United States
              Environmental Protection
              Agency
              Office of Health and
              Environmental Assessment
              Washington DC 20460
EPA/600/8-83/012F
September 1985
Final Report
              Research and Development
vvEPA
Health Assessment
Document for
Nickel

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                                      EPA/600/8-83/012F
                                         September 1985
                                            Final Report
Health Assessment  Document
                    for
                 Nickel
        U.S. ENVIRONMENTAL PROTECTION AGENCY
           Office of Research and Development
       Office of Health and Environmental Assessment
        Environmental Criteria and Assessment Office
           Research Triangle Park, NC 27711

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                                  DISCLAIMER

     This document has been reviewed in accordance with the U.S.  Environmental
Protection Agency's peer and administrative review policies and approved for
presentation and publication.   Mention of trade names or commercial  products
does not constitute endorsement or recommendation for use.

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                                    PREFACE

     The Office of Health and Environmental Assessment, in consultation with
other Agency and non-Agency scientists, has prepared this health assessment to
serve as a "source document" for Agency-wide use.   Specifically, this document
was prepared at the request of the Office of Air Quality Planning and
Standards.
     In the development of this assessment document, the scientific literature
has been inventoried, key studies have been evaluated, and summary/conclusions
have been prepared such that the toxicity of nickel and nickel compounds is
qualitatively and, where possible, quantitatively identified.   Observed effect
levels and dose-response relationships are discussed where appropriate in
order to place adverse health responses in perspective with observed
environmental levels.

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                                   ABSTRACT

     Nickel  is  found in  nature  as a component  of  silicate,  sulfide, or,
occasionally arsenide ores.   It is a valuable mineral  commodity because of its
resistance to corrosion.  Uses  for nickel  and its compounds  include nickel
alloys,  electroplating  baths,  batteries,  textile  dyes and  mordants, and
catalysts.  The  predominant forms  of  nickel in the  atmosphere  are nickel
sulfate,  nickel  oxides and  complex  oxides of nickel.  Nickel  is also  found in
ambient  and  drinking waters and  soils  as  a result  of  both natural and
anthropogenic sources.
     Routes of nickel intake for man and animals are inhalation, ingestion and
percutaneous absorption.  The pulmonary absorption of nickel  compounds varies
according to chemical and physical  form,  with insoluble compounds  generally
being  cleared  more slowly.  Gastrointestinal  intake of  nickel  by man is
relatively high  ranging from 300  to 500 ug daily; however, absorption is  low,
averaging one to ten percent of  intake.  Percutaneous absorption  of nickel
often  occurs through  contact with nickel-containing commodities used in food
preparation; such  contact is related to hypersensitivity and skin disorders.
Absorbed  nickel  is carried  by  the  blood and  distributed  to various tissues
depending on route of intake.  Inhaled nickel compounds lead to highest levels
in  lung,  brain,  kidney and liver.  In humans,  age-dependent accumulation
appears  to  occur only in  the lung.  Unabsorbed dietary nickel is lost in the
feces;  urinary  excretion  is the major clearance route for absorbed  nickel.
     Nickel exposure  produces  chronic  dermatological, respiratory, endocrine
and cardiovascular effects.  Reproductive and developmental effects have  been
noted  in  animals but  not  in humans.  Various nickel compounds have  been tested
for mutagenicity.   In aggregate,  these  tests  have demonstrated the  ability of
nickel  compounds to produce genotoxic effects;  however,  the  translation of
these  effects into actual  mutations is still not clearly understood.  There is
evidence  both  in humans  and animals for  the carcinogenicity of nickel,  at
least  in  some forms.  Lifetime cancer risks for continuous inhalation exposure
                 o
at  1  ug nickel/m  have been estimated  for  nickel  refinery dust and nickel
subsulfide.
     Although  not conclusively established,  there  is growing evidence that
nickel  may be an essential  element  for humans.
                                   IV

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                               TABLE OF CONTENTS
LIST OF TABLES 	      xi1
LIST OF FIGURES 	      xv

1.   INTRODUCTION 	      1-1
2.   SUMMARY AND CONCLUSIONS 	      2-1
    2.1  BACKGROUND INFORMATION 	      2-1
         2.1.1  Chemical/Physical  Properties of Nickel  and Nickel
                Compounds 	      2-1
         2.1.2  Nickel  in the Ambient Air 	      2-1
         2.1.3  Nickel  in Ambient  and Drinking Water	      2-2
         2.1.4  Nickel  in Soil and Sediment	      2-3
         2.1.5  Nickel  in Plants and Food 	      2-3
         2.1.6  The Global Cycling of Nickel 	      2-4
    2.2  NICKEL METABOLISM 	      2-4
         2.2.1  Absorption 	      2-4
         2.2.2  Transport and Distribution	      2-5
         2.2.3  Excretion 	      2-6
         2.2.4  Factors Affecting  Nickel  Metabolism	      2-6
    2.3  NICKEL TOXICOLOGY 	      2-6
         2.3.1  Subcellular and Cellular  Aspects of Nickel Toxicity ..      2-6
         2.3.2  Acute Effects of Nickel Exposure 	      2-7
         2.3.3  Chronic Effects of Nickel Exposure 	      2-8
                2.3.3.1  Dermatologlcal Aspects of Nickel  	      2-8
                2.3.3.2  Respiratory Effects of Nickel	      2-8
                2.3.3.3  Endocrine Effects of Nickel	      2-9
                2.3.3.4  Cardiovascular Effects of Nickel	      2-9
                2.3.3.5  Reproductive and Developmental  Effects of
                         Nickel 	      2-9
                2.3.3.6  Mutagenic Effects of Nickel	      2-10
                2.3.3.7  Carcinogenic Effects of Nickel  	      2-10
                2.3.3.8  Other Toxic Effects of Nickel	      2-11
    2.4  NICKEL AS AN ESSENTIAL ELEMENT	      2-12
    2.5  POPULATIONS AT RISK	      2-12

3.   NICKEL BACKGROUND INFORMATION  	      3-1
    3.1  PHYSICAL AND CHEMICAL PROPERTIES OF NICKEL AND NICKEL
         COMPOUNDS 	      3-1
         3.1.1  Properties of Nickel and  Nickel Compounds  	      3-1
                3.1.1.1  Nickel 	      3-1
                3.1.1.2  Nickel Compounds and Complexes 	      3-1
         3.1.2  Environmental Chemistry of Nickel 	      3-5
                3.1.2.1  Air	      3-5
                3.1.2.2  Water	      3-5
                3.1.2.3  Soil and  Sediments 	      3-7
    3.2  SAMPLING AND ANALYTICAL METHODS  	      3-8
         3.2.1  Sampling for Nickel in Air	."...      3-8
         3.2.2  Analytical Procedures for Nickel in Air	      3-9
         3.2.3  Sampling for Nickel in Water	      3-13
         3.2.4  Analytical Procedures for Nickel in Water  	      3-14

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                        TABLE OF CONTENTS (continued)


                                                                          Page

                                                                          3-14
                                                                          3-15
                                                                          3-15

                                                                          3-15
                                                                          3-16
                                                                          3-16
                                                                          3-17
                                                                          3-18
                                                                          3-21
                                                                          3-22
                                                                          3-23
                                                                          3-24
                                                                          3-25
                                                                          3-26
                                                                          3-26
                                                                          3-27
                                                                          3-27
                                                                          3-28

                                                                          3-29
                                                                          3-31
                                                                          3-34
                                                                          3-34
                                                                          3-38
                                                                          3-40
                                                                          3-42
                                                                          3-42
                                                                          3-43
                                                                          3-45
                                                                          3-47
                                                                          3-49

4.  NICKEL METABOLISM IN MAN AND  ANIMALS  	     4-1
                                                                          4-1
                                                                          4-2
                                                                          4-9
                                                                          4-10
                                                                          4-11

                                                                          4-12
                                                                          4-12
                                                                          4-14
                                                                          4-14
                                                                          4-16
                                                                          4-19
                                                                          4-20
                                                                          4-23
                                                                          4-26
                                   VI
3.3
3.4
3.5
3.6
3.7
NICK
4.1
4.2
4.3
4.4
4.5
3.2.6 Analytical Procedures for Nickel in Soil ....
3.2.7 Sampling for Nickel in Biological Materials .
3.2.8 Analytical Procedures for Nickel in Biologici
Materi al s 	 	 	
NICKEL IN AMBIENT AIR 	
3.3.1 Nickel Species in Ambient Air 	
3.3.1.1 Primary Nickel Production 	
3.3.1.2 Combustion and Incineration 	
3.3.1.3 Metallurgical Processes 	
3.3.1.4 Nickel Chemicals and Catalysts 	
3.3.1.5 Miscellaneous Nickel Sources 	
3.3.2 Ambient Air Nickel Levels 	
NICKEL IN AMBIENT WATERS 	
3.4.1 Nickel Species in Water 	
3.4.1.1 Primary Nickel Production 	
3 4.1.2 Metallurgical Processes 	
3.4.1.3 Combustion and Incineration 	
3 4 1.4 Nickel Chemicals and Catalysts
3.4.1.5 Other Sources of Aqueous Discharges
Nickel 	
342 Concentrations of Nickel in Ambient Waters ..
NICKEL IN OTHER MEDIA . . 	
3.5.1 Nickel in Soils 	
3 5.2 Nickel in Plants 	
3.5.3 Nickel in Food 	
3.5.4 Nickel in Cigarettes 	
GLOBAL CYCLE OF NICKEL 	
3.6.1 Atmosphere 	 	 	
362 Water . . 	 	
363 Soil and Sediments 	 	
REFERENCES 	
EL METABOLISM IN MAN AND ANIMALS 	
ROUTES OF NICKEL ABSORPTION 	
411 Nickel Absorption by Inhalation 	
412 Gastrointestinal Absorption of Nickel 	
413 Percutaneous Absorption of Nickel 	
414 Transplacental Transfer of Nickel 	


il














of

















TRANSPORT AND DEPOSITION OF NICKEL IN MAN AND EXPERIMENTAL
ANIMALS 	
421 Nickel in Blood 	
422 Tissue Distribution of Nickel 	
4221 Human Studi es 	
4222 Animal Studies . 	
423 Subcellular Distribution of Nickel ....
RETENTION AND EXCRETION OF NICKEL IN MAN AND ANIMAL
FACTORS AFFECTING NICKEL METABOLISM 	
REFERENCES 	





S 	



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                         TABLE OF CONTENTS (continued)
5.   NICKEL TOXICOLOGY 	     5-1
    5.1  ACUTE EFFECTS OF NICKEL EXPOSURE IN MAN AND ANIMALS 	     5-1
         5.1.1  Human Studies 	     5-1
         5.1.2  Animal Studies 	     5-2
    5.2  CHRONIC EFFECTS OF NICKEL EXPOSURE IN MAN AND ANIMALS 	     5-2
         5.2.1  Nickel Allergen1c1ty	     5-2
                5.2.1.1  Clinical Aspects of Nickel Hypersensitivity ..     5-3
                5.2.1.2  Epidemiological  Studies of Nickel  Dermatitis .     5-8
                         5.2.1.2.1  Nickel Sensitivity and  Contact
                                    Dermatitis 	     5-9
                         5.2.1.2.2  Sensitivity to Nickel  in
                                    Prostheses 	     5-13
                5.2.1.3  Animal  Studies of Nickel Sensitivity 	     5-15
         5.2.2  Respiratory Effects of Nickel 	     5-15
         5.2.3  Endocrine Effects of Nickel	     5-19
         5.2.4  Cardiovascular Effects of Nickel 	     5-20
         5.2.5  Renal Effects of Nickel 	     5-22
         5.2.6  Other Toxic Effects of Nickel 	     5-23
    5.3  INTERACTIVE RELATIONSHIPS OF NICKEL WITH OTHER FACTORS 	     5-24
    5.4  REFERENCES 	     5-26

6.   REPRODUCTIVE AND DEVELOPMENTAL TOXICITY OF NICKEL 	     6-1
    6.1  REPRODUCTIVE FUNCTION/FERTILITY EFFECTS 	     6-1
    6.2  MALE REPRODUCTIVE SYSTEM EFFECTS 	     6-2
    6.3  FEMALE REPRODUCTIVE SYSTEM EFFECTS 	     6-4
    6.4  DEVELOPMENTAL EFFECTS 	     6-4
    6.5  SUMMARY	     6-8
    6.6  REFERENCES 	     6-10

7.   MUTAGENIC EFFECTS OF NICKEL 	     7-1
    7.1  GENE MUTATION STUDIES	     7-1
         7.1.1  Prokaryotic Test Systems (Bacteria) 	     7-1
         7.1.2  Eukaryotic Microorganisms (Yeast) 	     7-3
         7.1.3  Mammalian Cells In Vitro 	     7-7
    7.2  CHROMOSOMAL ABERRATION STUUTK"	     7-8
         7.2.1  Chromosomal Aberrations In Vitro 	     7-8
         7.2.2  Chromosomal Aberrations Tn Vivo 	     7-11
    7.3  SISTER CHROMATID EXCHANGE (SCE)~5TUl5TE~S IN VITRO 	     7-14
    7.4  OTHER STUDIES INDICATIVE OF MUTAGENIC DAflA"GF777	     7-16
         7.4.1  Rec Assay in Bacteria	     7-16
         7.4.2  S-Phase-Specific Cell Cycle Block	     7-17
         7.4.3  Mammalian Cell Transformation Assay 	     7-17
         7.4.4  Biochemical Genotoxicity	     7-18
    7.5  REFERENCES 	     7-20

8.   CARCINOGENIC EFFECTS OF NICKEL 	     8-1
    8.1  EPIDEMIOLOGIC STUDIES 	     8-1
         8.1.1  Clydach Nickel Refinery (Clydach, Wales)	     8-1
                                  VII

