A Pilgrimage Into the Archives of Nickel Toxicology

A Pilgrimage into the Archives of Nickel Toxicology

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

Institute for Clinical Science, Pennsylvania Hospital,. Philadelphia, PA 19107 Introduction the contributors to this and the three previous symposia, with special com It is my great pleasure to address this mendation to my beloved son, Bill Jr. assembly of learned scientists on the My memory with respect to nickel tox occasion of the Fourth International icology goes back to 1943 when I Conference on Nickel Metabolism and attended my first nickel meeting at Los Toxicology. Alamos, New Mexico. This initial meet When I seriously sat down to prepare ing was arranged out of necessity. It was remarks for this evening’s program, I held for the purpose of devising methods became aghast as I pondered upon the to protect workers in nuclear energy title that I had submitted. How could I from the hazards of acute and chronic presume to cover such a colossal subject exposure to nickel tetracarbonyl in the course of a brief address? It is true Ni(CO)4. It was recognized then that that the hazards of exposure to nickel nickel carbonyl was one of the most toxic and nickel compounds have been recog of all gases. At our first meeting, those in nized only within recent decades; how attendance set three goals: (1 ) to obtain ever, the number of research contribu accurate toxicity data on nickel carbonyl; tions and publications on nickel (2 ) to establish programs for the protec toxicology that have appeared during the tion and treatment of workers who might past three decades has been substantial. in ad v ertan tly be exposed; and (3) to In my ponderings, I harbored the wish undertake studies for the acquisition of that I could call for help from my knowledge on the metabolism of nickel. esteemed friends and scientific col It is heartening to note that these initial leagues of World War II who instigated goals have, in large measure, been real many of our early interests in the toxicol ized. And now, 45 years later, the extent ogy of nickel. These eminent scientists to which studies on nickel metabolism are now deceased. At this time may I pay have expanded, as evidenced by this tribute to them and to the early pioneer conference, is noteworthy and evokes a ing contributions of the International modicum of satisfaction. Nickel Company especially through Although metals have been known and their Medical Director, J. Gwynne Mor used by man since antiquity, it is note gan; to the U.S. Atomic Energy Com worthy that it has been only within the mission and the Rohm and Haas Com past two centuries that nickel was pany, — the two organizations which acknowledged to be a primary element. supported our research studies; and to Furthermore, nickel has been refined for large scale commercial distribution only Plenary Address given at the Fourth International within the last 1 0 0 years. Conference on Nickel Metabolism and Toxicology, Hanasaari Cultural Centre, Espoo, Finland, Sep Nickel is ubiquitous and is estimated tem ber 5, 1988. to be present in 0.008 percent of the

1 0091-7370/89/0100-0001 $02.00 © Institute for Cìinicaì Science, Inc. 2 SUNDERMAN earth’s crust. The core of the earth is The hazards from exposure to nickel believed to be similar in composition to appear to have been first recognized meteorites, which consist of iron-nickel during the period of the Renaissance. alloys averaging about 8.5 percent Agricola (1490-1555) referred to the nickel. The presence of nickel may be toxic effects of “Kupfer-nickel” ores on detected spectrographically in the sun the lungs of workers in the Schneeberg and celestial bodies in which the ele area in Germany.22 Nickel does not occur ments are present as incandescent gases. in nature by itself but is associated with Nickel in the sun is estimated to be cobalt or as an alloy with copper, zinc, present in 0 .0 0 0 2 percent by volume. iron, and arsenic. In the 17th century, In an interesting review on the medic the German Erzgeburg miners found a inal use of nickel, Koplinski in 1911 red-colored ore which they mistakenly stated, “Nickel and nickel salts, except thought was copper and which they ing for the very poisonous nickel car named “Kuper-nickel” (copper-nickel). bonyl, have no place or record in toxicol While possessing the appearance of cop ogy ” . 28 Koplinski elaborated on the per ore, it yielded no copper when exceptional medicinal value of nickel treated with the process then used to salts for the treatment of epilepsy, extract copper. Later, the red colored chorea, migraine, and neuralgia. He also ore was identified as nickel arsenide noted that “nickel acts as a sedative and (NiAs). A silver appearing metal emanat tonic of peculiar and elective power in ing from China during this period was controlling the damaging effects of sexual given the trade name “German Silver.” vice on the nervous system ”. And now, This is essentially a mixture of nickel, since World War II, the uses of nickel for copper, and zinc.59 medicinal purposes have been com The word “Kobalt” in German denotes pletely abandoned, and it has become a goblin and “Nickel ”, a scamp. These recognized that, in addition to nickel evil spirits (Kobalt and Nickel) were carbonyl, exposure to nickel and other believed to haunt the mines and do harm nickel compounds may be exceptionally to the miners. The church services dur deleterious to health. ing the 17th century in the mining dis On the other hand, nickel is probably tricts in Germany included prayers for an essential trace element required for the protection of miners from “Kobalt” mammalian life. In 1936, the studies of and “Kupfer-Nickel”. Howard-White20 Bertrand and Nakamura suggested that notes that the fume-emitting reddish ore nickel may play a normal physiological had a harmful effect on the health of the role in metabolism . 6 In 1974, Schwartz miners, so that they naturally thought indicated that nickel is probably an that the evil spirits or “Old Nick” himself essential element for the life and health had been at work. of anim als. 41 Within the past decade, Nickel was isolated as a metal early in nickel has been shown to be a compo the 19th century by Berthier. 5 Following nent of four plant enzymes of physiologic this isolation, a world-wide search for im portance.61 nickel-containing ores was made by a number of commercial companies. Dur ing the middle of the last century, ores Historical Items Pertaining to Nickel were found both in Europe and in the United States which contained from one A synopsis of historical items pertain to two percent nickel. These ores fur ing to nickel and its toxicology has been nished the only available nickel until the assembled (table I). A few of the perti much richer ore (called Garnierite, — a nent starred items will be discussed. silicate of nickel) was discovered in the A PILGRIMAGE INTO THE ARCHIVES OF NICKEL TOXICOLOGY 3

