U.S. DEPARTMENT OF COMMERCE National Technical Information Service PB-245 986 PRELIMINARY INVESTIGATION OF EFFECTS ON THE ENVIRONMENT OF BORON, INDIUM NICKEL SELENIUM, TIN, VANADIUM AND THEIR COMPOUNDS VOLUME III - NICKEL VERSAR, INCORPORATED PREPARED FOR ENVIRONMENTAL PROTECTION AGENCY AUGUST 1975 ------- This information product distributed by NTIS U.S. DEPARTMENT OF COMMERCE National Technical Information Service 5285 Port Royal Road Springfield, Virginia 22161 KEEP UP TO DATE Between the time you ordered this report— which is only one of the hundreds of thou- sands in the NTIS information collection avail- able to you—and the time you are reading this message, several new reports relevant to your interests probably have entered the col- lection. search activities. And you’ll get this impor- tant information within two weeks of the time it’s released by originating agencies. 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If you have specific questions concerning this serv- ice, please call (703) 451-1558, or write NTIS, attention SRIM Product Manager. ------- pfe-245-986 EPA-S60/2-75-005C PRELIM INARy INVESTIGA TION OF EFFECTS OH THE ENVIRONMENT OF BORON, INDIUM NICKEL, SELENIUM, TIN. VANADIUM AND THEIR COMPOUNDS VOLUME III HICKIL OFFICE OF TOXIC SUBSTANCES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON. D.C. 204iO AUGUST. 1975 ------- EPA-560/2-75-005c PRELIMINARY INVESTIGATION OF EFFECTS ON THE ENVIRONMENT OF BORON, INDIUM NICKEL, SELENIUM, TIN, VANADIUM AND THEIR COMPOUNDS Volume III Nickel Contract No. 68-01-2215 Project Officer Farley Fisher Prepared for Office of Toxic Substances Environmental Protection Agency Washington, D.C. 20460 August 1975 ------- Y RJAR INC. NIQ L TABlE CF C)N’I 2 flS Pa A. New and Old Nickel Scrap B. Nickel C. Table of Uses D. Substitute Materials IV. (IJRRENT PRACI ICE A. Transportation and Handling V. EVIFCNMENJ AL CONTN4INATION A. Fran Use B. Fran Prod xticn C. Fran In 1\ertent Sources 1. Carbustion of Oil 2. Cathustionof coal 3. Inci ntal For, ation of D. ‘Ibtal Nickel E issions VI. AND ANALYSIS . A. ? bnithrir B. Analysis 1. Nickel Carbaiyl . 2. Nickel in Particulates VII. G ECAL PEAL’1T/ITi’ I. P1 J1JCERS, SI’IES, AND (3JSFS 1 1 11 A. Producers and Sites B. Prices C. Physical Properties II. P1 IxJCrICE A. Quantities B. Process for Nickel ProcIucticn C. Nickel Carbonyl Process . D. Nickel Sulfate III. USES I l l—i I l l—il Il l—u 111—13 111—13 111—13 111—13 111—14 111—15 111—16 111—17 111—18 111—19 Regulations 111—19 111—20 111—20 111—21 111—21 111—21 111—22 Nickel ca.rbonyl 111—22 111—22 111—24 111—24 111—24 111—24 111—25 111—26 111—26 111—26 A. Envircnn nta1 and Use Associated I actions i. Effect of Nickel on Activated S1 xI and An rthic Digestion Processes ii ------- 1’ RJAR INC. NIQ L T AE OF c I IS (Con ‘t) . P e 2 . MaIT na1s 3. P].. its B. Nutrition ar 1 Gz th . 1. NcrthJ..m n Maimials 2. NonmaiTinalian Vertebrates 3. Plants 4. M1cxoorgaIu Ts . . . C. E1ectxc iysio1ogy 1. Nc*,] n.m n Mainna].s. . 2. Nornnaninalian Vertebrates. VIII. BIOLOGY 111—27 A. lthsorpticn, Distribution, E ccretion 111-27 1. i nans 111—27 a. Normal Le’ 1s in Healthy Inffviduals . . . 111-27 b. In Disease States . 111—28 111—31 111—34 111—34 111—34 111—35 111—35 111—35 111—36 111—36 111—36 111—37 111—37 111—37 111—40 111—40 111—42 111—42 111—42 111—42 111—42 111—45 111—45 contarnir iat.icri 111—45 111—45 111—45 111—46 111—47 111—47 D. Metabolic Effects 1. HLIm a iI 2 . r4a ro ls . . . . 3. Plants 4. Microorgani ns E. Cytotoxicity. F. Therapeutic Uses 1. Hunans . . 2. In rtebrates 3. Plants IX. 1IE I4E L rs. A. Persisten and t gr 3ation B. Envircnnental Transport and 1. EridogencLis. 2. Fran Use. 3. industrial. C. Bioaccunulation and itent . . . . . 1. HLZ I S . . ------- V RJAR JxC. NIO EL TABLE OF O TEN1S (Con ‘t) Page 2. liTnals 111—47 3. I brm nalian Vertebrates 111-47 4. In .ertebrates 111—48 5. Plants 111—48 X. ‘1t XIcETY 111—50 A. I flS 111—50 1. ( LtC UC Tt)XlCity 111—50 2. Acute Toxicity 111-50 3. Allex ies and Sensitization 111—51 4. CarClnogen].Clty 111—53 B. M turals 111—54 1. !Ibxicity 111—54 a. Tcpical Application 111—54 b. Inhalation 111—54 c. Oral Administration 111-55 d. Injection. 111—56 e. Inplantation 111—57 2. Sensitizaticn 111—58 3.Carcinoç nicity 111—58 C. rm aIrffnalan VerUbrates 111-61 1. Bixtis 111—61 2. Fish 111—61 D. Invertebrates 111-61 a. ‘lbx.icity 111—61 b. rata nicity 111-61 E. Plants 111-62 F. Microorgani sr 111-62 G. su1ts of Personal Contacts with dical Personnel 111—6 4 XI. ST1 NDN )S 111—65 iii. ------- RJAR JjYC. NIO J T BIE OF flS ( n’t) czI. . . . . . . . . . . . . . . . . . . 111—66 A. Stnti xy . . . . . . . . . . . . . . . 111—66 B. nc1 .si.ons . . . . . . . . . . . . . . . . . . . . • • 111—67 c. _ 011 ndat.ions . . . . . . . . . . . . • . III’68 ------- V RJAR iNc. LIST OF TABLES 1. ( micals, Poduc rs and Plant Locations . 1 1 1-1 2. PhysicalProperties . 111—12 3. 1972 Dcu stic Nickel Production, tric Tons Nickel 111—U 4. 1972 O.su ption, tric Pans Nickel :111—15 5. 1972 Constzrpticn of Nickel (Exclusive of Scrap) by Use and P nn (t tric Tons) . . III— .6 6. b1e of Uses 111—17 7. 1968 Nickel nissions 111—20 8. Nickel E nission . . . . 111—23 9. ‘bra1SerumNicke1Leve1s . ... 111—27 10. Se.ri.mi Nickel Levels in Hospital Patients With VarioUs OrJflditlCrlS . . . 111—28 11. Effects of Various Statss of Diuresis on Urinary Nickel ccxet.iat . . . . . . . . . . • . . . . 111—31 1.2. Bo d and Ultrafiltrable Senm Nickel in Various eci s . 111-31 13. Cczipostion and Effects of Nickel Proô ction Plant Dusts 111-54 14. Synergistic Carcinc enic Effects of Nickel and 3,4— Benz :! zJ.reIIe . . . . . . . . . . . . . • . . . . . . . . . 111—60 ------- RJAR Ixc. Volune III Preliminary Irn esti9ation of Effects on flwizament of Widel and Its kDn ow ds This is Volure III of a series of six reports on the environnental effects of,, boron, indium, nidcel, seleniim , tin, and vanadi’jrn and their cx 1poLuids. information is based on literature reviews, direct crntact with representati s of ocvpanies invol ed in the production or use of the materials, and nsu1tation with Ic cM1ed ab1e individuals fran industry, acath nic institutions and the deral Govexnirent. ------- V RJAR INC. hI-i I. PRODUCERS, SITES, AND COSTS A. Producers and Sites Table 1 lists commercially significant chemical products and the companies involved. For this study significant is defined as production exceeding 1/2 kkg or $1,000 value per year. Other materials may also be included because of their unusual properties, such as toxicity, or their anticipated future significance. Table 1 (1,2) Chemicals, Producers and Plant Locations Producer Chemical Company and Subordination Location Nickel (metal) Ashland Chem. Co., md. Chems. Dublin, Ohio and Solvents Div. Bram MetallurgicalChem. Co. Philadelphia, Pa. Chemetron Corp. Inorg. Chems. Div. Cleveland, Ohio City Chem. Corp. New York, N.Y. Electronic Space Products Inc. Los Angeles, Cal. Kewanee Oil Co., Hanshaw Chem. Co. Cleveland, Ohio Indussa Corp. New York, N.Y. McKesson Chem. Co. San Francisco, Cal. Pfizer Minerals, Pigments & Metals Div. New York, N.Y. SEC Corp. El Paso, Tex. United Minerals & Chem. Corp. New York, N.Y. Ventron Corp., Alfa Products Div. Beverly, Mass. Nickel (powder) Alcan Aluminum Corp., Alcan Metal Powders Div. Elizabeth, N.J. Gallard—Schiesinger, Atomergic Chems. Co. Div. Carle Place, N.Y. Bram MetallurgiCal-Chem. Co. Philadelphia, Pa. ------- RJAR Jxc. III—? Chemical Nickel (powder) (cont.) Nickel acetate (Nickelous ace- tate) Nickel acetyl- acetonate (Nick- elous acetylace- tonate) Nickel animonium chloride (Nick- elous ammoniuni chloride) Nickel ammoniuni sulfate (Nick- elous ammoniuin sulfate) Nickel benzen- esulfonate Table 1 (1,2) (cont.) Producer Company, subordination Electronic Space Products Inc. SCM Corp., Glidden Metals, GlidrRen -Durkee Div. Goldsmith, D.F. Chem. & Metal Corp. Var-Lac-Qjd Chem. Co. Ventron Corp., Alfa Products Div. C.P. Chems., Inc. Fi].o Color and Chem. Corp. Kewanee Oil Co. Harshaw Chem. Co., div. Indust. Chems. Dept. The Shepherd Chem. Co. Tenneco Inc. Tenneco Chems., Inc. Intermediates Div. MacKenzie Chem. Works, Inc. The Shepherd Chem. Co. City Chem. Corp. Chemetron Corp. Chems. Group Inorganic Cheins. Div. Rlchardson-Merrell, Inc. J.T. Baker Chem. Co., subsid. The Shepherd Chem. Co. City Chem. Corp. Location Los Angeles, Cal. Cleveland, Ohio Evanston, Ill. Elizabeth, N.j. Beverly, Mass. Sewaren, N.J. Newark, N.J. Cleveland, Ohio Cincinnati, Ohio Elizabeth, N.J. Long Beach, Cal. Central Islip, N.Y. Cincinnati, Ohio Jersey City, N.J. Cleveland, Ohio Phillipsburg, N.J. Cincinnati, Ohio Jersey City, N.J. ------- 4 / . 111—3 VERJAR INC. Table 1 (1,2) (cont.) Producer Chemical Company, subordination Location Nickel bromate City Chem. Corp. Jersey City, N.J. Nickel bromide City Chem. Corp. Jersey City, N.J. (Nickelous bro- Harstan Chern. Corp. Brooklyn, N.Y. The Shepherd Chem. Co. Cincinnati, Ohio Nickel caprylate The Shepherd Chem. Co. Cincinnati, Ohio (Nickelous capry- late) Nickel carbonate American Can Co. (Nickelous car- M&T Chems., Inc., subsid. East Chicago, Irid. bon ate) Chemetron Corp. Chems. Group Inorganic Chems. Div. Cleveland, Ohio C.P. Chems., Inc. Sewaren, N.J. Kewanee Oil o. Harshaw Chem. Co., Div. Indust. Chems. Dept. Cleveland, Ohio PVO Internat’l, Inc. Boonton, N.J. Richardson-Merrell, Inc. J.T. Baker Chem. Co., subsid. Phillipsburq, N.J. The Shepherd Chem. Co. Cincinnati, Ohio Tenneco Inc. Tenneco Chems., Inc. Intermediates Div. Elizabeth, N.J. Long Beach, Cal. Nickel carbonyl Pressure Chern. Co. Pittsburgh, Pa. Nickel chloride Allied Chem. Corp. (Nickelous chior- Specialty Chems. Div. Marcus Hook, Pa. ide) American Can Co. M&T Chems. Inc., subsid. East Chicago, md. Pico Rivera, Cal. Associated Metals & Minerals Corp. Gulf Chem. Metallurgical Co., div. Texas City, Tex. ------- - / 111—4 VERJAR JxC. Table 1 (1,2) (cont.) Producer Chemical Company, subordination Location Nickel chloride Chemetron Corp. (cont.) Chems. Group Inorganic Chems. Div. Cleveland, Ohio C.P. Chems., Inc. Sewaren, N.J. Fib Color and Chern. Corp. Newark, N.J. Harstan Chem. Corp. Brooklyn, N.Y. Kewanee Oil Co. Harshaw Chem. Co., div. Indust. Chems. Dept. Cleveland, Ohio Mallinckrodt Chem. Works Indust. Chems. Div. St. Louis, Mo. Pearsall Chem. Corp. La Porte, Tex. Richardson—Merrell, Inc. J.T. Baker Chem. Co., s bsid. Phillipsburg, N.J. Tenneco Inc. Tenneco Chems., Inc. Intermediates Div. Elizabeth, N.J. Long Beach, Cal. Nickel chromate City Chern. Corp. Jersey City, N.J. Nickel citrate City Chern. Corp. Jersey City, N.J. Nickel cyanide City Chem. Corp. Jersey City, N.J. Nickel dimethyl- City Chem. Corp. Jersey City, N.J. glyoxime Nickel 2-ethyl- Mooney Chems., Inc. Franklin, Pa. hexanoate (Nick- elous octanoate) The Shepherd Chem. Co. Cincinnati, Ohio Tenneco Inc. Tenneco Chems., Inc. Intermediates Div. Elizabeth, N.J. Long Beach, Cal. Nickel ethyl City Chem. Corp. Jersey City, N.J. sulfate ------- / 1 11—5 YERJAR JxC. Table 1 (1,2) (cont.) Producer Chemical Company, subordination Location Nickel fluobor- Allied Chem. Corp. ate (Nickelous Specialty Chems. Div. Marcus Hook, Pa. fluoborate) American Can Co. M&T Cherns. Inc., subsid. East Chicago, tnd. Harstan Chem. Corp. Brooklyn, N.Y. Kewanee Oil Co. Harshaw Chem. Co., div. Indust. Cheins. Dept. Cleveland, Ohio Ozark—Mahoning Co. Tulsa, Okia. Ventron Corp., Alfa Products Div. Beverly, Mass. Nickel fluoride Allied Chem. Corp. Specialty Chems. Div. Marcus Hook, Pa. American Can Co. M&T Chems. Inc., subsidi. East Chicago, md. Ozark-Mahoning Co. Tulsa, Okla. Nickel formate Chernetron Corp. (Nickelous for- Chems. Group mate) Inorganic Chems. Div. Cleveland, Ohio Fib Color and Chem. Corp. Newark, N.J. PVO Internat’l, Inc. Boonton, N.J. The Shepherd Chem. Co. Cincinnati, Ohio Tenneco Inc. Tenneco Chems., Inc. Intermediates Div. Elizabeth, N.J. Long Beach, Cal. Nickel halide Ventron Corp., Alfa Products Div. Beverly, Mass. Nickel hexamine Ventron Corp., fluoborate (Hex- Alfa Products Div. Beverly, Mass. amniino-nickel fluoborate) ------- 1 111—6 VERJAR Jxc. Table 1 (1,2) (cont.) Producer Chemical Company, subordination Location Nickel hydrate Chemetron Corp. Cherns. Group Inorganic Chems. Div. Cleveland, Ohio PVO Internat’l, Inc. Boonton, N.J. Nickel hydroxide Fib Color and Chem. Corp. Newark, N.J. (Nickelous hydrox- The Shepherd Chem. Co. Cincinnati, Ohio Nickel iodide City Chem. Corp. Jersey City, N.J. (Nickebous io- dide) Nickel metasil- City Chem. Corp. Jersey City, N.J. icate Nickel naph- The Shepherd Chem. Co. Cincinnati, Ohio thenate (Nick- Troy Chem. Corp. Newark, N.J. elous naphthen- ate) Nickel neode- The Shepherd Chem. Co. Cincinnati, Ohio canoate (Nick- elous neodecan- oate) Nickel nitrate Chemetron Corp. (Nickelous ni- Chems. Group trate) Inorganic Chems. Div. Cleveland, Ohio Fib Color and Chem. Corp. Newark, N.J. Kewanee Oil Co. Harshaw Chem. Co., div. Indust. Chems. Dept. Cleveland, Ohio Mallinckrodt Chem. Works Indust. Chems. Div. St. Louis, Mo. Richardson-Merrell, Inc. J.T. Baker Chem. co. , subsid. Phillipsburq, N.J. The Shepherd Chem. Co. Cincinnati, Ohio Tenneco Inc. Tenneco Chems., Inc. Intermediates Div. Long Beach, Cal. Elizabeth, N.J. ------- Y RJAR INc. “-7 Table 1 (1,2) (cont.) Producer Chemical Company, subordination Location Nickel octoate (see: Nickel 2-ethyihexoate) Nickel oxide Richardson-Merrell, Inc. (Nickelous ox- J.T. Baker Chem. Co., subsid. Phillipsburg, N.J. ide)(Nick: lous The Shepherd Chem. Co. Cincinnati, Ohio Nickel oxide, Chemetron Corp. black (Nickel— Chems. Group ic oxide) (Nick- Inorganic Chems. Div. Cleveland, Ohio el peroxide) (Nickel ses— quioxide) Nickel phosphate The Shepherd Chem. Co. Cincinnati, Ohio (Nickelous phos- phate) (Trinick— elous orthophos- phate) Nickel potassium City Chem. Corp. Jersey City, N.J. chromate (Nick- elous potassium chromate) (Potas- siurn nickel chro- mate) Nickel potassium City Chem. Corp. Jersey City, N.J. cyanide (Nickel- ous potassium cya- nide) Nickel potassium Allied Chem. Corp. fluoride (Potas- Specialty Chems. Div. Marcus Hook, Pa. sium nickel fluor- City Chem. Corp. Jersey City,. N.J. Nickel potassium City Chem. Corp. Jersey City, N.J. sulfate (Potassi- urn nickel sulfate) ------- 3’ RJAR J C. 111-8 Table 1 (1,2) (cont.) Producer Chemical Company, subordination Location Nickel propio- The Shepherd Chem. Co. Cincinnati, Ohio nate (Nickel- ous propionate) Nickel sesqui- oxide (See: Nickel oxide, black) Nickel silico- City Chem. Corp. Jersey City, N.J. fluoride (Nick- elous silico- fluoride) Nickel stannate American Can Co. M&T Chems. Inc., subsid. Carroilton, Ky. Nickel stearate The Norac Co., Inc. (Nickelous stea- Mathe Chem. Co., div. Lodi, N.J. rate) The Shepherd Chem. Co. Cincinnati, Ohio Witco Chem. Corp. Organics Div. Clearing, Ill. Los Angeles, Cal. Perth Arnboy, N.J. Nickel sulfa- American Can Co. mate M&T Chems. Inc., subsid. East Chicago, md. Pico Rivera, Cal. City Chem. Corp. Jersey City, N.J. Harstan Chem. Corp. Brooklyn, N.Y. Kewanee Oil Co. Harshaw Chem. Co., div. Indust. Chems. Dept. Cleveland, Ohio The Shepherd Chem. Co. Cincinnati, Ohio Nickel sulfate American Can Co. (Nickelous sul- M&T Chems. Inc., subsid. East Chicaao, md. fate) (Nickel salts, Pico Rivera, Cal. single) ------- RJAR JXC. 111—9 Chemical Nickel sulfate (cont.) Nickel sulfide Nickel sulfite Nickel thiocya- nate Table 1 (1,2) (cont.) Producer Company, subordination Associated Metals & Minerals Corp. Gulf Chem. & Metallurgical Co., 1) iv. Chemetron Corp. Chems. Group Inorganic Chems. Div. C.P. Chems., Inc. Fib Color and Chem. Corp. Harstan Chem. Corp. Kennecott Copper Corp. Metal Mining Div. Utah Copper Div. Kewanee Oil Co. Harshaw Chem. Co., div. Indust. Chems. Dept. Mallinckrodt Chem. Works Indust. Chems. Div. Phelps Dodge Corp. Phelps Dodge Refining Corp., subsid. PVO Internat’l, Inc. Richardson-Merrell, Inc. J.T. Baker Chem. Co., subsid. The Shepherd Chem. Co. Tenneco Inc. Tenneco Chems., Inc. Intermediates Div. City Chem. Corp. City Chem. Corp. City Chem. Corp. Location Texas City, Tex. Cleveland, Ohio Sewaren, N.J. Newark, N.J. Brooklyn, N.Y. Salt Lake City, Ut. Cleveland, Ohio St. Louis, Mo. Maspeth, N.Y. Boonton, N.J. Phillipsburg, N.J. Cincinnati, Ohio Elizabeth, N.J. Long Beach, Cal. Jersey City, N.J. Jersey City, N.J. Jersey City, N.J. ------- 1’ RJAR INC. 111—10 Chemical Nickel tita— nate (Nickel- ous titanate) Nickel zirconate Table 1 (1,2) (cont.) Producer Company, subordination N L Indust., Inc. TAM Div. The Shepherd Chem. Co. N L Indust., Inc. TAM Div. Location Niagara Falls, N.Y. Cincinnati, Ohio Niagara Falls, N.Y. Nickel alloys Atomergic Chemetals Co., Gallard Schlesinger Mfg. Co. Bram Metallurgical-Chem. Co. Electronic Space Products, Inc. Engeihard Minerals & Chem. Corp. Glidden Metals, Glidden-Durkee Div., SCM Corp. Hanna Mining Co.