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                TABLE OF CONTENTS (continued)
                                                                  Page
       8.1.1.1  Hill  (1939,  unpublished) 	     8-3
       8.1.1.2  Morgan (1958) 	     8-5
       8.1.1.3  Doll  (1958)  	      8-6
       8.1.1.4  Doll  et al.  (1970) 	      8-8
       8.1.1.5  Dol 1  et al.  (1977) 	      8-10
       8.1.1.6  Cuckle et al. (1980, unpublished)	      8-11
       8.1.1.7  Peto et al.  (1984) 	      8-12
       8.1.1.8  Summary of Studies on the Clydach Nickel
                Ref 1 nery	      8-17
8.1.2  International  Nickel  Company, Inc. (INCO) Work
       Force (Ontario, Canada) 	      8-18
       8.1.2.1  Early Studies	      8-20
                8.1.2.1.1  Sutherland (1959),
                           Mastromatteo (1967), and INCO
                           (1976) 	      8-20
                8.1.2.1.2  Sutherland (1969) 	      8-22
                8.1.2.1.3  Sutherland (1971) 	      8-23
                8.1.2.1.4  Chovil et al. (1981)	      8-24
       8.1.2.2  Recent Studies	      8-25
                8.1.2.2.1  Roberts and Julian (1982) 	      8-26
                8.1.2.2.2  Roberts et al. (1982, unpublished)     8-27
                8.1.2.2.3  Roberts et al. (1983, unpublished;
                           1984) 	      8-31
                8.1.2.2.4  Copper Cliff Medical Screening
                           (Sudbury, Ontario) 	      8-32
       8.1.2.3  Summary of Studies on the Ontario
                INCO Mining and Refining Processes 	      8-34
8.1.3  Falconbridge, Ltd., Work Force (Falconbridge,
       Ontario)	      8-35
8.1.4  Falconbridge Refinery Work Force (Kristiansand,
       Norway) 	      8-39
       8.1.4.1  Pedersen et al. (1973)  	      8-40
       8.1.4.2  Hdgetveit and Barton (1976)	      8-42
       8.1.4.3  Kreyberg (1978) 	     8-43
       8.1.4.4  Hrfgetveit et al. (1978)	     8-44
       8.1.4.5  Torjussen et al. (1978)	     8-45
       8.1.4.6  Torjussen and Andersen  (1979) 	     8-46
       8.1.4.7  Torjussen et al. (1979a) 	     8-47
       8.1.4.8  Torjussen et al. (1979b) 	     8-48
       8.1.4.9  Hrfgetveit et al. (1980)  	     8-50
       8.1.4.10 Magnus et al. (1982) 	     8-50
       8.1.4.11 Kotlar et al. (1982) 	     8-52
       8.1.4.12 Summary of Studies on the Falconbridge
                Refi nery (Norway) 	     8-53
8.1.5  Hanna Miners and Smelting Workers, Oregon
       (U.S.A.) 	     8-54
8.1.6  Nickel Refinery and Alloy Manufacturing Workers,
       West Virginia  (U.S.A.)  	     8-56
8.1.7  Sherritt Gordon Mines Workers (Alberta, Canada)  	     8-57
8.1.8  Nickel Refinery Workers (U.S.S.R.) 	     8-59

                             viii

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                     TABLE OF CONTENTS (continued)
                                                                       Page
     8.1.9  Oak Ridge Nuclear Facilities  (Tennessee,  U.S.A.)  	      8-60
            8.1.9.1  Oak Ridge Gaseous Diffusion Plant,  Metallic
                     Nickel  Powder Exposure 	      8-60
                     8.1.9.1.1  Godbold and Tompkins  (1979)	      8-62
                     8.1.9.1.2  Cragle et al.  (1983,  unpublished;
                                1984)  	      8-64
            8.1.9.2  Oak Ridge Plants, Primarily Nickel  Oxide
                     Exposure to Welders  	      8-66
     8.1.10 Nickel-Using Industries 	      8-68
            8.1.10.1 Die-casting and Electroplating Workers
                     (Scandinavia) 	      8-68
            8.1.10.2 Metal  Polishing and  Plating Workers
                     (U.S.A.) 	      8-69
            8.1.10.3 Nickel  Alloy Manufacturing Workers
                     (Hereford, England)  	      8-71
            8.1.10.4 High-Nickel Alloy Plant Workers  (U.S.A)  	      8-72
            8.1.10.5 Nickel-Chromium Alloy Workers (U.S.A.)  	      8-76
            8.1.10.6 Stainless Steel Production and Manufacturing
                     Workers (U.S.A.)  	      8-78
            8.1.10.7 Nickel-Cadmium Battery Workers (England) 	      8-80
            8.1.10.8 Stainless Steel Welders (Sweden) 	      8-81
     8.1.11 Community-Based Case-Control  Studies 	      8-82
            8.1.11.1 Hernberg et al. (1983) 	      8-82
            8.1.11.2 Lessard et al. (1978) 	      8-83
            8.1.11.3 Burch et al.  (1981)  	      8-84
     8.1.12 Summary of Epidemiologic Studies 	      8-85
            8.1.12.1 Mining of Nickel  Ore 	      8-87
            8.1.12.2 Nickel  Ore Refining  	      8-91
            8.1.12.3 Nickel  Matte Refining 	      8-92
            8.1.12.4 Other Nickel-Related Industries  	      8-96
8.2  EXPERIMENTAL STUDIES 	      8-96
     8.2.1  Animal Studies by Inhalation  and Ingestion 	      8-96
            8.2.1.1  Inhalation Studies	      8-96
            8.2.1.2  Oral Studies 	      8-10-
     8.2.2  Animal Studies of Specific Nickel Compounds  	      8-105
            8.2.2.1  Nickel  Subsulfide (Ni,S9)	  8-105
            8.2.2.2  Nickel  Metal	      8-112
            8.2.2.3  Nickel  Oxide 	      8-116
            8.2.2.4  Nickel  Refinery Dusts	      8-116
            8.2.2.5  Soluble and Sparingly Soluble
                     Nickel  Compounds 	      8-119
            8.2.2.6  Speciality Nickel Compounds	      8-123
            8.2.2.7  Potentiations and Inhibitions of
                     Nickel  Carcinogenesis 	      8-123
     8.2.3  Physical, Chemical, Biological, and Toxicological
            Correlates of Carcinogenic Activities 		      8-125
                                 IX

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                     TABLE  OF  CONTENTS  (continued)
            8.2.3.1  Solubilization  of Nickel  Compounds  	     8-125
            8.2.3.2  Phagocytosis  of Nickel  Compounds  	     8-129
            8.2.3.3  Erythrocytosis  Induced  by Nickel
                     Compounds  	     8-135
            8.2.3.4  Interaction of  Nickel Compounds with
                     DNA and Other Macromolecules  	    8-138
            8.2.3.5  Induction  of  Morphological  Transformation
                     of Mammalian  Cells in Culture 	     8-140
            8.2.3.6  Relative Carcinogenic Activity	     8-142
     8.2.4  Summary of Experimental  Studies  	     8-143
8.3  QUANTITATIVE RISK ESTIMATION  FOR NICKEL 	     8-154
     8.3.1  Introduction	     8-154
     8.3.2  Quantitative Risk Estimates Based on Animal
            Data	     8-154
            8.3.2.1  Procedures for  Determination  of Unit
                     Risk from  Animal Data	     8-154
                     8.3.2.1.1   Description  of the Low-Dose
                                Animal-to-Human Extrapolation
                                Model 	     8-155
                     8.3.2.1.2   Calculation  of Human Equivalent
                                Dosages from Animal Data	     8-156
                     8.3.2.1.3   Calculation  of the Unit Risk 	     8-158
                     8.3.2.1.4   Interpretation of  Quantitative
                                Estimates 	     8-159
                     8.3.2.1.5   Alternative  Methodological
                                Approaches  	     8-159
            8.3.2.2  Calculation of  Cancer  Unit Risk Estimates
                     Based on Animal Studies 	     8-160
     8.3.3  Quantitative Risk Estimates Based on Epidemiologic
            Data	     8-162
            8.3.3.1  Choice of  Epidemiologic Models:
                     Investigation of Dose-Response and
                     Time-Response Relationships for
                     Lung Cancer	     8-163
                     8.3.3.1.1   Description  of Basic Models	     8-163
                     8.3.3.1.2   Investigation of Data  Sets 	     8-165
                                8.3.3.1.2.1  Huntington, West
                                             Virginia	     8-166
                                8.3.3.1.2.2  Copper Cliff,
                                             Ontario 	     8-166
                                8.3.3.1.2.3  Clydach,  Wales 	     8-170
                                8.3.3.1.2.4  Kristiansand,
                                             Norway 	     8-175
                                8.3.3.1.2.5  Conclusion —
                                             Choice of Models 	      8-179
            8.3.3.2  Calculation of the Incremental Unit Risk
                     from Human Data  	      8-179
                     8.3.3.2.1  Huntington,  West Virginia	      8-179

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                         TABLE OF CONTENTS (continued)
                                                                           Page
                                    8.3.3.2.1.1  Refinery Workers ....      8-179
                                    8.3.3.2.1.2  Non-Refinery
                                                 Workers 	      8-184
                                    8.3.3.2.1.3  Use of Estimates of
                                                 A to Estimate Unit
                                                 Risk	      8-184
                         8.3.3.2.2  Copper Cliff, Ontario	      8-190
                         8.3.3.2.3  Kristiansand, Norway	      8-193
                         8.3.3.2.4  Clydach,  Wales 	      8-195
                         8.3.3.2.5  Conclusion and Discussion:
                                    Recommended Unit Risk Estimates
                                    Based on  Human Studies 	      8-195
         8.3.4  Relative Potency 	      8-197
    8.4  SUMMARY	      8-203
         8.4.1  Qualitative Analysis 	      8-203
                8.4.1.1  Nickel  Subsulfide (Ni,S9) 	      8-204
                8.4.1.2  Nickel  Refinery Dust	      8-205
                8.4.1.3  Nickel  Carbonyl [N1(CO),] 	      8-205
                8.4.1.4  Nickel  Oxide (NiO) ....?	      8-205
                8.4.1.5  Nickelic Oxide (Ni90,)	      8-206
                8.4.1.6  Soluble Nickel CompoDnds	      8-206
                8.4.1.7  Nickel  Sulfide (NiS) 	      8-207
                8.4.1.8  Nickel  Metal (Ni) 	      8-208
         8.4.2  Quantitative Analysis 	      8-209
    8.5  CONCLUSIONS 	      8-210
    8.6  REFERENCES	      8-211

9.   NICKEL AS AN ESSENTIAL ELEMENT	     9-1
    9.1  REFERENCES 	     9-4
                                    XI

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                                LIST OF TABLES
3-1  Physical properties of nickel  and nickel  compounds 	     3-2
3-2  Cumulative frequency distribution of individual  24-hour
     ambient air nickel levels 	     3-10
3-3  Nickel concentrations in U.S.  ambient surface waters:   1980-1982 .     3-32
3-4  Nickel concentrations in groundwater:   1980-1982 	     3-35
3-5  Natural levels of nickel in selected soil types  	     3-37
3-6  Nickel concentrations in enriched soils 	     3-37
3-7  Accumulation of nickel in plants 	     3-39
3-8  Nickel content of various classes of foods in U.S. diets 	    3-41

4-1  Serum nickel in healthy adults of several species 	     4-15
4-2  Tissue distribution of nickel(II) after parenteral
     administration 	     4-18

5-1  Rates of positive reactors in large patient and  population
     studies 	      5-10
5-2  North American contact dermatitis group patch test results 	      5-12
5-3  Hand eczema in persons sensitive to nickel 	      5-12

7-1  Mutagenicity evaluation of nickel:  gene mutations in
     prokaryotes	      7-2
7-2  The mutagenic effect of nickel chloride on a homoserine-
     dependent strai n of Cornebacterium	      7-4
7-3  Mutagenicity evaluation of nickel:  gene mutations in yeast
     and cultured mammalian cells 	      7-6
7-4  Mutagenicity evaluation of nickel:  in vitro chromosomal
     aberrations 	      7-9
7-5  Mutagenicity evaluation of nickel:  iiri vivo chromosomal
     aberrati ons	      7-10
7-6  Mutagenicity evaluation of nickel:  1^ vitro sister chromatid
     exchanges 	      7-15

8-1  Exposures by work area  (Clydach, Wales)  	      8-4
8-2  Percent of  lung and nasal cancer deaths among workers by year
     of entry and length of  employment (Clydach, Wales) 	      8-7
8-3  Clydach, Wales nickel refiners:  relative risks for lung and
     nasal  cancer mortality  in pre-1925 cohort, adjusting for
     concomitant factors 	      8-15
8-4  Minimum number of years of employment and years between first
     employment  and the beginning of follow-up for cohorts from the
     Clydach plant, defined  by year of first  employment 	      8-17
8-5  A priori causes of cancer deaths among Ontario  sinter
     pi ant  workers	      8-29
8-6  Nasal  cancer mortality  rate among Ontario sinter  plant
     workers with at least 15 years of exposure,  by  duration
     of exposure 	      8-33
8-7  Mortality 1950-1976 by  exposure category  for lung, laryngeal,
     and  kidney  cancer, at Falconbridge,  Ltd., Ontario 	      8-38
8-8  Standardized mortality  ratios  (SMRs) for selected causes of
     death  among nickel workers and  unexposed workers  	     8-65