French penal colony, Noumea, — the this finding led to the economical com English name of which is New Cale mercial production of nickel.34* donia. The Noumean ores were found to The first deaths from nickel carbonyl contain from 1 0 to 2 0 percent nickel; were reported in 1903. Two workmen they were found to be abundant, near died from exposure to nickel carbonyl at the surface, easily mined, and close to the Mond Nickel Works at Clydach. The the seaboard so that they could be deliv report to the coroner’s jury by Dr. Tun- ered worldwide at a small cost for nicliffe stated, “Death was caused by freight. The Noumean mines were nickel carbonyl, a substance inhaled developed by a French company under from the dust given off during employ the House of Rothchild. In retrospect, m ent. ” 36 It might be noted that in the some of the difficulties and hardships previous decade, McKendrick and Snod that were encountered in their efforts to grass had reported a case of nickel car mine the ores are amusing. For example, bonyl poisoning in the same plant. 32 in trying to recruit laborers in New An important study on the toxicity of Caledonia, J. Garland wrote, “The native nickel carbonyl was reported in 1907 by Kanakas . . . hold strong views as to the Armit. 1 He studied the effects of expo folly of work and the stupidity of the sure to nickel carbonyl on rabbits, cats, white man who is addicted to it. ” 22 and dogs and found that nickel was the The first malleable nickel was pro toxic component in nickel carbonyl and duced in Philadelphia in 1865 by Joseph not carbon monoxide. Wharton (1826-1909) from ores mined A number of toxicologic investigations in Pennsylvania. The International on nickel toxicology were reported dur Nickel Company issued a medal in 1904 ing the beginning and middle of this commemorating this event (figure 1). It century (table I) and these have been might be noted that the U.S. Mint pur reviewed in some of our earlier pa chased $600,000 worth of nickel from p e rs .26'27,45,47 A noteworthy discovery Wharton in the course of 20 years to was made in our laboratory in 1957 when make three cent nickel coins (1865- sodium diethyldithiocarbamate (Dithio- 1889). It is also noteworthy that W harton carb) was found to be an effective anti donated $100,000 in 1881 to the Univer dote for nickel carbonyl poisoning. 12,54,56 sity of Pennsylvania to start a business school to be known as the Wharton Toxicity of Nickel in School of the University of Pennsylvania. Experimental Animals T. P. Anderson Stuart is credited with undertaking the first systematic investi Scientific data of the hazards of expo gations in nickel toxicology in 1884 while sure to nickel and nickel compounds working as a graduate student in have been obtained in experimental ani Schmeideberg’s laboratory in Strasburg, mals only within recent decades. A sum Germany. He investigated the physio marization of toxicity values of nickel and logical properties of the salts of nickel its compounds, many of them from our and cobalt metabolism and presented laboratory, is given in table II. the results of his studies in a doctoral * Nickel has an unique chemical property. Nickel thesis, for which he was awarded a gold or nickel compounds in a finely divided state have a medal. 8 great affinity for carbon monoxide to form the highly poisonous nickel carbonyl at environmental tempera Nickel carbonyl was discovered by tures and normal atmospheric pressure. Maximal Mond and coworkers in 1890. The physi concentrations at normal pressure are obtained at 45° cal and chemical properties of nickel car to 50°C. At approximately 200°C, carbon monoxide becomes dissociated from the nickel carbonyl with bonyl were found to be especially useful the deposit of a high grade nickel and the release of in separating nickel from its ores, and carbon monoxide for recycling. TABLE I