* Pfizer Minerals, Pigments & Metals Div. United Mineral & Chem. Corp. Ventron Corp., Alfa Products Z iv. Carle Place, N.Y. Philadelphia, Pa. Los Angeles, Cal. Murray Hill, N.J. Cleveland, Ohio Riddle, Oregon NeW York, N.Y. New York, N.Y. Beverly, Mass. *produces ferroriickel (approximately 50% nickel-50% iron) which commercially and for tax purposes is considered as primary nickel. ------- / V! RfAR JXC. B. Prices The producers’ price for electrolytic nickel was raised from $2.93 to $3.37 per kilogram in September, 1972. The price of domestic ferronickel was $2.83 per kilogram until December, 1973, when it was raised to $3.05 per kilogram. C. Physical Properties Physical properties of nickel metal and nickel compounds are presented in Table 2. ------- Table 2 (4) Physical Properties Melting Boiling Solubility Specific Point Point Water Chemical Gravity °C 0 C g/lOOcc Nickel 8.90 1453 2732 i Nickel sul— 3.68 d848 76 ° 29.30, 83.7100 fate Nickel chlor— 3.55 1001 subi 973 64.220, 87.6100 ide Nickel carbonyl 1.32 —25 43 0.0189.8 ‘-4 p’) ------- / . VERJAR JX( . II. PRODUCTION A. Quantities In 1972 the Hanna Mining Company at Riddle, Oregon, was the sole producer of primary nickel from domestic nickel ore. Primary nickel was a by—product in the refining of other metals. In addition, nickel, either as metal, alloy, or chemical compounc , was recovered from nonferrous scrap. Table 3 shows the domestic supply of nickel in 1972. In 1972, 157,500 metric tons of nickel were imported, over (3) three times the amount produced domestically. Table 3 1972 Domestic Nickel Production, metric tons nickel From domestic ore— 11,998 By-product of metal refining- 2,273 Recovered from nonferrous scrap- 32,592 Total 46,863 Disposal of the nickel held in the national stockpile was authorized on July 26, 1972. None, however, reached the open mark- et during the year. B. Process for Nickel Production The entire domestic production of nickel ore comes from an open-pit mine near Riddle, Oregon. The ore is approximately 1.4 per cent nickel. it is extracted from the mountain and transported about two thousand feet to the smelter where it is melted in elec- tric furnaces and poured into reaction ladles. In the ladles the melted ore is reduced by the additior. of crushed ferrosilicon to the molten ferronickel. C. Nickel Carbonyl Process (Nickel Recovery and Refining) This process produces high purity nickel in powder form. During the Manhattan Project of World War II, the product from this process was a key factor in the gaseous diffusion barrier used in the separation of uranium—235. Although this process is still wide- ly used, the compound nickel carbonyl is an intermediate and is usu- ally a captive material. Only one company is listed in Table 1 as offering the compound for sale. ------- I4RJAR INc. 111-14 In the nickel carbonyl process, nickel anc carbon monoxide are heated to form nickel carbonyl which, when heated, reverts back to nickel and carbon monoxide. Pressures of the order of 20 atmos— pheres and temperatures of about 150C are used for the decomposition. 0 Nickel Sulfate 1. Nickel sulfate is produced from two different raw mater- ials, pure nickel or nickel oxide or spent nickel plating solutions. With the first case the metal or oxide is digested in sulfuric acid, filtered, and either packaged for sale or processed to recover the solid hexahydrate. The sludges recovered by filtration can be fur- ther processed to produce more nickel sulfate. (6) 2. When spent nickel plating solution is the raw material, the first step is also treatment with sulfuric acid. The resulting solution has to be treated sequentially with oxidizers, lime, and sulfides to precipitate impurities. The solution is filtered and marketed or else further processed to provide a solid product. To recover a sol3d product from either process, the nickel sulfate solutions are first concentrated, filtered, and fed to a crystallizer. The resulting suspensions are fed to a classifier and the solid pro- duct recovered. This is then dried, cooled, screened, and packaqed for sale. The recovered solids from the filtration step and mother liquor from the classifiers are recycled to an earlier part of the process. (6) ------- 1 RfAR 1i c. II]. USE : A. New and Old Nickel Scrap Table 4 (3) 1972 Consumption, metric tons nickel New and Old Scrap III— 15 Cupronicke l* Nickel residues Total Grand Total Nickel and nickel alloys Monel metal Nickel silver* Cupronickel* Nickel residues Total *Excluded from totals because it containing considerable nickel. 4,990 6,205 8,030 91 141 25,605 Total 6, 597 2,648 2,615 476 4,990 14,235 25,342 132 10 , 877 14, 715 141 25,615 Consumer Smelters and Refiners: Nickel and nickel alloys Monel Metal Nickel silver* Type of Scrap New Old 661 554 739 5,936 2,094 1,875 476 Foundries and Plants of Othcr Manufacturers: Nickel and nickel alloys 1 25,341 Monel metal 9 123 Nickel silver* 10,877 14, 624 Cupronickel * Nickel residues Total 10 662 31,277 31,939 563 2,217 2,781 11,617 1,875 13,492 14,624 567 15,191 4,990 141 5,131 6,215 33,635 39,851 is copper-base scrap, although ------- B. Nickel Use Steel: Stainless & heat resisting Alloy (excludes stainless) Superalloys Ni—Ca alloys Permanent mag- net alloys Other Ni-alloys Cast Irons Electroplating 1 Chemical Uses 2 Other Uses Total reported and estimated 41,065 17,559 11, 133 7,749 3,810 26,212 A 26,341 1,071 5,265 144,229 Table 5 (3) 1972 Consumption of Nickel (Exclusive of by Use and Form (Metric tons) Total of Figures Shown Commercially Pure Unwrought Nickel 15,563 7,194 10,465 7,536 3,561 25,286 2,563 22,998 822 4,186 100: 154 Ferro— Nickel 15, 230 4,540 228 200 244 247 1 20,690 Nickel Oxide 10,157 5,813 44 33 49 633 364 28 64 337 17,522 Scrap) Nickel Sul- fate and Other Salts 5 3,218 185 166 3,574 Other Forms 206 193 396 181 44 851 97 576 2,544 1 Based on monthly estimated sales to platers. 2 lncludes batteries, catalysts, ceramics, and other alloys containing nickel. -4 1-4 a’ ------- C. Table of Uses Table 6 (7,8,9) Nickel Compound Use Purpose Comments Nickel Alloying Ele— Used for corrosive-resistant ment steels and special property alloys Nickel Car- Nond Process Intermediate in refining nickel “Mond° nickel used for metallic mirrors and bonyl to coat objects Catalyst Used in the carbonylation reaction, i.e., reaction of olefins, acety- lene, haloacetylenes, alcohols, and anyl halides with carbon monoxide Other Powder metallurgy Nickel powder can be produced by the Ofl- trolle decomposition of nickel carbonyl Nickel Sul— Nickel—plating fate Mordant Used for dyeing and printing fab- rics, coloring metals, ceramics, and for producing driers for use in protective coatings Other Food additive Permitted in the feed and drirking water of animals, and for treat ing food producing ani mals. Also permitted in food fdr human con— sumpt ion Nickel Nickel—plating Chloride Antiseptic Gas Masks hsorbent for ammonia ------- / 11118 VERJAR INC. D. Substitute Materials The use of nickel in alloy systems, especially alloy steels, constitutes the bulk of the demand. The specific properties sought vary with the different alloys, but the major features are toughness, corrosion resistance, hardness, and strength. There are other ways of obtaining these properties such as substituting chromium or molyb- denuin as alloy ingredients or by the use of a coating. One could also tolerate a slightly inferior product. Nickel, however, appears to be more economical than the substitutes. Also the available supply of nickel in the United States is adequate. This has not always been true because of worldwide imbalance between supply and demand. Dur- ing a period of nickel shortage, aluminum began replacing stainless trim. This trend is still continuing. ------- / JERJAR INC. IV. CURRENT PRACTICE A. Transportation and Handling Regulations 1. Nickel powder or finely divided nickel, also nickel catalyst, activated or spent, are classified as flammable solids. The Interstate Commerce Commission requires a yellow label on ship- ping containers and limits loads to 45 kilograms These are not accepted for transport by air unless mixed with 40 per cent water or some other suitable liquid. Air transport containers require a yel- low label. 2. Nickel carbonyl is classified as a flammable liquid by the CC and is not accepted for transport by land or air. This compound is given the highest ‘Toxic Hazard Rating.” 9 3. No special transportation and handling regulations exist for other nickel compounds with the exception of nickel cya- nide. ------- J( RJAR [ NC. 111-20 V• ENVIRONMENTAL CONTAMINATION A. From Use The principal use of nickel is as an alloying element. For purposes of this application, the metal or the composition used is insoluble and unlikely to escape into the environment except by emis- sion to the atmosphere. At the high temperatures involved in the melting and alloying of the various steel alloys, non-ferrous alloys, special electrical resistance alloys, and cast iron, the emissions to the atmosphere are in the form of nickel oxide or a complex oxide involving other l1oying elements. Nickel emission factors for these various operations were obtained from manufactures and together with (11) the 1968 emissions are presented in Table 7. Table 7 (11) 1968 Nickel Emissions to the Atmosphere Nickel Emission Factor, Emissions, Product kg/metric ton Nickel Charged metric tons Nickel alloys 2 48 Cast iron 20 72 Copper-base alloys 2 5 Electrical Resist— 2 5 ance alloys Alloy steels 10 130 The use of nickel or its compounds in electroplating is a potential source for environmental contamination of the waters with soluble nickel salts. The plating solutions normally used contain nickel sulfate r nickel chloride. Accordihq to a survey conducted by Battelle in 1965, the estimated daily raw waste from nickel plating amounted to 54,430 kilograms per day of these nickel salts. Also, only 17 per cent of the total nickel salts used was consumed by pla- ting. In addition to particles of the plating solution, raw waste may contain small concentrations of other heavy metals, depending on the kind of material being processed. Leakage from filters, pipes, ------- RJAR INc. 111-21 and pumps is a secondary source of nickel wastes. The relatively high value of nickel has encouraged the adoption of process controls for minimizing losses-into the rinse water after the plating. 1\lso because of their relatively high value, nickel plating baths are rarely dumped. (12) B. From Production The ecological consequences of heavy metal damage are pro- bably masked by the damage caused by sulfur dioxide emitted by the metal smelters. In the case of the smelter at Sudbury, Canada, east and south of the smelters, soil and vegetation, plant leaves, dust, and rainfall were sampled and analyzed. Elevated levels of nickel was detected up to 50 ki]ometers from the smelters and toxic water levels extended to 15 kilometers. The soil contamination had a pat- tern indicative of an airborne smelter source. Nickel levels were 2835 ppm at 0.8 kilometers, 1522 ppm at 5.5—8 kilometers, 306 ppm at 20 kilometers and 83 ppm at 50 kilometers from the source. Average Soil levels were 40 ppm for nickel. 13) Nickel ions (+2,+3) may be present in significant amounts in the waste water from the manufacture of nickel sulfate. (6) This is of concern because of its toxicity to aquatic organisms at certain concentrations. (14) Workers in plants for the electrolytic refining of nickel contracted diseases of the upper respiratory passage as a consequence of the inhalation of air containing nickel chloride and nickel sulk- fate. Nickel production using the Mond process involves the use as an intermediate of nickel carbonyl, which is an extremely toxic material. (15) C. From Inadvertent Sources 1. Combustion of oil Nickel is present in most crude oils and remains in the residuals after the crude oil is refined. The residual fuel oil burned by utilities and for commercial heating contains essentially the same amount of nickel as was present in the crude. The amount ------- . / 111—22 VERJAR INC. Varies widely for domestic and imported crude oils. The extremes for eleven sources of domestic crude were 1.4 to 64.0 ppm nickel, for 24 imported crudes from 0.3 to 29.5 ppm nickel. For the most part controls are not used in oil-fired units. P ssuming an average nickel content of ten ppm, the emissions to the atmosphere for 1968 from the combustion of residual fuel oil was estimated at 4,509 metric tons of nickel. 2. Combustion of coal The emissions from a coal-fired power plant were col- lected and analyzed. The nickel concentrations found in the fly ash ranged from 1.3 to 7.0 x grams per cubic meter. Based on 272,000,000 metric tons of coal consumed by power plants in 1968, 75 per cent particulate control, nickel concentration of 1.3 x grams per cubic meter, the nickel emissions were 90 metric tons. 3. Incidental formation of nickel carbonyl Nickel carbonyl is formed from a reaction between nicke. and hot carbon monoxide probably in incinerators where nickel is (16) found in sewaqe sludge or solid waste. This could occur in inter- nal combustion engines if an additive containing nickel •ias used. Such additives are banned in the United States and should not be per- mitted in the future. 0. Total Nickel Emissions Nickel release to the environment in the United States from various sources on a yea±ly basis is estimated below. Most of the values are based on 1968 figures or estimations. ------- Table 8 Nickel Emission Total Nickel Source Emission (kkg/yr) Year Comments Product Use 260 1968 Atmosphere, waters Fuel Oil Combustion 4,509 1968 Atmosphere Coal Combustion 90 1968 Atmosphere Nickel Sulfate Manufacture 1 1971 Only from spent plating baths as raw material— into waters Wastes from Nickel Electroplating 15 1971 Based on data from Efflu- ent Guidelines Develop- ment Document EPA-440/ 1—73—003 (1973) Phosphate Rock Mining 5 1972 Based on 30 ppm Ni; to landfill Other Mineral and Ore Mining 10 Current Estimated; primarily to land and water Miscellaneous 5 Current Estimated Total ________ 4,895 Mostly from oil combust- ion and emitted to atmos- phere as oxides 1-4 l -) ------- / 111—24 VERJAR INC. Vt. MONITORING AND ANALYSIS A. Monitoring The last extensive survey of the air quality over the United States was conducted in 1968-1969 by the Quality Assurance and Environmental Monitoring Laboratory of the National Environmental Research Center, in Research Triangle Park, with the assistance and cooperation of state and local agencies. Among the data compiled by the National Air Surveillance Networks of the U.S. Environmental Protection Agency were the concentrations of nickel particulateS over urban and nonurban regions for various seasons. The maximum value reported was 1.30 jg/m 3 for Portland, Maine. The nickel concentrations were considerably lower for nonurban vs. urban areas. 17 There was a greater concentration of nickel in the air over urban vs. nonurban areas. This is a direct result of greater urban industrialization. Nickel concentration appeared to be greater in the first arid fourth quarters of the year (the colder months) than in the sec- ond and third quarters. Presumably this could reflect the use of coal and oil for heating. B. Analysis 1. Nickel carbonyl Inirared spectrophotOifletrY usiiiy multiple—reflection long-path cells was used in the quantative analysis of nickel car- bonyl vapors. By using the very strong carbonyl stretching frequen- cies near 2,000/cm, detectability limits on the order of 0.01—0.00). ppm were attained. The method is rapid, specific, and free from interference. Accuracy iS estimated at + 10 per cent. (18) The American Industrial Hygiene Association indicates that a direct field instrument is commercially available for contin- uous monitoring of operations involving nickel carbonyl. The instru- ment can be usec over a range of 10 ppb to 1,500 ppb. (19) Investigations to find a granulated chemical sorbent for the efficient absorption of nickel carbonyl at high rates of air passage were conducted. Of all the chemical sorbents investigated, ------- / 111—25 VERJ AR Ixc. The best results were given by finely porous silica gel with grain size 0.25—0.5 nun. impregnated with a solution of potassium iodate in sulfuric acid. To prepare the sorbent the silica gel was purified by boiling with diluted hydrochloric acid (1:1), washed with hot water to a negative reaction to chloride, dried at 200C and ignited for 30 minutes at 600c. On cooling, the silica gel was impregnated with five per cent solution of potassium iodate in ten per cent solution (by weight) sulfuric acid, using one volume Of the iodate per three vol- umes powder. The impregnated silica gel was distributed in a thin layer in a porcelain dish, heated at l8OC for two hours and then trans- ferred, while still hot, to a flask with a tight fitting ground-glass stopper. The sorbent prepared was used to fill beaded glass tubes. It was found that with three ml. sorbent, the air alloy should be sampled at the rate of 15 cu. m./min. The loss of nickel carbonyl did not exceed 1.5% even at comparatively high concentrations of the substance. The method makes possible the determination of thousandths of a milligram of nickel carbonyl in a cu. m. air, by sampling 0.5 cu. in. air in 30 minutes. (20) 2. Nickel in particulates To detect nickel in airborne contaminants collected in air filters a small portion of the filter is rolled up into a cylin- der and placed in a hollow graphite electrode. This portion of the air filter is directly excited by the condensed spark discharge i i an oxygen atmosphere. The sample burns, exciting the spectra. A photographic