                                    xi i

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                             LIST OF TABLES (continued)
8-9  Possible nickel exposures and levels of exposure by category of
     work in the high-nickel alloy industry 	      8-73
8-10 Industries for which epidemiologic studies of cancer risks
     from nickel exposure have been reviewed 	      8-86
8-11 Summary of cancer risks by nickel industry and worker
     groups 	      8-88
8-12 Hyperplastic and neoplastic changes in lungs of rats exposed
     to nickel sulfide 	      8-98
8-13 Experimental studies of nickel subsulfide carcinogenesis 	      8-106
8-14 Species differences to Ni3S2:  intramuscular injection 	      8-109
8-15 Strain differences in rats to Ni3S2: intramuscular injection 	      8-109
8-16 Strain differences:  carcinogen!city of Ni3S2 after a single
     intrarenal injection in four rat strains 	      8-110
8-17 Route of administration differences and dose-response:
     carcinogenicity of Ni3S2 in male Fischer rats 	      8-111
8-18 Experimental studies of nickel metal carcinogenesis 	      8-113
8-19 Experimental studies of nickel oxide carcinogenesis 	      8-117
8-20 Experimental carcinogenesis studies of nickel refinery and
     other dusts 	      8-120
8-21 Experimental carcinogenesis studies of soluble and sparingly
     soluble nickel compounds 	      8-121
8-22 Experimental carcinogenesis studies of specialty nickel
     compounds 	      8-124
8-23 Potentiations and inhibitions of nickel compounds with other
     agents 	      8-126
8-24 Rank correlations between chemical and biological parameters
     of nickel compounds 	      8-132
8-25 Biological characteristics of nickel compounds 	      8-133
8-26 Summary of survival data and sarcoma incidences in carcino-
     genesis tests by intramuscular injections of 18 nickel
     compounds 	      8-134
8-27 Cancers in the injected kidney of rats following intrarenal
     injection of nickel compounds 	      8-136
8-28 Relationship between phagocytosis and induction of morphological
     transformation by specific metal compounds 	      8-140
8-29 Mammalian cell transformation by nickel 	      8-141
8-30 Summary of animal and iji vitro test results of specific
     nickel compounds 	      8-144
8-31 Hyperplastic and neoplastic changes in lungs of rats exposed
     to nickel sulfide 	      8-161
8-32 West Virginia nickel refinery and alloy workers (non-refinery):
     observed and expected deaths from larynx and lung cancer
     and SMR for male nickel workers 20 years after first exposure
     by cumulative nickel exposure up to 20 years from onset of
     exposure	      8-167
8-33 Copper Cliff refinery workers: lung cancer incidence and
     deaths by seven weighted exposure subgroups, follow-up from
     January 1963 to December 1978	      8-169
                                   xm

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                             LIST OF TABLES (continued)


                                                                           Page

8-34 Copper Cliff sinter plant:  lung cancer mortality 15-29 years
     since first exposure by workers first exposed before and since
     1952, by duration of exposure 	      8-171
8-35 Clydach, Wales nickel refinery workers:  total mortality by
     year of first employment	      8-173
8-36 Clydach, Wales nickel refinery workers:  lung cancer mortality
     by duration of years in calcining furnaces before 1925
     (chi-square tests) 	      8-174
8-37 Clydach, Wales nickel refinery workers:  lung cancer mortality
     by type and duration of exposure for men first employed before
     1925 	      8-174
8-38 Clydach, Wales nickel refinery workers:  lung cancer mortality
     by time since first exposure for workers exposed before 1925 	      8-176
8-39 Kristiansand, Norway data:   ratio between observed and expected
     number of cases of lung cancer among Norwegian nickel workers
     before and after adjustment for smoking habits 	    8-177
8-40 Kristiansand, Norway data:  age-standardized incidence of cancer
     of the lung among nonsmokers and smokers in a sample of the
     general population of Norway and among employees at the nickel
     refinery 	      8-178
8-41 Data used to estimate A and its variance: Enterline and Marsh
     refi nery workers subgroup 	      8-182
8-42 Expected lung cancer deaths based on the additive and relative
     risk models and bounds fitted to the Enterline and Marsh
     refinery data	      8-185
8-43 Data used to estimate A and its variance: Enterline and Marsh
     non-refinery workers pre-1947 subgroup 	      8-186
8-44 Expected lung cancer deaths based on the additive and relative
     risk models and bounds fitted to the Enterline and Marsh pre-1947
     non-refinery workers data 	    8-187
8-45 Estimated risks for the additive and multiplicative models based
     on the Enterline and Marsh refinery workers data	    8-189
8-46 Estimated risks for the additive and multiplicative models
     based on the Enterline and Marsh non-refinery workers data 	    8-190
8-47 Data on lung cancer deaths used to estimate A and its variance:
     Copper Cliff refinery workers (Chovil et al.) relative risk
     model only  	   8-192
8-48 Estimation  of fraction of lifetime exposed to nickel in the
     workplace,  Clydach, Wales 	   8-195
8-49 Estimates of incremental unit risks for  lung cancer due to
     exposure to 1 ug Ni/m3 for a lifetime based on extrapolations
     from epidemiologic data sets 	   8-196
8-50 Relative carcinogenic potencies among 55 chemicals evaluated by
     the Carcinogen Assessment Group as suspect human  carcinogens  	   8-199
                                     xiv

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                                LIST OF FIGURES
3-1  Nickel hydrolysis distribution diagram 	     3-6
3-2  Concentrations of nickel in surface waters, 1982 	     3-33
3-3  The global cycle of nickel  on a one-year frame 	     3-44

7-1  The+relationship between the lethal and mutagenic effect of
     Ni2  by means of the clone  method 	     7-5

8-1  Histogram representing the  frequency distribution of the
     potency indices of 55 suspected carcinogens evaluated by the
     Card nogen Assessment Group 	     8-198
                                    xv

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                             AUTHORS AND REVIEWERS
The principal authors of this document are:

Dr. Steven Bayard
Carcinogen Assessment Group
U.S. Environmental Protection Agency
Washington, D.C.

Dr. Robert Beliles
Carcinogen Assessment Group
U.S. Environmental Protection Agency
Washington, D.C.

Mr. Garry Brooks
Radian Corporation
Research Triangle Park, North Carolina

Dr. Margaret Chu
Carcinogen Assessment Group
U.S. Environmental Protection Agency
Washington, D.C.

Dr. Annemarie Crocetti
New York Medical College
New York, New York

Mr. Herman Gibb
Carcinogen Assessment Group
U.S. Environmental Protection Agency
Washington, D.C.

Dr. Gary Kimmel
Reproductive Effects Assessment Group
U.S. Environmental Protection Agency
Washington, D.C.

Dr. Kantharajapura S. Lavappa
U.S. Food and Drug Administration
Washington, D.C.

Dr. Steven Lavenhar
ICAIR  Life Systems,  Inc.
Cleveland, Ohio

Dr. Genevieve Matanoski
Department of Epidemiology
Johns  Hopkins University
Baltimore, Maryland
                                    xvi

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Dr.  Paul Mushak
Department of Pathology
University of North Carolina
Chapel Hill, North Carolina

Dr.  Carol Newill
Department of Epidemiology
Johns Hopkins University
Baltimore, Maryland

Ms.  Donna Sivulka
Environmental Criteria and Assessment Office
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina

Dr.  Walter Stewart
Department of Epidemiology
Johns Hopkins University
Baltimore, Maryland

Contributing authors are:

Ms.  Patricia Cruse
Radian Corporation
Research Triangle Park, North Carolina

Dr.  John DeSesso
Mitre Corporation
McLean, Virginia

Mr.  Richard Pandullo
Radian Corporation
Research Triangle Park, North Carolina
 Project Manager:

 Ms. Donna  Sivulka
 Environmental  Criteria  and Assessment  Office
 U.S.  Environmental  Protection  Agency
 Research Triangle  Park,  North  Carolina

 Special assistance  to the project manager  provided  by  Ms.  Darcy Campbell.

 The cardnogenicity chapter was  reviewed by the  Carcinogen Assessment Group
 (CAG)  of the  U.S.  Environmental  Protection Agency.   Participating members  of
 the CAG are:

 Roy E. Albert, M.D.  (Chairman)
 Elizabeth  L.  Anderson,  Ph.D.
 David L. Bayliss,  M.S.
 Chao  W. Chen,  P.O.
 Bernard H.  Haberman, D.V.M., M.S.
 Charalingayya B. Hiremath,  Ph.D.
 Robert E.  McGaughy, Ph.D.

                                    xvi i

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Jean C. Parker, Ph.D.
Charles H. Ris, M.S.,  P.E.
Dharm V. Singh, D.V.M., Ph.D.
Todd W. Thorslund, Sc.D.


     In addition, there are several scientists who contributed valuable
information and/or constructive criticism to successive drafts of this report.
Of specific note are the contributions of Gerald Akland, Mike Berry, Joseph
Borzelleca, Thomas Clarkson, Christopher DeRosa, Philip Enterline, Lester Grant,
Paul Hammond, Ernest Jackson,  Casy Jason, Dinko Kello, Donna Kuroda, Si Duk Lee,
Debdas Mukerjee, Charles Nauman, Magnus Piscator, John Schaum, Steven Seilkop,
Robert Shaw, Samuel Shibko, William Sunderman, and Stuart Warner.


             SCIENCE ADVISORY BOARD ENVIRONMENTAL HEALTH COMMITTEE


     An earlier draft of this document was independently peer-reviewed in
public session by the Environmental Health Committee, Environmental Protection
Agency, Science Advisory Board.  The following were members of that Committee:


Chairman, Environmental Health Committee

Dr.  Herschel E. Griffin, Associate Dean, College of Human Services, San Diego
     State University, San Diego, California  92182

Director, Science Advisory Board

Dr.  Terry F. Yosie, Science Advisory Board, U.S. Environmental Protection
     Agency, Washington, D.C.   20460

Executive Secretary

Mr.  Ernst Linde, Scientist Administrator, Science Advisory Board,  A-101,  U.S.
     Environmental Protection Agency, Washington, D.C.  20460


Members

Dr.  Herman E. Collier Jr.,  President, Moravian College, Bethlehem,
     Pennsylvania  18018

Dr.  Morton Corn, Professor and Director, Division of Environmental Health
     Engineering, School of Hygiene and Public Health, The Johns Hopkins
     University, 615 N.  Wolfe Street, Baltimore, Maryland  21205

Dr.  John Doull, Professor of Pharmacology and Toxicology, University of Kansas
     Medical Center,  Kansas City, Kansas  66207
                                  xvm

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Dr.  Jack D.  Hackney, Chief, Environmental  Health Laboratories,  Professor of
     Medicine, Rancho Los Amigos Hospital  Campus of the University of Southern
     California, 7601 Imperial Highway, Downey,  California  90242

Dr.  Marvin Kuschner, Dean of School  of Medicine, Health Science Center,
     Level 4, State University of New York, Stony Brook, New York  11794

Dr.  Daniel Menzel,  Director and Professor, Pharmacology and Medicine,
     Director, Cancer Toxicology and Chemical Carcinogenesis Program, Duke
     University Medical Center, Durham, North Carolina  27710

Dr.  D.  Warner North, Principal, Decision Focus Inc., Los Altos  Office Center,
     Suite 200, 4984 El Camino Real, Los Altos,  California  94022

Dr.  William J. Schull, Director and Professor of Population Genetics, Center
     for Demographic and Population Genetics, School of Public  Health,
     University of Texas Health Science Center at Houston, Houston, Texas
     77030

Dr.  Michael J. Symons, Professor, Department of Biostatisties,  School of
     Public Health, University of North Carolina, Chapel Hill,  North Carolina
     27711
Consultants

Dr. Seymour Abrahamson, Professor of Zoology and Genetics, Department of
     Zoology, University of Wisconsin, Madison, Wisconsin  53706

Dr. Thomas W. Clarkson, Professor and Head, Division of Toxicology, University
     of Rochester, School of Medicine, P.O. Box RBB, Rochester, New York
     14642

Dr. Edward F. Ferrand, Assistant Commissioner for Science and Technology, New
     York City Department of Environmental Protection, 51 Astor Place, New
     York, New York  10003

Dr. Ronald D. Hood, Professor, Department of Biology, P.O. Box 1927,
     University of Alabama, University, Alabama  35486

Dr. William F. Sunderman, Jr., Professor of Laboratory Medicine and Pharmacology,
     and Head of Department of Laboratory Medicine, University of Connecticut
     Health Center, Room C 2021, Farmington, Connecticut  06032

Dr. Bernard Weiss, Professor, Division of Toxicology, P.O. Box RBB, University
     of Rochester, School of Medicine, Rochester, New York  14642
                                     xix

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                             TECHNICAL ASSISTANCE


     Project management, editing, production, and word processing from Northrop
Services, Inc. and WAPORA, Inc., under contract to the Office of Health and
Environmental Assessment:

Ms. Barbara Best-Nichols
Mr. David C. Brock
Ms. Anita Flintall
Ms. Kathryn Flynn
Ms. Miriam Gattis
Ms. Lorrie Godley
Ms. Rhoda Granat
Ms. Varetta Powell
Ms. Shelia Ross
Ms. Carolyn Stephens
Ms. Patricia Tierney
Ms. Jane Winn
Ms. Sharon Woods
     Word processing and other technical assistance at the Office of Health  and
Environmental Assessment:

Ms. Frances P. Bradow
Mr. Doug Fennel 1
Ms. Lisa Gray
Mr. Allen Hoyt
Ms. Barbara Kearney
Ms. Theresa Konova
Ms. Emily Lee
Ms. Marie Pfaff
Ms. Diane Ray
Ms. Tonya Richardson
Ms. Scottie Schaeffer
Ms. Judy Theisen
Ms. Donna Wicker
                                     xx