Synopsis of Historical Items Pertaining to Nickel and Its Toxicity

945 The first references to nickel as an alloy were probably those pertaining to so-called "white copper" that was wrought by Chinese craftsmen into objects of art and utility. It is presumed that this alloy may date as far back as 300 A.D.29

★1490-1555 Agricola referred to the toxic effects on lungs of workers by "Kupfer-nickel" bearing ores in the Schneeberg area in Germany.^2

1637 An inexpensive silvery-appearing metal was supplied to Europe from the Province of Yunnan in China. This metal was given the trade name of "German Silver", a mixture of copper, nickel, and other metals. The standard formula was copper, 50%? nickel, 25%; and zinc, 25%.59

1754 Nickel was recognized as an element by Axel Frederick Cronstedt who named the metal "nickel."^

1804 Richter published a paper entitled "Our Absolutely Pure Nickel, Proof That It is a Noble Metal."40

★1820-1890 Nickel was isolated as a metal in 1820 by Berthier.^ This isolation stimulated a world wide search for nickel-containing ores. ★1865 Malleable nickel was first produced by Joseph Wharton in Philadelphia, Pa, USA. Nickel was first used in U.S. coinage in 1865. The U.S. Mint produced a three cent piece that contained 75 percent nickel and 25 percent copper.

★1884 T.P. Anderson Stuart undertook the first systematic studies in nickel toxicology while working in Oswald Schmeideberg's laboratory in Strasbourg, Germany.®

1890 Nickel carbonyl was discovered by L. Mond, C. Langer, and F. Imiche. Its ease of formation and high volatility were found to be properties that are especially useful in separating nickel from its o r e s . 34

1891 First case of nickel carbonyl poisoning was reported by McKendrick and Snodgrass. 32

1892 Mond carbonyl process for the extraction of nickel was inaugurated. 33

1900 Mond Nickel Company, Ltd. was founded at Clydach, Wales.

★1903 The deaths of two workmen were reported to have occurred at the Mond Nickel Works at Clydach, Wales. The report to the coroner's jury by Dr. Tunnicliffe stated: "Death was caused by nickel carbonyl, a substance inhaled from the dust given off during employment. . . . " 10

★1907-1908 Armit studied the toxicity of nickel carbonyl in experimental animals and found that nickel was the toxic component and not carbon monoxide.^- 1929-1933 Skin sensitivity to nickel became recognized.^

1934 Brandes reported a case of nickel carbonyl poisoning from "cracking gasoline" with the use of nickel as a catalyst.^

1937 Baader was the first investigator to report the high incidence of pulmonary cancer in nickel

workers. 2 TOXICOLOGY NICKEL OF ARCHIVES THE INTO PILGRIMAGE A

1939 Bayer reviewed the toxicology of nickel carbonyl and the pathological lesions resulting from exposure.^

1943 Nickel conference held at Los Alamos, New Mexico for the purpose of devising methods to protect workers in nuclear energy from the hazards of acute and chronic exposure to nickel carbonyl.

1953 Gulf Oil Company accidental exposure of over 100 workmen to nickel carbonyl. The seriously injured were treated with BAL. Two of the workmen died; 20 became critically ill and were hospitalized. With the exception of three men, the remainder had not been able to return to work two months after exposure.

*1957 Sodium diethyldithiocarbamate was discoverdd to be an effective antidote in the treatment of animals exposed to nickel carbonyl.

1958 Doll collected data from death records to estimate the incidence of cancer of the lung and nose in nickel workers. He estimated that from 1948 to 1956 the risk of nickel workers dying from cancer of the lung was approximately five times normal. During the same period, the risk of nickel workers dying from cancer of the nose was approximately 150 times normal.13

1958 Dithiocarb proved to be an effective antidote in the treatment of human exposure to nickel carbonyl.54

1958 W. Jones Williams studied pathology of the lungs in five nickel workers, - four of whom had developed pulmonary carcinoma.^3

1962 Passey tabulated 144 deaths from cancer of the lung in nickel workers computed the average age at death in these workers to be 57.6 y e a r s . 37

★1965-1988 During this period, extensive experimental studies were undertaken on the induction of nickel carcinogenesis.31,48

1969 Toa Gosei Chemical Industries, Nagoya, Japan - 156 workmen exposed of which 137 showed symptoms of intoxication, and 96 were hospitalized in the 13 hospitals of Nagoya. The critically ill were treated with Antabuse until supplies of Dithiocarb became available. No deaths occurred although convalescence in seven men was protracted.

