While NIOSH estimates that no more than 500 US workers are subject to nickel carbonyl exposure from activities directly relating to these industrial operations, this number may increase by an order of magnitude when considering the possible inadvertent formation of nickel carbonyl. Such can occur with the use of nickel catalysts in hydrogenation, in coal gasification, and in petroleum refining.
Nickel carbonyl is an extremely volatile and flammable liquid (igniting spontaneously in air at room temperature) whose toxicity in the vapor form is well documented.
Toxic effects in animals have resulted from inhalation exposures of 17-70 mg nickel carbonyl/cu m (2400-10,000 ppb) for 5-30 minutes and included edema of the lungs and brain and high mortality . Human effects resulting from accidental exposure to nickel carbonyl have included pulmonary edema, interstitial pneumonitis, reduced lung capacity, cardiac irregularities, liver enlargement, and in severe exposure cases, death  .
In animal carcinogenicity studies-, rats developed lung tumors from both long-term (inhalation of 30 mg/cu m air (4300 ppb), for 30 minutes, 3 times weekly, for 1 year) and acute (single dose of 600 mg/cu m (8 6 , 0 0 0 ppb) for 30 minutes) exposure to nickel carbonyl vapor . Induction of malignant tumors of several organs has also been reported following intravenous injections of nickel carbonyl.
From an occupational health viewpoint, those occurring following inhalation of nickel carbonyl vapor are considered of greater relevance. The nature of its biochemical interactions may support a carcinogenic potential for nickel carbonyl . For many years the increased incidence of lung and nasal cancers occurring in nickel refinery workers was attributed to nickel carbonyl. A later analysis of these workers refuted this association. At the present time human epidemiologic data  are insufficient to either confirm or deny a causal relationship.
In view of its extreme toxicity from either acute or chronic exposure, nickel carbonyl should be designated as a highly hazardous material and regulated as a carcinogen. After a review of the existing data NIOSH supports the current US standard for nickel carbonyl of 1 ppb which approximates the least detectable level for this substance and does not recommend a change in the environmental level. The 1 ppb standard should protect workers from any carcinogenic potential which nickel carbonyl may have, as well as any of the other adverse health effects associated with nickel carbonyl exposure. In 1951, Barnes and Denz  exposed rats to nickel carbonyl at concentrations ranging from 17-70 milligrams per cubic meter of air (mg/cu m) (2400-10,000 ppb) for 5-30 minutes and rabbits at concentrations ranging from 10-32 mg/cu m (1400-4600 ppb) for 10-30 minutes. The animals were killed at intervals up to several months after exposure. Mortality and the effects seen upon gross and microscopic examination were very similar to those described by Armit . In addition, they described the presence of an early compensatory fibrogenic lung reaction in those animals which were killed between one and four months after exposure and a complete resolution of that reaction in animals which were killed a year or more after exposure. Also, they found that only 5 to 10% of the calculated amount of nickel inhaled by the animals was retained in the lungs, suggesting rapid relocation and excretion of that which was absorbed.
Sunderman and Selin  investigated the metabolism of nickel carbonyl. Radioactive nickel carbonyl was administered to 78 adult male rats by either intravenous (IV) injection or inhalation. The LD50 value of 5juL/100g body weight, as determined by Hackett and Sunderman , was used.
Determination of radioactive nickel in urine, feces, and expired air revealed that 38.4% of the injected dose was exhaled as nickel carbonyl, 31.2% was excreted in the urine, and 2.4% was excreted in the feces. A total of 66.2% of the injected dose was excreted within 24 hours following exposure.
Further excretion of nickel carbonyl was extremely slow and reached a maximum of 72.0% of the injected dose at the end of the fourth day. Tissue analyses of rats killed 24 hours after injection revealed 7.3% of the dose in muscle and fat, 5.5% in bone and connective tissue, 4.7% in viscera and blood, and 0.2% in the brain and spinal cord. According to the authors, excretion values obtained after inhalation were not practicable in that there was significant fecal and exhalant contamination as a result of nickel carbonyl adsorbed onto the animals' fur during exposure.

