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.
WGA newsletters are computer produced
and electronically photocomposed to slash
the time gap between the release of a report
and Its availability. You can learn about
technical innovations immediately—and use
them in the most meaningful and productive
ways possible for your organization. Please
request NTIS-PR-205/PCW for more infor-
mation.
Subscribe to the Weekly Government
Abstracts series that will bring you sum-
maries of new reports as soon as they are
received by NTIS from the originators of the
research. The WGA’s are an NTIS weekly
newsletter service covering the most recent
research findings in 25 areas of industrial,
technological, and sociological interest—
invaluable information for executives and
professionals who must keep up to date.
The executive and professional informa-
tion service provided by NTIS in the Weekly
Government Abstracts newsletters will give
you thorough and comprehensive coverage
of government-conducted or sponsored re-
The weekly newsletter series will keep you
current. But learn what you have missed In
the past by ordering a computer NTlSearch
of all the research reports in your area of
interest, dating as far back as 1964, if you
wish. Please request NTIS-PR-186/PCN for
more information.
WRITE: Managing Editor
5285 Port Royal Road
Springfield, VA 22161
Keep Up To Date With SRIM
I
microfiched report. Your SRIM service begins
as soon as your order is received and proc-
essed and you will receive biweekly ship-
ments thereafter. If you wish, your service
will be backdated to furnish you microfiche
of reports issued earlier.
SRIM (Selected Research in Microfiche)
provides you with regular, automatic distri-
bution of the complete texts of NTIS research
reports only in the subject areas you select.
SRIM covers almost all Government re-
search reports by subject area and/or the
originating Federal or local government
agency. You may subscribe by any category
or subcategory of our WGA (Weekly Govern-
ment Abstracts) or Government Reports
Announcements and Index categories, or to
the reports issued by a particular agency
such as the Department of Defense, Federal
Energy Administration, or Environmental
Protection Agency. Other options that will
give you greater selectivity are available on
request.
Because of contractual arrangements with
several Special Technology Groups, not all
NTIS reports are distributed in the SPIM
program. You will receive a notice in your
microfiche shipments identifying the excep-
tionally priced reports not available through
SRIM.
The cost of SRIM service is only 450
domestic (600 foreign) for each complete
A deposit account with NTIS is required
before this service can be initiated. 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. BBA. 198( 12):339—352 (1970).

-------
111-78
VERjA I? t 7 References
(lOB) Greenberg, David M., Albert E. Bagot, and Oliver A. Roholt, Jr. Uver
argiriase. Ill. Properties of highly purified arginase. Arch. Biochem. and
Biophys. 62(2):446-453 (1956).
(109) Rehner, G., and W. Stelte. Einfluss von Mangan, Kobalt und Nickel ouf die
Aktivtaet der Leberorginase in vitro and vivo. (Effect of manganese, cobalt
and nickel on the activity of liver arginase in vitro and in vivo.) Med Ernahr.
ll(2):32—35 (1970).
(110) Treagan, Lucy, and Arthur Furst. (Dep. Biol., Univ., San Francisco, Calif.,
USA.) Inhibition of interferon synthesis in mammalian cell cultures after nickel
treatment. Res Commun Chem Pathol Phormocol l(3):395—402 (1970).
(112) Medvedeva, E. A. Vliyanie nkelya no soderzhanie antotsanov v tsvetakh petun’i.
(Effect of nickel on the content of anthocyanins in petunia flowers.) Doki Akod
Nouk Tadzh Ssr (Moscow). 15(8):59—61 (1972).
(113) Chernavina, I. A. and E. A. Medvedeva. Vhyonie nikelya na aktivnost’
fermentov tsepi dvkhaniya v tsvetakh petunii. (Effect of nickel on the activity
of respiratory ch&n enzymes in petunia flowers.) Tr Vses Nauchno—Issled Inst
UbobrAgropochvoved. 53. 187—192 (1972).
(114) Wang, Dalton, and E. R. Waygood. Effect of benzimidazole and nickel on the
chlorophyll rnetobolism of detached leaves of khapi wheat. Canadian Jour. Bot.
37(5):743-750 (1959).
(115) Smirnov, Yu. S., R. R. Akhmetov and M. Ya. Shkol’nik. 0 nekotorykh
fiziologicheskikh prich inakh lezhashchikh v osnove serpenrinornorfozov. (Some
physiological causes of serpentine forms.) Bot Zh. 57(10)1290—1296 (1972).
(116) Fuhrmann, Gunter—Fred and Aster Rothstein. The mechanism of the partial
inhibition of fermentation in yeast by nickel ions. Biochem Biophys Acta
(Amsterdam). 163(3):33 1-338 (1968).
(117) Van Steveninck, J. The influence of nickelous ions on carbohydrate transport
in yeast cells. Biochim iophysActa (Amsterdam). 126(l): 154—162 (1966).