1984 Dithiocarb was found to have antitumorigenic properties in rats subjected to muscular implantations of nickel subsulfide (Ni3S2 )* ^ 3

------^ 6 SUNDERMAN

F ig u r e 1. P h o to graph of medal presented to Joseph Wharton of Phil adelphia by the Interna tional Nickel Company in 1904 at the St. Louis exposition to commemo rate the first production of malleable nickel in 1865. The medal was given to F. W. S. by Dr. W. Red wood W right, great grandson of Joseph Whar ton.

It will be seen that solutions of colloi rats are 0.067 and 0.24 mg per liter, cor dal nickel or nickel salts have a high responding to 10 and 33 ppm, respec degree of toxicity when given either tively.47 It may be noted that there are intravenously or subcutaneously. On the now more than 180 organonickel com other hand, the ingestion of nickel or pounds commercially available, and that nickel salts has a relatively low degree of toxicity studies have been reported for toxicity. When given orally, it will be only a few of them. seen that dogs are able to tolerate doses of metallic nickel and nickel compounds Routes of Exposure to Nickel as high as three g per kg of body weight. The most toxic of all of the compounds Any considerations of nickel toxicology of nickel that are encountered in indus require a knowledge of the physical and trial operations is nickel carbonyl chemical characteristics of the nickel [Ni(CO)4]. The LD50 values for a 30 min compound to which the subject has been ute exposure to Ni(CO)4 for mice and exposed, the concentration, length and type of exposure as well as the sensitivity TABLE II of the host and the presence of disease in Toxicity of Nickel and Its Compounds the individual. The physiologic responses also depend in large measure Nickel (Colloidal and Powdered) upon the route by which nickel com Intravenous Dogs LD = 10 to 20 mg/kg Acute oral Dogs Tolerated: 1 to 3 g/kg pounds enter the body and are distrib

Nickel Salts (Cl, NO3 , SO4 , Q) uted in the tissues. The routes to which Intravenous Dogs LD = 10 to 20 mg/kg nickel may enter the body and the types Subcutaneous Rabbits LD = 1.3 g/kg Acute oral Rats LD50 = 2.0 g/kg of nickel poisoning are given in table III. Chronic oral Cats Tolerated: 25 mg/kg/day for 200 days Skin application Human 1:10,000 evokes T o x ic it y o f N ic k e l T etracarbonyl sensitivity reaction Nickel Carbonyl - Ni(CO)4 Our investigations on the toxicity of Inhalation Mice LC50 = 0.067 mg/liter for 30 minutes Ni(CO)4 were undertaken by means of Inhalation Rats LC50 = 0.24 mg/liter for 30 minutes an especially designed exposure Inhalation Cats LC50 = 1.9 mg/liter chamber50 (figures 2A and 2B). The for 30 minutes Intravenous Rats LD50 = 22 ± 1.1 mg/kg chamber provides constant flow of gas, Subcutaneous Rats LD50 = 21 ± 4.2 mg/kg Intraperitoneal Rats LD50 = 13 ± 1.4 mg/kg controllable over a wide range of flow- rates. The construction permits the use A PILGRIMAGE INTO THE ARCHIVES OF NICKEL TOXICOLOGY 7

TABLE III normally were approximately 80 per Types of Nickel Poisoning cent of those computed from the known rates of air-flow and injection of Inhalation [Ni(CO>4 , Ni, Ni3S2 , NiO, IU2O3] Acute nickel carbonyl. The analysis made Pneumonitis with adrenal cortical insufficiency; hyaline membrane formation; pulmonary edema and directly on the air in the chamber was hemorrhage; hepatic degeneration? brain and accepted as yielding the correct value. renal congestion C hronic Cancer of respiratory tract; pulmonary eosinophilia (Loeffler's syndrome); asthma Gulf Oil Company Refinery Accident