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                              1.  INTRODUCTION
     In September,  1983,  EPA's  Office of Health and Environmental Assessment
(OHEA) presented  an external  review draft of the Health Assessment  Document
for Nickel  to  the general public and to the Science Advisory Board  (SAB) of
the U.S.  Environmental  Protection  Agency.   At a public meeting  in which the
document was reviewed,  the SAB  advised EPA to assess health risks associated
with specific nickel compounds.
     In response  to the SAB's advice, the Agency initiated  a research project
to study  the health effects associated with exposure to specific nickel com-
pounds, as determined from reanalyses of epidemiologic studies.   This study is
a collaborative effort  of the EPA; the Ontario Ministry of Labour;  National
Health and  Welfare,  Canada; the Nickel Producers Environmental Research Asso-
ciation; and the  Commission of  European Communities.  The  results from this
research  project  are expected  to  be available in mid-1987.  The EPA also
undertook to  revise the  Health Assessment Document for Nickel  to provide
analyses of individual nickel compounds based upon existing information where
possible.
     The revised  document is  organized  into chapters which include an execu-
tive summary of the information contained within the text  of later  chapters
(Chapter 2); background information on the chemical and environmental aspects
of nickel,  including levels of  various  nickel compounds in media with which
the U.S.  population comes  into contact  (Chapter  3);  information on nickel
metabolism,  where  factors of  absorption,  tissue distribution, and excretion
are discussed  with reference to the  toxicity  of  specific   nickel compounds
(Chapter 4); information on nickel  toxicity,  where acute,  subacute, and chronic
health effects of various nickel  compounds in man and animals are discussed
(Chapter  5);  information  on developmental and  reproductive effects  due to
exposure  to  nickel compounds (Chapter  6);  nickel  mutagenesis information,
where the ability of nickel compounds to cause mutations  and other genotoxic
effects are presented  (Chapter  7);  information on carcinogenesis, including
dose-effect  and dose-response relationships  (chapter 8);  and information on
nickel  as an essential element (Chapter  9).
                                   1-1

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     This report is not intended to be an exhaustive review of all the nickel
literature,  but  is focused upon those  data thought to be most  useful  and
relevant for human  health  risk assessment purposes.  Particular emphasis  is
placed on the delineation of health effects and risks associated with exposure
to airborne nickel.   The  primary  purpose of this  document  is  to serve as a
basis for decision-making regarding the regulation of nickel  and nickel  compounds
as hazardous air pollutants under pertinent sections of the Clean Air Act, as
amended in 1977.   Health  effects  associated with  the ingestion of nickel  or
with  exposure  via  other  routes are also discussed, providing a  basis  for
possible use for multimedia risk assessment purposes as well.  The background
information provided at the outset on sources,  emissions,  and ambient concentra-
tions of nickel compounds  in various media  is presented in order to provide a
general perspective  against which  to  view the  health  effects  evaluations
contained in later chapters of the document.
     As evidenced  by  the  EPA's participation in further research,  the Agency
recognizes that the  regulatory decision-making process  is a continuous one.
As new  information  that  would warrant a re-evaluation of the present report
becomes available, the Agency  will  undertake to evaluate  this  information as
part of its mandate to protect the health of the general  population.
                                   1-2

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                         2.   SUMMARY AND CONCLUSIONS
2.1  BACKGROUND INFORMATION
2.1.1  Chemical/Physical Properties of Nickel and Nickel Compounds
     Nickel is  found in  nature  as a  component  of silicate, sulfide, or,
occasionally,  arsenide  ores.   It  is a valuable mineral commodity because of
its  resistance  to corrosion and  its  siderophilic nature which facilitates
the  formation  of  nickel-iron  alloys.   Stainless steel is the most well-known
alloy; others  include permanent  magnet  and super alloys,  used  in  radios,
generators and  turbochargers,  and copper-nickel  alloys, used when resistance
to extreme  stress and temperature  is  required.   Other  uses for nickel and
its  compounds  include  electroplating  baths, batteries,  textile  dyes and
mordants, and catalysts.
     As  a  member of  the  transition metal  series,  nickel is resistant to
alkalis,  but  generally dissolves  in  dilute oxidizing  acids.   Nickel may
                                                              2+
exist  in many  oxidation  states,  the  most  prevalent being Ni  .   Of  some
commercial  and/or environmental  significance  are  several  binary  nickel
compounds  including  nickel  oxide  (both black,  which  is chemically reactive,
and  green,  which is  inert and refractory)  and  complex oxides of nickel,
nickel sulfate,  nickel nitrate,  nickel carbonate,  nickel hydroxide,  nickel
sulfide  and nickel carbonyl.

2.1.2  Nickel in the Ambient Air
      In  the  atmosphere,  nickel  is present  as  a constituent of  suspended
particulate  matter.   The  primary stationary source  categories  that  emit
nickel into ambient  air are:   primary production sources (nickel ore mining/
smelting and  nickel  matte  refining);  combustion  and incineration sources
(coal  and  oil  burning units in utility,  industrial,  commercial and residen-
tial  use  sectors,  and municipal and sewage  sludge incinerators);  high
temperature metallurgical  sources (steel  manufacturing,  nickel alloy  manufac-
turing,  secondary nickel  smelting, secondary nonferrous  metals smelting  and
gray iron  foundries);  chemical and catalyst sources (nickel chemical manu-
facturing, electroplating,  nickel-cadmium battery manufacturing and catalyst
production,  use  and  reclamation); and  miscellaneous sources (co-product
nickel recovery,  cement  manufacturing, coke ovens,  asbestos mining/milling
and  cooling towers).

                                    2-1

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     While nickel in  its  elemental  state can be measured in the ambient air,
determination of specific compounds is difficult to achieve.  Techniques used
to break down inorganic compounds into their ionic or atomic states change the
form of the  compound  in the attempt to determine the total concentration of
the element.   In addition, the very low level of nickel  present in ambient air
samples (average  of 0.008 ug/m  ;  1982  figures) complicates the situation.
Nevertheless, by analyzing the physical  and chemical  properties of nickel, the
forms of nickel  input to various source processes, and the reaction conditions
encountered  in  various  source categories,  it  is possible to estimate forms of
nickel  emitted  into the ambient air.   From such analyses, the predominant
forms appear to be  nickel  sulfate, complex oxides of nickel and other metals
(chiefly iron),  nickel oxide, and to a much lesser extent, metallic nickel and
nickel  subsulfide.  Of  the  total volume of  nickel emitted into the ambient
air, the greatest contribution is from the combustion of fossil fuels in which
nickel appears to be in the form of nickel sulfate, followed by lesser amounts
of nickel  oxide and complex oxides of nickel.

2.1.3  Nickel in Ambient and Drinking Water
                                   2+
     Nickel  is  usually  found as Ni   in  aquatic  systems.   Chemical factors
which can  affect  the  form of nickel  in  aquatic systems include pH  and  the
presence of  organic and inorganic  ligands.   Nickel is found in  ambient waters
as a result of chemical and physical degradation of rocks and soils, deposition
of atmospheric nickel-containing particulate matter,  and direct (and indirect)
discharges from industrial  processes.  Of the anthropogenic sources of  nickel
in  water,  primary  nickel  production,  metallurgical  processes, fossil  fuel
combustion and  incineration, and chemical and catalyst production are predomi-
nant.
     Measurements of  nickel  in  aqueous  environments  are generally  reported  as
total  nickel.   The  mean concentration  of nickel  in U.S.  surface waters  (based
upon 1982  figures)  ranges from less than 5 ug/1 in the Great Basin  of southern
Nevada  to  greater than 600 ug/1 in the  Ohio River Basin.   Concentrations  in
groundwater  are also  highly variable  with means ranging from  4430  ug/1  in the
Ohio River basin to 2.95 ug/1 in the Upper Mississippi River basin  (based upon
1982  figures).   A mean nickel concentration  of 4.8  ug/1  has  been  calculated
for  drinking water  from eight metropolitan  areas  (based upon 1970 figures).
                                    2-2

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     Specific forms of nickel  in ambient waters
determinations of  species expected to be fDund
on the nature of source processes and the
species in  wastewaters from the major  anthropogenic
include dissolved  salts  (such  as sulfate,
oxides of nickel and other metals,  and metil
      have not been reported; however,
     in effluents can be made based
Aqueous chemistry of nickel.   Nickel
            sources  are likely to
 chloride and phosphate),  insoluble
  lie nickel powder.
2.1.4  Nickel in Soil  and Sediment
     Many of the same chemical  and physical  properties which govern the behavior
of nickel in aqueous environments also affect the behavior of nickel in soils
and sediments.   In soils, nickel may exist in several forms such as inorganic
crystalline minerals or precipitates, as free ion or chelated metal complexes
in soil  solution, and as complexed with, or adsorbed to, inorganic cation ex-
change surfaces such as clays.
     Naturally occurring nickel in soils depends upon the elemental composition
of rocks in the upper crust of the earth.   The natural concentration of nickel
in soils usually ranges from 5 to 500 ppm, with an average level estimated at
50 ppm.  Soils  derived from serpentine rock (naturally high in nickel  content)
may contain nickel levels up to 5000 ppm.  Anthropogenic sources of nickel to
soils  include  emissions from  primary smelters and metal refineries, disposal
of sewage sludge or application of sludge as a fertilizer,  auto emissions, and
emissions from electric power utilities; the most significant of these sources
being  smelting and refining operations and sludge  applications.   Depending
upon the source, nickel  soil  concentrations have been reported to range from
0.90 ppm (from auto emissions) to as much as 24,000 ppm (near metal refineries)
to 53,000 ppm  (from  dried  sludge).   These figures are  based  upon elemental
nickel as specific forms of nickel in soils have not been reported.

2.1.5  Nickel  in Plants and Food
     The primary  route for nickel  accumulation in plants  is  through  root
uptake from soil.  Nickel  is  present in vegetation  usually  below the 1 ppm
level, although  plants grown  in  serpentine soils have been  shown to  have
nickel concentrations  as  high as 100 ppm.  For  crops  grown in soils where
sewage sludge  has  been  applied,  nickel  concentrations  have been reported to
range from 0.3 to 1150 ppm.
                                   2-3

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     In addition to nickel  uptake via soils, food processing methods have been
shown to add to nickel levels already present in foodstuffs via leaching from
nickel-containing alloys in  food-processing equipment,  the milling of flour,
and the catalytic  hydrogenation  of fats and oils by use of nickel  catalysts.
The nickel content of various classes of food in U.S. diets has been  reported
to range from  0.02 ppm  (wet weight) in food  items  such as fresh tomatoes,
frozen swordfish and  pork  chops  to 1.50 ppm in fresh oysters and 1.70 ppm in
salmon.

2.1.6  The Global Cycling of Nickel
     Nickel in  all  environmental  compartments  is continuously transferred
between compartments by natural  chemical and physical processes such as weather-
ing, erosion,  runoff, precipitation,  stream/river flow and leaching.   Nickel
introduced into the environment  by anthropogenic means  is  subject to  the same
chemical and physical  processes,  but can account for increased ambient concen-
trations in all  environmental  compartments.  The ultimate sink for nickel  is
the ocean; however, the cycle is  continuous because some nickel will leave the
ocean  as sea  spray aerosols which burst and release minute nickel-containing
particles into the atmosphere.
2.2  NICKEL METABOLISM
2.2.1  Absorption
     Routes of nickel intake for man and animals are inhalation, ingestion and
percutaneous  absorption.   Parenteral exposure  is  mainly  of  importance in
experimental animal studies.
     The  relative  amount of inhaled  nickel  which  is absorbed  from  various
compartments of the pulmonary tract is a function of both chemical and physical
forms.   Insoluble  particulate nickel  deposited in the various  respiratory
compartments in both occupationally exposed subjects and the general population
is very slowly absorbed with accumulation over time.  Experimental animal data
show very slow clearance of deposited insoluble nickel oxide from the respira-
tory  tract,  moderate clearance  (around  3  days)  of the carbonate and  rapid
clearance (hours to  several days) of soluble  nickel  salts.   In the case of
nickel  oxide,  clearance  from lung involves  both direct  absorption into the
blood  stream  and  clearance via  the lymphatic system.  While most respiratory
                                    2-4

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absorption  studies  demonstrate that  differences  in  compound  solubilities
relate to pulmonary  clearance,  with inert compounds having relatively slower
clearance, the relationship of respiratory absorption to pathogenic effects is
still not clearly understood.
     Gastrointestinal intake of nickel  by man is  relatively high compared to
other toxic elements  and  can  be partially accounted  for by contributions of
nickel from utensils and equipment in processing and home preparation of food.
Average human dietary values range from 300 to 500 ug daily with absorption on
the order of one to ten percent.  Recent studies show that nickel bioavailabi-
lity in human diets appears to be dependent on dietary composition.
     Percutaneous absorption of nickel occurs and is related to nickel-induced
hypersensitivity and  skin disorders;  however,  the extent  to  which nickel
enters the  bloodstream  by way of the  skin cannot be stated at  the  present
time.  Transplacental transfer  of nickel  has been evidenced in rats and mice
and several reports indicate that such passage can also occur in man.

2.2.2  Transport and Distribution
     The  kinetic processes  governing  the  transport  and  distribution  of  nickel
in various  organisms  are  dependent  upon the  modes of  absorption,  the rate  and
level of  nickel  exposure, the chemical form  of nickel  and  the  physiological
status of the organism.   Absorbed nickel is carried by the blood, and although
the  extent  of partitioning  between  erythrocytes and plasma  or  serum  cannot be
precisely stated,  serum levels can be useful indicators of blood burden and,
to a more limited extent, exposure status (excluding exposure to  insoluble and
unabsorbed  nickel deposited in  lungs).  In unexposed individuals, serum nickel
values are  approximately 0.2 to 0.3 ug/dl.  Albumin is the main macromolecular
carrier of  nickel  in a number  of species,  including man, while  in  man and
rabbit there  also appear to be  nickel-specific  proteins.
     Tissue distribution  of absorbed nickel  appears  to  be  dependent on the
route of  intake.   Inhaled nickel  carbonyl leads  to highest levels  in  lung,
brain, kidney, liver, and adrenals.   Parenteral administration of nickel salts
usually results in highest  levels in  the kidney,  with significant uptake shown
by endocrine  glands,  liver, and lung.  Nickel absorption and tissue  distribution
following oral  exposure appear to be  dependent upon  the relative amounts  of
the  agent employed.  Animal  studies  suggest  that  a homeostatic mechanism
exists to regulate low levels  of nickel intake (around 5 ppm),  but  that such
regulation  is overwhelmed in the face of  large levels of  nickel challenge.