(118) Witlecke, Klaus, Eva—Maria Gries and Peter Oehr. Coupled transport of citrate
and magnesium in Bacillus subtilis. J Biol Chem. 248(3):807—814 (1973).
(119) Andrivon, C. Preuves de l’esistence d un transport actif de l’ion nickel a travers
Ia membrane cellulaire de Paramecium caudotum. (Proof of the existence of active
transport of nickcl ions across the cell membrane of Paramecium caudatum.)
Protistologica. 6(4) :445—455 (1971).
(120) Andrivon, Claude. Action des quelques inhibiteurs du metabolisme sur Ia resistance.
aux sels de nickel chez paramecium coudatum. (Action of some inhibitors of the
metabolism on the resistance to nickel salts in Paramecium caudatum.) C R Hebd
Seances Acad Sci Ser D Sci Natur (Paris). 265(23):1831—l833 (1967).

-------
111-79
1’ i ji R fX( 1 .
References
(121) Rausch, Cloir G. The antagonistic effect of strontium ions for anesthetization
of Paramecium coudatum with nickel ioi s. Proc Iowa Acad Sci. 72. 477—485
(1967).
(122) Levinson, Warren, Anthony Faras, Bruce Woodson, Jean Jackson and J.
Michael Bishop. Inhibition of RNA-.’dependent DNA polymerase of Rous
sarcoma virus by thiosemicarbazones and several cotions. Proc NatI Acad
Sci USA. 70(l):164- 168 (1973).
(123) Waters, Michael D., Donald E. Gardni r, and David L. Coffin. Metal Toxicity
for Rabbit Alveolar Macrophages in vitrD I. Effects on cell viability, cell
numbers and a lysosomal hydrolase. Nc iionol Environmental Research Center,
U. S. Environmental Protection Agency. Research Triangle Park, North
Carolina. In: Twelfth Annual Meeting of the Society of Toxicology, March
18—22, 1973.
(124) Waters, Michael D., D. E. Gardner, cind D. L. Coffin. Metal Cytotoxicity :
Comparative Studies with Rabbit Alveolc r Macrophages and Human Lung
Fibroblasts (Strain Wl—38). U.S. Envirnmental Prptection Agency. Research
Triangle Park, North Carolina. In: Thirteenth Annual Meeting of the Society
of Toxicology, March 10-14, 1974.
(125) Butler, Hildred M., J. C. Lover, A. Shulman, and R. D. Wright. The use of
phenanthroline metal chelates for the c,ntrol of topical infections due to
bacteria, fungi and protozoa. Med J Aust (Sydney). 57—2(7):309—3l4 (1970).
(126) Karpov, A. Ye. Doslidzhennya vplyvu solei kobal’tu ta nikelyu no chastotu
zakhvoryuvan’ no zhovtyantsyu u shovk vychnoho shovkopryoda v umovakh
vyrobnytstva. (A study of the effect of cobalt and nickel salts on the frequency
of silkworm jaundice (polyhedrosis of the silkworm) under industricl conditions.)
Mikrobiol 7h Akad Nauk Ukr Rsr. 26( ):54—58 (1964).
(127) Forsyth, F. R. Inhibition by nickel of he respiration and development c
established nfections on Thatcher wheat caused by Puccinia recondita Rob
ex Desm. Canadian Journ. Bot. 40(3) 415-423 (1962).
(128) Forsyth, F. R., and 3. Peturson. Contvol of leaf rust of wheat with inorganic
nickel. Plant Dis. Reporter. 43(l):5—8 (1959).
(129) Forsyth, F. R., and B. Peturson. Contiot of leaf and stem rust of wheat by
zineb and inorganic nickel salts. Plant Dis. Reporter. 44(3):208—3 1 1 (1960).
(130) Peturson, B., F. R. Forsyth, and C. B. Lyon. Chemkal control of cereal rusts.
II. Control of leaf rust of wheat with experimental chemicals under field
conditions. Phytopathol. 48(12) :655-657 (l95 .
(131) Rosa, Mario. (Preliminary tests on chemical control of black stem rust of wheat
(Puccinia graminis tritici erkiss) with nickel salts). Boll. Staz. Patol. Veg.
19(2):l25—132 (1961).

-------
111-80
RJAR 1 References
(132) Rowell, J. B. Factors affecting field performance of nickel salt plus dithio—
carbarrate fungicide mixtures for the control of wheat rusts. Phytopathology
54(8):999-1008 (1964).
(133) Michel, L. J., and M. D. Simons. Comparison of zineb and maneb with a
nickel —maneb mixture for control of oat crown rust. Plant Dis Rep. 52(3):
205-208 (1968).