Skin Contact Primary irritant dermatitis; allergic dermatitis; Within the past 35 years, an opportu eczema Parenteral (Prosthetic Implantations) nity has been afforded to examine per Allergenic reactions; osteomyelitis; osteonecrosis; malignant tumors sonally or to review the medical records Oral of several hundred persons acutely Food and beverage; drugs exposed to nickel carbonyl. My first large scale medical experience in treat ing such patients occurred in April 1953 of a variety of experimental animals when I was called as a consultant to that may range in size from mice to 25 supervise the treatment of workmen kg dogs. A special feature of the accidentally exposed at the Gulf Oil chamber is the insertion of baffles in Company refinery at Port Arthur, Texas. order to provide a uniform distribution In this tragic accident, more than 100 of the toxic agent. 42 A syringe mecha men were exposed to nickel carbonyl; 31 nism was used to introduce nickel car of the men required hospitalization, and bonyl into the chamber. For our toxi two died. The workmen were exposed cologic investigations, nickel carbonyl during the repair of a reactor in one of is dissolved in a 50—50 mixture of USP the company’s chemical plants. The grade ether and anhydrous ethanol. reactor was surrounded by a stall which The solution is introduced into the hindered the dispersal of fumes. Only chamber through a motor-driven Luer- workmen who entered this stall became type syringe fitted with a 2 2 gauge ill. The 31 hospitalized employees were needle. Syringes with capacities from treated with BAL* since Dithiocarb had 1 0 to 1 0 0 ml are convenient for pro not been discovered to be an effective ducing various concentrations of nickel antidote until 1957. carbonyl in the chamber, ranging by The opportunity to examine these volume from one to approximately 1 0 0 exposed workmen over a protracted parts per million in air. The material period of time proved to be a valuable fed through the syringe drops onto a experience. Without personal contact plug of glass wool supported on a wire with the critically ill patients, it would screen. No trouble with immediate have been difficult to appreciate the evaporation is encountered with the insidious manner in which the symptoms 50—50 mixture of ether and alcohol. develop in nickel carbonyl poisoning and When absolute alcohol alone was used the severity of the illness that occurs as the solvent, evaporation was slug without febrile response. gish. When ether alone was used, bub In table IV is given a tabulation of bles formed in the syringe leading to symptoms that developed in the exposed an erratic rate of feeding. Concentrations of Ni(CO )4 in th e * British antilewisite, 2,3-dimercaptopropanol, chamber, as determined by analysis,26 usually called dimercaprol or BAL. SUNDERMAN

CONSTANT FLOW CHAMBER

LEGEND:- I - STAINLESS STEEL EXPOSURE CHAMBER, SIZE 30" X 30" X 30" 2 -3 “ DIA. GLASS PIPE INLET CONNECTION 2A-GLASS WOOL EVAPORATION PLUG 3 - MECHANICALLY ACTUATED HYPODERMIC SYRINGE FEEDING MECHANISM 4 - FUME HOOD 5 «5 D IA. DRAIN INCLUDING DRAIN PLUG WITHIN CHAM BER 6 - 3" DIA. OUTLET CONNECTION 7* CONDENSATE TRAP AND CLEANOUT 6 - BY-PASS FLOW CONTROL 6A~ COARSE ADJUSTMENT 60- FINE ADJUSTMENT 9 - ORIFICE FLANGE 10-MULTIPLE ORlFiCE PLATE (MERIAM INSTRUMENT CO.)

11- M ANO M ETER U 12-EXHAUSTER F ig u r e 2A . S c h e matic diagram of equip ment for exposure of ani mals.

workmen, which could be divided into enced a sense of constriction in the chest two categories: (1 ) those with immediate with concomitant shortness of breath and reactions after exposure and (2 ) those a dry, hacking, unproductive cough. In a with delayed reactions. 46 A latent period number of the patients, the initial symp of one to five days may occur in which toms emerged gradually into the more the exposed workmen may be essentially severe, delayed reactions; in others, the asymptomatic. transition from one stage to the other The most common initial symptoms was more abrupt. Usually, the delayed were dizziness accompanied by frontal stage was ushered in by a paroxysm of throbbing headache and sternal and epi coughing. The onset of the severe symp gastric pains. More than one-half of the toms varied from 1 0 hours to six days fol men became nauseated following expo lowing exposure. sure and many of them vomited. Soon An almost universal complaint of the after exposure, most of the men experi critically ill men was that of extreme A PILGRIMAGE INTO THE ARCHIVES OF NICKEL TOXICOLOGY 9

F ig u r e 2B. Equip ment for exposure of ani m als.

weakness and ready fatigue. Some stated the patients, respirations could not be that they felt too exhausted to breathe sustained without pressure oxygen ther and, indeed, such statements were apy. Breathing in the exposed subjects borne out by the fact that in about half of was rapid and shallow. The pulse rates were increased but not usually in pro TABLE IV portion to the increased respiratory Symptoms of Acute Nickel Carbonyl Poisoning rates.

