACUTE EXPOSURE to Ni(C0>4

Figure 5. N ickel con­centration in urine in pa­t ie n t after ex p o su re to acute nickel carbonyl.

D ITH IO CA RB IN A CU TE N IC K EL CARBONYL PO ISO N IN G 7

concentration of nickel in the patient’s urine was 200 (xg per dl. This is the high­est concentration we have ever observed in any exposed person.

During the past score of years, more than 350 persons exposed to the inhala­tion of nickel carbonyl vapor have been tre a te d u n d e r ou r su p e rv is io n w ith dithiocarb. To our knowledge, no death from acute nickel carbonyl poisoning oc­c u rre d in any p e rso n w ho re c e iv e d adequate dithiocarb m edication w ithin two to three days after exposure. It is also notew orthy that the adm inistration of d ithiocarb is not attended by the pro­tracted undesirable side effects that are observed with chelating drugs such as BAL and d-penicillam ine. However, pa­tients receiving dithiocarb who ingest al­coho lic b ev e rag es may ex p e rien c e symptoms similar to those described for Antabuse.

Efficacy of Dithiocarb

The efficacy of dithiocarb as a specific antidote for acute nickel carbonyl poison­ing is dem onstrated by the outcome of an accident that occurred in a chemical plant in which nickel carbonyl was used as a catalyst in the manufacture of acrylic plas­tics. Four workmen unbolted a flange on one of the scrubbers used in the manufac­turing process in order to make necessary repairs. Although the four workers were aware of the hazards of exposure to nickel carbonyl, nevertheless, since the scrub­ber was not in operation, it did not occur to them that they might still become exposed to the vapors that were trapped within the scrubber. A “ sooty” oder was noted by the m en on removal of the flange; however, this was interpreted by them to be due to the penetrating oil used in loosening the bolts.

The workmen com pleted their assigned duties and returned to their respective homes where all of them soon developed severe respiratory symptoms. W hen the

four men failed to report for work the next afternoon and reported sick with respira­tory symptoms, an alert safety director surm ised that perhaps they had been ex­posed to nickel carbonyl. Stat urinalyses for nickel were made on specim ens from all of the m en and revealed concentrations of nickel in the range of 50 (i g per dl (45 to 58). From these analyses, it was inferred that all of the men suffered from acute nickel carbonyl poisoning and were sub­jected to approximately the same severe degree of exposure. The safety director requested all of the m en to go immedi­a te ly to the in d u stria l d ispensary for exam ination and to receive dithiocarb m edication, Three of the men went and w ere im m ediately adm in istered d ith i­ocarb. These three m en became symp- tomless and returned to work w ithin 48 hours after having received the m edica­tion. In the m eantim e, the fourth work­man consulted his family physician who gave him an injection of penicillin and had him a d m itte d to the com m unity hospital.

Case ReportThe patient, W. P., 47 years of age, was admitted to

his community hospital with cough, nausea, vomit­ing and weakness. Soon after exposure he developed cough, hot and cold sweats, chills, fever, vertigo and chest pains. His past medical history included treat­ment for prostatitis and for symptoms suggestive of peptic ulcer three years previously and for influenza one year previous to the present administration.

The examining physician noted that the patient was w ell nourished, weighing210 pounds; his blood pressure was 150/84 mm of mercury; pulse rate on admission was 88 and respiration 22 per minute; his temperature was 100.1° F. The chest examination re­vealed bronchial breathing and the chest x-ray re­vealed diffuse densities throughout both lung fields which were interpreted as bronchopneumonia and pulmonary edema. An electrocardiogram was re­ported to be within normal limits excepting for a tachycardia of 104 beats per minute. The hemoglo­bin concentration was 15.9 g per dl; hemotocrit 40 percent; leucocytes, 12,400 per cmm.

The patient was treated with antibiotics and tran­quillizers. The attending physicians were reluctant to administer dithiocarb since this was an investiga­tive drug with which they had had no experience. On the fourth day after exposure when the patient was

8 SUNDERM AN

moribund, it appears that a minimal amount of dithiocarb was offered to the patient but that he was unable to swallow the capsules. No dithiocarb was administered intravenously. The patient died on the fifth day after exposure. Prior to death, a tracheos­tomy was performed.

Pathologic Findings

At autopsy, the external examination revealed a tracheostomy opening from w h ich flu id and b lood e sca p e d on p ressu re . The lungs had a com bined weight o f2,430 g. The trachea and bronchi con tained a generous am ount of san­guineous m ucoid m aterial. The lungs were firm on palpation and sectioning re­vealed marked congestion. The heart was enlarged, w eighing 540 g. The myocar­dium appeared normal. A small amount of coffee-brown liquid material was found in the stomach. The liver, spleen, adrenals and pancreas showed no significant ab­normalities.

T he m ost s ig n ifican t m icroscop ic changes were observed in the lungs. Most p rom inent among these w ere hyaline membrane formation, damage to alveolar lin ing cells and dilatation of alveolar capillaries secondary to congestion (fig­ure 6). The alveoli contained granular, pink edem a fluid, occasional acute in­flammatory cells and a moderate num ber of desquam ated pneumocytes. Attached to the alveolar septae in numerous areas w ere hyaline m em branes com posed of eosinophilic homogeneous material (fig­ure 7). The alveolar lining cells in most areas d isp la y e d e ith e r d eg e n era tiv e changes or were totally absent leaving denuded and dilated capillaries and inter­stitial cells as alveolar landmarks. Occa­sional pneumocytes were hypertrophied or had prom inent nuclei and nucleoli. Mitoses and giant cells were seen only rarely. The alveolar septas were widened owing mainly to the capillary dilatation and interstitial edema. Inflammatory cells and fibroblasts were present w ithin the septas, but this feature was not prominent.