                                    2-5

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     Based on animal  studies,  nickel  appears to have a very short half-time in
the body of several days with little evidence for tissue accumulation.  Human
studies have shown that age-dependent accumulation of nickel appears to occur
only in the case of the lung with other soft and mineralizing tissues showing
no accumulation.  There are very few data concerning nickel tissue levels and
total  body burden in humans.  One estimate  is that the total nickel burden in
man is about 10 mg.

2.2.3  Excretion
     The excretory routes for nickel in man and animals depend in part on the
chemical forms  of nickel  and  the mode of nickel intake.  Unabsorbed dietary
nickel  is lost  in the feces.  Urinary excretion in man and animals is usually
the major clearance route  for absorbed nickel, with biliary  excretion  also
occurring in experimental  animals.   Sweat can also  constitute a major route of
nickel  excretion.   Recent studies  suggest  that normal  levels  of nickel in
urine vary from 2 to 4 ug/1.
     While hair deposition of  nickel  also appears  to be an excretory mechanism,
the relative magnitude of  this  route,  compared to urinary excretion, is not
fully known at present.

2.2.4  Factors Affecting Nickel  Metabolism
     A  number of disease states or other physiological stresses can influence
nickel metabolism in man.   In  particular,  heart and renal  disease,  burn trauma,
and heat exposure can  either  raise or lower serum  nickel  levels.   To what
extent  factors  such as  age or nutritional  status  affect nickel  metabolism in
man is  presently unknown.  In  animals,  both  antagonistic  and  synergistic
relationships have been demonstrated  for  both nutritional factors and other
toxicants.
2.3  NICKEL TOXICOLOGY
2.3.1  Subcellular and Cellular Aspects of Nickel Toxicity
     Nickel, as the divalent ion, is known to bind to a variety of biomolecular
species,  such  as  nucleic acids and proteins,  as well  as their constituent
units.  Strongest  interactions  occur  with sulfhydral,  aza- and ami no groups
with binding to peptide (amido) and carboxylate ligands also possible.
                                   2-6

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     A number of  reports  in the literature describe  various  iji vivo and jji
vitro effects of various nickel  compounds on enzyme systems as well as nucleic
acid and  protein  biosynthesis.    In  particular, effects are  seen  on drug-
detoxifying enzymes  in various  tissues,  enzymes that mediate  carbohydrate
metabolism and enzymes  that mediate  transmembrane transport,  such as ATPase.
     A number of  ultrastructural  alterations  are seen in cellular organelles
from experimental animals exposed to various nickel compounds.  Most  of  these
changes involve the  nucleus  and mitochondria and range from slight changes  in
conformation to evidence of degeneration.
     The behavior of cells  in culture exposed  to  nickel  compounds has been
reported from different laboratories.  Nickel ion, at varying  levels,  affects
both viability  and   phagocytic activity  of alveolar macrophages,  which  may
explain the  role  of  nickel  in retarding  resistance to respiratory tract in-
fections in animal models.
     Nickel-induced  human  lymphocyte transformation  has  been studied as  a
sensitive  iji vitro  screening technique for nickel hypersensitivity  and  this
procedure  appears to be a reliable alternative  to  classical  patch testing.
     Various studies have been directed to the response of cells in culture to
insoluble  nickel  dusts  which are implicated in  human and experimental animal
carcinogenesis.   In  particular, rat embryo myoblasts  show drastic  reduction of
mitotic index and viability when exposed to nickel subsulfide.

2.3.2  Acute Effects of Nickel Exposure
     In terms of  human  health effects, probably the most  acutely  toxic nickel
compound  is  nickel  carbonyl  Ni(CO)4,  exposure to which has  been through  acci-
dental release  to nickel-processing  workers.  Acute nickel  carbonyl  poisoning
is clinically manifested by both immediate and delayed symptomology.  With the
onset of the delayed, insidious symptomology there is constrictive chest pain,
dry  coughing,   hyperpnea,  cyanosis,  occasional  gastrointestinal   symptoms,
sweating,  visual  disturbances,  and severe weakness.  Most  of these  symptoms
strongly resemble those of viral pneumonia.
     The lung is the target  organ in nickel carbonyl  poisoning  in  both man and
animals.   The pathological  pulmonary lesions observed in  acute human exposure
include pulmonary hemorrhage, edema and  cellular derangement.   Patients  survi-
ving an acute episode of exposure may be  left with pulmonary  fibroses.
                                    2-7

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2.3.3  Chronic Effects of Nickel Exposure
2.3.3.1  Dermatological Aspects of Nickel.  Nickel dermatitis and other derma-
tological effects of nickel have been documented in both nickel worker popula-
tions and  populations  at large.  Originally considered  to  be a problem  in
occupational medicine, the  more recent clinical and epidemiological  reports
suggest that nonoccupational  exposures to nickel-containing commodities  may
present significant problems to the general populace.   Nonoccupational exposure
to nickel  leading to dermatitis  includes  nickel-containing jewelry,  coins,
tools, cooking utensils,  stainless-steel  kitchens, prostheses, and clothing
fasteners.
     Clinically,   nickel  dermatitis is  usually  manifested  as  a papular or
papulovesicular dermatitis  with a  tendency toward  lichenification, having the
characteristics of atopic  rather  than  eczematous dermatitis.   The hand  eczema
associated with nickel allergy appears to be of the pompholyx type,  i.e., a
recurring itching eruption with deeply seated fresh vesicles and little erythema
localized on the  palms, volar aspects, and sides of fingers.
     A role for oral nickel  in  dermatitic responses by sensitive subjects has
recently been described.   Nickel-limited diets  in  one clinical  trial  resulted
in marked improvement of hand eczema in half of the subjects while in a second
study, nickel  added to the diets of patients appeared to aggravate the allergic
response.   Further  study  of  oral  nickel-nickel  sensitivity  relationships
should be conducted.
     Nickel-containing implanted prostheses  may provoke  flare-ups of nickel
dermatitis in nickel-sensitive individuals.   The extent of this problem appears
to depend  on the  relative ease with which nickel  can be solubilized from the
surface .of the devices by action of extracellular fluid.
     The underlying mechanisms of nickel sensitivity presumably include diffu-
sion of nickel  through the skin and subsequent binding of nickel ion.
     Useful animal experimental models  of nickel sensitivity are few  and  have
been conducted only under very specialized conditions.
2.3.3.2  Respiratory Effects of Nickel.  Noncarcinogenic effects of nickel in
the human  respiratory  tract mainly derive from studies of  nickel workers in
various production categories who have been exposed to various forms of nickel.
In the aggregate,  assessment of available human and animal  data show two areas
of possible concern for humans:  (1) direct respiratory effects such as asthma,
nasal septal perforations, and chronic rhinitis and sinusitis; and (2) increased
                                    2-8

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risk for  chronic respiratory  tract  infections secondary to  the  effect of
nickel  on the respiratory immune system.
2.3.3.3  Endocrine Effects of Nickel.  A number of effects of nickel on endo-
crine-mediated physiological processes have  been  observed.   In carbohydrate
metabolism, nickel induces a rapid transitory  hyperglycemia in rats, rabbits,
and domestic fowl after parental exposure to nickel  (II) salts.   These changes
may be  associated with effects  on  alpha and beta cells  in  the  pancreatic
islets  of Langerhans.   Nickel  also appears to affect the hypothalamic tract in
animals, decreasing the release  of prolactin.  Decreased  iodine uptake by  the
thyroid has also  been  observed when nickel  chloride  is inhaled or  ingested.
Human endocrine  responses to nickel  have been  poorly  studied, although hyper-
glycemia has been reported in workmen accidentally exposed to nickel carbonyl.
2.3.3.4  Cardiovascular Effects of Nickel.   Experimental and clinical observa-
tions suggest that exogenous  nickel  (II) ion,  and possibly endogenous nickel
(II), has a marked vasoconstrictive action on coronary vessels.   Recent studies
show that  such  action  may be operative in patients with  ischemlc myocardial
injury  and in burn patients.   The large transitory rise in serum nickel  attend-
ing childbirth may similarly  be related  to  a  vasoconstrictive  action  which
results in a minimization of atonic bleeding.  Whether excessive nickel  exposure
in occupational  or nonoccupational populations  could exacerbate ischemic heart
disease or enhance the risk of myocardial  infarction in subjects  with coronary
artery  disease is unknown but merits further study.
2.3.3.5  Reproductive and Developmental Effects of Nickel.  Exposure to nickel
has been shown to cause both reproductive and developmental  effects in experi-
mental  animals;  however, such effects have not  been noted in man.
     Specific reproductive  effects  seen  in  male  rats include degenerative
changes 1n the testis, epididymis and  spermatozoa.  Limited studies  in female
rats and hamsters  suggest an  effect on embryo  viability and the implantation
process.  Such effects have been noted in animals  exposed to excess amounts of
nickel.   In contrast,  1t  has  been demonstrated that  a deficiency of dietary
nickel  can also  lead  to reproductive effects  in  the  form of reduced Utter
sizes and decreased viability of newborn.
     With respect to developmental toxicity, nickel exposure of animals prior
to  Implantation  has  been  associated with delayed embryonic  development and
possibly with increased resorptions.   Structural  malformations have been noted
in avian species  exposed  to  nickel  salts.   While similar malformations have
                                    2-9

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also been seen  in  mammals,  the data have been  lacking  in sufficient detail
making determinations about  significance  difficult.   Teratogenic effects of
nickel carbonyl  in mammals  have  been demonstrated in two  rodent species.
2.3.3.6  Mutagem'c Effects of Nickel.  Various  inorganic  compounds  of nickel
have been tested for mutagenicity and other genotoxic effects in  a variety of
test systems.   From  these  tests  it appears  that nickel  may induce gene muta-
tions  in  bacteria  and  cultured  mammalian cells; however,  the  evidence is
fairly weak.  In addition,  nickel  appears to induce chromosomal  aberrations in
cultured mammalian cells and sister chromatid exchange in both cultured mamma-
lian  cells  and human  lymphocytes.   However, the  induction of  chromosomal
aberrations i_n vivo has not been observed.  More definitive studies are needed
to determine whether or not nickel is clastogenic.   Nickel does  appear to have
the  ability to induce  morphological  cell transformations  j_n vitro  and to
interact with  DNA  resulting  in cross-links  and strand breaks.   In aggregate,
studies have  demonstrated  the  ability of  nickel  compounds to induce  genotoxic
effects; however,  the  translation of these  effects into  actual  mutations  is
still not clearly understood.
2.3.3.7  Carcinogenic Effects of Nickel.   There is evidence both  in humans and
animals for the carcinogenicity of  nickel, at least in some forms.   The human
evidence of a cancer risk is  strongest  via  inhalation in the sulfide  nickel
matte  refining industry.   This evidence  includes  a consistency of findings
across many different  studies  in several different countries, specificity of
tumor site  (lung and nose), high relative risks, particularly for nasal cancer,
and  a dose-response relationship by length of exposure.   There are also animal
and  jn vitro  studies on nickel compounds which support the  concern that nickel,
at  least in some forms, should be considered carcinogenic.  The animal  studies
have employed mainly injection as  the route of exposure with  some  studies
using  inhalation  as  the exposure route.   While the majority of the compounds
tested in the  injection studies have caused tumors at the injection site only,
nickel acetate,  a  soluble salt, and  nickel  carbonyl  have caused distal site
primary tumors.   The relevance of  injection site  only  tumors 1n animals to
human  carcinogenic hazard  via  inhalation, ingestion,  or  cutaneous exposure is
uncertain.   Orally,  in animals,  three low-dose  drinking  water studies and one
diet study  with soluble nickel compounds  have not shown any increase  in tumors.
Thus,  nickel at least  in  some forms, should be considered carcinogenic to
humans via  inhalation, while the  evidence via ingestion  is  inadequate.
                                    2-10

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     Based on analysis of all the available data there are only three compounds
or mixtures of  nickel  compounds that can currently  be  classified as either
Group A (known human carcinogens) or B (probable human carcinogens), according
to EPA's classification  scheme  for evaluating carcinogens  (U.S.  EPA, 1984).
Nickel refinery dust from pyrometallurgical  sulfide nickel matte refineries is
classified as Group  A.   The fact that nickel  subsulfide  is a major nickel
component of this  refinery  dust, along with the evidence from animal and  i_n
vitro studies,  is  sufficient to conclude that nickel subsulfide  is also in
Group A.  While  there  is inadequate evidence from epidemiologic studies with
regard to evaluating the carcinogenicity of nickel  carbonyl, there is sufficient
evidence from animal studies to classify it as Group B2.  The available evidence
for other nickel compounds  is insufficient to  evaluate  their carcinogenicity.
However, there is a reasonable probability that the ultimate carcinogenic form
of nickel is the nickel  ion.  On this basis, all compounds  of nickel might  be
regarded as potential  human carcinogens,  with potency  differences  among the
compounds related  to  their  ability to enter the cell and be converted to the
nickel ion.   At the present, the bioavailability of different nickel compounds
is not well  understood.
     Quantitatively, several data  sets  from nickel refinery workers provide
sufficient exposure-response information  both  for  testing model fits and for
estimating incremental unit cancer risk.   While the data partially support the
use of  both  the additive and multiplicative excess  risk  models,  neither is
entirely satisfactory.   Using both  models  and four data sets, a range of
                                    C      *J  1            A      O*1
incremental  unit risks  from 1 x  10    (pg/m  )   to  6 x 10    (ug/m  )   has been
calculated.   Taking  the  midpoint of this range, the quantitative incremental
                                                          -4      3 -1
unit  risk  estimate for  nickel  refinery  dust is 3.0 x  10   (pg/m )  ;  the
quantitative unit  risk estimate for nickel  subsulfide,  the most carcinogenic
nickel compound  in animals  is twice  that  for nickel refinery dust.   Comparing
the potency  of nickel  subsulfide  to 54  other compounds  which  the EPA has
evaluated as suspect or  known human  carcinogens, nickel subsulfide  would rank
in the third quartile.
2.3.3.8  Other Toxic Effects of  Nickel.   Except  for  acute  fatal exposures to
nickel  carbonyl, nickel  compounds  appear to possess  low  general  neurotoxic
potential.    Lesions  observed in neural  tissue by nickel  carbonyl include
diffuse  punctate  hemorrhages,  neural fiber degeneration, and  marked edema.
     Nickel   subsulfide,  when administered intrarenally to  rats,  provokes  a
pronounced,  dose-dependent erythrocytosis associated with erythroid hyperplasia
                                    2-11