(134) Keil, Harry L., Hans P. Frohlich, and Charles E. Glossick. Chemical control
of cereal rusts. Ill. The influence of nickel compounds on rye leaf rust in the
greenhouse. Phytopath. 48(12):690—695 (1958).
(135) Farkas, G. L,, G. Molnar, and Z. Kiraly. Control of the mint rust fungus,
Puccinia menthae, by nickel salts. Phytopathology. 50(ll):866 (1960).
(136) DeSilvo, R. L. The use of nickel chloride and Perezin for the control of
blister blight (Exobasidium vexans Massee) on tea. Tea Quart. 36(4)
191 (1965).
(137) Venkata Ram, C. S. Action of nickel salts on the blister blight fungus in situ.
Phytopathology. 53(3) :276—278 (1963).
(138) Lesis, G. D., and P. B. Shoemaker. Control of asparagus rust (Pussinia
osporogi) with a mixture of maneb and a nickel sulfate. Plantdisreporter.
48(6) :436-437 (1964).
(l3 McDermott, Gerald N., Mildred A. Post, Burner N. Jackson, and Morris
B. Ettinger. Nickel in relation to activated sludge and anaerobic digestion
processes. J Water Pollut Contr Federation. 37(2); 163— 177 (1965).
(140) Perhac, Ralph M. Distribution of Cd, Co, Cu, Fe, Mn, Ni, Pb and 7n in
dissolved and particulate solids from two streams in Tennessee. J Hydrol
(Amsf). 15(3):l77— 186 (1972).
(141) Soane, B. D., and D. H. Sounder. Nickel and chromium toxicity of serpentine
soils in Southern Rhodesia. Soil Sci. 88(6):322—330 (1959).
(142) Sequeira, E. Menezes De. Toxicity and movement of heavy metals in serpentinic
soils (North-eastern Portugal). Agron Lusitana. 30(2) :115—154 (1968).
(143) Nevorol, V. Die Best immung von Kobalt - und Niickelspuren in Mineralwaessern.
(The determination of traces of cobalt and of nickel in mineral waters. Z Physic
Ther (Leipzig). 23(4):263—269 (1971).
(144) Eschnouer, H. Verhalten von Nickel and nickeihaltigen Werkstoffen gegenuber
Wein. (Behavior of nickel and nickel iferous raw materials with respect to wine.)
Weinberg U Keller. Il(l):35—44 (1964).

-------
1 11-8 1
YI I?JA R
References
(145) Gray, Philip P., and Irwin Stone. Metal-induced wildness in beers. Wallerstein
Lab. Commun. 19(67):345372 (1956).
(146) Wahlberg, Jan E., and Erik Skog. Nickel allergy and atopy: Threshold of
nickel sensitivity and irrmunoglobulin E deerminotions. Br J Dermatol
(London). 85(2):97-104 (1971).
(147) Szadkow ki, D., H. Schultze, K. H. Schciller, and G. Lehnert. Zur
okoiogischen Bedeutung des Schwermetailgehaltes von 7igaretten. (The
significance of the heavy—metal content of cigarettes.) Arch Hyg Bakteriol
(Munchen). 153(l):i—8 (1969).
(148) Sunderman, F. William, and F. f-illiam Sunderman, Jr. Loeffler’s syndrome
associated with nickel sensitivity. Trans. and Stud. Coil. Physicians Philadelphia.
29(2):8 1 (1961)
(149) Menden, Edward E., Victor J. Eiia, Lesii W. -Michael and Harold G. Petering.
Distribution of cadmium and nickel of tobccco during cigarette smoking.
Environ Sci Technol. 6(9):830-832 (1972)
(150) Lagerwerff, J. V., and A. W. Specht. (ontamination of roadside soil and
vegetation with cadmium, nickel, lead and zinc. Environ Sd Technol.
4(7):583586 (1970).
(151) Ruhling, Ake, and Germund Tyler. Ecology of heavy metals: A regional and
historical study. Bot Notiser. 122(2):248-259 (1969).
(152) Bombowna, Maria, and Stanislaw Wrobei. Sklad chemiczny wody Wisloka w
rejonie Krosna I zanieczyszczenia metalaini ciezkimi (Cu, Cr, Ni). (The
chemical composition of the water of the Wslok in the region of Krosno and
its pollution with heavy metals (Cu, Cr, NL) Acta Hydrobiol. l0(4):439-
452 (1969).
(153) Costescu, L. and Hutchinson, 1. C. Soil contamination by airborne metallic
dust particles and its effect on plants in tlic Subdury Basin Ontario. Am J Bot.
58(5Pt2) :481 (1971).
(154) Nielsen, F. H. Effect of dietary level o Ni on the responsiveness of chicks to
changes in hormonal status. Fed Proc. 31(2):700 (1972).
(155) McNeeley, Michael D., Maria W. NecEay and F. William Sunderman, Jr.