# B. Carcinogenicity in Animals
Three animal studies  have been conducted to assess the carcinogenic potential of nickel carbonyl. Two studies were conducted by inhalation and one by intravenous injection using either multiple or single exposures. Details of the experimental design and pertinent results are presented in Table I.
In the first two studies  Sunderman and his coworkers observed a single pulmonary carcinoma in each of six groups of exposed rats. A total of six lung cancers occurred in 157 nickel carbonyl-exposed rats that survived at least 12 months. No lung cancers were observed in 82 controls.
This difference is of only marginal statistical significance (P=.073).
Spontaneously occurring lung cancer is extremely rare in rats and according to Sunderman and Donnelly  none had been observed in their 12-year series of experiments.
Comparing the incidence of lung cancer in nickel carbonyl-exposed rats to this much larger, historical control population would increase the level of significance.
These six lung cancers consisted of 2 squamous cell carcinomas, 2 adenocarcinomas, and 2 anaplastic carcinomas, all found between 24-27 months after initial exposure.
In addition, lung cancers occurred equally in rats subjected to either a large single exposure or repeated exposures at much lower levels for a long period of time. The major sites of metastases were the kidneys, liver, and heart ,
A wide variety of tumors other than pulmonary cancers was observed in both nickel carbonyl-exposed and control groups in the second Sunderman study .
While the total incidence of tumors in the nickel carbonylexposed rats was greater than that in the controls, 50% vs 33%, a causal relationship was considered doubtful . There were no tumors other than the lung cancers reported in the Sunderman et al.  study. However, the number of animals that survived to 24 months was very small and the thoroughness of the pathology examination could not be ascertained from the report.
In the studies of Lau et al. , nickel carbonyl was injected intravenously into the tail vein of Sprague-Dawley rats, either as a single injection or in six injections administered 2-4 weeks apart. The total dose administered to the multiple -dose group was approximately 2 1 / 2 times that of the single-injection group.
For the single-injected group, there was little overall difference in the survival or in the incidences of benign tumors of treated and control animals. The incidence of malignant tumors was slightly increased over the controls, 8.3% vs 4.3%. Rats administered multiple injections had a greater increase, 15% vs 4.3%, in the overall incidence of malignant tumors which was of statistical significance (P<0.05). Other than two pulmonary lymphomas, no malignant tumors were observed in the controls. Considering only non-lymphomatous malignant tumors, the difference between the exposed and control groups is of greater statistical significance (P<0.02). The tumors originated in many organs and most were observed to have metastasized.
In an additional study, not tabulated in Table I, Sanina  reported the induction of malignant tumors in various organs including the uterus, ovaries and mammary glands in rats exposed by inhalation for two hours, once every two weeks, at a concentration of 0.0005 -0.0017 mg/L (70-240 ppb) . Tumors were found during examination after having killed the animals at various time intervals up to six months. While the report indicated no tumors in the controls, the total number of exposed animals was small (2 0 ) and no data were given on the incidence of each type of tumor or on the time of killing. Due to its lack of details, very little information can be derived from this report.
Thus, the carcinogenicity of nickel carbonyl has been demonstrated in at least three different experiments, by two routes of exposure (inhalation and intravenous injection) and in different organ systems. Perhaps, the most pertinent finding is that of lung cancers in the inhalation studies, closely simulating the most probable route of occupational exposure to this compound.
The extent of carcinogen testing has been limited to only one species, the rat. While it is difficult to determine whether other species, and indeed man, would show a similar response to that of the rat, Laskin and Sellakumar  concluded that the common laboratory rat most clearly meets the requirements of the ideal animal model for respiratory carcinogenesis.
Their conclusion was based upon the induction of tumors in rats which are similar in morphology and origin to those of man, and the extreme rarity with which these tumors spontaneously occur.
In addition, the inhalation and retention kinetics of inhaled particulates and vapors of the rat resembles that of man moreso than do those of the smaller laboratory rodents.

# C. Toxic Effects in Humans
In view of its volatility and its general use in the vapor state, the major occupational exposure to nickel carbonyl is by inhalation. Skin absorption  and ingestion  also may be routes of entry into the body.
The initial signs and symptoms resulting from exposure to toxic amounts of nickel carbonyl have been most often described as dyspnea, fatigue, nausea, and headache . These signs and symptoms, except in the most severe exposures, usually ceased in the first 24 .
In the two fatal-exposure cases, the investigators, Brandes  in 1934 and Jones  in 1973 reported finding edema of the brain in addition to damage of the lungs in the decedents.
A report was published in Lancet  in 1903 concerning two other deaths associated with exposure to nickel carbonyl but the description of pathologic changes found in the bodies of the victims is of questionable accuracy.
Cardiac irregularities , liver enlargement , and spleen enlargement  are some of the other significant human health effects of nickel carbonyl exposure reported in the literature. A case of an allergic reaction known as Loffler's Syndrome was attributed to nickel carbonyl exposure by Sunderman and Sunderman .