Immediate Latent Delayed Seven of the critically ill patients from the Gulf refinery accident developed Mild, non-specific 1 to 5 days Constriction in chest Symptoms disappear May be Chills, sweating neurological symptoms; two had convul when subject essentially Shortness of breath removed to asymptomatic Unproductive cough sions and others became irrational. Diar uncontaminated air Muscle pains Headache; dizziness Weakness, fatigue rhea and abdominal distention occurred Sternal and epigastric Gastrointestinal pains symptoms in several of the patients two or three Nausea and vomiting occasionally occasionally Convulsions and days following exposure. This might sug delirium - sometimes gest that nickel was being excreted by terminally the bowel similar to the diarrhea that 10 SUNDERMAN follows arsenic poisoning; however, no of the accident and in which we had analytical data were obtained to support shown that BAL increased the tolerance this concept.25 of rats to nickel carbonyl by a factor of Fever was not a predominate symp approximately two.27 tom in the critically ill patients. With At the time of the Gulf Oil Company few exceptions, the temperatures of the accident, the Rohm and Haas Company patients were not elevated above 101°F. was in the midst of constructing a pilot Almost all of the exposed men developed plant in Pasadena, Texas in which nickel a moderate leucocytosis of 1 0 , 0 0 0 to carbonyl was to be used as an interme 15,000 leucocytes per cmm. The two diary in the synthesis of acrylic esters for fatalities from the exposure occurred on the production of plastics.* the fourth and 1 1 th day after the acci Under a patent granted to the Com dent. pany, the nickel carbonyl in the process Alterations in the serum electrolytes was utilized under high pressure, — thus followed the pattern encountered during increasing the risk of accidental expo the precritical period of pneumonia. sure. In reflecting on the accident at the These included diminished concentra Gulf Oil Company, Mr. Otto Haas, one tions of sodium and chloride accompa of the two founders of the Rohm and nied by increased concentrations of Haas Company, became deeply con potassium .52 Similar serum electrolyte cerned about the industrial use of nickel changes are observed in acute adrenal carbonyl in his company’s operations and cortical insufficiency, and, as a conse told me that he would abandon the proj quence, supplemental corticosteroid ect completely if the operation would therapy was administered as an adjunct jeopardize the lives of his workmen. I to antidotal BAL therapy. replied that we had learned to handle In practically all of the cases, convales plutonium safely during World War II cence was protracted. On examination and, that if adequate safeguards were two months after exposure, several of the provided, I felt that the lives of workmen men appeared cyanotic and a few of in the nickel carbonyl operation could be them had residual tenderness over the adequately protected. During our con hepatic and splenic areas. In most of the versation, I extracted a promise from exposed workmen, the pulse rates Mr. Haas that he would permit me to set remained elevated above the normal up the medical safeguards at the without range. interference or rejection by plant man An attending physician unfamiliar agement. with the symptoms following exposure to At this point, I might digress to men nickel carbonyl might tend to minimize tion briefly the results of our nickel the seriousness of the illness. Practi metabolism studies on dogs since they tioners could readily be led to consider apply to the safeguards which we were convalescing patients as being unduly about to propose. Three day metabolic apprehensive, or even malingerers, if balance studies were undertaken in dogs they were unacquainted with the course before and after exposure to nickel car of the intoxication. bonyl. To undertake nickel balance stud In retrospect, it is our considered ies, it was necessary to measure the opinion that many of the exposed Gulf Company employees owe their lives to the administration of BAL. This therapy * Walter Reppe, the German chemist, had made a major contribution in the field of organic chemistry was based upon the investigations when he discovered the oxo and related reactions undertaken in our laboratory at the time with nickel carbonyl as a catalyst.35 A PILGRIMAGE INTO THE ARCHIVES OF NICKEL TOXICOLOGY 11 Monitoring Workmen Exposed to Nickel Carbonyl When the time came to set up medical safeguards at the nickel carbonyl opera tion at the Rohm and Haas plant, I pro posed that in addition to monitoring the nickel carbonyl areas with automatic recording detectors and the use of hygienic safeguards (masks, working gar ments, etc.), each worker would be required, before leaving the plant, to submit a specimen of urine for nickel analysis. As anticipated, this proposal brought an outcry from plant manage ment that this procedure would require the construction of a separate building, the hiring of additional technicians, and

F ig u r e 3. Schematic diagram to illustrate would substantially increase the costs of method for measuring respiratory exchange during maintenance. However, I had had a pre exposure to nickel carbonyl. A: Spirometer; B: Out vious commitment from Mr. Haas, and let for sampling exhaled air; C: Two way valve sys tem; D: Exposure chamber. the plant administrators had to accept the safeguards which were proposed. Nickel analysis of urine specimens from the workmen continued throughout the 25 years in which nickel carbonyl amounts of nickel inhaled and exhaled was utilized in the Rohm and Haas plant. during the exposure to nickel carbonyl.