recording is used to interpret the spectra and, when improved precision is required, line intensities are measured with a microphotometer. The limits of detection are 0.1 to 1.0 micro- grams. The results obtained from the rapid emission spectrographic method are compatible with results obtained with the more conven- tional technique of ashing the filter, mixing it with a spectrogra- phic buffer, and exciting it in a D.C. arc. (21) ------- 4/ 111-26 VERJAR Ixc. VII. CHEMICAL REACTIVITY A. Environmental and Use Associated Reactions Nickel air pollution usually stems from particulate emis- sions from burning coal, oil, or incinerators of nickel—containing material and is normally an oxide. This can be ccntrolled with the usual dust handling equipment such as bag filters, precipitators, and scrubbers. When the pollutant is gaseous nickel carbonyl, it can be passed through a furnace and decomposed into nickel and car- bon monoxide. Nickel carbonyl is reportedly formed when hot carbon monoxide is passed over nickel. This can occur in the burning of solid wastes con ain1ng nickelU 5 )or in cigarette smoke. (22) 1. Effect of nickel on activated sludge and anaerobic digestion processes Studies were made to determine the nickel tolerance of the activated sludge process and its related capacity to remove nickel from sewage. Significant but modest adverse effects on bio- Jogical and chemical oxygen demands, suspended solids, and turbidity were noted at 2.5 ppm nickel. Digestion of primary and activated sludge was not impaired at influent conc:entratiori a high as 40 ppm. Treatment removed 30 per cent of the influent nickel. (23) ------- / 111—27 I RfA R INC. VIII. BIOLOGY A. Absorption, Distrthution Excreticn 1. Fhmans a. Normal le e1s in healthy individuals Nickel ocairs in two fo in the blood: a so—called ultra- filtrable fraction and a protein bound fraction, whith together acooi rtt for 87 to 89 per .nt of the nicicel in man. (24) Various le’ e1s for r rmal serun nickel ntrations ha’c .e b n reported as s n in Table 9. Table 9. Normal Serum Nickel Levels Total Sert.un Ni ( .x /l) ! th d of na1ysis 1 feren 3.05 ± 0.15 (25) 2.3 AAS (26) 2.6 ± 0.8 AAS (27) 0.78 emission spectxo xtorretzy (28) 3.3 — 142.7 (29) 2.2 uv spectrophotaretry (30) 2.6 ± 0.8 (31) 1.52 ± 0.05 ( 2) ! asuremants of nickel in fractions of human serum proteins prepared by electrqhoresis and by oold-ethanol precipitation revealed the highest ooncEntrations of nickel in the serum beta-globulins. an urine nickel ajnc ntration from 17 normal h ens, terinimd by atcmic absorption spectro- photaretry after a dinethyiglyoxine extraction to con ntrate the nickel was 1.8 pg ± 0.8 pg per 100 ml or 1.98 pg ± 1.0 per 24 hours. Waveliice variations in nickel cx tent in the blood of healthy children, ages 8 to 14 years, re found to be unrelated to age or ( :34) sex. Nickel was found in only a few sanpies of palatine tonsils rerroved fr thirty-six patients. (35) ------- 3 4 RjAI? INC. 111—28 b. in Disease States Attenpts have been made to cxrrelate nickel le’vels with various disease states. Levels of nickel found in the patients of or hospital are sh n in Table 10. (27) Table 10. Serum Nickel Le’s 1s in }bspital Patients with Various Conditions Condition healthy acute rnyocardial infarction acute stroke acute burns (<25% of body) hepatic cirrhosis chronic uremia aoute n jocardia.]. isdieinia without infarction acute trauma with bone fractures acute delirium trenens nuscular dystrophy iTuTed ate postpartum irothers uibilical ard 13—36 37—72 37—72 13—36 13—36 13—36 Serum Ni (pg/l) 2.6 ± 0.8 (47) 5.2 ± 2.8 (33) 4.5 (12) 7.2 (3) 1.6 ± 0.8 (18) 1.7 ± 0.7 (12) 3.3 ± 1.6 (22) 2.7 ± 0.9 (19) 2.3 ± 0.9 (25) 2.3 ± 1.4 (10) 3.0 ± 1.3 (12) 3.0 ± 1.2 (12) ± S.D. (n) (P<0.000l) (P<0.005) (Pan = 4.1—10.9) (P<0 .005) (P<0 .005) Chanc s in levels of trace elenents in patients during stenocartha attack may reflect an increase in the tore of the s ipathetic ner ous syst n. Heparinized blood from 146 patients with chronic pneutonia was analyzed for nickel. An increase in nickel was found in patients with the asthmatic canponent. but r t if the pneunonia was cxzrplicated by respiratory insufficiency. A direct oDrrelaticn bei en serum nickel and beta-globulin was observed. (32) In hi.niens with r1- umatoid arthritis, increases in serum nickel and oo er re observed, depending upon t] activity of the disease. A substantial increase in nickel in the blood of patients with r 3iation dermatitis has been reported. (38) In patients suffering fran endenu.c fluorosis in the psheron peninsula in the USSR, an increase in the oonc ntration of ni ckel in the blcxxl occurs. I penthng on the type of develo nt and clinical forms of the disease, the nickel ca itent in the blood and cerebrospinal fluid increased in patients exhibiting a oontiruxus oourse of schizophrenia. Nickel increased in Hrs. After Onset ------- / 111—29 FRIAR Jxc. the blood and cErebrospinal fluid of patients with siir le, hebephrenic, paranoid forns and lucid catatonia, but the increase was even greater in patients with acute Kandinsky syndrcne, c epressive paranoid sthizophreriia and oneiroid catatonia. Brain, liver, rmiscie and spleen nickel levels ze lc r in scü phxenic than in normals( but sdii phrenics had elevated nickel levels in the kidney, b. ng and adrenals. A pzmmced drop in blood nickel levels occurred in patients with the beginning stages of rickets. This crease occurred prior to the develcçrrent of ana ia. Si ificant d-ianges in serum nickel ooncentrations have been observed in sa chiidren with leukemia: Condition Nidcel in Blood (Mg % ) healthy 18 (7.5—40) leukeinic 12.5 (2.5—45) anemic leukenic 7.7 No changes in nickel cEntration occurred after treatiTent even when the patient’s dition inproved. ( anges in tie nickel oontent of the bones have also been reported in children with kukemia. Increases in nickel, zinc, cxpper and manganese occurred in ie bone mariu and peripheral blood cElls in 34 patients with varicus leukemias. nickel oontent in the sp].eens and livers of 41 patients who died fran leukemia was lc r than normal. ‘Ite nest severe decreases o urred in victins of chronic leukemia. Less severe dec ients v re found in acute leukemia victine. ’ ‘rie nonnal range of nickel, 3.3 to 142.7 icro rans par liter, in human serinn was not altered by 1eukemia. Electron micitprthe analysis of tram elerents in normal and malignant human tissue revealed extrenely high cx ntration of nickel, o er, zinc, calcium, titani .in, thraniurn and iron. The freq .enc j of occurren of these Tretals appeared to be greater in malignant tissi . 6) Nidcel ooncEntra- tions re normal in patients with can r and precan rous oondition of the (47) uterine cErvix; hc ver, manganese was 1cx i, and thranium, lugh. wean serum nickel ±thled in victins of acute myoca.rdial in- farction 12 to 36 hours after the onset of the attack, reaching a level of 5.4 ± 2.7 ig/l as c Jn ared with an average control valie of 2.6 ± 0.8 Mg/i based on 40 healthy controls. Elevated serum nickel was observed in 72 r nt of the ------- / 111—30 VI RJAR l W. patients with infarctions (P< 0.0005). No significant change in nean ser in nickel cxncentration occurred in 17 patients with acute myocardial ischemia without infarction, or in 132 other hospital patients with noncardiac diseases. Nickel binding and absorption by htnnan skin has been studied using cadavers. The corneal epidermis prevented nickel sulfate penetration, but the Mal -tigian layer, dermis and hypodermis were easily penetrab1e. 8) Nickel (II) ions are bound by the dermis of cadaver skin as rreasured by changes in dennis potential, swelling and absorption. The binding is reversible, but is stronger than would be expected due to electrostatic forces alone. Nickel ions are especially strongly bound at 1CM concentrations Organ] c solvents rubbed into skin of the plantar arch did not facilitate nickel nenetration except as the solvent was able to cause darrage to the thickness of the keratin layer. Nickel was observed only in the external part of the keratin lr. 50 Fecal excretion of nickel by healthy hi. rians without occ a- tional exposure to nickel averaged 3.3 micrograms per gram wet weight (2.1 - 4.4 pg/gm), cxmpared with a value for occ ationa1ly exposed workers of 14.2 micrograms per gram dry weight, (10.8 - 18.7 ug/g) or 258 micrograms per day (80 - 540 pg/day) (51) Normal, unexposed adults excreted 0.027 micrograms nickel per ml of urine. rkers in a nickel snelting plant, where the rrean nickel xmcEntration in the air was 0.349 micrograms per liter, had an average urinary nickel concentration of 0.240 microgr ie per (52) Individuals knc n to be ingesting 41.5 — 77.7 pg nickel in the daily diet, 7.08 to 22.1 pg (17.0 to 28.4%) was excreted in the urine, and 8.8 to 54.1 pg (21.2 to 69.6%) was excreted in the feces In acblescents, a sensitive balance between nickel arid cobalt has been described. If the diet contains 30-3 3 g of cobalt per day and 280 - 310 g of nickel, the rninint n daily requLrelTents axe a1nt st con letely filled. The cobalt:nickel ratio in the urine is twice that in the feces and diet. The anount of nickel excreted in the urine was 10.6% of the anount ingested (22.6% for cobalt), and the rest was excreted in the feces. Kidney excretion of nickel was largely independent of kidney henodynainic values. Large individual variation is observed. In an experirrent ------- / 111-31 VtR/AR iNC. examing t effects of various states of diuresis on nickel excretion, tl-e results sF n in Table 11 were obtained: (54) Table fl ffects of Various States of Diuresis an Urinaxy Nickel Excretion (54) Urine F1 Ni Excretion Condition ( zn1/n ) ( ng Ni/mm) (rig Ni/mi urine ) ntid±uretic I a1tiiy 1.08 ÷ 0.72 4.27 + 4.79 3.95 1- 4.43 & kidney patients Diuresig 4.43 + 2.11 29.7 -1- 31.2 6.70 ÷ 7.04 Osnotic diuresis 23.5 + 7.2 84.2 + 94.9 3.58 + 4.03 Tl conan tration of nickel excreted in the scales of patients with psoriasis was found to exceed tiiat in normal desquamation. Humans suf- fering frc n chronic gastritis or stomach cancer have reduced seri nickel levels due to disturbed resorption and excretion of microelenents in tFe digestive tract. (56) 2. Maimals Ser levels of total and ultrafiltrabie nickel have been determined by atcmic absorption spectrcz etxy for several species. in an equilibrium dial- ysis study, in vitro binding of nickei-63 (II) to serum albumin of several species was determined, and the first association cxnstants were calculated. (58) This data is suimax&zed in Table 12. Table 12 Bound and Ultrafiltrable Serum Nickel in Various Species (58) Total Serum Ni % Ultrafil- 63% Ni (II) First assoc- Species ( pg/i) trable Ni bound in vitro iation ristant man 2.3 41 87—89 3 x i0 rat 6.6 27 87—89 2 x 1O 5 rabbit 9.0 16 87—89 >3 x 1O dog 2.3 >85 55 2.5 x pig 75 8x10 4 lobster 8.8 38 ------- / 111—32 YE RJA R INC. The species differeno2s in the ability of semn aThumin to bind nickel accx)unt for differences in àirounts of ultrafiltrable nic e1. (24) The rrean caicentratia’ of nickel in the ultracentrifugal super- natant of harogenates of rat li.rig and rat liver were detennired to l e: Organ g Ni/gin R IA (Rang e ) lung 48 (34—64) liver 29 (21—39) Seriin nickel levels in oz s suffering from lynphoid leukemia were 1.5 to 2 tines the levels of normal anils. No d ange in serum nickel or nickel in affected skin areas was thser’. ed in rabbits with radiation dermatitis. R bthg the skin of the abdrninal wall of the guinea pig with various organic solvents and nickel sulfate for ten minutes resulted in ab— sorption of nickel, which was detected in the skin, kidreys and liver. (50) Nickel was not absorbed from cx pressesof nickel sulfate applied to rabbit skin unless skin lesions were present.’ / Calves fed rations ritaining 62.5, 250 or 1000 ppm nickel as nickel carbonate actually ingested 0.4, 1.3 and 1.6 gin nickel per day. As a result, a significant increase in the nickel cxncentration in many tissues occurred in the group ingesting 1000 ppm nickel rations. The order of tissue accunulation was serum>kidney>vitreous huror> lung> tes tis>bile> tongue>pancreas> rib>spleen>brain. Liver and heart levels were not significantly different fran antrols. Of the total nickel excreted, 97.1% was excreted in the feces. (61) No change in milk production, cxlrposition, nickel centent, animaJ. health, or feeding habits occurred in lactating dairy ws fed diets ccntaining 0, 50 or 250 ppm nickel as nickel carbaiate. (62) ------- 1 11—33 P’H?/AR [ Ni. In rats subjected to nickel carbonyl Lnhalation, r4ckel carbonyl was cètected in the blood stream. In rats injected with nickel carbonyl, the intact compound was found in the expired breath revealnq that nickel carbonyl can cross the aleveolar I entDranes in both directica-is Subcellular nickel distribution is such that nickel is principally located in the lung and liver microsxes and supeinatant. After acute and cthrcnic inhalation exposures to nickel carbonyl, nickel was elevated in these fractions. Chronic exposures resulted in nickel elevation in the nuclear and mitothondriaJ. fractions as n. (64) The distribution of rickel-63 carbonyl, either injected into or inhaled by rats, was deterinired at various tiires after treatsent. After one hour, 48 per cent of the nidcel-63 in the blood was contair in the red blood cells, but only 8 per cent reneined in the erythrocytes after six hours, when tr t of the nickel in the blood was bound to serum alb mdri. Thirty—eight per cEnt of the ruckel-63 dose was expired in the breath during the first six hours after treabrent. During the four days follcwing exposure, 31 per cent of the nickel-63 was excreted in the urine, but only bx per cent in the feces. nty- four hours after exposure, nickel—63 was found in DNA, I A and protein of lung and liver haro nates, and was distributed throughout the nuclear, nu.tocthoridrial, microsorr al and supernatant fractions in proportion to their j4•i•t (65) A significant oorrelaticri bet seen blood volune and nickel-63 ontent of organs was thsen ied in rats injected intravencxzsly with nickel-63 at 15 minutes, 2, 6 and 16 hours after injection. Sixty-one per cent of a s ng1e injection appeared in the urine and 5.9% in the feces after 72 hours. Nickel-63 activity had disappeared from whole blood by 48 hours after injection. relative distributicn of the reniai.ning nickel was: kic ey>adrenal>ovary>lung> heart>e ’e >thyrnus>pancreas> spleen> liver>epiderinis>GI tract>i usc1e> incisor> femur = brain>adipose tisste. The nickel-63 decreased rapidly in all tiss s, and only the kidney xntained significant axrounts after 72 hours. In rabbits injected intravenously with 0.24 mg n.ickel-63 per kg body ight, 78% of the radioactivity was excreted in the urire diring the first 24 hours. The half life (t 1 / 2 ) of serum nickel was 8.2 hours for the period from one to 48 hours follcMing injection. During the first 24 hours, ------- 111-34 VI’ RJA I? Ixc. 90 per cent of the ser n nickel-63 was protein bound, with only 10 per cent ultra- filt.rable.. Colunn chromatcxraphy on Sephadex G-25 of the ul t .rafi1trab1e fraction revealed the presence of five distinct cx plexes, only three of which appeared in urine. The half life of nickel—63 in the serum for tie period from fc ir to seven days following injection was found to be 95 days. (67) Nickel and cobalt distribution re sttx3 .ied in tie irouse zygote and early blastci eres. Nickel and cobalt s re redistributed in the cytoplasm of the blastarreres during the formation of the b1astoc ’st. After the eighth blastcnere stage, granules that retained the nickel alnost disappeared. (68) 3. Plants In many green plants, degree of absorption of nickel by the roots appears to be dependent upon the soil pH. Raising the pH of serpentine or high nickel soils by the adiition of lire usually sorrewhat alleviates the toxic effects of nickel. (69) 1te excessive absorption of nickel is thought to reduce tie cation exchange capacity of roots in such diverse 1 plants as oats, beans, peas, sunflc rs and tomatoes. (70) Scme plants indigenous to serpentine soils accunu ilate nickel less readily than r nserpentire species. Other plants accumulate nickel in large aTounts. A stixly on the effects of nronium and nitrate fertilizers on the uptake of nickel by saie crop plants (wheat, barley, cotton, peanut, rye grass, rice, sor- ghum) and eds revealed that riore nickel is taken up from sandy or low nickel soils when the plants are fertilized, aniivnium stimulating itore uptake than nitrate. The concentration of nickel in tie roots was greater than in the shoots of all plants with all treatrrents. (73 B. Nutrition and Gnwth 1. NCrthuman Marm als The grcv. th of male dairy clays was retarded by dietary nickel levels of 250 or 1000 ppm as nickel carbonate. (72) The feeding by gelatin capsu] of 500 n of nickel as nickel chloride or nickel carbonate to calves resulted in a decrease in 1untary intake of the regular diet. In a cafeteria feeding exper ent, the palatability of regular feed to tie calves was decreased by tie addition of 100 ppm nickel as nickel chloride or 500 ppm nickel as nickel carbonate to the feed. A linear depression of feed palatability as nickel concentration in the feed was observed. Nickel as the chloride had five tines as much effect as nickel as tie carbonate. ------- J/ RJAR INC. “-35 en 700 mice re given drinkin water taining 5 n nickel t et r with a cadmium-deficient diet, an increase in the n rtality of males, but not females, was cbserwd. No carcino nic effects here detected, and the turror incidence in females actually decreased. A rroc’erate increase in nickel cLntents of organs occurred. ¶I1 addition of nickel to nouse eirbryo cell cultures resulted in a decrease in mitotic index and an increase in the nt nther of abnormal mitotic figures cbserved. Nickel treated cultures s1- ed increased retention of a histothemical stain specific for protein- bound sulfhydryl groups during telc hase and post-telc iase staç s. 2. Nonmainr 1ian Vertebrates ‘I growth of chicks up to four eks of a was significantly depressed by dietary nickel levels of 700 rn an aixve (76) 3. Plants Cottcn developnent arKi yield was positively infliEnced by the aldition of nickel and zinc to th soil d to enhancenent of the exchange of nitro nous substances in tie plant. The green alga, lorel1a vulgaris , shows cptimum growth on a purified nediurn ntaining three microgran nickel (78) per liter. 