Measurements of nickel in serum and urine as indices of environmental exposure
to nickel. Clin Chem. I8(9):992-995 (i 72).
(156) Massey, H. F. pH and soluble Cu, Ni aid Zn in eastern Kentucky coal mine
spoil materials. Soil Sci. l 14(3):217—221 (1972).

-------
111-82
V RJAR Jxc.
References
(157) Winchester, John W., and Gordon D. Nifong. Water pollution in Lake Michigan
by trace elements from pollution aerosol fallout. Water Air Pollut. l(l):50—64
(1971).
(l5 Hendershot, Leland C., Ralph E. Mansell, and Janet Forsaith. The effect of
zinc, nickel and manganese on rat dental caries and dental enamel metal levels.
In: Seven and Johnson, Eds, Metal—binding in Medicine. J. B. Lippincott
Company: Philadelphia. p. 306—311, 1960.
(159) Kariya, Teiji, Kuniaki Kawase, Hideo Haga, and Tsutomu Tsuda. (Studies on
the post—mortem identification of the pollutant in fish killed by water pollution.
VII. Detection of nickel in the fish.) Bull Jap Soc Sci Fish. 34(5):385—390
(1968).
(160) Stevenson, Robert A., and Sara Lugo Ufret. Iron, manganes and nickel in
skeltons and food of the sea urchins Tripneustes es lentus and Echinometra
lucunter. Limnol Oceanogr. 11( 1):! (1966).
(161) Lyon, G. L., P. J. Peterson, R. R. Brooks, and G. W. Butler. Calcium
magnesium and trace elements in a New Zealand serpentine flora. J
Ecol. 59(2):42l—429 (1971).
(162) Ritter—Studncka, Hilda, and Krunoslova Dursun-Grom. Ueber den Eisen—,
Nickel —und C’iromgehalt in einigen Serpentinpflanzen Bosniens. (On the
iron—, nickel—and chromium content in some serpentine plants of Bosnia.)
Qesterr Bot Z. 121(l/2):25—49 (1973).
(163) Sarosiek, J. Roslinnosc hald kopolniano—hutniczych niklu zklarach k.
Zabkowic SI. i warunki jej wystepowani. (Vegetation the mining—smelting
nickel heaps in Szklary near Zobkowice Slaskie conditions of its occurrence.)
Acta Soc. Bot. Polon. 26(2):27 1-290 (1957).
(164) Severne, B. C. and R. R. Brooks. A nickel—accumulating plant from western
Australia. Ptonta (Ben). 103(I):91—94 (1974).
(165) Baumslag, Naomi, and Paul Keen. Trace elements in soil and plants and antral
cancer. Arch Environ Health. 25(l):23—25 (1972).
(166) Suciu, T., and L. Ivanof. Prezenta cuprlui, nichelulul, zinului, cobaltiului
si manganului in sot si in semintele citorva plante de cultura. (The presence of
copper, nickel, cobalt, zinc and manganese in the soil and in seeds of some
cultivated plants. Stud Si Cercetari Agron (CLUJ). 14:79—83(1963).
(167) Chebotorev, I. I., 1. R. Proskuryakova and 1. V. Lankova. Mikroelementy
zhelezo, kobal’t, med’ , marganets, titan i nikel’ v mede I pyl’tse rastenii z
razlichnykh raionov Primorskogo kraya. (Trace elements irOn, cobalt, copper,
manganese, titanium and nickel in honey and pollen of plants from various
regions of the Maritime Territory.) Uch Zap DaI’nevost Univ. 57. 80—82 (1972).

-------
1 111-83
VL’RJA R J1V 7.
References
(168) Karvanek, Milan, and Jana Bohmova. The ntent of copper, iron, nickel,
mangonese, zinc and molybdenum in spinach leaves. Sb Vysoke Sk Chem
Technol Proze Potrov. 11:73—82 (1966).
(169) Kucharin, G. M. Sochetannye professional’nye porazheniya nosa i pridatochnykh
pazukh u rabochikh tsekha elektrol iticheskoçpo rafinirovaniya nikelya. (Combined
occupational lesions of the nose and accessory sinuses in workers engaged in
electrolytic refining of nickel.) Gig Tr Prof 7abol. 14(9):38—40 (1970).
(170) Nechaeva, A. N. Kartino krovi u lits, zanyatykh no proizvodstve nikelevykh
i margantseykh ferritovykh poroshkov. (Blood picture in persons engaged in the
production of nickel and manganese ferrite Fowders.) Gig Tr Prof Zabol (Moscow).
l5(l):55—56 (1971).
(171) Sidyakov, P. V. 1 M. M. Tuchenko, and V. S. Matytska. Naibolee vazhnye
rezul’ tat>’ gigieni cheskogo izucheniya nekotrykh protesessov pol uchemya
nikelya i kobal’ta. (The most important rest.Its of a hygienic study of some
processes for producing nickel and cobalt.) In: Materialy k Ncuchnoi sessil,
posvyashchenne 40—letiyu Gosudarslvenriogci nauchno—issledovatel’ nogo
instituta gigieny truda i profzabolevanii, Leningrad. 24—26, 1964.