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in bone marrow.
     The effects of nickel  chloride on the cellular and humoral  immune responses
of mice have been studied.   Of particular note is the ability of nickel  chloride
to suppress the  activity of natural killer cells within 24 hours of a single
intramuscular injection.  Such cells are thought to be one of the first lines
of nonspecific defense against certain types of infection and tumors.
2.4  NICKEL AS AN ESSENTIAL ELEMENT
     There is a growing body of literature which establishes an essential  role
for nickel, at least in experimental animals.
     One key criteria  for element essentiality-existence of specific nickel-
deficiency syndromes—is reasonably satisfied for nickel.   Various researchers
have shown different  systemic  lesions in various animals  deprived of dietary
nickel.  Nickel  deprivation  has  an effect on body weight, reproductive capa-
bility, and  viability of offspring and induces an  anemia  through reduced
absorption of  iron.  Both antagonistic and synergistic interactions of nickel
with various  compounds have been noted  to affect  nutritional  requirements.
     Nickel also appears to be required in several  proteins and enzymes.   Jack
bean urease (and possibly rumen microbial urease) has been shown to be such an
enzyme.  Recent studies on the activation of the calmodulin-dependent phospho-
protein phosphatase, calcineurin, suggests that nickel (II) may play a physio-
logical role in the structural stability and full activation of this particular
enzyme.
     Further information  in  support of nickel as an essential  element is  the
apparent existence of a homeostatic mechanism for regulating nickel metabolism
and the existence of nickel  proteins in man and rabbit.   Although the evidence
for the role  of nickel in human physiology is  not conclusively  established,
the transitory  rise  in circulatory nickel observed shortly after parturition
has been linked to a possible role in control of atonic bleeding and placenta!
separation.
2.5  POPULATIONS AT RISK
     Among various subgroups of the U.S. population who may be at special risk
for adverse  effects  of nickel  are those who have nickel hypersensitivity and
suffer  chronic  flare-ups  of skin disorders with frank exposure.  Within this
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category would be Individuals predisposed to sensitization to nickel by virtue
of familial history.   In terms of the extent of nickel exposure among hyper-
sensitive individuals, women who are housewives seem to be at particular risk.
However, no data  base exists by which to determine the prevalence  of nickel
hypersensitivity in the general U.S. population.
     The extent to  which nickel  in inhaled cigarette  smoke  is a cofactor in
the demonstrated  association of smoking with various respiratory disorders is
not defined at present,  although recent studies have shown that the amount of
nickel in mainstream  smoke  is  minimal and that the  transfer of nickel  from
cigarettes to the lung is likely negligible.
     Nickel crosses the  placenta  barrier  in animals and  apparently in  man,
thus exposing the  conceptus  to nickel.   There  is  no  information  at present
that nickel exposure  jiji  utero  under conditions  of  nickel  exposure encountered
by pregnant women in the U.S. population leads to adverse effects.
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                       3.   NICKEL BACKGROUND INFORMATION
3.1  PHYSICAL AND CHEMICAL PROPERTIES OF NICKEL AND NICKEL COMPOUNDS
     Nickel is a silvery-white metal  usually found in nature as a component of
silicate,  sulfide,  or,  occasionally,  arsenide  ores.   Although  the nickel
content of some nickel-containing minerals is relatively high (up to 70 percent
for heazlewoodite), it  actually  constitutes only about 0.008 percent of the
earth's crust  (National Academy  of Sciences, 1975).  The principal minerals
associated with these  ores are garnierite [(Ni ,Mg)gSi .0-.g(OH)8], nickeliferous
limonite  [(Fe,Ni)0(OH)'NH20]  (Warner,  1984b),  and  pentlandite  [(FeNi)gSg]
(Duke,  1980).   Native metallic  nickel  in  a pure form is  rarely,  if  ever,
observed.  In  the  United  States, nickel is mined as garnierite, a  lateritic
silicate ore, in which nickel  is  incorporated into the mineral's iron-magnesium
lattice.
     Nickel  is  a valuable  mineral  commodity because of  its  resistance to
corrosion  and  its  siderophilic  nature which facilitates  the  formation of
nickel-iron alloys.   Stainless steel  is perhaps the most  well  known  alloy;
others  include permanent  magnet  and  super alloys, which are used in radios,
generators, and  turbochargers.   Copper-nickel  and nickel-copper alloys, such
        n
as MONEL *, are used when resistance to corrosion is required.   Nickel  and its
compounds  are  also  used in electroplating baths, batteries, textile dyes and
mordants, and catalysts.

3.1.1  Properties of Nickel and Nickel  Compounds
3.1.1.1  Nickel.   Elemental nickel, Ni,  is  a  member of the  Group VIII transi-
tion metal series  and exhibits the properties presented in  Table 3-1.   Nickel
is resistant to  alkalis,  but  reacts with dilute  oxidizing  acids  (e.g.,  nitric
acid), with  the  concommitant  evolution of hydrogen.  In certain situations,
even oxidizing salts  do not corrode nickel  because the metal is  made passive,
or incapable of  displacing hydrogen,  by formation of a surficial oxide film
(Tien and Howson, 1980).
3.1.1.2   Nickel  Compounds  and Complexes.   Transition metals  such  as  nickel
have unfilled  electron  subshells.   Therefore, nickel may exist in the -1, 0,

* MONEL is a registered trademark of INCO, LIMITED.
                                    3-1

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                                TABLE 3-1.   PHYSICAL  PROPERTIES OF  NICKEL AND NICKEL  COMPOUNDS
Name
Nickel
Nickel acetate
tetrahydrate
Nickel arsenlte
Nickel bromate
hexahydrate
Nickel bromide
trl hydrate
Nickel carbonate
Nickel carbonate
hydroxide
Nickel chloride
Nickel chloride
hexahydrate
Nickel fluoride
Nickel hydroxide
(hydrate)
Nickel nitrate
hexahydrate
Nickel oxide
Nickel phosphate
octahydrate
Nickel sulfate
hexahydrate '
Nickel subsulflde
Formula
N1
N1(C2H302)2 • 4H20
N13(As04)2
N1(Br03)2 • 6H20
N1Brz • 3H20
N1C03
N1CO, • 2N1(OH)2
N1C12
N1C12 • 6H20
N1F2
N1(OH)2 • H20
N1(N03)2 • 6H20
N10
N13(P04)2 • 8H20
N1S04 • 6H20
N13S2
Formula
Weight
58.71
248.86
453.97
422.62
272. 57
118. 72
304. 17
129.62
237. 70
96.71
110.74
290.81
74.71
510.20
262.86
240.26
Color,
Crystalline Form
silver, face-centered
cubic
green pyramidal
yellow-green powder
green monocllnlc
yellow-green deliquescent
needles
light green rhombic
green cubic
yellow deliquescent
green monocllnlc
yellow-green tetragonal
green powder
green monocllnlc
deliquescent
green cubic
light green powder
a blue-green tetragonal
p green monocllnlc
light yellow cubic
Density
8.90
1.744
4.982
2.60
—
—
2.6
3.55
—
4.72
—
2.05
7.45
2.07
5.82
Melting
Point (°C)
1455
Boiling Solubility In
Point (*C) 100 parts water
2920 Insoluble; soluble
dilute HN03

1n
16; soluble In alcohol
—
—
loses H20 200
—
—
1030
—
1450
decomposes 230
56.7
2090
decomposes 600
53.3 (forms 3)
loses water at 280
790
Insoluble
28 (20°C)
very soluble
0.009 (25°C)
Insoluble
sublimes 60.8 (20°C)
at 970
111 (20°C)
1740 2.56 (20°C)
solubility
0.0013 (20°C)
136.7 150 (20°C)
Insoluble; soluble
Insoluble; soluble
40.1 (20°C)
44.1 (20°C)
Insoluble; soluble










In acid
In acid
In HN03
Dash Indicates data not available.
Source:  Antonsen (1980) and Dean  (1979).

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+1, +2, +3, or +4 oxidation states (Antonsen, 1980).   The most prevalent form,
however, is Ni II.   The lower oxidation states usually occur in situations not
normally encountered in  the  ambient environment (Cotton and Wilkinson, 1980)
and the higher oxidation states of  nickel are associated with compounds which
are strong  oxidizing agents  and  are not stable in water  (Nieboer,  1981).
Several binary nickel compounds are commercially and environmentally significant;
a brief description of the chemistry of several  of these compounds is presented
below.  Physical  and chemical properties of nickel  compounds are summarized in
Table 3-1.
     Nickel oxide,  NiO, is available in two forms,  each with different proper-
ties which  are dependent upon the method of preparation.   Black nickel oxide
is chemically reactive and forms simple nickel salts in the presence of acids.
It is  used  mainly  in chemical processes.  Green nickel  oxide is inert and
refractory. It is  used primarily  in  metallurgical operations.  Complex oxides
of nickel  and other metals  may be  formed during certain  high temperature
processes.   An example is ferrHe, NiFe,,04, which could be produced during the
melting of material containing nickel and iron (Warner, 1983).
     Nickel sulfate, produced commercially in larger quantities than any other
nickel  compound,  is usually  found  as  the hexahydrate salt,  (NiSO^  •  6H20)
which is prepared commercially by adding nickel  powder to sulfuric acid (Antonsen,
1980).  At  high temperatures  (>800°C),  the salt  loses  water and  decomposes to
nickel  oxide  and sulfur  trioxide  (Antonsen, 1980).   The sulfate is extremely
soluble in water and ethanol.
     Nickel nitrate hexahydrate,  Ni(N03)2 • 6H,,0,  also  decomposes at high
temperatures,  with  the intermediate  formation of nickel nitrate.  This nickel
salt  has a  relatively  low  boiling point,  137°C  (279°F), and is water  soluble.
The nitrate may  be prepared by reacting  nickel  metal  and  nitric acid and is
used in batteries and sulfur-sensitive catalysts (Antonsen, 1980).
     Nickel carbonate,  NiCO,, is only slightly soluble in water, but is soluble
in acids and  ammonium  salt solutions.   Commercially, the basic salt,  2NiCO~  •
3Ni(OH)2 • 4H20,  is  the  most important form.  Nickel  carbonate  is used as a
glass colorant, in catalysts, and in electroplating baths.
     Nickel hydroxide, N1(OH)2, is  very insoluble in  water but  reacts with
acids and  aqueous  ammonia  (Cotton and Wilkinson, 1980).   When  dissolved  in
aqueous ammonia, the hydroxide  forms the  complex hexaamminenickel (II) hydro-
xide,  [Ni(NH3)6](OH)2, and is rendered soluble (Cotton and Wilkinson, 1980).

                                    3-3

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The hydroxide decomposes  into  nickel  oxide and water at temperatures greater
than 230°C (446°F) (Antonsen, 1980).
     Nickel forms hydrous and anhydrous halides such as nickel chloride  hexa-
hydrate,  NiCU  •  SH^O,  and   nickel chloride,  NiCU;  all  nickel halides  are
soluble in water  (Cotton  and Wilkinson, 1980).  These compounds are prepared
from nickel metal  or salts and the corresponding acid (Antonsen, 1980).
     Nickel sulfide,  NiS,  is insoluble in water  and  may  form naturally  in
bottom sediments  of  rivers  and lakes under  reducing conditions (Richter and
Theis, 1980).    The  sulfide  may be prepared  commercially  by  the addition of
                                                               2+
sulfide ions (from ammonium  sulfide) to aqueous solutions  of Ni   ions,  forming
a black precipitate.   The sulfide  is originally freely soluble in acids,  but,
when exposed to air,  the  compound oxidizes  to the  insoluble  Ni(OH)S  (Cotton
and Wilkinson,  1980).   Subsulfides,  Ni,,S and  NigSp, are  also known.  Nickel
subsulfide, Ni.-.Sp, is  insoluble in water but soluble in nitric acid.
     Nickel carbonyl,  Ni(CO)., is a colorless  volatile liquid formed by passing
carbon monoxide over metallic nickel.  The vapor density of nickel carbonyl is
about  four times  that of air (Antonsen, 1980) indicating  that Ni(CO)4  in
ambient air would tend to settle and not disperse.  The compound decomposes at
high temperatures and pressures,  depositing  pure  metallic nickel.   In ambient
air,  nickel  carbonyl  is  relatively  unstable and has a half  life of about
100 seconds (Stedman  and  Hikade,  1980).  The  carbonyl is insoluble in water,
but is miscible with most organic solvents.
     Nickel forms coordination complexes in  aqueous solutions  in which negative
groups  or neutral polar  molecules  are attached to the nickel ion  or atom
(Stoeppler, 1980).   Usual  coordination numbers of  these  complexes  are  4, 5,
and 6,  indicating that 4, 5, or 6 electron  pairs are attracted by the nickel
cation  to form  the  complex  (Cotton and Wilkinson, 1980).   The geometric  con-
figurations of  nickel  complexes are octahedral or tetrahedral.  For  example,
[Ni(NH3)6](C104)2 exhibits   octrahedral  configuration;  the  [NiCl4]2" ion  is
tetrahedral in  structure.   The rate  of formation  of nickel  complexes is  rela-
tively  slow  compared to other divalent cations (Nieboer, 1981).  The differ-
ence  in rate of  complex  formation  in  solution is  due  in part to the high
energy  of formation of the  trigonal  pyramidal intermediates  from  the original
octahedral configuration.   In  aqueous  solutions,  the Ni + ion is surrounded by
six water molecules forming an octahedral  [Ni(H20)g] +;  the loss of a  water
molecule  has  been determined to  be  the rate  limiting step  (Nieboer, 1981).
                                     3-4

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Several  neutral ligands, especially  amines,  can displace water molecules of
the complex nickel  ion.