A schematic diagram to illustrate our 3.8 i- method for determining the nickel expi 3 6 - ratory exchange is shown in figure 3. Under normal conditions (pre-expo I I FO O D sure period), approximately 90 percent of ingested nickel is excreted in the stools and 1 0 percent in the urine (figure 4) . 59 However, when nickel vapors are inhaled, the converse is observed, i.e., most of the inhaled nickel is excreted in the urine and a relatively small percent age of inhaled nickel is excreted in the stools. This observation that there is a sharp increase in the nickel excretion in the urine immediately after exposure and before the onset of any obvious symptoms proved to be of enormous practical importance and led to the development of procedures for detecting PRÉ“EXPOSURE PERIOD I PERIOD tt accidental exposure to minimal amounts THREE DAY WETABOUC PERIODS of nickel carbonyl in concentrations too F ig u r e 4. Nickel balance studies in dogs before low to produce immediate symptoms. and after exposure to nickel carbonyl. 12 SUNDERMAN

It was heartening to me to have adminis TABLE V trative officers who objected initially to Analyses of Nickel in Tissues our program admit publicly in later years (Sudden Deaths in Previously Healthy Subjects) that this innovation of submitting urine Lung Liver Lung Liver specimens at the end of the working day (]ig Ni/100 g (\xg Ni/100 g had been lifesaving and had “paid off Subject Wet Weight Dry Weight) handsomely for the Company.” During Stab wound 2 .4 0 0 .5 2 14.6 1 . 1 the 25 years in which nickel carbonyl Drug intoxication 2.20 0.86 12.1 3.2 was used, scores of workmen were found Hanging 0.81 0.76 3.3 2 .6 Carbon monoxide 0.96 1.32 4.3 4.8 to have elevated concentrations of nickel in their urines. These workmen were Mean : 1.59 0.87 8 .6 2.9 given Dithiocarb as a preventive mea Acute nickel sure as soon as any increased concentra carbonyl poisoning 17.3 5.3 115.0 20.7 tion was detected, and practically all of them returned to work the next day benefit of Dithiocarb. An autopsy was symptomless and without complaints. performed and analyses were made of Without Dithiocarb, doubtless a number the concentrations of nickel in the lung would have died and/or developed and liver tissues from this patient. It is severe undiagnosed pneumonitis within seen in table V that the concentrations of a week or so after exposure. nickel in the lung and liver tissues were In the 25 years in which nickel car 1 1 and 6 times greater than the average bonyl was used in the plant, only one concentrations of nickel in lung and liver workman lost his life from accidental tissues obtained at autopsy from persons exposure, and this death could not in any who had died suddenly from causes way be attributed to Company negli unrelated to nickel exposure. gence. The incident is worth noting. These nickel measurements in addi Four men, working as a crew in the tion to the history, physical examination, nickel carbonyl area, were found to have autopsy, and chemical measurements in elevated concentrations of nickel in their the deceased workman who had not urine specimens. Three of the men were received Dithiocarb, left no doubt that contacted immediately after the this workman died of acute nickel car increased urinary concentrations of bonyl poisoning. nickel were discovered. These three Toa Cosei Chemical Company Accident men were given Dithiocarb and they returned to work symptomless within 48 The second large scale nickel carbonyl hours. The fourth man became ill soon accident in which I became remotely after leaving the plant and consulted his involved occurred in January 1969 at the private physician who gave him an injec Toa Gosei Chemical plant in Nagoya, tion of penicillin and had him admitted Japan. At the accident, 156 men were to the community hospital before he exposed to nickel carbonyl, of whom 137 could be reached by Company personnel showed symptoms of intoxication. and given Dithiocarb. The attending Ninety-six men from the group were physician was unwilling to administer hospitalized in 13 hospitals in the Dithiocarb to his patient, stating that Nagoya area. (Nagoya at that time had a Dithiocarb was listed as an investiga population of two million and was well tional drug and that he was confident in supplied with hospitals.) The Japanese his ability to treat pneumonia. On the authorities appealed to us for supplies of fifth day after exposure, the patient Dithiocarb which were immediately dis became moribund and died without the patched by plane. In the meantime, the A PILGRIMAGE INTO THE ARCHIVES OF NICKEL TOXICOLOGY 13 attending physicians were advised to information from the reports which I treat the critically ill patients with Anta gleaned is summarized in table VI. buse (which was available in Japan) until To date, more than 375 workmen the supplies of Dithiocarb arrived. This exposed to nickel carbonyl have received decision was based on our published Dithiocarb under our supervision. To our studies showing that the metabolic path knowledge, no exposed workmen died ways of Antabuse were similar to Dithio who received Dithiocarb within the first carb and that Antabuse provided limited four days after exposure. The efficacy of protection against the acute toxic effects Dithiocarb as a specific antidote for acute of nickel carbonyl. 56 nickel carbonyl poisoning is now well- When our supplies of Dithiocarb recognized. arrived in Nagoya 36 hours after the accident, seven of the exposed men had Carcinogenicity of Nickel become delirious, irrational, and uncon scious. In some of the subjects, Dithio In recent years, the carcinogenicity of carb had to be administered by stomach nickel and nickel compounds has tube. However, all of the men treated become of increasing concern. The high with Dithiocarb recovered, although in incidence of pulmonary cancer occurring three subjects convalescence was pro in nickel workers was first recognized in tracted. It is noteworthy that no deaths 1937 by Baader. 2 Since that time, the were reported from the Nagoya acci relation of nickel to pulmonary carcino dent. genesis has been the subject of many At the invitation of the Toa Gosei in v e s tig a tio n s .3-913-15-16-17>18'20’21’23- Chemical Company, I had an opportu 24,30,35,37,47,48,50,55,57,58,63 carcinoge nity to review the medical records with nicity of nickel has probably been more the attending physicians and scientists in thoroughly investigated than that of any Nagoya. The Toa Gosei Company had other element. undertaken a detailed clinical investiga In 1958, Doll reported that 35.5 per tion of the exposed workmen through cent of nickel workers in Wales died of several committees composed of special cancer of the lung or upper respiratory ists in various medical disciplines. The tract, whereas the incidence among col liery workers was only 1.5 percent. 13 In 1962, Passey tabulated 144 deaths from TABLE VI cancer of the lung in nickel workers and Summarization of Major Medical Findings in computed the average age at death in Nagoya Workmen Acutely Exposed to Nickel Carbonyl these workers to be 57.6 years. 37 The