(172) Zhdaneeva, G. S. 0 rentgenologicheskikh izmeneniyakh v legkikh pri
intoksikatsii karbonl—nikelem v ostrom I otthlennom periodakh. (X—ray
changes in the lungs with nickel carbonyl pcisoning in the acute phase and
later.) Kazan Med Zh. I. 47-50 (1970).
(173) Jones, Carroll C. Nickel carbonyl poisoning: Report of a Fatal case. Arch
Environ Health. 26(5):245-248 (1973).
(174) Sunderman, F. William Jr. Studies of nick l carcinogenesis: Fractionations
of nickel in ultrocentrifugal supernatants of lung and liver by dextron gel
chromatography. Amer J. Clin Pathol. 42(3):228-236 (1964).
(175) Calnan, C. D. Nickel sensitivity in women. Internati. Arch. Allergy and
AppI. lmmunol.(Basel). ll(l/2):73—80 (1957.
(176) Watt, Thomas L., and Robert R. Baumann. Nickel earlobe dermatitis. Arch
Dematol. 98(2):l55-l58 (1968).
(177) Borranco, V. P. and H. Solomon. Eczemat,us Dermatitis From Nickel.
Jama. 220:1244 (May, 1972).
(178) Sullivan, Ralph J. Air Pollution Aspects of nickel and its compound. Litton
Systems, Incorporated. Bethesda, Marylanc. For National Air Pollution
Control Administration Consumer Protection and Environmental Health Service,
U.S. Department of Heolth, Education, anc Welfare (Contract No. PH—22—68—25),
September, 1969.

-------
Ill-U4
14 RJAR 1M7.
Ref erences
(I7 Ado, A. D. and I. E. Sosonkin. Spetsificheskaya desensibilizatsiya pri konnol
allergii, vyzvannoi soedineniyarni metallov. (Specific desensiti ition contact
allergy due to metal compounds.) Vestn Dermatol Venerol (Moscow). 45(l):
45-50 (1971).
(180) Rhodes, E. L., and J. Warner. Contact eczema. A follow—up study. Brit
J Dermatol (London). 78( 12):640-644 (1966).
(181) Duperrat, B., and J.—N. Lamberton. Allergie Cu nickel (200 epiderrno—
reactions). (Allergy to nickel (200 patch tests). Bull. Franc. Dermatol. et
Syphiligr. 69(2):202—205 (1962).
(182) Fregert, Sigfrid, and Hans Rorsman. Allergy to chromium, nickel and cobalt.
Acta Derrnato-Venerol (Stockholm). 49(2/3) :144-148 (1966).
(183) Cronin, Etain. Clinical prediction of patch test results. Trans St. John’s
Hosp Dermotol Soc. (London). 58(2):l53-162 (1972).
(184) Caron, G. A. Nickel sensitivity and atopy (in contact—dermatitis of man). Brit
J Dermatol (London). 76(8/9):384—387 (1964).
(185) Himmelhoch, S. R., Sober, H. A., Vallee, B. L., Peterson, E. A., and
Fuwa, K. Spectrographic and Chromatographic resolution of metalloproteins
in human serum. Biochemistry. 5(8):2523-2530 (1966).
(186) Pirila, Veikko, and Lars Forstrom. Pseudo—cross—sensitivity between cobalt
and nickel. Acta Derma To Vernereol (Stockholm). 46(l):40—45 (1966).
(187) Pirila, Veikko, and Heikki Kajanne. Sensitization to cobalt and nickel in
cement eczema. Acta Dermato—Venereol (Stockholm). 45(l):9-l4 (1965).
(188) Malten, K. E., and D. Spruit. The relative importance of various environmental
exposures to nickel in causing contact hypersensitivity. Acta Dermato—Venereol
(Stockholm). 49(l):l4—l9 (l96 .
(l8 Grosfeld, J. C. M., A. J. M. Penders, R. DeGrood, and L. Verwilghen.
In vitro investigations of chromium—and nickel-hypersensitivity with culture of
skin and peripheral lymphocytes. In: 169th Meeting of Netherland’s Society
of Dermatologists, Nijmegen, 1964. Dermatologica (Basel). 132(2) :189—198
(1966).
(l ) Forman, Louis and Suzanne Alexander. Nickel antibodies. Br J Dermatol
(London). 87(4):320-326 (1972).
(191) Aspegren, Nils, and Hans Rorsman. Short—term culture of leucocytes in nickel
hypersensitivity. Acta Dermato—Venereol (Stockholm). 42(5) :412—417 (1962).