TABLE I I I

Nickel in Tissues

W et W e ig h t D r y W e ig h t( v g / i o o g ) l v g / 1 0 0 <3)

L u n g L i v e r L u n g L i v e r

W.P. Ni(CO)^ 17.3 5.3 115.0 20.7poisoning

Mean of 4 control 1.59 0.87 8.6 2.9subjects

The histologic features appeared to be those of an acute interstitial penum onitis displaying m ainly degenerative rather than reactive or regenerative changes.

The histologic findings in the liver con­sisted of congestion of central and portal ve in b ran ch es w ith s lig h t ce n tra l hepatodegenera tion . An inflam m atory cell reaction was not conspicuous. Sec­tions of brain and kidneys revealed only congestive changes.

M easurements of nickel in the lung and liver tissues obtained at autopsy were 11 and 6 times greater than the average con­centrations of lung and liver tissues ob­tained at autopsy from persons who had died suddenly from causes not related to nickel exposure (table III).

The history, physical examination and labo ra to ry find ings in the d eceased w orkm an w ho had n o t rec e iv e d dithiocarb left no doubt that this workman died of acute nickel carbonyl poisoning.

Summary

In summary, reference has been made to some of the early studies which led to the d e v e lo p m en t o f d ith io ca rb as a specific antidote for acute nickel carbonyl poisoning. A case report was presented to illustrate not only the therapeutic effec­tiveness of dithiocarb in treating nickel carbonyl poisoning but also to emphasize the fact that the diagnosis of acute nickel carbonyl poisoning may be readily over­looked in hospital practice. In any patient suffering from an undiagnosed fulminat-

DITH IO CA RB IN A C U TE N ICK EL CARBONYL PO ISO NING 9

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SUNDERM AN 10

ing pneum onitis, consideration should be given to the possibility that the patient might have been exposed unknowingly to nickel carbonyl.

Acknowledgm ent

Thanks are extended to Dr. Geoffrey Kent and Dr. Roy Smith for their comments on the histopathology and to Dr. F. William Sunderman, Jr. for nickel analyses o f the tissues.

References

1. A l e x a n d e r , O. R., G o d a r , E. M., and L in d e , N. J .: Spectrophotometric determination of traces of nickel. Indust. Eng. Chem. (Anal. Ed.) i 8:206, 1946.

2. A n o n y m o u s : N ickel carbonyl poisoning. Lancet 1 ¡268-269, 1903.

3. D o m a r , G., F r e d g a , A., and L i n d e r h o l m , H.: The determination of tetraethylthiuramdi- sulfide (Antabuse, Abstinyl) and its reduced form, diethyldithiocarbamic acid, as found in excreta. Acta Chem. Scand. 3:1441, 1949.

4. G a r a t t i n i , S. and LEONARDI, A.: Attivita antitubercolare di sostanze dotate di potere chelante (nota preventiva). Giorn. Ital. Chemotherap. 2:18-22, 1955.

5. G o t h , A. and R o b i n s o n , F . J.: Chemotherapeutic studies on a series of dithio- carbamates and their bismuth derivatives. J. Pharmacol. Exp. Therap. 93:430-433, 1948.

6. H a l d , J ., J a c o b s e n , E ., and L a r s e n , V.: The Antabuse effect of some compound. Related to Antabuse and cyanamide. Acta Pharmacol. Toxicol. 8:329-337, 1952.

7. H a l d , J ., J a c o b s e n , E., and L a r s e n , V.: The sensitizing effect of tetraethylthiuramdisul-

phide (Antabuse) to ethylalcohol. Acta Phar­macol. 4:285-296, 1948.

8. K in c a id , J. F., S t a n l e y , E. L., B e c k w o r t h , C.H., and SUNDERMAN, F. W .: Nickel poisoning. III. Procedures for detection, prevention, and treatment of nickel carbonyl exposure includ­ing a method for the determination of nickel in bio log ic m aterials. Amer. J . C lin. Path. 26:107-119, 1956.

9. K in c a id , J . F., S t r o n g , J . S., and S u n d e r m a n ,F. W.: Nickel poisoning. I. Experimental study of the effects o f acute and subacute exposure to nickel carbonyl. A.M.A. Arch. Indust. Hyg. Oc- cup. Med. 8:48-60, 1953.

10. Personal communication.11. S u n d e r m a n , F. W. and K in c a id , J . F.: Nickel

poisoning. II. Studies on patients suffering from acute exposure to vapors of nickel carbonyl. J. Amer. Med. Assoc. i55:889-894, 1954.

12. S u n d e r m a n , F. W . and S u n d e r m a n , F. W., J r . : Nickel poisoning. VIII. Dithiocarb: A new therapeutic agent for persons exposed to nickel carbonyl. Amer. J. Med. Sci. 236:26-31, 1958.

13. T e d e s c h i , R. E. and S u n d e r m a n , F. W.: Nickel poisoning. V. The metabolism of nickel under normal conditions and after exposure to nickel carbonyl. A.M.A. Arch. Indust. Health 16:486-488, 1957.

14. VACIAGO, A. and FASANA, A.: Crystal structure and polymorphism of nickel bisdiethyldithio- carbamate. Atti acad. nazl. Lincei. Rend, (classe sci. fis. mat. nat.) 25:528, 1958.

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