3.1.2  Environmental  Chemistry of Nickel
3.1.2.1  Air.  In  the  atmosphere,  nickel  is  present as a constituent of sus-
pended particulate matter  (Barrie,  1981).   Photooxidation and volatilization
are not important chemical  processes for nickel present on particles in ambient
air.   The  properties of the  individual  nickel compound(s) associated with
particulate matter determine the behavior of  the element.  For example, nickel's
affinity for sulfur  and  its tendency to volatilize at high temperatures may
lead  to  the emission  of  nickel sulfate-containing particulates  from high
temperature or combustion sources.   In the absence of sulfur,  oxides of nickel
may form.   Differences in  the solubilities of  nickel sulfate and  nickel oxide
will  affect the mobility of nickel  in other environmental compartments following
removal   of  nickel-containing particles from  the atmosphere.   As mentioned
previously, complex  oxides  of nickel  and other  metals may be formed during
high temperature processes involving these metals.
3.1.2.2  Water.  Nickel  is usually found as  Ni II species in aquatic systems
(Cotton and Wilkinson,  1980).   The pH of the  water, the redox potential and
temperature of the system,  and the presence  of organic and inorganic ligands
govern the form of nickel expected to be present in a given water system.   For
                                                      2+
example, in  natural  fresh  waters at pH 5 to 9,  the Ni    ion  (or  more  likely
[Ni(H0Oc)]2+)  is the dominant form (Richter and  Theis,  1980).  The  divalent
     f. b
ion is extremely stable in aqueous solutions  and can migrate over long distances
(Callahan et al.,  1979).  In this pH range, nickel will also exist adsorbed to
particulates,  especially oxides of manganese and iron.  Nickel complexes may
form  at  this  pH  with the  likelihood  of formation as follows:  OH" > S042" >
Cl~ > NFL  (Richter and Theis, 1980).  However,  in aerobic environments, at pH
         o                                                                  2+
<  9,  these  nickel  compounds are sufficiently soluble to  maintain  aqueous Ni
concentrations greater  than 10   M  (Callahan  et  al., 1979).   Above pH  9, the
carbonate and/or hydroxide precipitates out of solution.
     The hydrolysis  reaction, Ni2+ + 2H20  -»  Ni(OH)2 + 2H+, occurs most often
in basic or alkaline systems.  The various hydroxides of nickel which may be
present  as  a  function  of pH and nickel concentration are shown  in Figure 3-1.
     Sulfate  is  a relatively weak  nickel  complex form  (Richter  and Theis,
1980), but  at  relatively high  sulfate concentrations, nickel  sulfate  may be
the dominant soluble form.
                                    3-5

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100
 90-
 80-
 70-
 60-
 50-
 40-
 30-
 20-
  10-
                               pH
         Figure 3-1.  Nickel hydrolysis distribution diagram.
         Source:  Richter and Theis (1980)
                              3-6

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     Based on a computer model, Sibley and Morgan (1975) report that in seawater,
the  predominant  nickel species would  be  the dissolved ion.  Little nickel
would be  predicted  to be adsorbed to  particulate matter because  of the high
ionic strength  of seawater and the  competition  for binding sites by  other
cations such as Mg  , Ca  , and Na  (Sibley and Morgan, 1975).
3.1.2.3  Soil and Sediments.  Many of the same chemical and physical  properties
which govern the  behavior of nickel  in aqueous  environments also affect the
behavior  of  nickel  in soils and sediments.   In  soils,  nickel  may exist in
several  forms (Hutchinson et al., 1981) including:

          inorganic crystalline minerals or precipitates,
          complexed with or adsorbed to inorganic cation exchange surfaces
          such as clays,
          free ion  or chelated metal complexes  in  soil solution  (water
          soluble forms).

Nickel  is held in  the lattice structure of  iron-magnesium minerals.   The
radius of the nickel ion, 0.69A, may facilitate its  substitution for magnesium
(Mg2+) (radius 0.65A) or iron (Fe2+)  (radius 0.74A)  (Duke,  1980).   As mentioned
earlier,  nickel  compounds are often  octahedrally coordinated;  in rocks  and
minerals, it is  usually so coordinated with  oxygen  as  in  the rock forming
mineral  olivine in which iron, magnesium,  and nickel occur in octahedral  sites
(Duke, 1980).  These ferromagnesium minerals are fairly susceptible to weathering,
and the nickel  released is usually held in the weathered material  in association
with clay particles  (Duke,  1980).   As such,  nickel  is  not considered to be
very mobile in a soil surface environment.
     In a soil/water  system,  nickel  in the form  of  a divalent cation may form
                                                                         2-
compounds with  free organic or inorganic ligands present,  including  SO.   ,
             2-
Cl , OH  , CO.,   ,  humic/fulvic acids.   Under anaerobic conditions  and  in the
presence of sulfur,  the insoluble sulfide, NiS,  may form (MAS,  1975).
     The pH  is a  dominant controlling  factor  in  soil as well as water  systems
in determining adsorption, compound formation, and chemical precipitation.   At
pH >9,  the  carbonate  or hydroxide may precipitate.  As the pH increases,
nickel adsorption by  iron and manganese oxides  increases because  of greater
                                                                           2+
electrostatic attraction  between the negative oxide surface and positive N1
cation (Richter and Theis, 1980).
                                    3-7

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3.2  SAMPLING AND ANALYTICAL METHODS
3.2.1  Sampling for Nickel  in Air
     Trace amounts of nickel associated with atmospheric pollutants are almost
always detected  in the form of particulate matter.  Accordingly, the sampling
methods available for collecting air  pollutants containing nickel are based
upon principles of particulate measurement.   Nickel may be measured in associa-
tion with  parti cul ate  matter in  flue  gas streams and  in  the  ambient air.
Nickel compounds may also  be present in flue gas streams in vaporized forms.
The principal methods for collecting nickel  in emission streams are EPA Method 5,
EPA Source Assessment Sampling  System (SASS), or  modifications of these two
procedures.  Nickel  in the ambient air may be collected by high volume, dichoto-
mous, cascade, and cyclone samplers.
     The EPA reference method for sampling particulate emissions from stationary
sources  is  EPA Method 5 as modified  (F.R.  1977 August 18).  This sampling
method is  excellent  to  use for  nickel associated  with  particulate emissions
from  flue  gas streams.    It is  not, however, designed  to collect volatile
inorganic  components  efficiently.  Details  on  the sampling  equipment and
procedures of  the method  are given in the  F.R.  1977 August 18 reference.
     A method  similar to EPA  Method 5  has been  developed  by Peters (Peters et
al.,  1980)  to sample inorganic  compound  emissions from stationary sources.
The impinger  system  of  the Peters  method is  appropriate  for nickel  sampling
and can  be easily modified if special trapping solutions  are  to be  used for
organometallic components  from  fuel combustion.  A sample  is  collected from
the system by  combining  the particulate matter  collected on the filter with
the impinger catches and the probe washes (acetone and nitric acid).
     Several methods are available  for collecting  nickel that exists in a flue
gas stream in both solid and gaseous phases.  The  EPA SASS  has been a frequently
used  method  for measuring  nickel  compounds from  stationary sources.  This
method  enables the collection  of  large  quantities  of particulate matter,
classified according  to size, and  also  enables the collection of volatile
species  that  can be absorbed in  liquid.  A sample is recovered as in the EPA
Method 5 train except that the solvent used for the probe wash is a 1:1 mixture
of methylene chloride and methanol  for the front half of the train and methylene
chloride  alone for  the  impinger  system  (Lentzen  et  al.,  1978; Duke et al.,
1977).
                                    3-8

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     A  flue  gas sampling system  designed  to measure high pressure  outputs
under  isokinetic  conditions has  been  developed by Hamersma.  The sampling
method  is  used  for emission streams at  temperatures  up  to 500°C  (932°F)  and
pressures  greater  than 300 psig.   The detection  limit  is 60 pg/m  of the
volatile trace element (e.g., nickel) in the gas stream (Hamersma and Reynolds,
1975).
     A  system  for  measuring trace  inorganic  compounds  from  normal pressure
streams has  been developed  by Flegal (Flegal et al., 1975).   The system is a
modification of the  EPA  SASS methodology.   The  sampling  method  is used for
emission streams at  temperatures  up to 270°C  (518°F)  and  sampling  rates up to
0.08 m3 (3 ft3)/min (Flegal  et al., 1975).
     The National  Air Surveillance  Network (NASN)  has  used a high-volume
filtration sampler to measure for nickel  compounds in the ambient air (C.F.R.,
1977).  This method is used only for the measurement of particulate matter and
is not capable of detecting volatile compounds such as nickel carbonyl.

3.2.2  Analytical  Procedures for Nickel in Air
     The determination of nickel  in its  elemental  state  can  be satisfactorily
accomplished through  various methods.  However,  a  more specific determination
of nickel  to  identify the  types of  nickel  compounds  present is difficult to
achieve, particularly for  ambient air samples.  The  analysis of individual
nickel compounds is complicated because techniques used to break down inorganic
compounds into their ionic or atomic states change the form of the compound in
the attempt  to  determine  the total concentration  of  the  element.  Thus,  the
actual  form  and concentration of  the nickel  species present  in the sample may
not be accurately represented by the modified compound.   The  very low level of
                                                              o
nickel  present  in  ambient  air samples (average  of 0.008 pg/m  in 1982, see
Table 3-2) complicates this situation.
     Atomic absorption spectrophotometry with flame (AAF) is  the most commonly
used analytical procedure for measuring  nickel  in  air samples.  The  detection
limit for  nickel by  AAF has been  identified as  0.005  Mg/ml (Sachdev  and West,
1970; Pickett and Koirtyohann, 1969).  The linear range for accurate measurement
is reported  as 0.2 to  0.5 p/ml for  a 232.0  nm wavelength  setting.  Generally,
the known interferences for the analysis of nickel  by AAF have been thought to
be limited.  However,  there  has  been a reported case (National Institute for
Occupational  Safety  and Health,  1977)  where a  hundred-fold  excess  of iron,
                                    3-9

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TABLE 3-2.   CUMULATIVE FREQUENCY DISTRIBUTION OF INDIVIDUAL 24-HOUR AMBIENT AIR NICKEL LEVELS
Year
1977
1978
1979





1980





1981





1982







Network
NASN
NASN
NASN
IP
IP
IP
IP
IP
NAMFS
IP
IP
IP
IP
IP
NAMFS
IP
IP
IP
IP
IP
NAMFS
IP
IP
IP
IP
IP
IP
IP
Sampler
Type
HiVol
HiVol
HiVol
HiVol
SSI
Dicot
Dicot
Dicot
HiVol
HiVol
SSI
Dicot
Dicot
Dicot
HiVol
HiVol
SSI
Dicot
Dicot
Dicot
HiVol
HiVol
Dicot
Dicot
Dicot
Dicot
Dicot
Dicot





T
C
F



T
C
F



T
C
F


T
C
F
T*
C*
F*
Number
of
Sites
238
195
160
65
15
49
49
49
142
132
105
72
72
72
160
150
131
119
119
119
119
90
128
128
128
19
19
19
Number
of Obser-
vations
5400
4147
2931
602
211
364
364
364
2881
1731
1302
759
759
759
3438
1338
1039
847
847
847
2864
645
872
872
872
34
34
34
Percent! lec
30
0.006
0.003
0.003
0.006
0.011
0.010
0.005
0.005
0.002
0.002
0.001
0.010
0.005
0.005
0.002
0.002
0.002
0.047
0.031
0.010
0.002
0.002
0.010
0.001
0.001
0.013
0.001
0.004
50
0.006
0.006
0.005
0.015
0.017
0.012
0.005
0.006
0.003
0.004
0.003
0.010
0.005
0.005
0.003
0.003
0.003
0.098
0.067
0.018
0.004
0.004
0.010
0.001
0.002
0.013
0.001
0.004
70
0.009
0.010
0.010
0.023
0.026
0.019
0.006
0.012
0.007
0.009
0.007
0.012
0.005
0.006
0.007
0.005
0.005
0.255
0.196
0.036
0.006
0.005
0.011
0.001
0.002
0.013
0.001
0.004
99
0.062
0.067
0.057
0.128
0.135
0.078
0.026
0.053
0.052
0.062
0.058
0.057
0.020
0.040
0.023
0.018
0.015
1.83
1.63
0.274
0.030
0.014
0.025
0.004
0.014
0.014
0.001
0.005
Arithmetic
Mean (SD)
0.012
0.010
0.009
0.021
0.024
0.019
0.007
0.012
0.007
0.009
0.008
0.015
0.006
0.009
0.008
0.007
0.007
0.056
0.047
0.009
0.008
o.oog
NC°
NC
NC
0.007
NC
NC
(0.019)
(0.022)
(0.012)
(0.022)
(0.023)
(0.018)
(0.006)
(0.012)
(0.013)
(0.014)
(0.013)
(0.012)
(0.003)
(0.010)
(0.007)
(0.005)
(0.005)
(0.024)
(0.084)
(0.095)
(0.009)
(0.004)
NC
NC
NC
NC
NC
NC
 Network:  NASN  is the National Air Surveillance Network which in 1980 was changed to the
 National Air Monitoring Filter Sites.  IP is the Inhalable Particulate Network.
  Sampler Type:  HiVol is the high volume air sampler which collects particles less than
  50 urn  diameter.  SSI is the size selective (<15 urn) version of the HiVol.  Dicot (T,C,F)
  is the dichotomous sampler where T is <15 urn, F is < 2.5 urn, and C is the difference, i.e.,
  greater than 2.5 urn and <15 urn.  Dicot (T*,C*,F*) is the dichotomous sampler, where T*
  <10 jjm, F* <2.5 urn, and C* is the difference, i.e., greater than 2.5 urn and less than 10 (jm.

 cValues under given percentile indicate the percentage of stations below the given air level.
  Values in ug/m3.
 Statistics not calculated if more than 50 percent of the values are below the lower limit
  of discrimination, approximately 0.001 ug/m3.