-------
1 1 11—85
‘ERJAR INC.
References
(192) Dvizhkov, p• p. 0 blastomogennykh svoish akh promyshlennykh metollov I
ikh soedinenil. (Blastomogenic properties of industrial metals and their
compounds (human, rat).) Arkh Patol (Moscow). 29(3):3—ll (1967).
(193) Boumslag, Naomi, and Paul Keen. Trace elements in soil and plants and antral
cancer. Arch Environ Health. 25(l):23—25 (1972).
(194) Doll, R., L. G. Morgan, and F. E. Speizer Cancers of the lung and nasal
sinuses in nickel workers. Brit J Cancer (London). 24(4):623—632 (1970).
(195) Saknyn’, A. V., and N. K. Shabynino. N kotorye statisticheskie materialy o
kantserogennoi opasnosti v proizvodstve nikelya no baza ok.islennykh rud. (Some
statistical data on the carcinogenic hazards or workers engaged in the production
of nickel from oxidized ores.) Gig Tr Prof 2abol (Moscow). l4(ll):l0-l3 (1970).
(196) Kolpakov, F. I. Gistokhmicheskii metod oredeleniya nikelya v tkanyakh
organizma i toksichnost’ ego pri vvedenii cherez kozhu. (Histochemical method
for determining nickel in tissues and its toxi :ity when administered through the
skin.) Farmakol Toksikol (Moscow). 27(3):167-369 (1964).
(197) Belobragina, 0. V., and A. V. Scknyn’. lssledovaniya deistviyo pyli nikelevogo
proizvodstav v eksperimente. (An experimental study of the action of nickel
production dust.) Gigiena Ti Professional’n re Zabolevaniyo (Moscow). 12.
8—15 (1963).
(198) Bingham, Eula, William Barkley, Mary Zer ,as, Klaus Stemmer and Purcell
Taylor. Responses of alveolar macrophages o metals: I. Inhalation of lead
and nickel. Arch Environ Health. 25(6):406—4l4 (1972).
(199) Selivanova, L. N., and V. I. Ponomar’kov, 0 deistvii malykh dozmelkodispersnogo
metallicheskogo nikelya v khronicheskom eksperimente. (The effect of small
doses of finely dispersed metallic nickel in chronic experiments.) Farmakol I
Toksikol (Moscow). 26(6):743-750 (1963).
(200) Wehner, AlfredP. and Douglas K. Craig. roxicology of inhaled NiO and CoO
in Syrian golden hamsters. Am lnd Hyg Assoc J. 33(3):l46— 155 (1972).
(201) Chernen’kii, I. K., and L. V. Smirnova. 0 toksicheskom deistvii nikelya pri
peroral’nom vvedenii. (Toxic action of nickel with peroral administration.)
Gig Sanit (Moscow). 3l(8):l09 (1966).
(202) Waltschewa, W. , M. Slatewa and I. Michoilow. Hodenveraenderungen bei
weissen Rotten durch chronische Verabreich’ing von Nickelsulfat. (Testicular
changes due to longterm administration of n ckel sulfate in rats.) Exp Pathol
(Jena). 6(3/4) :Il6—120 (1972).
(203) Miltimore, J. E., J. M. McArthur, J. L. Mason, and D. L. Ashby. Bloat
investigations: The threshold fraction I (l8S) protein concentration for bloat
and relationships between bloat and lipid, tannin, Ca, Mg, Ni, and 7n
concentrations in alfalfa. Can J Anim Sci. 50(l):61—68 (1970).

-------
111-86
1% RJAR Jxc.
References
(204) Hackett, Raymond L., and F. William Sunderman, Jr. Nickel carbonyl:
Effects upon the ultrastructure of hepatic parenchymal cells. Arch Environ
Health. 19(3):337-343 (1969).
(205) Gvishiani, G. S., L. S. Gegenava, and Sh. A. Tsitsuoshvil. K farmakologii
nekotorykh quanidinovykh proizvodnykh nikelya i kobalta. (The pharmacology
of some guanidine derivatives of nickel and cobalt.) Sb Tr Nauch—issled Inst
Eksp Kim Ter Gruz Ssr. 4:61—67 (1968).
(206) Sights, Warren P., and Robert J. Bye. The fate of retained ir.tracerebrai
shotgun pellets: An experimental study. J Neurosurg. 33(6 Part)646—ó5 3 (1970).
(207) Chusiel, J. G. and Kopeloff, L. M. Epileptogenic effects of pure metals
implanted in motor contex of monkeys. J. AppI. Physicol. 17(4):697—700 (1962).
(208) Tsyrkunov, L. P. Eksperimental’noe izuchenie allergiziruyushchego deistviya
penitsillina, streptomitsina i nikelya. (Experimental study of the allergizing
effect of penicillin, streptomycin and nickel.) Vrach Delo (Kiev). 2. 101—103
(1967).