4. Microorganisne After six hours giu .ith in a nEdiurn o ntaining 4 x l0 M nickel chloride the marine bacterium, Arthrcbacter marinus , was greatly enlar d from its normal 2 by 4 rnicrai si to 10 to 15 microns in dianeter. Electron micro- graphs revealed a greatly plasnolyzed megalarorph, in hith the inner dense layer of the cell wall ha disappeared, leaving a light-dense profile. ¶1 cytoplasmic rrenbrane and the nuclear material did not appear than d. No cell division occurred when nickel chloride c icentraticn was 5 x 10 4 M, and tie lag phase of the culture was increased fran the normal three hours without nickel to nore than 70 hours with 4 x l0 M nickel chloride. As nickel n- (80) centration increased, the maximum cell pcpulation decreased. ------- RJAR INc. 111-36 C. Ei.ectzophysiolOgy 1. Nonhuman rt als In m alian nuscie preparations, nickel (II) can abolish cnn- tractions, but not excitation. Increasing the calcium (II) concentration can overcxxre the inhibition of contraction. The application of 2irM nickel (II) via I’yro electxoc to pig papillary nuiscie in the presence of 1.8 nM calcii.vn (II) produced the above irthibition effect. then applied to the surface of the nuscle, nickel (II) could replace calcium (II), and the action potential retained its normal shape. (81) In the rabbit puirionary artery preparation hc ver, nickel (II) could not substitute for calcium (II) in the normal cnntractile response to applied noradrenalin or syrrpathetic nerve stimulation. (82) In isolated cat trabecul (n cardial fibers), 2nt4 nickel (II) prevented contraction by re- ducing calcium (II) conductancE of the nenbrane, but sodium conductance was not affected. Increasing the calcium (II) concentration o” ercanE the effect of the nickel. (83) The addition of nickel (II) to a preparation of kitten atrial fibers produced a rapid and ex ential cay of contractile force generated, but no apparent effect on ventricular electrical activity. The calcium (II) dose-response curve was shifted to the right without a reduction in inaxinurn tension, so that increasing the calcium (II) could produce in the original contractile force. That no calcium (II) could be detected in the effluent of the perfusate sIx is that calcium (II) was not displaced by nickel (II). Gas perfusion of the preparation after nickel (II) had reduced the contractile force to one gram resulted in a gradual increase to 60% of the control value. (84) 2. nrnanmalian Vertthrates Studies on am ibian nerve and nu scle preparations reveal that the major effect of nickel (II) is the prolongation of the action potential. Nickel (II) increases n nbrane perneability to sodium and potassium ions, re- sulting in less of a concentration gradient and a higher resting potential. (85) Increasing the nickel (II) concentration applied to a frcx ventricular strip fran 0.42 to 20 n14 produced the eveloptent of a focus of spontaneous activity, an artificially created rhythm initiator similar to the natural sinus venosus rhythm initiator.’ 6) icke1 (II) increased the duration of the action potential ------- RfAR Ixc. by activating the Mn - irthibitable sodium-calcium thannel (60) The action potential amplitude was not affected. 87 en calcium (II) was replaced by nickel (II) in a frog toe muscle preparation, the threshold of ntraction stimulated by potassium ions was raised. ‘Ihe si of crntractions was also (88) increased. The application of nickel (II) to the nodes of Ranvier of isolated frog nerve fibers produoed a prolonged action potential with an in- creased airplitix1e, but less steep ascending slope. The tirre required for repolarization was longer, resulting in longer duration of the refractory period to anot1 r action potential. (90) maximum decrease in neithraz inpedance cxincided with the action potential peak, and inpedance did not re- tun to the resting level until 7 to 43 n ec after the end of the action (91) current. D. tabo1ic Effects 1. Human Nickel inhibits human breast 5-tiucleotidase, but not aflzaline phosphatase. (92,93, L phocytes from 7 out of 12 nickel hypersensitive patients re observed to take carbon-14-thyrriidine when the culture was incubated with nickel at a cxincentration of rreq per ml. No crmtrol lyrrphocytes re so stimulated by the presence of nickel ions. 2. ManiT als rretabolic fate of nickel ca±onyl has been studied with Ni ( 14 cD) 4 and 63 Ni ((D) 4 in rats injected intravenously with an I D 50 dose. Thirty- six per cent was ethaled und anged within six hours after injection. Intracellular degradation of nost of the r nainder to nickel (II) and carbon nu ioxide took place, and carbon rronoxide reached maxiimim heirog1 in saturation levels t o hours foUc iing injection. oily 1.1% of the injected Ni(’ 4 C0) was exhaled and less than 1% was excreted in the urine after 24 hours. Injection of rats with an ID 50 c se of nickel carbonyl (2.2 rrg Ni/lOU n body waight) drastically reduced liver RMA syrithesic 24 hours after ------- 1 111—38 VERJAI? LW]. injection as neasured by carbcn-14-orotic acid inr rporation into liver EVA. WithcLlt nickel carbonyl treatnent, the nean specific liver A activity in rats killed 40 minutes after an injection of 14 C—orotic acid was 318 ± 133 nmies per rrole rinose. The rate of R A synthesis by a chromatin-PMA polyxterase oDnplex was decreased six hours after rD injection of rats fr 0.3 ± 0.03 to 0.16 ± 0.02 tnoles tritiated-cytidire tri ±iosphate per g n Ct A. The nolar ratio of nickel to DNA nucleotic?es in the chroinatin- po1 m rase averaged 0.046, the oxioentration of nickel in the final assay mixture equalling 3.4 x 10 6 M. The in vitro adlition of 1 x 10 parts of nickel carbonyl or nickel thloride to thraietin-1 A olynerase ccxplex fran oDntrols did r t inhibit inoDrporation of 3 H-cytidire tri thosphate. ‘I ’CI site of in i’iü inhibition is unclear sincE the fact that an intact nuclear neiribrane is un- r oessary for the inhibitory action of nickel carbonyl irKlicates that it does not e rt its effect by inpairing transnerrbrane transport of PNA nucleotides . ) Nickel caxix yl does not decrease 1 ig 1 A synthesis as it does in liver • 98) Perhaps the effect of nickel carbonyl on RNA synthesis in the liver can at least partially acxxunt for the way in whi.th it redu s the activity of several liver detoxification enzynEs. Rats exposed to nickel carbonyl by inhalation (0.2 rrg Ni per liter of air) or injection (2 im Ni per 100 gm body ight) had diminished benzpyrene hydroxylase activity in liver and lung. In lung the enz e activity in treated rats 52 hours after exposure was 1.1 ± 1.0 units corrpared with the c ntro1, 9.5 ± 4.3 units, in liver, the activity droiped to 113 ± 24 units oDitpared with 295 ± 123 units. minim rn activity ocxurred to thx days after exposure d returned to nor l after a week. Nickel car— bcr y1 did not inhibit enzpyrene hydroxylase in vitro. (30) The sane dose of nickel carbonyl reduoed the activity of hepatic txypto an pyrrolase fran 36 ± 7 units in rats treated with artisone and nickel carbonyl. Nickel carbonyl did not inhibit tryptophan pyrrolase in vitro. (30) An LD dose of nickel carbonyl had a similar effect on aminopyririe deiiethylase in rats. Nickel carbonyl ney exert its carcin- ogenic effects by repressing these det cifying enzyires, prolonging the tisst reten- tion tines of the carcinogenic substrates for the enzynes. ------- / ERJAR piG. 1 1: 1 -39 Otber liver effects have been thserved in rats after exposure to nidcel carbonyl. Elevation of hepatic NIP by 12% occurred 30 minutes after an ID injection of nickel carbonyl to rats, and ATP of injected rats was still 13% above cxntrol levels 24 hours after injection. ‘1 nty-four hours after exposure to nickel carbonyl by inhalation (80 pp’n for 30 minutes), tl 3 ito lar sodium chloride precipitable fraction of both liver and lung PN Z was elevated 196% and 50% respectively. This I A fraction accounts for 50% respectively. This I ZP fraction accounts for 34% of the lung 1 ’4A and 23% of the liver I in a tr ,IJS(]Ol) In rat adipose tisst (from the epididymal fat pal), nickel (II) enhanced carbon-14-glucose uptake, oxidation of 14 C-glucose to l4 2 arid in- corporaticn of labelled glucose into fat pal lipids, as i ll as g1yn. 02 Nickel (II) - inoacid corrplexes affected serum lipids in rabbits by incxi asing total serum lipids, and in particular free fattyacids and diolesterol. (103) Guix a pig uteri were stimulated by treatirent with 0.01 - 3.0 mM nickel (II). The aBcaline p os thatase activity and localization of saie nickel- stimulated uteri differed frrzn the normal histamine-stimulated uteri. Especially strong alicaline hosithatase activity was thserved in the cell ireirbranes of the (l04 en&inetrium. In isolated spleens treated with theno cybenzamine and 3 H-r repinephrir , 3 H-norepinephrine released by rer e stinuilation was tra cedly reduced by perfusion with 1, 2.5 and 5nt4 (105) Inhibition of beef liver glutatnic d ydrogenase by rretal binding agents such as 1, 10-p -ienanthro1ine could be prevented by the addition of nidcel (II), as ll as zinc (II), cx per (II), calmium (II), iron (11), x a1t (II), manganese (II), but not magnesium (II). (106) Nickel (II) restores activity to netal-free allantoicase, and protects the enzyrre against heat denaturation at 30 and above (107) Purified horse liver ar thase was also therxnafly stabili d by Ni , (108) but feeding experirrents with rats sh d no activation of liver aralnase by nickel (II) in In n se L929 cell cultures grci. in on Eagle’ s ininimwn essential nedi .mi, interferon synthesis induced by Newcastle Disease virus was consic rab1y inhibited by the presence of nickel chloride (0.18 n /7 ml) in the tredium. ¶11 ------- Y IRJAR Jxc. 111-40 inhibition persisted for se eral days, but was not F.erTnanent. ° 3. Plants Nidcel (II) ions a arent1y inhibit degradative cthanges in plants associated with snescenc and injury. In detached rice ( Oryza sativa ) leaves, treabtent with nidcel (II) retarded the breakdc n of chlorophyll, protein and I A. 111 Treatnent of petunias with nickel sulfate suppressed t destxuction of anthocyanin pignents in tle fl ers, preserving the color. Ite effects of nickel (II) an respiratory chain enzyrres in different-cxlored petwiias was studied by inoibating half-opened buds for two days in 2rrM NiS0 4 .• Nickel (II) cxxisicbrably reduced tie activities of specific dehydrogenases in all 1ors, except that pyruvate and a -ketoglutarate dehydrogenaseS were activated by nickel (II) in white flc rs, and r t affected by nickel (II) in colored fl ers except in Lilac flc rs, which had slightly reduced activity for these enzynes. ‘fte activities of ascorbate oxidase and polyphenol oxidase were in- creased by nickel (II), but cytothrcite oxidase was considerably inhibited. Nickel (II) inhibited chlorophyll formation in detached leaves of khapli wheat. (114) The effects of nickel on two species ( Vicia faba L. and F lianthus annuus L.) grc n hydropczücafly with catiplete nutrients indicated that surplus nickel may cause changes in ti structural characteristics and c±ernical organ- ization of biopolyners. High nickel concentrations produced decreased rnitotic activity in V. faba and structural changes in the cell chromatin in H. annuus . (115) 4. Microorganisms In yeast cells, nickel (II) can exert an inhibitory effect on ferrrentation in at least two ways: inhibition of alcohol dehydrogenase and inhibition of active transport of netabolizable sugars into the yeast cells. (117) ‘Ihe uptake of netal ions into a nonexchangeable rthent by yeast cells was small in starved cells, but stimulated 5 to 20 fold by glucose and phosphate pro- treatirent. The rretal ion uptake, in which two potassium ions (or t sodium ions) were exchanged for each d.ivalent netal cation, occurred under rthic or an rcbic cxnditions. t duced uptake occurred at 1a pH ‘s less than 5.0. Nickel (II) inhibition of feineiitation was alleviated at low pH’s inplicating a tranS- ------- V RJAR Jxc. port effect, but flushing the cultures with gas, the presence of aJ.(x)ho I ai id acetal hyde, or increased glucose or oven concentration can also affect sugar transport and enzyiie activities. Nickel a ears to inhibit the first step in sugar transport by interactions with the poly thos ates in’ olved. Increasing the tenperature increased the inhibition. Hcy ’zever, in icxloacetate- treated cells, the carrier-irediated facilitated diffusion of sorbose and glucose was not affected by nickel (II ) In Bacillus subtilis , nickel (II) was found to be able to re- place rnaresium (II) for citrate transport. 118 The narcotic effects of nickel (II) on ciliated protozoans ere deiionstrated to be related to precise enzymatic reactions in studies with Pararreciuni caudaturn , P. aurelia, Colpicliwn, ¶ [ trahyrrena rostrata and Euplotes patella . } sistance ni.ckel (II) -induced anesthesia varied with pH, nickel (II) concentration, and subclone type, and was enhanced by the presence of certain netabolic inhibitors whith reduced the available ATP. A parent1y, resistance to nickel (II) narx is is determined by the neithrane perneability to nidcel. 9 ’ 120) Evidence for the acti e transport of nickel (II) by Paranecium caudatum is as follc is: (1) ionic noveirents occur against the concentration gradient; (2) the intracellular nickel concentration is inexplicably by passi’ .e diffusion; (3) the kinetics of penetration follc i Mich 1is laws; (4) only a limited nuirber of penetration sites exist; and (5) I? is required. Strontium ions antagoni nickel (II) anesthesia in Paranecium and reduce the inhibitory effects of nickel (II) on fissicn.U 2 U The RN —depen nt DNA polynerase of Rous sar virus was in- hibited by nickel (II), hc er, nickel (II) had little effect on the trans- forming ability of the virus’ / (perhaps related to nickel (II) inhibition of interferon synthesis). ------- 3 4 Rf41? j 111-42 E. Cytotoxicity The effects of nickel (II) on laved rabbit alveolar rnacrcphages ze ex nir d in vitro. The cell viability was reduced by 50% after 20 hc .irs with 4.17 millinolar nickel (II) chloride. C ll nunber was not decreased until the nickel cxiwentration was 12.8 milli 1ar. Nickel (II) inhibited acid os hatase activity by 50% at a concentration of 3.80 mi11ijio1ar. 1 - 23 Cultured human lung fibroblasts re nore sensitive to nickel (II) than rabbit alveolar macrophages. The LC 50 was 2.83 milthrolar nickel (II) chloride. Uptake of precursors of nucleic acid and protein synthesis was 50% inhibited by much lci r nickel cx icentrations. Nickel (II) considerably reduced phagocj’tic activity of rabbit alveolar macrophages, arid the effect was cxu icentration dependent. For exanple, with 1.11 inillinolar nickel (II) chloride, cell viability was still itore than 80% of control vali.s, but the phagocytic index, a neasuze of the ability of trypsini d tnacropha s to ingest polystyrene- latex spheres 1 micron in dianeter, was less than 20% of control. 