# D. Epidemiology Studies of Cancer in Humans
In 1939, Hill  observed an apparent increase in lung and nasal cavity cancers occurring in Mond nickel refinery workers in South Wales.
Morgan  and Doll et al.  conducted followup studies on these same workers and confirmed Hill's earlier findings.
Of 482 workers, 113 died of lung cancer and 39 of nasal cancer. Of these, all nasal cancers and all but 8 lung cancers occurred in workers employed prior to 1925. The risk of developing lung cancer for those employed prior to 1925 was 5-10 times that expected and that for nasal cancer, 100-900 times that expected . For those employed after 1925, the observed incidences approximated the national averages, perhaps indicating the reduction or elimination of a causal factor.
Based upon the observations of Hill  the British government attributed nickel carbonyl as the causative agent for development of these cancers .
Morgan  and Doll et al.  refuted an association with exposure to nickel carbonyl and believed that metal dust, copper sulfate, and/or arsenic were the more likely causative agents. This conclusion was based upon the following considerations; (1 ) although no changes had been made in the nickel carbonyl process for 50 years prior to 1958, the occurrence of lung and nasal cancers was confined exclusively to those workers employed prior to 1925, (2) very few cases of acute toxicity attributable to nickel carbonyl inhalation were recorded, indicating that substantial exposure to the vapor of nickel carbonyl was unlikely, (3) between 1920 and 1925, major changes were made in the refinery that resulted in less dust, use of masks to reduce dust inhalation, and use of arsenic-free sulfuric acid, and (4) studies of the personnel in nickel refineries not using the nickel carbonyl process also indicated an increased risk to develop cancers of the lungs and nasal sinuses .
Additionally, Doll et al.  have speculated that differences in cigarette smoking might help to account for the difference between the incidences of cancer of the lungs in the Welsh workers hired before and after 1925.
From a review of the epidemiologic data it is not possible to confirm or deny an association of lung cancer with nickel carbonyl exposure .

# D. Engineering and Other Control Technology
Areas where nickel carbonyl is manufactured, used, or stored, should be isolated from all other process areas.
In any event, regulated areas, except for outdoor systems, should be maintained under pressure, negative with respect to non-regulated areas.
In order to accomplish this, each nickel carbonyl operation should be provided with continuous local exhaust ventilation so that air movement is always from nonregulated to regulated areas. Where a fan is used to affect such air movement, the fan blades and 1 8
throat should be made of a nonsparking material.
Exhaust air should not be discharged to regulated areas, nonregulated areas or the external environment unless decontaminated. This may be accomplished by discharging exhaust air directly to the fire box of a decontamination furnace, with subsequent discharge of this air to the environment. A portable suctionvent system is recommended so that in the event of a localized leakage of process gas into the regulated area, a hood and suction hose could be placed near the leak for direct removal of the process gas.
Laboratory work involving the use of nickel carbonyl should adhere to the same ventilation and decontamination strategies as stated above.
All work should be done under laboratory hoods and only the amount of nickel carbonyl needed for that day's work should be at hand. There should be no connection between the regulated laboratory areas and nonregulated areas through the ventilation system.