(209) Bezian, J. H., E. Dervillee, M. Tordivel, andY. Vervialle. Etude experimentale
de Ia sensibilisation au nickel. (Experimental study of sensitization to
nickel.) Arch Mal Prof Med Tray Secur Soc. 26(4/5):229—233 (1965).
(210) Stone, Orville J., and Dallas A. Johnson. Pustular patch test: Experimentally
induced (in experimental Corynebacterium ocnes infection). Arch Dermatol
95(6):6l8-6l9 (1967).
(211) Tsyrkunov, L P. Spivvidnoshennyo bilkovykh fraktsii syrovatky krovi mors’kykh
svynok, sensybil izovanykh penitsylinom, streptomi tsynom ta khiorystym nikeièm.
(Protein fraction ratio in blood serum of guinea—pigs sensitized with penicillin,
streptomycin and nickel chloride.) Ukr Biokhim 7h (Kiev). 40(5):469—473 (1968).
(212) Cotton, D. W. K. Studies on the binding of protein by nickel with special
reference to its role in nickel sensitivity. Brit J Dermatol (London). 76(3):
99—109 (1964).
(213) Aoki, Koichiro, Joji Hori, and Kazuro Kawashimo. Effect of metallic cations
on human serum: Study by starch—gel electrophoresis: II. Effect of Hg++,
Crl-++, Ag+, NJi++, Cd+÷, Zr -rH-, Ba+f, Mg++, Al+++, and Fe++-F. Arch
Biochem Ciophys. 120(2):255-267 (1967).
(214) Corbeil, Lynette B. Antigenicity of rhabdomyosarcomas induced by nickel
sulfide (Ni3S2). Cancer. 21(2):184—189 (1968).
(215) Hueper, W. C. Experimental studies in metal cancerigenesis. IX. Pulmonary
lesions in guinea pigs and rats exposed to prolonged inhalation of powdered metallic
nickel. Arch. Pathol. 65(6):600-607(l958).

-------
111-87
RJ41? Jive.
Reference;
(216) Stanton, Mean F., and Constance Wrench. Mechanisms mesothelioma induction
with asbestos and Fibrous glass. J Nati Cancer Inst. 48(3):797—82 1 (1972).
(217) Furst, A., Haro, 1. 1. and Schlauder, M. Experimental chemotherapy of
nickel induced fibrosarcomas. Oncology (Basel). 26(5) :422—426 (1972).
(218) Heath, J. C., and M. Webb. Content and intracellular distribution of the
inducing metal in the primary rhabdomyosarcomota induced in the rat by
cobalt, nickel and cadmium. Brit J Cancr (London). 21(4):768—779 (1967).
(2l Daniel, Mary R. Strain differences in the response of rats to the injection of
nickel sulphide. Brit J Cancer (London). 20(4):886—895 (1966).
(220) Gilman, J. P. W., and H. Herchen. The effect of physical form of implant
on nickel sulphide tumorigenesis in the rat. In: 8th International Cancer
Congress, 1962. Acta Unlo Internati. Contra Concrum. 19(3/4):6l5-6l9 (1963).
(221) Jusmin, G., E. Bajusz and A. Mongeau. (Influence of sex and castration on
the induction of muscle tumors in the rat b ’ nickel sulfide). Rev. Canadienne
Biol. (Montreal). 22(l):l13—1l4 (1963).
(222) Nath, N., Parvathi K. Basrur and R. LimEbeer. A new cell line derived from
nickel sulfide—induced rat rhabdomyosarcorno. In Vitro. 7(3): 158—l60 (1971).
(223) Basrur, Parvathi, K., and John P. W. Gilr an. Morphologic and synthetic
response of normal and tumor muscle cultur s to nickel sulfide (rat). Cancer
Res. 27(6 Pt. l):lI68-. 1l77 (1967).
(224) Basrur, Parvathi K., Anthony K. Sykes, and J. P. W. GiIm n. Changes in
mitochondrial ultrostructure in nickel sulfide—induced rhabdomyosarcoma.
Cancer. 25(5):1 142-l152 (1970).
(225) Jasmin, Gaetan. Effects of methandrosten)lone on muscle carcinogeness
induced in rats by nickel suiphide. Brit Jour Cancer (London). l7(4) :68 1-
686 (1963).
(226) Maenza, Ronald M., Arun M. Pradhan anc F. William Sunderman, Jr. Rapid
induction of sarcomas in rats by combination of nickel sulfide and 3,4—benzpyrene.
Cancer Res. 3 1(12):206—207 (1971).
(227) Brown, V. M., and R. A. Dalton. The acute lethal toxicity to rainbow trout
of mixtures of copper, phenol, zinc and nii:kel. J Fish Biol. 2(3):211-2 16
(1970).