1. X-ray examinations of 35 out of 72 exposed workmen average length of time that the affected (48.6%) revealed abnormal densities which workers were employed in nickel refin disappeared within six months after the accident. 2. Sixty-two of 96 exposed workmen (64.6%) were found eries was 27 years while the average to have abnormal liver function tests within the first two months after exposure. Thereafter, the time between the first exposure and level decreased. death from lung cancer was 30.5 years. 3. Twenty-six of 92 exposed workmen (27.1%) had more than traces of protein in the urine during the The carcinogenicity of nickel com first two months after exposure. 4. The phenolsulfonephthalein and Fishberg renal pounds has been documented in experi function tests were normal in all exposed workmen mental animals, including several strains who were tested. 5. Thirty-seven of the 96 inpatient workmen (38.5%) of rats as well as mice, guinea pigs, rab developed skin lesions which lasted in some cases bits, and cats. 38 Carcinogenic potency as long as six months after exposure. 6 . Four of the exposed workmen developed symptoms of appears to be inversely related to the encephalopathy which disappeared within three to five weeks without sequela. solubilities of the nickel compounds in water. The carcinogenic compounds 14 SUNDERMAN which are sparingly soluble in water at noma, and anaplastic carcinoma. These 37°C. include nickel dust, nickel sulfide, tumors closely resemble the cancers nickel carbonate, nickel oxide, nickel which occur in nickel workers. carbonyl, and nickel bisdimethylglyox- ime. Soluble nickel salts, such as nickel Concluding Remarks chloride, nickel sulfate, and nickel ammonium sulfate, have not been shown Nickel is a noble metal, and its uses in to be carcinogenic. The lesions that furthering the welfare of mankind are develop after the injection of insoluble legion. However, it must be recognized nickel compounds into various body tis that under certain conditions, human sues are, in the main, malignant fibrous contacts with the metal and some of its histiocytomas. 31 complexes are fraught with danger. The relationship between the inhala When considering the use of nickel, it is tion of nickel and pulmonary cancer has an obligation for each of us to anticipate been the subject of a number of investi untoward effects that might possibly gations from our laboratory . 48,50,55>58 ensue. May I cite an example? A number These studies established that pulmo of years ago, one of the major oil compa nary cancer may be induced in rats nies at that time launched a nationwide exposed to a single heavy concentration advertising campaign in the United of nickel carbonyl as well as in rats States through leading newspapers, exposed to repeated inhalations of sub- news magazines, and billboard displays lethal concentrations for a period of a announcing that a nickel compound, year. It is noteworthy that cancers were which the company was adding to gaso not observed in these animals until two line, was the most important gasoline or more years after the initial exposure.48 improvement since World War II (figure The lesions that develop in rats after the 4). On seeing this advertisement, I wrote inhalations of nickel carbonyl include the to the president of the company stating common types of pulmonary cancer, — that undoubtedly the company officials squamous cell carcinoma, adenocarci- did not realize that the so called “improved gasoline” had the potential of spewing deadly nickel carbonyl over the ^ew Sinclair Nickel compound... face of America. The company promptly \ JX invited me to become one of their con y < \ most Important gasoline sultants, following which the addition of V Y ^improvement since World War II nickel to gasoline was abruptly discon tinued, and the advertising quietly V \ recalled. Non est vivere, sed valere, vita. Life is V not mere living but the enjoyment of health.

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