1.24) F. ¶fl erapeutic Uses 1. Humans ¶fl ie nickel (II) d elate of 3, 4, 7, 8-tetranethyl-1, lO—phenanthro— (Nipher) proved to be as effective as hexachiorophene in the prq ylaxis of staphylococcal injections in the r om and patients undergoing elective obstetric or gynecological surgery. Ni * n also provided rapid relief of s ptar of thrcxiic nonilial and tricha Dna1 vaginitis. Successful control of secrnidaxy infections in &olescnts with longstanding aa e vulgaris was also achieved with Niphen. No toxic manifestations s re observed in any clinical trials. (125) 2. Invertebrates SilJc DrTn losses from “srontaneous” jaundice re decreased by 3.8 tin-es after spraying the mulberry leaves with 0.05% nickel sulfate. This treat- rrent increased cocoon formation by 18 per cent. (126) 3. Plants The effectiveness of nickel (II) salts in the treatrent of fungal infections of grains has been derronstrated repeatedly. Treatrent of Thatcher wheat with 179 ppm nidc.elous ion 2, 3 or 4 days after injection of leaf tips ------- J/(rRJAR f c. with the leaf rust, Puccinia reOondita , stcpped the respiration and grcMth (127) Protective fungicidal activity against the leaf rust, Puccinia rubigo-vera f. sp. tritici , and stein rust, Puccinia gratinis var. tritici , of wheat was athieved by application of the acetate, sulfate, nitrate and düoride salts of nid e1 (II) at a nickel c centratiai of 70 ppn. The nickel salt anine cxinpiex RH, (bis (N- (2 hydroxyethyl) dodecylbenzylarnine I nickel (II) cth1ori ), was effective at 280 in nickel. The order of effect- iveness as er licative fungicides was: RH-I nitrate = dfloride>sulfate = fiixride = acetate. The nickel c centraticii necessary for the eradication of stem rust was twice that needed for leaf rust. Eradication of the a n rust of oats ( Puccinia cx)ronata aven ) and sunfl r rust ( Puccinia helianthi ) required nickel concentrations very close to phytotoxic levels. Simulated rain renoved the protective action of the inorganic nickel salts nore easily than that of the A field study shø ed that or three a licaticns of nickel chloride or nitrate hexahydrate at seven or eight day intervals at ore pound per ac e in fifty gallons of water gave reascrLable o itrol of leaf rust and stein rust on Thatdier, Marguis and 1 d abs Wreat even if spraying was delayed until the rust was present. (128,129) PH-i was the nost effective nickel (II) salt amine c p1ex artong four wtuth exhibited eradicative and protective action against leaf rust of wheat (P. rthigo-vera) in a field stii y. (1 ) Wheat stem rust (P. graminis tritici Erkiss) infections were reduced after treathent with NiSO 4 , NiCI 2 and Ni O3) 2’ but Ni (NH 4 ) 2 (SO 4 ) 2 was ineffective (13t ) The application of well— tisred sprays c taining nickel salts and dithiocarbarnate to Mar pis wheat ( Triticum stivum L.) delayed leaf rust (P. graminis f. sp. tritici ) develop- nertt for 18 days and stem rust (P. recondita ) develc irent for 12 days, resulting in 66% control of rust. (132) addition of nick i salts to the organic fungicides mareb or zineb clearly inproved the cxntrol of cr n rust (P. coronata Cda. var. avenae Fraser and Led.) of oats ( Avena sativa ) over the use of maneb or zineb alone. (1 Rye leaf rust (P. rubigo—vera f.) was eradicated by topical aç lic- ations of nickel salts during the “Fleck stage”. The protective, but not the eradicative, ability of the nickel salts was destr d by artifical rainP Nickel salts are also useful in t’re cx trol of the mint rust fungus, P. i-&ttha . (135) ------- 3 RjAR Jxc. ‘fl-a blister blight futigus ( E basidiwn i xans 4 ssee) an tea lea s may be trolled by NiCI. Sporulation of E. iexans on tea lea s was s pressed by the applications of nidel chloride, nickel sulfate, nickel nitrate or nickel acetate at rianphytotoxic crmncentrations of or or o grai per liter in the lab and field. (Three grane per liter was slightly phytotoxic). Blister developrent was inhibited 16% and 55% by NiC1 2 appli at strengths of 0.4 and 1 gran per liter, respectively. fl io gran of NiC1 2 per liter prevented lesion formation even 48 hours after application. (137) Asparagus rust (P. asparagi ) lesions re decreased by treatirent of asparagus with a mixture of maneb and nickel sulfate. (138) ------- 1’ RJAR [ MG. IX. ENVIRONMENTAL EFFECTS A. Persistence and Degradation The distribution of metals in the solids of waters of t io streams in Tennesee was studied. The dissolved solids had the lowest concentration of metals, but contained 90 per cent of the total metal. The colloidal particle fraction, consisting of particles from 100 to 1500 A, had the highest metal concentration, but contained less than one per cent of the total. The coarse particulates, greater than 0 1500 A in diameter, contained less than ten per cent of the total (140) metal. B. Environmental Transport and Contamination 1. Endogerious Some soils and waters in the world contain significant amounts of nickel. For example, endogenously high levels of nickel and some other metals occur in the serpentine soils of Scotland, New (141,142) Zealand, Southern Rhodesia and Portugal. The nickel content of mineral waters in Germany may vary from 0.1 to 370 micrograms per (143) kiloqram. The Co:Ni ratio ranges from 1:3 to 1:6. 2. From Use Environmental exposures of humans to large amounts of nickel may occur through foods and other commodities. Wine and beer (144,145) quality is reduced by the presence of nickel in trace amounts. The effect can be eliminated by the addition of EDTA. Some commercial detergents in the Netherlands contain 2 to 9 ppm nickel (0.2 - 0.8 micromolar), almost a sufficient enough level to induce allergic reactions in nickel sensitive persons. The addition of EDTA to detergents yielded no discernible decrease in nickel contact allergic reactions. (146) Investigations on the heavy metal content of tobacco smoke have led to conflicting conclusions. In one study çf the anal- ysis of smoke from eight different types of cigarettes, the workers concluded that it was doubtful that amounts of nickel inhaled reach cancerigenic levels. (147) Another study revealed that 20 per cent of the total nickel content in cigarettes (1.59 to 3.07 micrograms of ------- / 111—46 V’ERJAI? INC. nickel per cigarette) was present in the mainstream of smoke inhalec . At this rate, the amount of nickel in the smoke inhaled by a heavy smoker in one year is equal to three times the amount necessary to induce pulmonary cancer in the rat. (148) In a third study using cig- arettes containing 4.25 to 7.55 micrograms nickel per cigarette, 0.4 to 2.4 per cent of the nickel in the smoked portion of the cigarette was present in the particulate fraction of the mainstream smoke. Elev- en to thirty-three per cent of the nickel was found in the sidestream smoke, indicating a possible hazard to non-smokers. (149) Concentrations of nickel in roadside soil and grasses, and variation with increasing distance from the road and increasing soil depth have been studied. (150) 3. Industrial Environmental increases in nickel content due to man’s activities have been reported in several areas of the world. Nickel analysis of plant samples ( Hypnum cupressiforrne ) collected from two regions of Sweden from 1870 to 1943 revealed that a large rise in nickel content occurred around 1920, when nickel was introduced into world production. The nickel content of the plant samples collected in 1968-1969 was twice the 1920 levels. Samples collected from Skane in southern Sweden contained significantly greater amounts of nickel than those from Gotaland, in the northeast. This rise in nickel is attributed to the increase in airborne nickel due to human activities. Skane samples contained more nickel because they were located closer to the industrial sources in Central Europe. (151) Studies on the hydrochernistry and hydrobioloqy of the Wislok River in the Krosno Region of Russia, an area polluted with heavy metals and cyanide, revealed that high concentrations of metals sterilized the river, but even lower concentrations unfavorably affec- ted the communities involved in self purification. (152) ------- !ERJAR JXC The soil in the heavily industrialized Sudbury Ba- sin in Ontario contains high levels of metals due to airborne con- tamination. The lichens in the area have a high content of heavy metals. Since metals are less toxic to lichens and other piphytes, these organisms are potentially the mcst useful inOi— cators of heavy metal fallout around industrial areas. (154) The tap water of Sudbury, Ontario contains almost 200 times the nickel concentration of the water of Hartford, Connecticut, which •is 1.1 + 0. 3 micrograms nickel pe liter. (1 5) A nickel concentration of 122 ppm was found in soil solutions from acidic coal mine spoils material. More nickel was extracted in solutions of higher It appeared that even after adjustment of soil pH for otherwise satisfactory plant growth, nickel was likely to remain in solution in toxic amounts. The introduction of nickel, zinc and copper into Lake Michigan by atmoshperic fallout evidently exceeds the input from unpolluted streams emptying into the lake. C. Bioaccumulation and Content 1. Humans Serum and urinary nickel in healthy persons in two cities reflected nickel levels in tap water in kind, but not in degree: Nickel Concentration (mg/i) Site Tap Water Serum Urine Sudbury, Orit. 200 + 43 4.6 + 1.4 7.9 + 3.7 Hartford, Ct. 1,1 ÷ 0.3 2.6 + 1.0 2.5 ÷ 1.4 2. Mammals Nickel elevation in the tooth enamel of rats fed a can- ogenic diet containing nickel acetate was observed. Caries inhi- bition in females, but not males, was obtained on this diet, but no definite correlation between caries and level of nickel in enam- el could be ascertained. 58) 3. Nonmainmalian Vertebrates Nickel was clearly detected in bodies of fish killed by nickel sulfate and nickel plating solutions, and also in fish liv- ing in such solutions. Nickel was not detected in the bodies of normal fish. (l 9) ------- Y RJAR Jxc. 111-48 4. Invertebrates Nickel was determined in the skeletons and forage plants of two species of sea urchins, but no direct correlation was ob- served. Echinometra lucunter L. contained more nickel than Tn- pneustes esculentus , but the principal forage plant, Padina gymno- sperma , of the latter, had higher nickel levels than Thalassia test- udinum , the principal forage plant of the former. l6Or 5. Plants Nickel analysis of the foliage ash of six species of plants grown on serpentine soil in New Zealand revealed species dif- ferences in ability to accumulate nickel. Pirnelea suteri , a ser- pentine endemic, showed the highest nickel concentrations. No uni- versal mechanism of tolerance or exclusion however, could be applied to explain differences. (1.6U Nickel contents of plants grown on serpentine soils, limestone and dolomite were studied in Bosnia. All plants grown on serpentine soils had higher metal contents than plants grown on limestone. The highesc: levels were found in some plants grown on any soil: Teucriuin inontanum, Potentilla tonmasiniana and Sedum achroleucum . Definite serpentine plants, subh as Halacsya sendtneri, Scrophularia tristis and Silene willdenowii var serpentina , often had lower nickel levels than many species grown on any soil. Plants grown on dolomite were rich in nickel, poor in iron, and sick- ly in appearance. (162) In the shallow serpentine soils of north- east Portugal, nickel toxicity is more or less intense, and the pre- dominance of Alyssum serpylifc lium ssp. lusitaniucm, a nickel accumu- lator, was noted. (142) The intense infertility of serpentine soils of southern Rhodesia is related to the high nickel and chromium content (maxi- mum 4000 ppm). The amount of exchangeable (HcI soluble) soil nick- el closely correlated with nickel coAtent of indigenous grass . On a soil with 70 ppm exchangeable nickel, oats exhibited transverse- banded leaves due to white chiorosis, and lucerne exhibited intense yellow chiorosis within two days of emergence, and died within for- ty. The addition of CaCO 3 to the soil increased soil pH from 5.9 to 8.2, and reduced the nickel content of dried oat leaves and sterns from 233 to 84 ppm. The toxic effects were reduced, but not elimi- ------- 14 fAR JXC. 111-49 .- ated. (141) Plants growing on mining and smelting heaps in Silesia, which contain high nickel, as well as iron, calcium, and magnesium, but decreased organic compounds and water, exhibit wide diversity in kind, degree, coverage, and level of succession. Of 45 species exam- ined, Cerastiurn arvenae, Plantage lanceolata, Tussilago farfara , and Campanula rotundifolia (in dwarfed form) accumulated nickel. The ash of these four species contained ten times the nickel normally found, perhaps explaining the dwarfing of C. rotundifolia . (163) A small shrub in western Australia may represent the highest relative accumu- lation of nickel on record. Hybanthus floribundus contains up to 23 (164) per cent nickel by weight in its leaf ash. The nickel and cobalt content of plants used in Swazi snuff (165) ‘as closely related to the soil content of these metals. The seeds of leguminous plants have a higher nickel content than the seeds of grasses grown in the same area.U 66 ) The amount of nickel in honey and pollen from the Maritime Regions of the Ukraine varies widely in relation to geographical zone. A range of 0.28 to 0.84 mg nickel per kg was found in honey ashes, and from 0.14 to 1.29 mg nick- el per kg pollen ash. (167) The average nickel content of 44 varieties of spinach from all over the world was 0.42 mg nickel per 100 gin dry (168) leaves. ------- RJAR Ixc. 1I 15 0 X. WXICITY A. Humans 1. clronic Toxicity Ebur hundrod fifty-eight workers in the nickel electrolytic refining industry in eastern Eurtç e were examired by x-ray. Infla mmatory processes of subatrophic and atr üc character were associated with the d ratic inflanination of accEssory sinus cavities in 33.07% of the workers. 1 fl se processes were apparent in 17.75% of workers suffering fran acute sinusitis and in 22.05% with cysts and cyst-like forifations. U69) High incidence of various blood irregularities were noted in eastern European ‘ rkers producing nickel ferrite pc ers. ¶I nty-five percent developed thranboc ’topenia, anemia and leukopenia, 35% exhibited sincphilia, 14% had nonocytosis and 50 per cent had decreased osnotic erythrocyte resistance. U70) Occupational diseases of workers in the electrolytic refining of nickel are apparently caused by the inhalation of an athosphexe of roso1 solutions of nickel chlorides and sulfates. ‘1 microclimate of such plants is also d aracterized by heat and mDisture. Pure nickel production via the carbonyl cycle is related to the danger of oontamth- ation of the air by nickel caz ony1. (171) Nickel carbonyl poisoning by in- halation in 46 workers in a soda and aniline factory in Lud igshafen, Germany, on the Rhine during the period 1952-1967 wnsisted of .39 light poisonings, 7 severe cases and 2 deaths. The clinical synptxrns were headache, dizziness, dest pain, nausea, fever, oouhing, and bronchial pneuronia; pulnonary edema occurred from one to forty-eight hours after exposure. ‘lie urine nickel ooncentration was a good index of degree of poisoning: greater than 10 micrograms per deciliter indicated poisoning and greater than 50 micrograne per deciliter indicated that hospitalization was r& uired. 2. Ao.ite ‘Ibxicity The synptoms of acute Ni (CO) 4 toxicity in humans inciwie the abnorir 1ly high position of tie diaphragm, limited or absent respiratory notions, a significant decrease in pneunatization of pulnonary areas. intensification and lubricability of pulnonary patterns, the bilateral focality of various degrees of manifestation and a high position of the cardiovascular bundle. (172) in several young people pulnonary thanr s fol1 ing Ni CD 4 intoxication were cb- served via x-ray. In o patients, intensification of the overall lung picture, ------- Y RJAR fxc. IL 5 1 as well as the roots of the lungs, was observed. Bilateral foci of exposure were observed in all. Retrograde development of chan- ges in the x—ray patterns began 7 to 12 days after initial exposure. The principal Ni(CO) 4 effect appears -to be the disturbance nf lung capilliaries and arterioles. 72 Nickel carhonyl intoxica- tion apparently does not leave any after-effects in healthy people. (172) Treatment of more than 300 workmen with acute nickel car- bonyl poisoning with the chelating agent, diethyldithiocarbonate (Dithiocarb), prevented death in 100% of the cases. U In one se- vere case of total nickel carbonyl poisoning, diethyldithiocarba— mate sodium did not Prevent death, probably due to severe pulmonary and cerebral edema. (173) Dithiocarb has been shown to be effec- tive in the mobilization of copper and nickel in patients with hep— atolenticular degeneration (Wilson’s disease). 3, Allergies and Sensitization Nickel dermatitis can be induced in humans through contact with nickel-plated articles, ‘ industrial exno- sures to nickelous dusts or baths, or internal exposure to nickel. (177) The symptoms comprise two levels: 1) a simple dermatitis at the area of contact, the typical “nicJce) itch”, consisting of burning and itching of the exposed skin; and 2) a chronic eczema- tous reaction, in which erythema occurs, and later nodules, which may eventually form pustules, appear in the web of the finqers and the forearm. (178) Symptoms may be relieved within a week by removal from exposure, but a rash may persist for some weeks. Specific desensitization to allergic dermatosis induced by nickel, chrom- ium or cobalt, can be achieved by increasing doses of the specific allergen or one of the other two meta1s. 79 The duration of the rash after avoidance of contact with an allergen is highly vari- able, but it seems to last longer in cases of nickel sensitivity than in other types. 