(228) Molacea, L., and E. Gruia. Contributii l cunoasterea actiurii toxice a
cuprulu, zinccului, plumbului si nichelulLi asupra unor specii de pesti si a
dafniei. (Contribution to the study of the loxc effect of copper, zinc, lead,
nickel on some species of fish and on Daphnia.) Stud Protect Epurarea Apelor
Inst Stud Cercetari Hidrotehnice. 6. 391—451 (1965).

-------
111—00
Y RJAR Jxc.
References
(229) Doudoroff, P. Some experiments on the toxicity of complex cyanides to fish.
Sewage and Indust. Wastes. 28(8):1020- 1040 (1956).
(230) Whitley, L. Stephen, and Richard A. Sikora. The effect of three common
pollutants on the respiration rote of tubificid wornis. J. Water Pollut Contr
Fed. 42(2 Part 2):R57-R66 (1970).
(231) Calabrese, A., R. S. Collier, D. A. Nelson and J. R. Maclnnes. The
toxicity of heavy metals to embryos of the American oyster Crassostrea virginica.
Mar Biol (Ben). 18(3):162— 166 (1973).
(232) Timourian, Hector and George Watchmaker. Nickel uptake by sea urchin
embryos and their subsequent development. J Exp Zool. 182(3):379—388 (1972).
(233) Williams, Philip C. Nickel, iron, and manganese in the metabolism of the
oat plant. Nature (London). 2l4(5088):628. (1967).
(234) lshihara, Mascyoshi, Yoshiomi Hase, Hisashi Yokomizo, Sanji Konno, and
Kokhi Sato. The nutritional disease of Satsuma mandarin trees in serpentine
soil. IV. The influence of the application of slaked lime, nickel, chromium,
and sulphur with molybdenum treatment on the growth and fruiting of Satsuma
mandarin trees grown in serpetine soil. Bull Hort Res Sta Mm Agr Forest Ser
A (Hirotsuka). 7. 55-72 (1968).
(235) De La Fuente, R. K. Nickel as the possible cause of nut “boang” in the
Tibiawan Plantation, Davao. Philippine Agric. 45(1/2): 41—43 (1961).
(236) Upitis, V. V., D. S. Pakalne, and A. F. Nollendorfa. Maloizuchennye
mikroelementy v kul’ture khlorelly. lI.Nikel’. (Little studied trace elements
in Chlorella. ll.Nickel.) Latv Psr 7inat Akad Vestis. 4. 24—34 (1971).
(237) Elorza, Victoria. Toxicidad de los iones metalicos para Aspergillus nidulans.
(Toxicity of metal ions for Aspergillus nidulans.) Microbiol Espan (Madrid).
22(2):131—l38 (1969).
(238) Bormann, E. J. Spektrogrophische Untersuchungen zur fungiciden Wirkung von
Schwermetallchelaten (S ilber—, Cadmium-, Nickel— und KobaltdialkyldithiOCarbamat).
(Spectrographic studies on the fungicidal effect of heavy metal chelates (sHyer,
cadmium, nickel and cobalt dialkyl dithiocarbomate). Arch Mikrobiol (Berlin). 53
(I) :12-16 (1966).
(239) Troger, R. Studien zur Fungi cidwirkung der Schwermetallsalze. (Studies on the
fungicidal activity of heavy metal salts.) Arch. Mikrobiol. (Berlin). 29(4):
430-437 (1958).
(240) Lindegren, Carl C., Susumu Nogai, and Hideko Nagoi. Induction of respiratory
deficiency in yeast by manganese, copper, cobalt and nickel. Nature. 182
(4633) :446-448 (1958).

-------
111-89
1’ RJAR INC.
References
(241) dePuytorac, P., C. Andrivon, and F. Serre. Sur (‘action cytonorcotique
des sels de nickel chez Paramecium caudatun, Erhb. (Cytonarcotic action
of nickel salts on Pormecium caudatum Erhb.) In: Fifteenth Meeting of the
Society of Protozoologists, Corvallis, Oregor, August 1962. J Protozool
9(Suppl.):ll. ((962).
(242) Grebecki, Andrezej, and Ewa Mikolajczyk. Ciliary reversal and re—normaUzaf ion
in Paramecium coudatum immobilized by Ni ins. Acta Protozool. 5(l :297-303
(1968).
(243) Roth, L. E., and Y. Shigenaka. Microtubules in the heliozoan axopodium: II.
Rapid degradation by cupric and nickelous ous. J Ultrastruct Res. 31(3/4):
356-374 ((970).
(244) Parducz, Bela. Inversed spiral movement of l’aramecium multimicronucleotum
evoked by nickel salts. In: Fifteenth Meetirg of the Society of Protozoologists
Corvalis, Oregon, August 962. J Protozool. 9(Suppl.): 27 (1962).

-------