# E. Confined Spaces
Entry into such confined spaces as tanks, pits, process vessels, and trenches should be restricted to authorized personnel only and the following precautionary measures should be instituted: Non-sophisticated instruments and methods have been developed for detecting nickel carbonyl leaks. The color change of a butane flame in the presence of nickel carbonyl has been used for leak testing with a reported sensitivity of 1-2 ppm (1000-2000 ppb)  . A Draeger tube  with a sensitivity of 50 ppb and a "Sniffer" , with a detection range of 4-70 ppm (4000-70,000 ppb), have also been used. The second generally accepted instrumental method for continuous monitoring of nickel carbonyl is plasma chromatography. The plasma chromatograph has a detection range of 0.2-2.0 ppb . Both the FTIR and the plasma chromatograph are commercially available.
A third instrumental method which is not commercially available has been developed by Stedman and Tammara [2 \ They have demonstrated the chemilumunescent detection of nickel carbonyl in air using a reaction with oxygen/ozone and purified CO. Th detection limit of their prototype detector is 0.01 ppb. Since their original system was conceived, a portable detector has been built which has a response time of 3-5
seconds, with about a 1 . 0 ppb detection limit (written communication, David A. Tammaro, 1976).
In analyses performed in the field, plasma chromatography and FTIR have been superior to chemical methods for area monitoring of nickel carbonyl at the 1 ppb level  . While the major users of nickel carbonyl have been innovative in the development of these superior instrumental methods of analysis, their cost may be prohibitive to the short-term or intermittent user of nickel carbonyl.
Only for this reason should the following chemical method be used as an alternative.
The chemical method .
In general, an air sample containing nickel carbonyl is bubbled through an alcoholic-iodine solution. The entire bubbler solution is dried and dissolved in dilute acid, this solution is neutralized and alpha-furildioxime is added to form a chloroform-extractable complex with nickel. The absorbance at 425 nanometers (nm) is determined and compared to the absorbance of standards.
The detection limit of nickel carbonyl is in the sub-ppb to ppm range.
The specific materials and methods used to carry-out this analysis are as follows:

# Collection of samples
The air sample is bubbled through 80-100 ml of alcoholic-iodine solution. A 0.8 micron millipore filter is placed in front of the scrubber to exclude nickel particulates. For long collection times, the scrubbing liquid volume may be replenished with isopropyl alcohol. The sampling rate is measured at the start and end of the sample period, and the average of the two rates is used to calculate the volume of air sampled. Sampling times usually range from 6-24 hours. Nickel carbonyl has found some application in the nickel plating industry . By using nickel carbonyl, nickel can be deposited on metal or other surfaces without the use of electric current. The process simply involves decomposition of nickel carbonyl vapor by heat in the presence of the target surface.
irregularity, liver enlargement, elevated blood and urinary glucose levels, and in severe cases, death.

# Chronic Long-term Effects
If treatment is prompt and effective or if exposure is only slight the adverse health effects should disappear in 2-3 weeks. However, in one reported case, four patients who had appeared to have recovered were found to have radiographic evidence of fibrosis, a year after exposure.

# C. Reporting Signs and Symptoms
Signs and symptoms of acute exposure to nickel carbonyl can include, shortness of breath, fatigue, nausea, and headache. These initial signs and symptoms may pass away except in the case of massive exposures. In most exposure cases, the effects are not immediately disabling and the exposed persons are able to report to the appropriate health personnel under their own power. In extreme cases where the degree of asphyxia is severe, the immediate treatment should be that for carbon monoxide 32 poisoning.
A mixture of 95% oxygen and 5% carbon dioxide should be administered.
It is of great importance to keep the patient warm but if no oxygen supply equipment is available, he should be removed into fresh air regardless of the surrounding temperature.
In addition it may be necessary to apply artificial respiration.
If so, the arm-lift-back pressure (Nielsen) method should be employed and not mouth-to-mouth resuscitation.

# B. Precautions for Safe Use
Precautions taken in any area where nickel carbonyl is manufactured and/or used should include proper ventilation. Continuous local exhaust ventilation should provide air movement which is always from non-nickel carbonyl areas to areas containing nickel carbonyl. Where a fan is used to affect such air movement, the fan blades and throat should be made of a nonsparking material. Further, the exhaust from such exposure-risk areas should pass through a decontamination furnace before emission into the environment. These practices should be followed in the laboratory as well as in the commercial processing plant.

# C. Handling and Storage Precautions
Because nickel carbonyl is extremely volatile and flammable, it should be handled only when it is contained in steel bottles. Carbon dioxide fire extinguishers should be readily accessible in all nickel carbonyl storage and handling areas.

# IV. RESPIRATORS AND PROTECTIVE CLOTHING

# A. Respirators
In all areas where nickel carbonyl is manufactured, stored, or used, workers should wear full facepiece supplied-air respirators. The extreme toxicity and volatility of nickel carbonyl coupled with its nearly undetectable odor emphasize the need for careful observance of this recommendation.

# B. Protective Clothing
Absorption of nickel carbonyl through the skin has not been demonstrated but has been suggested. Therefore, the necessity for the use of protective gloves and impervious (e.g., rubber) clothing is uncertain.
However, in view of nickel carbonyl's volatility and the major threat of exposure to its vapor, the use of protective clothing is not suggested.