80) ------- J’ RjAR mc. 111 -52 Nickel sensitivity is usually determined by patch testing with a 5% NiSO 4 solution. Out of 200 patients tested in one study, 13.5% exhibited positive tests, 85.2% of whom had a re- vious history of nickel contact dermatitis. (181) In a study of 5416 persons tested for nickel, chromium or cobalt allergy, 9.9 % showed a positive reaction. Seventy-seven per cent of the aller- gic women were sensitive to nickel; 87% of the allergic men were sensitive to chromium. This difference in sensitivity is presum- ably due to differences in exposures to sensitizinq contacts. (182) In another study on 1000 patients, 64% of sensitive women were sus- pected of nickel allergy. (183) Nickel sensitivity and atopy are apparently unrelated. Only 11% of the persons with a personal or family history of pro- ven nickel dermatitis exhibited atopy. (184) A study of 25 workers engaged in e1ectroplatir a with nickel, chromium, copper, and zinc revealed seven who suffered der- matosis. The dermatosis disappeared when workers took their annu- al vacation but recurred when they returned to work. The propor- tion of nickel dermatosis was much greater when the bath temperature (185) was 60W than when the temperature was 35 to 40 C. Apparent cross-sensitization between nickel and chro- mium or cobalt seems to be due to the presence of several allergen- ic metals in the sensitizing contact rather than to true cross- sensitization. In a study of nickel platers in Finland from 1949— 1964, only 16% of nickel—sensitive workers also showed cobalt sens- itivity; in all but two of these cases, the cross sensitization occurred du inq a period when cobalt was added to th nicke1 platinq bath as a brightener. (186) &ixty three per cent of 87 patients with suspender ec ma exhibited cross-sensitivity. Suspenders con- tain both metals. More people with cement eczema were sen- sitive t Q 1 q,, 9 ba1t than to nickel, but cement also contains both el- ernents. The nickel sensitivity threshold in eczematous pa- tients with nickel allergy was investigated by patch testing. The mean threshold (n 53) was 0.43% when distilled wat.er was the sol- ------- RfAR Jxc. vent, and 0.51% when the solvent was petrolatum. Patients with combined nickel-cobalt sensitivity had the lowest thresholds (be- low 0.039%). No correlation was observed between degree of sensi- tivity and severity of skin disease. 46 The eliciting safety limit, or the concentration of nickel which ddes not elicit any contact allergic reaction in highly sensitized persons, is one micromole of nickel per liter. This is also assumed to be t e sensitizing safety limit of nick- (1 8) el. Evidence of cellular hypersensitivity in cultured (189)’ - lymphocytes and leucocytes, but not skin explants, from nick- el—sensitive patients as compared with normals has been reported. When treated with nickel sulfate or nickelacetate (lO 4 meq Ni /m1), cultured lymphocytes from nickel-sensitive patients exhibited an increased perc ntage of conversion to lymphoblasts, accompanied by an increase in 14 C-thymidine uptake, indicating DNA synthesis. Macrophage migration inhibition was also observed. 94 ’ 19 ’ 0 However, no differences we’re observed in the effects of different nickel concentrations on mitotic capacity of leucocytes from nick- el-sensitive and normal patients, (191) 4. Carcinogenic y The blastomogenic properties of nickel compounds (192) in humans and in rats have been well established. Various environmental exposures to nickel seem to correlate with increased incidence of tumors in man. For example, cancer in the maxillary antrurn of snuff users may result from using plant material grown on soil high in nickel. In Bantus, carcinoma of the maxillary an— truin accounts for 45.5% of all respiratory cancers observed. The Swazi snuff used by these people contains high concentrations of nickel, chromium,and zinc. (193) The incidence of lung cancer was studied in 845 men employed by a nickel refinery in South Wales for at least five years beginning during or before April, 1944. In men first employed before 1925, the incidence of death due to lung cancer was 5 t 10 ti” es the national average, and to nasal can- cer, 100 to 900 times the expected mortality. After 1925, death ------- RJAR Jxc. “-54 rates due to lung and nasal cancer were comparable to those of other men in the same geographical region. Susceptibility to nasal cancer varied with age at first exposure, but susceptibility to lung cancer varied irregularly. (194) In a study of the high mortality of nickel concentration and smelting workers due to various cancers and sarcomas compared with the general population, the highest incidence of pulmon- ary carcinoma was observed among forty-year-old males. The incidence was higher for workers in roasting, reduction and cobalt departments who were exposed to nickel sulfides and oxides, as well as cobalt and and arsenic compounds. Fernoral and lung sarcomas were most prevalent among these workers, the males alone being affected. (195) A recent increase in the incidence of cancer of the nose and accessory sinuses in workers in the industry producing pure nickel by electrolysis warranted a reevaluation of maximum allowable exposures, according to Tatarskaya. (195) B. Mammals 1. Toxicity a. Topical Application Nickel sulfate applied as compresses to skin lesions in rabbits caused lethal intoxication. (196) b. Inhalation A single intratracheal administration of 50 mg of nickel production plant dust to rats resulted in hyperplasia of the lymphoid apparatus in all animals. The nickel content of the dust varied with the source, and additional effects were observed as shown in Table 13. (197) Table 13 Composition and Effects of Nickel Production Plant Dusts Source of Dust Composition Effects agglomerate 2% Ni, 45.5% Si0 2 , siderosilicosis 25.9% iron oxides, 12.4% aluminum oxides furnace 64.4% nickel oxides and connective tissue sulfides nodes electric furnace 95% nickel oxides diffuse sclerosis of interalveolar walls ------- J 4 RJAR JxC. Rats were subjected to the inhalation of soluble and insoluble aerosols of nickel compounds. After two weeks exposure the inhalations of nickel oxides caused a, significant increase in the number of alveolar macrophages (measured by a standard washing procedure): increased mucus production was observed in the rats after nickel chloride inhalation. Histopathological examinations of rats after exposure to either compound revealed morphalogical alterations and changes in cell sizes depending upon the length of exposure. 198) The effects of the aspiration of finely dispersed par- ticles (0.19 microgram) of metallic nickel at a concentration of 0.005-0.006 mg per liter were studied in dogs. After six months exposure, various physioloqical changes including disturbed hemo- poiesis, changes in blood vessel wall permiability, and alterations in thyroid function were observed. Eleven to thirteen months after discontinuaticn of nickel exposures, the disturbed functions were partially restored, but local pneumosclerosis with gradual cardio- pulmonary insufficiency developed. (199) Syrian golden hamsters were exposed to nickel o ride inhalation at a concentration of 10 to 190 micrograms per liter. After initial clearance, 20% of the nick- el from the exposure remained in the lung, and 45% of this was still present 45 days later. However, no hamster died within the six month duration of the expeviment. (200) c. Oral Administration In rats given daily peroral doses of 0.06, 0 12, or 0.3 mg NiC1 2 per kg of body weight for 13 weeks, weight incre- ments were significantly less than that of controls, the lag being most pronounced in the 0.3 mg/kg group (only 10% hat of control). The erythrocyte count was somewhat lower in nickel—treated animals after 60 days, and the blood catalase activity was lower than con- trols, also. (201) In male rats, severe lesions in germ cells and reduction of spermiogenesis 1 developed after long term NISO 4 intoxication. The selective noxious effect was on the testicular parenchyma, with very few observed changes in the liver and kidney. (202) ------- 1 4 RJ4/? Jxc. 1 11 -56 Twenty-three male dairy calves were fed 0, 62.5 250 or 1000 ppm nickel as NiCO 3 in their diet from 13-21 weeks of age. Feed intake and growth rate were slightly retarded in the 250 ppm group. Feed intake was greatly retarded with the 1000 ppm nickel, and the animals lost weight, appearing younger, but not emaciated. During the recovery period in which all groups were fed a 0 ppm nickel diet, the growth rate of all was normal. Digestibility coefficients were not affected by a dietary nickel, but nickel retention was significantly lower than control in the 1000 ppm nickel group, probably due to the decreased feed intake. Rumen propionate increased and butyrate decreased on a molar ba- sis. Organ weights were unaffected by dietary nickel, but the kidneys became nephritic, the severity of nephritis increasing with higher dietary nickel levels. (72i Nickel chloride was much more toxic than nickel carbonate to young dairy calves fed 500 rag of nickel per day in gelatin capsules. Nickel as nickel chloride has five times as great an effect as nickel carbonate on reducing the palatability of feed presented to seven-month old dairy heifers in a cafeteria experimentJ 73 The incidence of lethal legume bloat in cattle was increased 10% in cattle fed alfalfa-containing nickel. Al- though incidence of bloat exhibited a positive correlation only with the alfalfa content of protein Fraction I , nickel was found to have an important relationship to the amount of bloat that (203) can occur. d. Injection Intravenous administration of Ni(CO) 4 to rats at the LD 50 dosage of 2.2 mg per kg of body weight :esulted in liv- er and lung effects. Electron micrographs of liver cells re- vealed diffuse dilatation of the rough endoplasmic reticulum and nucleolar aberrations two to twenty-four hours after injection, but mitochondria and other organelles appeared essentially unaf- fected. The earliest effects of LD 50 Ni(CO) 4 injection on ------- Y RJAR Jxc. pulmonary alveoli occurred six hours to two days after injection and were manifested by intense swelling of the alveolar endothel- iurn. Proliferation and hypertrophy of the alveolar epithelial cells occurred two to eight days after injection (peak at four to six days), and focal infiltration of the alveolar interstitith-n with connective tissue cells was present on the fourth and fifth days after injection. Histochemical studies of lung tissue two to six days after injection revealed the clumping of nuclear chro- matin, bizarre mitoses, increased nucleolar and cytoplasmic RNA and augmented protein staining. Ultra-structural changes were also observed. 204 The LD 50 for Ni(CO) 4 varied with the route of injection: Rat Mode of injection 5O (mg Ni/lOOa body wt. ) intravenous 2.2 + 0.11 subcutaneous 2.1 ± 0.42 intraperitoneal 1.3 + 0.14 The pulmonary parenchyma was observed to be the target organ re- gardless of the route of administration. (204) In mice the LD 50 for subcutaneous inject on of disulfonickelguanidine was found to be 240 mg per kg body weight. Subcutaneous injection of dogs with 4 mg of disulfonickelguani- dine resulted in a decrease in blood pressure of 10-15 mm Hg. Injection of 0.3 - 0.5mg/kg did not produce changes in coronary blood flow or volumes in cats. A 2-4 mg/kg injection caused a 40-45% increase in coronary blood flow 3 to 5 minutes after in- jection in the cats, which returned to normal in 10 to 15 minutes. A simultaneous 20-25 mm Hg drop in blood pressure and increase in the oxygen consumption of the myocardium were also observed. (205) e. Implantation The histopathological reaction of the brain to the presence of nickel-coated shotgun pellets was observed in cats. Copper—coated pellets stimulated a more severe reaction, and lead—coated a less severe reaction. (206) Pure nickel implants in the precentral motor cor- tex of monkeys produced evidence of severe nickel toxicity arid ------- 14 RJAR Jxc. 111-58 severe necrotizing foreign body reaction. Some epileptogenic ef- fects were observed. (207) 2. Sensitization Nickel allergic reactions may be induced Li guinea pigs following surface and subcutaneous administration of nickel salts. (208) Dietary vitanun C supplements protected guinea pigs from nickel dermatitis induced by repeated applications of 1:50,000 nick- el sulfate ointment to the skin, unless the nickel treatment was accompanied by local injections of Freund’s adjuvenant or potassi- um alum. (209) In experimental Corynebacterium acnes injection, pustular patch tests were regularly produced by five per cent NiSO 4 . ‘° An increase in nickel content of total serum protein, and especially in theg 1 andt3 2 globulins, accompanied nickel sensitiz- ation in guinea pigs, but no complete parallelism between degree of allergic reaction andg globulin nickel content was observed. / The quantitative reaction k inetics of nickel binding to various proteins, including human serum, as studied by equilibrium dialy- sis and paper electrophoresis, showed that binding is primarily to carboxyl and amino terminals, making it unlikely that nickel itself behaves as a hapten, capable of initiating allergic response) 212 Starch gel electrophoresis of serum protein revealed that the effect of nickel ions on serum protein precipitation was much less than the effect of mercury, lead or copper divalent Four or five “tumor—specific” antigens have been identi- fied in nickel sulfide—induced rhabdomyo sarcomas of rats. Serum from t- mor-bearin ’j and immunized rats contained tumor-specific an- tibodies. Cells from different tumors did not cross-react signifi- antly, but cells from the same transplanted tumor cross-reacted through several successive generations. The antigens appeared to be located in the cytoplasm of the tumor ceiis.C 2 14) 3. Carcinogenicity In rats and guinea pigs, the long-continued inhalation of powdered nickel metal resulted in multicentric adenomatoid forma- tions of alveoli and hyperplastic proliferations of terminal bron- ghiolar epitheliurn. Both malignant and benign pulmonary lesions ------- V RJAR INc. were observed in guinea pigs. (215) However, pulverized fraaments of nickel metal applied on a fibrous glass vehicle to the pleura of rats did not induce tumors within two years. (216) Nickel pow- der was used to induce fibrosarcomas in Fisher - 344 rats. The tu- mors could be transplanted to host rats of the same strain. (217) In primary rhabdomyosarcomas induced by the intramuscular implant of nickel in rats, the nickel concentration in the tumor was found to decrease from the center to the periphery and decrease with in- creasing age of tumor. Most of the nickel present was bound to the nuclear fraction, with smaller amounts in the mitochondrial and soluble fractions of the tumor cells. The tumors apparently did not need or concentrate nickel ions once induced. 218 In rats, the inhalation of an amount of Ni(CO) 4 comparable to that inhaled by a person smoking fifteen cigarettes a day for one year resulted in the appearance of various pulmonary cancers (squamous cell car- cinoma, adenocarcinoma,anaplaStic carcinoma) 24 to 27 months after exposure. The death rate in rats three years after exposure was three times that of controls. 33 Bethesda Black rats were found to be more resistant to tumors induced by intramuscular injection of nickel sulfide than Hooded rats. At the site of injection, in the Bethesda Blacks, large masses of phagocytic cells appeared and engulfed the nickel sulfide powder without undergoing obvious dam- age. The phagocyte aggregation persisted at the site at least four- teen months, in some cases becoming surrounded by lymphocytes. The phagocytic ingestion may result in subcarcinogenic levels of nickel remaining in the tissue. The lymphocytes may be involved in the (219) immune response. The form of tho nickel sulfide intramuscu- lar implant (free powder, powder within diffusion chamber, chips, discs) had no significant effect on the tumor incidence in rats, which was 71-95%. The average latent period for tumor development almost doubled when the carcinogen was contained within a diffusion chamber. The tumors produced were all locally—occurrinci rhabdomy- osarcomas. It was observed that neither the wallina-off of metal’ im- plants nor phagocytosis nor direct contact between the metal and the cells was necessary for tumorigenesis. (220) Induction of rhab- bornyosarcomas in rats is not influenced by sex, castration or an increase in rnyotrophic steroid. (221) A cell line from nickel ------- RJAR Ixc. 111-60 suif ide-induced rhabdoinyosarcoma cultured for 59 passages maintained its heteroploid identity. (222) Nickel sulfide—induced rhabdomyosarcorna cells, embryonic muscle cells and differentiating muscle cells were compared. Nickel sulfide greatly affects the morphology and pattern of DNA synthesis in the embryonic, but not in the differentiating of tumor cells, indicating that the “normal” mitotic cells are affected either by interference with the cell membrane, intracellular enzyme systems, and/or nucleic acids. Although nickel sulfide drastically reduced the number of cells reaching mitotic S phase, the presence of a few cells that make it to S phase indicates that in vivo tumor induc- tion involves the clonal proliferation of a few nickel—resistant cells. (223) Tumor cell mitochondria exhibit conforrnational changes, the accumulation of electron dense particles, and the elaboration of cris- tae which appears to coalesce and produce wavy or parallel stacks. Some enlargement and degenerative changes in the inner and outer mito- chondrial membranes occurs, with replacement of cristae with 50-60 A thick filaments. Similar changes are observed in normal rat muscle mitochondria after short exposure to nickel sulfide. (224) Administra- tion of methandrostenolone to rats which had received a single injec- tion of nickel sulfide in the gastrocnernius accelerated carcinogenic (225) activity and increased tumor incidence from 33 to 100 per cent. A synergistic carcinogenic effect was observed in rats treated with both intramuscular nickel sulfide and benzpyrerie. The latency and mortal- ity associated with tumors was as in Table 14. (226) Table 14 Synergistic Carcinogenic Effects of Nickel and 3,4-Benzpyrene Treatment Average weeks to tumor Weeks to death E ontro1 none none lOmgNi 2 S 3 26±5 33+5 5 mg 3, 4—benzpyrene 31 +- 10 41 - 11 10 mg Ni 2 S 3 + 5 ing 3,4— 18 + 3 24 + 5 benzpyrene ------- V RJAR jive. 111-61 C. Nonmammalian vertibrates 1. Birds The growth of chicks up to four weeks of age was signif 1- cantly depressed Ly the addition to the diet of 700 to 1300 ppm or more of nickel as the acetate or sulfate. Fat retention was not affected, but a reduction in nitrogen retention was observed with the higher nickel concentrations use .(1 7 6) 2. Fish Nickel was detected in the bodies of fish killed by N1SO 4 solutions or nickel—plating solutions. Nickel was also detected in living fish in nickel solutions, but not in the bodies of nor- mal fish. 59 Toxicities of mixtures of nickel, zinc, copper and phenal to the rainbow trout, Salmo gairdneri Richardson, could be adequately predicted by the summation of the toxicities of the individual poisons present. 227 The bitterling(Rhodeus sericeus phoxinus) , the carp ( - prinus carpio L.) and the minnow (Phoxinus phoxinus ) were observed to grow and develop normally in nickel oncentrations of 0.1 mg per liter, the maximum admissible nickel concentration. 228) At alkaline pH’s (8.0 or higher), nickel-c anide complexes are less toxic to minnows ( Pimephales promela ) trian cyanide alone due to the low degree of dissociation of the complex. (229) D. Invertebrates a. Toxicity The maximum admissible nickel concentration of 0.1 rnq per liter does not affect the normal growth and development of daphnia ( Daphnia rnagna) . A variable effect of the nickel concentration on the respiration rate of tubificid worm , ( Tubifex tuifec and Lim— nodrilus hoffmeisteri ) was observed as the pH was changed. 23 b. Tzratagenicity Studies on the effects of nicLel ion in solution on the development of two marine invertebrate species have been found. The concentration of nickelous ion at which 50% of the embryos of the American oyster, Crassostrea virginica , did not develop was .l8 ppm. ‘ The embryos and the f rtilized eggs of the sea urchin, Lytechnicus pictus , take up ra3ioactive nickel ions in the ------- 1/ RJAR J rc 111-62 free state, which can be released by the addition of exogenous non- radioactive nickel ions. Embryos incubated in solutions containing l0 to 10 2 M nickelous ions cleaved at the normal rate and formed blastulas, but did not gastrulate. These embryos failed to develop dorsoventral symmetry and formed abnormal radialized larvae. 232 E. Plants Nickel toxicity in the oat, bean, pea, tomato and sunflower is manifested by a decrease in the cation exchange capacity of the roots. (170) The severity of the nickel toxicity in the oat plant is increased in the presence of abundant manganese. These two me- tals effect the increased uptake of iron into the plant, but inhib- ited iron metabolism inside. 233) Nickel sulfate added to the soil of Satsuzna nandarin trees (2 gin per 30 cm diameter pot) sup- pressed tree growth, and increased amounts of nickel were observed in the twigs, leaves, large and fine roots. Soil and foliar appli- cations of molybdenum reduced the effects. of nickel, a d tree growth was more vigorous. 234 . In areas of the Phillipines with high nickel content soils, boang disease occurs, characterized by the production of empty or improperly fleshed nuts. 235 In Chiorella grown in medium containing more than 0.5 gin nick- el per liter, marked inhibition of growth and lowering of productiv— ity occurred. These effects could be reversed by the additi.on of zinc or several other trace elements, disodium EDTA or an increase in suspension density. (236) F. Microorganisms Many examples of the toxicity of nickel sal.ts to fungi which infect crops are presented under “Therapeutic Uses” and will not be reiterated here. Both nickel and tin are toxic to wild type Aspergillus ni- dulans . K+, NH 4 +, Mg and Ca can reverse the metal toxicities. Studies with a resistant mutant indicate that the resistance is due to an intracellular detoxification mechanism and not to reduced per- meability to the metals. 237 ------- Y RJAR Jxc. 111-63 The toxicity of various metal s d.ts, including nickel, to the fungus, Fusarium decemcellulare , can be reversed with sodium di- methyldithiocarbamate (DMDT). (238) Treatment of the conidia of F. decemcellulare with nickel salts 5 microgram Ni per ml for five hours) resulted in the excretion of ‘arious amino acids into the surrounding meuium. (239) The presence of nickel ions in the medium induces respiratory insufficiency in yeast. (240) A study on the cytonarcotic action of nickel salts on Parame- cium caudatum revealed that the time required for the protozoan to become motionless was proportional to the nickel concentration. The formation of digestive vacuoles decreases sensitivity to nickel nar- cosis, possibly because of associated decreases in cell membrane permeability. Twenty generations of ciliates must pass after nick- el narcosis before multiplication beeomes normal again. Different mating types have different sensitivities to nickel. The preser ce of Ba or Ca strongly antagonizes the effects of Ni t (24l) The weakening of the ciliary apparatus of Paramecium by nickel is a step by step process, progressively excluding movements one by one in the order corresponding to thEir hydrodynamic effectiveness. (242) Solutions of nickel cause retraction of the axopodia of hel- iozoans much like treatment with colcthicine or cold. Initially, a very fast axopodial shortening is observed, followed by a period of recovery, and then a slower retraction. Recovery from treatment is possible if exposure is not too Icing. (243) The growth of Lactobacilli and streptococci on agar plates is inhibited by nickel acetate and nick l-EDT chelates in the med- • (158) 1 urn. The addit’on of nickel salts to the medium induced abnormal inversed spiral movements in the ciLiate, Paramecium multirnicro- nucleatum . (244) ------- V RJAR INc. G. Results of Personal Contacts with Medical Personnel A total of 74 toxicologists and medical examiners throughout the United States were contacted by telephone arid letter with regard to professional acquaintance with accidental poisonings by nickel or nickel compounds. Of the 31 responses, one respondent had investiga- ted the death ot a child (age less than 5 years) who had ingested nickel chloride from a science project of an older sibling. This was the only positive response concerning nickel poisoning. ------- 111-65 XI. STANDARDS Nickel carbonyl TLV: (recommended) 0.001 ppn in air (0.007 milliqrams per cubic meter of air) Nickel and Nickel compounds TLV: (recommended) 1 milligram per cubic meter of air. (9) ------- 4/ 111-66 VERJAR INC. XII. STL}?. .RY N D aDNcItJSIONS A. Suirmary Nickel is widely used in ferroalloys, stainless steels and r tal plating. In steel alloys and as a plating imaterial nickel offers superior cxrrosion resist- ance and excellent kM—teuperatuxe porperties. O r 75 per cent of the nickel cca- sured yearly in the United States is in orthd; the iestic production (as ferro- nickel) occurs at Ri&Ile, Ore Dn and ani nts to about fji per cent of the nickel consunption. The r ainder, apprcDcir tely 20 per cent of Q sunpton, arises as a elter byproduct (minor) or through recxvery fran scrap. Nickel sulfate is the nost inpartant corrpound of nickel in c ii erce, and its pr inary use is in baths used for electrc lating of nidcel. Although nudi of the spent plating solution is reo3i.ered and used in nickel sulfate pruductian, a significant anount of nickel waste (15 kkg Ni per year) arises fran the electrcpla- th g industxy. Nickel nEtal and nickel oxide axe also used in nickel sulfate pro- duction. The waste effl .ents fran nickel sulfate production axe insignificant in cxnrpari son to other sources. Of the estimated 4,895 netric tons per year of nickel entering the environ- nent for the thited States, over 90 per cent arises fran the crmbusticn of fusi oil and enters the athosphexe as oxides. The world—wide nickel a ntent of the atiros- piiere began to increase during the 1920 ‘s and is ntinuing to increase. Nickel carbonyl, a particularly toxic airipound of nickel, may be forned by the react.ion beb en nickel (in sewage s1u e and other solid wastes) and hot carbon m oxide in incir rators and other n’bustion processes (carbcn ironoxide is fo red when insufficient oxy n is available during cxzrbustia-i of ca±onceous materials). Sud could occur in autczi*thile engines when nickel is used as a fiel additive; suth a itives axe currently banned in this o3tmtry. Toxic concentrations of nickel in soil and waters occur both naturally and as a result of man s activities in foreign countries (including Canada), but have not been reported to occur in the United States except as local effects of plating bath and similar efflients. Industrial arid other occupational exposures have pro- dt d severe effects including deaths in other countries. Suth hazards exist in this countxy, but reports of pathology other than dermatitis are few. ------- V RJAR [ Ye. III 67 Many persons exhibit allergic reacticris to nickel and nickel oaipounds. Several studies have indicated that t -thirds or n re of female allergy patients exhibit sensitivity to nickel. The percentage for males is lcz er. The aq cxis concentration of nickel at or bel whith rio xntact allergic reaction occurs in nickel-sensitive persons is one micr iTcle of nickel per liter. Sensitivity to n±ckel often occurs concurrently with sensitiv.ty to cthalt and thrcrtium. Various nickel conpounds, particular:Ly the sulfide arid the carborrjl, axe knc n carcinogens, arid various envir r ontal e.çosuxes to nickel in other countries seem to correlate with increased incidence of tors in man. It se include e of snuff made fr n tobacco gr in on soil of hi i nickel cxntent as ll as occt a- ticsial e qx su.tes. Nickel is absorted through the intestines, lungs and abraded skin. Uriri- ary excretion is U principal t ode of elimination of nickel. Nickel is present in both an ultrafiltrable and a protein-bound form in the blood. A dietary r& uireaent for nickel has not been established. Nickel ions can replace calcium ions in the reraticn of action potentials in muscle, but the duration of the potential is increased. Inorganic nickel salts axe useful p.ant fungicides. Phytotccdcity occurs with excessive nickel levels. Nickel is abso bed by the plant through the roots. Plants gr n on sex entine soils or industria 1. or mine waste heaps often have high nickel tents. Nickel ions inhibit gr ith f various microorganisms and produce a progressive narcosis in Paramacium. B. Conclusions The follci. nng conclusions are based on the information contained in this report: (1) Nickel exhibits significant th,dc effects tt &rd man, other animals, plants and microorganisms. (2) The nrst general toxic effect üf nickel t ’ard man involves wide- spread allergic sensitivity, but sy pt dii;a ear when a tact is avoided. 3) Alth igh nidel- cxxitaibibg industrial wastes are prthably insigmifi- cant except on a very localized basis, the n ckel content of petroleum has caused a continuing world-wide increase in ab csphe ic levels of nickel. This source of nickel could pose future health and environnRntal hazards if the increase xritinues. ------- III- 8 VERJAR INC. (4) Unc r certain cxnditions iri lving the presence of both nid e1 and hot caiton r noxide, t} very toxic nidel car±onyl can be forn d in cx thustian pro sses. C. F xmTendations The fol1 ing zexii ndations are based on the surnaxized results and cxr clusicris presented above: (1) Allergic persons sh ild be math aware of the high prthability of tbeir sensitivity to nickel (as ll as other ca uton iretals). (2) The future trend for atitospheric nickel content should be projected and cxrpared to levels at which thieterious environn ntal or health u1d be expec— ted th orthr to thterTni.ne whet1 r a future hazard frczn nickel mic t exist. ------- I I .6 ’) i/ RJAR INC. Nickel Referen:es (I) Stanford Research Institute. Chemical Informoton Services. 1974 Directory of Chemical Products, Nickel Chpt. Menlo Park, California, 1974. (2) Chemical Purchasing Chemicals Directory 1973-1974. Myers Publishing Company. New York, New York (October, 1973). (3) Minerals Yearbook 1972, Nickel Chpt. Bureau of Mines, U.S. Department of the Interior. Washington, D. C., 1974. (4) Handbook of Chemistry and Physics 1971-1972, 52nd ed. Robert C. Weast, ed. The Chemical Rubber Co., Cleveland, Ohio, 1971. (5) Encyclopedia of Chemical Technology, XIII, 2nd ed. R. Kirk and D. F. Othmer, eds. JohnWi leyond Sons, mc, 1964.’ (6) General Technologies Corp. Developmen Do :ument For Proposed Effluent Limitations Guidelines and New Source Performance Stancards for Significant Inorganic Products. U.S. Environmental Protection Agency, 68-01 -1513, December, 1973. (7) Matheson Gas Data Book, 5th ed., William Broker and AlIen 1. Mossman, eds. Matheson Gas Products. East Rutherford, New Jersey, 1971. (8) Dictionary of Commercial Chemicals, 3rd ed Snell and Snell, eds. D. Von Nostrand and Company, Inc. Princeton, Ness Jersey, 1962. (9) Sax, Irving N. Dangerous Properties of Indusrial Materials, 3rd ed. Van Nostrand Reinhold Company. New York, New York, 1)68. (10) Applications of Nickel. National Materials i dvisory Board — National Research Council, Nationai Academy of Sciences, Na onaI Academy of Engineering. Washington, D.C. NTIS:AD846-999, December, 1968. (II) Davis. W. and Associates. National Inventoy of Sources and Emissions of Cadnium Nickel and Asbestos. NTIS no. PB— 192—25l, February, 1970. (12) Development Document for Proposed Effluent Limitations Guidelines, Copper, Nickel, Chronium, and Zinc Segment of the Electropianting Joint Source Category. U.S. Environmental Protection Agency (EPA/440/l -73-003), August, 1973. (13) Costesque, 1. M. and L. C. Hutchinson. The Ecological Consequences of Soil Pollution by Metallic Dust from the Sudbury meIter . Proc. Inst. Environ. Sci. 18th Annual Tech. Meet. New York, New York. pp. 540-545 (May -4, 1972). (14) Trace Metals in Waters of the United States Federal Water Pollution Control Adminisfraton. Washington, D. C., 1967. ------- 111-70 RJAR INC. References (15) Sidyokov, P. J., M. M. Tuchenko and U.S. Matyskva. Ref. Zh. OlD Vypusk. Farmakol Tokisoki. No. 16.54.359(1965). (16) The Hazards of Trace Elements. Sd. News. 9(23):560—56l (J ine 6, 970). (I?) Air Quality Data for Metals, 1968 and 1969 from the National Air Surveillance Networks. U.S. Environmental Protection Agency. Washington, D. C. APTD—l467, June, 1973. ((8) McDowell, Robin S. Metal Carbonyl Vapors: Rapid quantities analysis by infrared spectrophotometry. Am Ind. Hyg. Assoc. J. 32(9):621-624 (September, 1971). (19) Nickel Carbonyl, Hygienic Guide Series. Am. Ind. Hyg. Assoc. J. 29:304 (1968). (20) Vol’berg, N. S. and E. F. Ger khovich. Determination of small amounts of nickel carbonyl in air. Hyg. Sant. (Moscow) 33(4—6):226—229, (April—June, 1968). (21) Webb, R. 1. and M. S. W. Webb. A Rapid Emission Spectron - graphic Method for the Analysis of Air Filters. Atomic Energy Research Establishment, Analytical Sciences Division (Harwell, England). NTIS: AERE—R2966, 1971. (22) Schroeder, Henry A. and Dan K. Darrow. Relation of trace metals to human health. Environmental Affairs. ll(I):222—236 (Spring, 1972). (23) McDermott, Gerald N., Mildred A. Post, Burney N. Jackson and Morris B. Ettinger. Nickel in relation to activated sludge and anoeroboic digestion process. J. Water Pollution Control Federation. 37(2):l63-177 (1965). (24) Callan, Walter M. and F. William Sunderrnan, Jr. Species variations in binding of 63 N 1(ll) by serus albumin. Res Comrnun Chem Pathol Pharmocol. 5(2):459— 472 (1973). (25) Fidarov, A. A. Soderzhanie nikelya I kobol’ta v syvorotke kroii bol’nykh psoriazom. (Blood serum nickel and cobalt concentrations in patients with psoriosis.) Vestn Dermatol Venerol (Moscow). 42(8):46-48 (1968). (26) Hendel, Robert C. and F. William Sunderman, Jr. Species variations in the proprotions of ultrafiltrable and proteinbound serum nickel. Res Commuri Chem Pathol Pharmacol. 4(I) l4t-l46 (1972). (27) McNeely, Michael D., F. William Sunderman, Jr., Maria W. Nechoy, and Howard Levine. Abnormal concentrations of nickel in serum in cases of myocordial infarction, stroke, burns, hepatic cirrhoss, and uremia. Clin Chem. 17(11): 1123—1128 (1971). ------- 111—71 1 R/AR INC. References (28) Mertz, D. P., R. Koschnick, G. Wilk, and K. Pfeilsticker. Untersuchugen uber den Stoffwechsel von Spurenelemeriten beim Menscien: I. Serumwerte von Kobalt, Nickel, Silver, Cadmium, Chrom, Molybdon, Mangan. (Investigations on the metabolism of trace elements in humans: Serum levels of cobalt, nickel, silver, cadmium, chromium, molybdenum, moganese.) 7 KIm Chem Kim Biochem (Berlin). 6(3):l7l-l74 (1968). (29) (30) Sunderman, William F., Jr. Nickel carboriyl inhibition of cortisone induction of hepotic tryptophan pyrrolase. Cancer Res. 27(7):1595—1599 (1967). (31) Sunderman, F. William Jr. Shozo Nomoto, iArun M. Pridhan, Howard Levine, Stanley Bernstein, and Robert Hirsch. lncreas d concentrations of serum nickel after acute my3cardial infaction. N Engl J Med. 283(l7):896—899 (1970). (32) Trubnikov, G. V. Soderzhanie nikelya, alyuniniyo i khroma v piaz me krovi bol’nykh khronicheskoi pne vmoniei. (Content of nickel, aluminium and chromium in the blood plasma of patients with chronic pneumonia). Ter Arkh (Moscow). 41(lO):69-72 (1969). (33) Sunderman, F. William, and Andrew J. Donn lly. Studies of nickel carcinogenesis: Metastasizing pulmonary tunors in rats inducec by the inhalation of nickel carbonyl. Amer J Pathol. 46(6):l027—1044 (1965). (34) Sushko, E. P. Mikroelementy (kobal’t, nikel’, tsink) v krovi zdorovykh detei. (Trace elements (cobalt, nickel, zinc) in the blood of healthy children.) DokI Akad Nauk Belor Uss Ssr (Moscow). l3(l0):95 -954 (1969). (35) Kytto, J. Acta Oto—Laryng. Einige Beobachrungen uber die Spurenelemente der Tonsellen. Trace Elements in Tonsils. Suppl. 224:173—176(1967). (36) Tarala, G. 1. Soderzhonie tsinka, medi, nil lyo, margantsa, svintsa i serebra v krovi bol’nykh stenokardiei v razlichnye pericdy zobolevaniya. (Zinc, copper, nickel, manganese, lead, and silver content of blood from patients with various stages of stenocordia.) Kordiologiya (Moscow). 10(1): 146—147 (1970). (37) Pshetokovskii, I. L. KIinicheskaya tsennost’ izucheniya obmena mikroelementov (Cu, Ni, Mn) i ikh patogeneticheskaya rol’ pri revmatoidnom artrite. (Clinical value of studying trace elements (copper, nicI el, manganese) metabolism and their pathogenetic role in rheumatoid arthritis.) T r Arkh (Moscow). 46(6) :23047 (1972) (38) Prakapchuk, A• Ya., . 1. Sasnowski, M. 7. Yagowdzik, and 7. I. Arlova. Vyznachennye nyekatorykh mikraelyemyentow pry pramyonyuvykh dermotytakh. (Determination of some trace elements — cobo t, nickel, copper, zinc — in radiation dermatitis) Vyestsi Akad Novuk Byelaruskoi 5sr Syeryya Biyalahichnykh Navuk I. 92-96 (l964’. ------- 111-72 RJAR Jxc. References (3 Nikolaev, V. I., V. I. Sidorkin and K. G. Kosyanova. Nekotorye mikroelementy- metally v krovi bol’nykh endemicheskim flyuorozom. (Some metal trace elements in the blood of patients with endemic fluorosis.) Vestn Akod Med Nauk Sssr. 26(10): 77-80 (1971). (40) Soroka, V. R., V. Y. Arsent’ev and M. S. Mukhaev. Obmen nikelya v organizme bol’nykh shizorfreniei. (Nickel metabolism in the body of schizophrenic patients.) zh Nevropatol Psikhia TrimS S Korsakova (Moscow). 72(l):69-72 (1972). (41) Myokisheva, L. S. Soderzhonie kobal’ta i nikelya v krovi pri rakhite. (The content of Co and Ni in the blood in rickets.) Kazan Med 7h 3. 62-64. (1970). (42) Boiko, V. A. Nikel’ v krovi zdorovykh detei I bol’nykh leikozami. (Nickel in the blood of healthy children and leukemia patients.) 2’dravookhr Beloruss 7. 14. (1965). From: Ref Zh Otd Vypusk Obshch Vop Patol Onkol, 1966, No. 6.53,525. (Translation). (43) Leonov, V. . Narusheniya obmena medi, tsinka, kobal, nikelyo, margontsa i khroma pr leikozakh u detei. (Disorders of copper, zinc, cobalt, nickel, manganese and chromium metabolism: leukemia in children). Material of the First Congress of Pediotricians of Belorussia, 1964. Minsk. 156 (1964). (44) Popova, L. V. Soderzhanie nekotorykh mikroelementov v organakh krov tvoreniya pri Ieikoz.akh. (Content of some trace elements in hematopoietic organs in leukemios.) Tr Voronezh Med Inst. 85:57—58 (1971). (45) Nalimova, L. S. Kobmenu kobol’ta i nikelya pu leikozakh u detei. (Cobalt and nickel metabolism r leukemia in children.) In: Proceedings of the First Congress of Pediatricians of Belorussia, 1964. Minsk. 160—161 (1964). From: Ref 7h Odt Vypusk Obshch Vop Patol Onkol, 1965, No. 6.53.203. (Translation) (46) Carroll, K. G., J. E. Muihern, Jr., and V. 1. O ’Brien. Microprobe analysis of localized concentrations of metals in various human tissues. Oncology (Basel) 25(i):Il— 18 (1971). (47) Starovoipov, I. M., and I. V. Duda. Kontsentrotsiyc mikroelementov krov bol’nykh rakom 1 predrakovymi sostoyaniyam shefid matkL (Concentration of trace elements in the blood of patients suffering from cancer and precancerous conditions of the uterine cervx.) Vop Onkol (Leningrad). 16(3):l4—18 (1970). (48) Kalpakov, F. I. Skin permeability of nickel compounds Areh Patol. 25(6):38- 45(1963). (49) Spruit, D., J. W. H. Mali, and N. DeGroot. The interaction of nickel ions with human cadaverous dermis. Electric potential, absorption, swelling. J Invest Dermatol. 44(2): 103- 106 (1965). ------- i ti-i 3 rnidI) 1 r,’ fILJ Ifl (JVI . Reference (50) Kolpckov, F. I. Vilyanie nekotorykh orgonicheskikh rosti no proniknovenie sernokislogo nikelya cherez kozhu. (The effftct of some organic solvents on the penetration of nickel sulfate the skin.) Gig Sanit (Moscow). I. 22—25 (1965). (51) Horok, Eva and F. William Sunderman, Jr. Fecol nickel excretion by healthy adults. Clin Chem l9(4);429—430 (1973). (52) Kemka, Rudolf. Stanovenie niklu a kobaltu vedla seba v mod a v ovzdusi. (Parallel determination of nickel and cobalt in urine and atmosphere.) Proc Lek. 23(3):80—85 (1971). (53) Nodiya, P. I. Izuchenie balansa kobal’to i nikelyc v organizme hashchikhsyo Ptu. (Study of the cobalt and nickel balance in vocational students.) Gig Salt (Moscow). 37(5): 108-109 (1972). (54) Mertz, D. P., R. Koschnick, and G. Wilk. Renale Ausscheidungsbedingungen von Nickel beim Menschen. Untersuchungen ueber den Stoffwechsel von Spurenelementen: IV. (The renal excretion of nickel by humans. Studies on the metabolism of trace elements: IV.) 2 KIm Chem Kim Biochem (Berlin). 8(4): 387-390 (1970). (55) Ponomareva, L. V. Soderzhanie i dinomik mikroelementov (tsinko, medi, zheleza, margantsa i nikiya)v cheshuikakh bol’nykh Fsoriazom. (Concentration and dynamics of trace elements (zinc, copper, iron, manganese, and nickel) in scales of patients with psoriasis.) Vestn Deimatol Venerol (Moscow). 40(11): 37-40 (1966). (56) Kas’yanenko, 1. V., and 0. A. KuI’skaya. Soderzhonie mikroelementov v krovi u bol’nykh rakom zheludka I khronichi skim gostritom $ sekretornoi nedostatochnost’yu. (Microelement content in the blood of patients with cancer of the stomach and chronic gastritis with sec:retory insufficiency.) Vop Eksp Okol Respub Mezhvedom Sb. 4. 101-107 (1969). (57) Hendel, Robert C. and F. William Sunderm’in, Jr. Species variations in the proportions of ultrafiltrable and proteinbound serum nickel. Res Commun chem Pathol Pharmacol. 4(l):14l—l46 (1972). (58) Coilan, Walter M. and F. William Sunderman, Jr. Species variations in binding of 63 N 1(Il) by serus albumin. Res Commun :hem Pathol Pharmacol. 5(2):459— 472 (1973). (59) Rusteika, P. B., and P. I. Tcrvidas. Sodeizhanie ,4l, Ni, 7n, Mn, Cu, Ti, tsel’noi krovi krupnogo rogatog skota pn kh,onicheskom limfoleikoze. (Content of aluminium, nickel, zinc, manganese, ccpper and titanium in the blood of cows with chronic lymphoid leukemia.) Tr Akad Nauk Lit Ssr Ser V Biol Noun I. 177-180(1970). ------- ERJi1 R [ NC. References (60) Babskii, E. B. and E. S. Donskikh. 0 protivopolozhnom kharaktere deistviya ionov margantsa i nikelya no potentsialy deistviya miokardiol’nykh volokon. (Opposite character of the effect of manganese and nickel ions on the action potential of myocardial fibers.) DokI Adad Nauk Sssr Ser Biol (Moscow). 207(5): 1250—1253 (1972). (61) O’Dell, Glen D., W. J. Miller, S. L. Moore, W. A. King, J. C. Ellers, and H. Jurecek. Effect of dietary nickel level on excretion and nickel content of tissues in male calves. J Anim Bci. 32(4): 769-773 (1971). (62) O’Dell, Glen D., W. J. Mfller, W. A. King, J. C. Ellers, and H. Jurecek. Effect of nickel supplementation on production and composition of milk. J Dairy Sci. 53(ll):l545—l548 (1970). (63) Sunderman, F. William, Jr., Norris 0. Roszel, and Ronald J. Clark. Gas chromatography of nickel carbonyl in blood and breath. Arch Environ Health. lo(6):836-843 (1968). (64) Sunderman, F. William, Jr., and F. William Sunderman. Studies of nickel carcinogenesis. The subcellulor partition of nickel in lung and liver following inhalation of nickel carbonyl. Amer J Clin Pothol. 40(6):563—575 (1963). (66) Smith, J. Cecil, and Betty Hackley. Distribution and excretion of nickel—63 administered intravenously to rats. J Nutr. 95(4):54 1—546 (1968). (67) Van Soestbergen, Maria and F. William Sundermon, Jr. 63 Ni complexes in rabbit serum and urine after injection of ó 3 NiCl 2 . Clin Chem. l8(12):l478—1484 (1972). (68) Simakov, Yu. G. Kobal’t, nikel’ I med ’ v drobyoshchikhsya yaitsekletkokh myshel. (Cobalt, nickel and copper in the dividing oocyte of mice.) Biol Nauki (Moscow). 15(11) :27—30 (1972). (6 Ishihora, Masayoshi, Yoshiomi Hase, Hisashi Yokomizo, Sanji Konno, and Koichi Sato. The nutritional disease of Satsuma mandarin trees in serpentine soil. Ill. The influence of excessive nickel or chromium application and molybdenum-nickel antagonism on the growth and fruiting of Satsuma mandarin trees. Bull Hort Res Sta Mm Agr Forest SerA (Hiratsuko). 7.39—54 (1968). (70) Crooke, W. M. Effect of heavy—metal toxicity on the cation—exchange capacity of plant roots. Soil Sci. 86(5):231—240 (1958). (71) Wiltshire, G. H. Effect of nitrogen source on translocation of nickel in some crop plants and weeds. Kirkia. 8(2):l03-l23 (1972). (72) O’Dell, Glen D., W. J. Miller, W. A. King, S. L. Moore, and D. M. Blackmon. Nickel toxicity in the young bovine. J Nutr. lOO(l2):1447— 1453 (1970). ------- 111—75 %RJAR IXC. Reference; (73) O’Dell, Glen D., W. J. Miller, S. L. Moore, and W. A. King. Effect of nickel as the chloride and the carbonate on palatalility of cattle feed. J Dairy Sci. 53(9): 1266-1269 (1970). (74) Schroeder, Henryi4., Joseph J. Balassa, arid William H. Vinton, Jr. Chromium, lead, cadmium, nickel and titanium in mice: Effect on mortality, tumors and tissue levels. J Njutr. 83(3):239—250 (1964). (75) Swierenga, Sabine H. H., and Parvathi K. 3asrur. (Dep. Anat., Univ., Guelph, Ont., Can.) Effect of nickel on cultured rat embryo muscle cells. Lab Invest. l9(6):663-674 (1968). (76) Weber, C. W., and B. L. Reid. Nickel to.dcity in growing chicks. J Nutr. 95(4) :612-616 (1968). (77) Kariev. A. A. Vliyanie nikelya i tsinka no azotistyi obmen i produktivnost’ kholpchctnika. (Nickel and zinc effects on nitrogenous exchange and productivity of cotton.) UzbBiol Zh. Il(6):l4— 16( 1967). (78) Bertrand, Didier, and Andre de Wolfe. Le ,ickel, oligoelement dynamique pour les vegetaux superieurs. (Nickel, dynamic oligoelement for the higher plants.) C R Hebd Seances Acad Sci Ser D Sci Natur (Paris). 265( 15): 1053- 1055 (1967). (79) Cobet, A. B., G. E. Jones, J. AIbright, Helen Simon, and C. Wirsen. The effect of nickel on a marine bacterium: Fin structure of Arthrobacter marinus. J Gen Microbiol. 66(2): 185-l96 (1971). (80) Cobet, A. B., C. Wirsen, Jun Jones, and G. E. Jones. The effect of nickel on a marine bacterium. Arthrobocter marint s sp. nov. J Gen Microbial. 62(2): 159-l69 (1970). (81) Kaufmann, R., and A. Fleckenstein. Ca++-competitive elektromechonische Entkoppel ung durch Ni++-und Co++-Ionen cm Warmbluetermyocord. (Calcium ions competitive electro mechanical uncoup ing by Nickel ions and cobalt ions in the warmblooded myocardium.) Arch G samte Physiol Mens here (Pfluegers). 282(3):290—297 (1965). (82) Sumie, Masacki. (Second Dep. Pharm., Kiimamofo Univ. Med. Sch., Kumamoto, Jap.) Effects of various cotions on the cant rnactile response of the rabbit pulmonary artery to noradrenaline and nerve stimulatio,. Kumomoto Med J. 24(I):20—29 (1971). (83) Kohlhardt, M. Herder—St. 7, D—7800 Freiburg im Breisgau, W. Ger.), B. Bauer, H. Krause and A. Fleckenstein. Selective inhibition of the transmembrane Ca conductivity of mammalian myocardial fibres by Ni, Co and Mn ions. Pfluegers Arch Eur J Physiol (Berlin). 338(!): 1l5— 123 (1973). ------- 1 1 1-76 I 1 ERJAR IXC. References (84) Ong, Seok Doo and Leslie E. Bailey. Uncoupling of excitation from contraction by nickel in cardiac muscle. Am J Physiol. 224(5): 1092— 1098 (1973). (85) Babskii, E. B., and E. A. Donskikh. Elektrofiziologicheskoe issledovanie deistviya inov nikelyo no miokard. (Electrophysiological study of the effect of nickel ions on the myocardium.) DokI Akad Nauk Sssr (Moscow). l78( ): 248—251 (1968). (86) Babskii, E. B., and E. A. Donskikh. 0 deistvii Cl2 no elektricheskuyu i mekhanicheskuyu oktivnost’ mokarda gushki. (Action of N1CI2 (nickel chloride) on the electrical and chanical activity of the frog myocardium.) Doki Akad Nauk Sssr (Moscow). (64(5) :1196—1200 (1965). (87) Kobayashi, H., Ebara, S. and Usuda, S. The effect of divalent metallic ions on the shape of the action potentials of toad’s atrial muscle fiber. J. Physiol. Soc. Jap. (Tokyo). 24( 12):6l4-622 (1962). (88) Lorkovic H. Effects of some divalent cations on frog twitch muscles. Amer. J. Physiol. 212(3):(23-238 (1967). (89) Khodorov, B. I., and VI. Belyaev. lzmeneniya kriticheskogo urovnya depolyarizotsii I potentsialov deisMya odinochnogo perekhvata Ranv’e pri elektrotone v usloviyakh vozdeistviya ionov kadmiya i nikelya. (Changes in the critical level for depolarization and action potentials produced by single nodes of Ranvier during electrotonus under the influence of codmium and nickel ions.) Biofizika (Moscow). 8(6): 707-714 (1963). (90) Khodorov, B. I. and V. I. Belyaev. Generatsiya potentsialov deistviya v odinochnykh perekhvatakh Ranv’e izolirovanny nervnykh volokon lyagushki pri deistvii ionov nikelya i kadmiya. (Generation of action potentials (in association with membrane depolarization( in single Ronvier’s nodes of isolaled frog nerve fibers under the acHon of nickel and cadmium ions.) Byul Eksp Biol Med. 57(4): 3—8 (1964). (91) Meves, H., and D. Weymann. (Impedance measurements on Ranvier’s node under the effect of nickel chloride). Arch. ges. Physiol. Menschen u. here. 276(4): 357-367 (1963). (92) Ahmed, Z., and J. L. Res. The activation and inhibition of 5—nucleotidase. Biochem. Jour. (London). 69(3):386—387 (1958). (93) Jensen, Henning. 5—Nucleotidase activity in the humas breast: Enzyme-histo— chemical studies. Acta Pathol Microbiol Scand Sect A Pathol (Copenhagen). 80(5): 665-670 (1972). (94) Macleod, 1. M., F. Hutchinson, and E. J. Raffle. The uptake of labeled thymidine by leucocytes of nickel sensitive patients. Brit J Dermatol (London). 82(5) :486-492 (1970). ------- 111—77 It I. / 1/? 1 AR J)VL. Reference) (95) Kasprzak, Kazimierz S., and F. William Sunderman, Jr. The metabolism nickel carbonyl -l4 . Toxicol Appi Pharmacol. l5 2):295 (1969). (96) Beach, Douglas J., and F. William Sunderman, Jr. Nickel carbonyl inhibition of l 4 C—orotc acid incorporation into rat liver RNA. Proc Soc Exp Biol Med. 13 1(2):32 1-322 (1969). (97) Beach, Douglas J., and F. William Sunderman, Jr. Nickel carbonyl inhibition of RNA synthesis by a chromatin—RNA polymerase complex from hepatic nuclei. Cancer Res. 30(l):48—50 (1970). (98) Witschi, Hanspeter. A comparative study of in vivo RNA and protein synthesis in rat liver and lung. Cancer Res. 32(8):l6 36—l694 (1972). (99) Sunderman, F. William, Jr., and Kenneth c:. Leibman. Nickel carbonyl inhibition of induction of aminopyrine demethylase activity in liver and lung. Cancer Res. 30(6):1645—1650 (1970). (100) Sunderman, William F., Sr. The treatment of acute nickel carbonyl poisoning with sodium diethyldithkarbamate. Ann Clin Res. 3(3):l82—185 (1971). (101) Sunderman, F. W., Jr. Studies of nickel cc rcinogenesis: alterations of ribonucleic acids following inhalation of nickel carbonyl. Amer J Clin Pathol. 39(6):549-56 1 (1963). (102) Dixit, Padmakar K., and Arnold Lazarow. Sch. Med., Univ. Minn., Minneapolis, Minn., USA.) Effects of metal ions and sulfhydryl inhibitors on glucose metabolism by adipose tissue. Amer J Physiol. 2l3(4):8 9-856 (1967). (103) Fiedler, H., and H. D. Hoffmann. Ueber die Wirkung von Nickel (ll)-L—glutamai” und verschiedenen Kobaltkomplexen ouf dos Verhalten einiger Lipidkomponenten bei Kaninchen. (The action of nickel (lI—L— lutamafe and of different cobalt complexes on the behavior of several lipid components in robbits.) Acta Med Ger. 25(3):389—398 (1971). (104) Cormane, R. H., D. Spruit, and J. P. Kup’ r. Simulcition of enzyme activity in the uterus of the guinea pig by nickel ions. Acta Physiol Phorrnacol Neer. 14(4):4.43-447 (1967). ( 105) Kirpekar, S. M., J. C. Prat, Margarita Pui and A. R. Wakade. Modification of the evoked release of noradrenoline from the perfused cat spleen by various ions and agents. J Physiol (Lond). 221(3):6C’P—6l5 (1972). (106) Adelstein, S. James, and Bert L. Yallee. The inhibition of beef liver glutamic dehydrogenase by metal—binding agents. J0Lr. Biol. Chem. 234(4):824—828 (1959). (107) Vander Drift, C. and Vogels, G. D. Effect of metal and hydrogen ions on the activity and stability of allantoicose. 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