 Source:  Evans  (1984) and Akland (1981).
                                         3-10

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manganese,  chromium,  copper, cobalt,  or zinc may  decrease  the absorbance
recorded for  nickel  by as much as 12 percent.  This situation may be avoided
by the use of an oxidizing flame and the maintenance of proper burner elevation.
In addition to  the  above case, a  high  concentration  of organic solvents or
solids  in  the aspirated  solution  will  decrease  absorbance at the 232.0  nm
setting (NIOSH, 1977; MAS, 1975).
     Atomic absorption spectrophotometry without flame is also a viable analy-
tical technique  for  measuring nickel in ambient air samples.   In this method
the  nickel-containing  sample is  atomized  directly in  a graphite furnace,
carbon rod, or tantalum filament instead of a flame.  The nickel concentration
is indicated  by  the  absorption of a specific wavelength of light by the free
atoms.  For 100  ml  of injected fluid, fTameless AA has a detection limit for
nickel of 0.1 ug/1 (Perkin-Elmer,  1981).
     X-ray  fluorescence  spectrometry (XRF)  has  been found to  be  a suitable
technique  for complex  samples  such as  fly ash due to good  reproducibility  and
rapid multi-element  capabilities  (Henry,  1979).   The main advantages of this
method are  that  the  form of the  sample  is  not  critical for measurement and
that  the  analysis procedure does  not  destroy the sample, thereby allowing
reanalysis.  The detection limit for XRF is 0.01 ug/cm2 (Wagman et al., 1976).
Inductively coupled  argon plasma  (ICAP)  spectroscopy has gained prominence as
a  fast  and reliable method  for multi-element analysis involving  inorganic
compounds  (F.R.  1979 December 3).  The  detection limit for  this method  is
15 ug/1 at  the 231.6 nm  setting (U.S.  Environmental Protection Agency,  1979).
Nickel may also be determined colorimetrically with a complexation step.  West
and  co-workers have  adapted  the ring-oven technique for the determination of
nickel in  particulate  matter using dimethylglyoxime as the complexing  agent
(West, 1960).   Spark source mass spectrometry (SSMS) has been used for compre-
hensive elemental analysis.   The SSMS procedure  is often used only to establish
the presence of certain elements in a sample because this method is limited by
low  accuracies,  usually  on  the order of 100 to  200 percent (Hamersma et al.,
1979).  However,  sensitivities  as low as 0.1 ug/g have been recorded (Henry,
1979).  Neutron  activation  analysis (NAA)  has also been used to  determine
nickel concentrations at the microgram level.   However, the detection limit of
NAA is only 0.7 ug/g.  A final method for nickel  determination is flame emission
spectrophotometry (FES);  this  method is sensitive to 0.03 ug/ml of nickel in
solution (Pickett and Koirtyohann, 1969).
                                    3-11

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     Direct analysis techniques  are  being studied and used more extensively
for determining specific  inorganic  compounds  such as nickel species.  These
methods can provide for extremely accurate analysis and spedation of compounds
because there  is  a low potential for  compound alteration during analysis.
However, problems  inherent  in this  approach are  that  the compound must be
analyzed in a  crystalline matrix and that often  only  surface  compounds are
detected.   X-ray diffraction (XRD) has been employed to determine the chemical
structure of fossil fuel combustion  fly ash.   The present lack of a simplified
and valid  reference  library for diffraction data  is a drawback  limiting the
use of this method.  This lack of reference information complicates the identi-
fication process  for compounds  with  unknown  diffraction  patterns (Henry,
1979).  X-ray  photoelectron  spectroscopy  (XPS) has been used to  differentiate
inorganic compounds that  are in nitrogen and sulfur forms.  Analysis for the
potential application of  this method for  nickel  speciation has not been done.
A major  limitation in  regard to the potential application of this method  to
nickel analysis is that nickel can exist in both nitrogen and sulfur compounds,
so  differentiation of compounds may be  difficult (Dod and Novakov, 1982).
Secondary  ion  mass spectrometry (SIMS) has been  used to  determine the depth
profile of  a  set  of elements without regard to chemical  form.   A shortcoming
of  the  method  is  that only  surface compounds  can  be detected and  thus, data
interpretation  is  more  difficult.   Additional  information about the chemical
form  of  the element may be  determined with  the  SIMS negative ion mode (Van
Craen et al., 1982; Henry, 1979).
      Fourier transform  infrared spectroscopy  (FT-IR) has also been  employed
for direct  nickel  measurement in coal  and fly  ash  samples.  The  problems with
this  approach  are:  the  specificity  is not good,  only  surface compounds may
be  detected, and the applicability to trace nickel concentrations is question-
able  (Gendreau  et  al., 1980; Henry and Knapp, 1980; Henry, 1979).  Information
regarding  compound form may be  provided  by  several  microscopy  instrumental
methods,  including scanning  electron  microscopy (SEM),  electron microprobe
(EMP),  scanning transmission electron microscopy  (STEM), electron microscopy
microanalyzer  (EMMA), and ion microanalyzer  (IMA).   Compositional  data  on  the
elements  present  in the  sample  are provided  by an energy dispersive  X-ray
analyzer  (EDXA).   These methods have been  used  alone  or in combination to
analyze coal combustion fly  ash  samples.  The analytical responses are sensitive
to  interferences   from  background,  particle mass, and interelement  effects
(Henry, 1979).
                                    3-12

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     Inorganic compounds  containing nickel in the  vapor phase are readily
speciated based  upon the volatility of  the compound.   Brief has described
several different  methods for the  determination  of nickel  carbonyl (Brief
et al., 1965).  The  range in sensitivity for these methods  is from 0.008 to
0.10 |jg/g.
     A more specific  method  to analyze for nickel carbonyl  is the chemilumi-
nescence method.   The  chemiluminescence  method  is faster than those methods
described by  Brief and can detect nickel carbonyl in air at parts per billion
(by volume) levels (Stedman et al.,  1979).   In this  method,  nickel carbonyl  is
mixed with purified carbon monoxide and  allowed to react with ozonized oxygen
(OO.  The chemiluminescence  generated  by  the reaction of these  materials is
measured as  a signal  of  intensity.  This intensity is proportional to  the
nickel carbonyl content of the sample.   The nickel carbonyl  content  of the
sample is determined  by  comparing  the intensity of the sample signal to the
intensity of a reference standard representing a  known  nickel carbonyl  concen-
tration.

3.2.3  Sampling for Nickel in Water
     Nickel compounds  in  water are  typically  obtained  by grab sampling.   The
type of grab  sampling employed depends  upon the form and consistency of the
liquid sample.  Any  of the  following three methods  are recommended:   (1) tap
sampling; (2) heat exchange  sampling;  and  (3) dipper sampling.   Tap sampling
is commonly used for contained liquids in motion  or  static liquids in  tanks  or
drums.  This  method may  also  be used  for  liquid slurries but there  is  an
increased potential for unrepresentative sampling if the solids content exceeds
10 percent.   The sample  is  removed  by a valve regulating  flow from a clean
Teflon line inserted  into the sampling bottle.   Heat exchange sampling works
in precisely the manner as tap sampling except that  it  is employed for streams
at temperatures > 50°C  (122°F) and  therefore  requires  a condenser coil.   The
dipper sampling method is used for  sampling sluices, ponds, or open discharge
streams of thick slurry or stratified composition.   The dipper sampling proce-
dure  is characterized  by  a  flared  bowl  and an attached handle of sufficient
height and breadth to reach a discharge area and provide for a cross-sectional
sample (Hamersma et al., 1979).
     The preservation  of  samples is accomplished by adding 0.1 N nitric acid
to bring the sample solution to a pH of 2.   This  preservation step is  necessary
to avoid degradation of the sample  during the  collection, storage, and analysis
                                    3-13

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period.   Significant loss of trace elements during storage has been identified
by several investigators (Owens et al., 1980; Struempler, 1973).   A preconcen-
tration  step  is often necessary  for  analytical  methods to measure nickel,
because  it  is  usually measured in water at  parts  per billion levels  (NAS,
1975).   Sachdev and  West (1970) recommend a concentration step using a mixed
ligand.   With preconcentration, there is also a potential for loss and contamina-
tion (Cassidy et al., 1982).

3.2.4  Analytical  Procedures for Nickel in Water
     Analysis  for  nickel  in water is  usually  performed by atomic  absorption
spectrophotometry.   The  optimal concentration range  for  analysis  is  0.3 to
5.0 mg/1  using  a  wavelength of 232.0 nm.   The  sensitivity of this method  is
0.15 mg/1 and the detection limit is 0.05 mg/1 (U.S. EPA, 1979).
     Other  analytical  procedures  for nickel  in  liquid  samples are employed.
Multi-element  techniques  such  as  inductively coupled  plasma  emission  spectro-
metry (ICPES)  and spark  source mass  spectrometry are  used when other  elements
besides  nickel are being investigated.  The  ICPES method  is used to give rapid
and reasonably accurate determination of a specific group of  26 elements.  The
SSMS  procedure  is used to  survey for the entire spectrum of  elements.  These
procedures  used for  multi-element analysis are described in  detail by Elgmork
et al. (1973) and Johnson et al.  (1972).  Direct analysis for nickel  in natural
waters  has  been performed  using  high  pressure liquid chromatography  (HPLC).
This  procedure  is capable of detecting  nickel  at pg/ml  and ng/ml concentrations.
A  problem with this technique  is the  significant potential  for interferences
from  organic  components  and colloids (Cassidy et al., 1982;  Ugden and Bigley,
1977).

3.2.5 Sampling for  Nickel  in  Soil
      Sampling  procedures for nickel  compounds  in soil  may include any of  the
following methods:    (a) trowel  or scoop; (b) soil auger; or (c) Veihmeyer
sampler.   The optimal method for a particular situation depends  upon the type
of soil  and the  depth of  soil profile required for analysis.  The trowel  or
scoop is commonly used  for dry surface soil.   When the required  soil  profile
is greater than 3 inches,  a soil  auger or Veihmeyer sampler should be used.
The  soil auger is not  capable of collecting an undisturbed  soil  sample.   The
Veihmeyer sampler is difficult to use on rocky or wet soil  (deVera  et  al.,
1980).
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     Soil samples collected by any of the above procedures should be preserved
for analysis in air-tight, high-density polyethylene containers.  Large samples
should be  stored  in metal containers lined with  polyethylene bags (Duke et
al., 1977).

3.2.6  Analytical Procedures for Nickel in Soil
     Atomic absorption  spectrophotometry  is the most typically  used method  of
analysis for nickel  in  soil  (Theis and Padgett, 1983;  Emmerich et al., 1982;
Wiersma  et  al.,  1979).   The spark source mass spectrometry procedure is also
frequently  used  (Hamersma et al., 1979;  Lentzen  et  al.,  1978).  The sample
must undergo acid  extraction (acetic acid or  nitric acid)  before analysis.
Several extraction test methods are available:  (a) U.S.  EPA extraction proce-
dure;  (b)  ASTM  Method A  and  Method  B;  and (c) IAEA  (International  Atomic
Energy Agency)  leach  test (F.R. 1980 May  19;  American  Society for Testing and
Materials, 1979; Hespe,  1971).

3.2.7  Sampling for Nickel in Biological Materials
     The sampling methodology  for  nickel  in biological materials requires the
use of properly designed  procedures to collect representative samples for
analysis.  The  test must  also  adhere to approved  guidelines  involving precau-
tionary  measures  to avoid contamination.   Contamination can  occur  from the
stainless steel  apparatus used to collect biological  samples or from containers
used to  store specimens  (Stoeppler, 1980; Sunderman, 1980; Tolg, 1972).  With
certain  biological  samples  such  as urine, long-term storage is necessary for
intercomparisons between  samples.  In  such  cases, the  potential for loss due
to  adsorption  on precipitates  is  significant and, thus, may result  in an
unrepresentative sample (Stoeppler, 1980).

3.2.8  Analytical Procedures for Nickel  in Biological  Materials
     Routine analysis for nickel  in biological materials  is commonly performed
by  atomic  absorption spectrophotometry.  Neutron activation analysis  and
colorimetric procedures  are  also  used.   Acid  extraction is  required  before
analysis of biological  samples.   Transfer of the  sample  into a form suitable
for extraction requires  wet- or dry-ashing (Stoeppler,  1980).   The EPA Level 1
assessment procedures describe the Parr oxygen combustion technique for the
preparation of all  combustible materials  for  inorganic analysis (Lentzen et
al., 1978).  The prominent sources of  error for these  techniques are  adsorp-
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tion losses on the walls of the combustion chamber (dry-ashing) and additions
through  leaching  from container walls  (wet-ashing)  (Stoeppler,  1980).   A
typical extraction procedure involves subjecting the  samples to acid digestion
and then separating the nickel  from interfering elements by chloroform extrac-
tion of nickel dimethylglyoximate at alkaline pH.   A  similar extraction proce-
dure involves ammonium pyrrolidine-methylisobutylketone (Horak and Sunderman,
1973;  Nechay  and Sunderman, 1973;  Sunderman, 1973; Nomoto  and  Sunderman,
1970).  Nickel  is converted to the diethyldithiocarbamate complex and extracted
into isomyl alcohol.   The  absorbance of nickel-bisdiethyldithiocarbamate  is
measured  at  325 nm (Sunderman,  1971;  Sunderman,  1967;  Sunderman,  1965).
Potential sources of  error in the analysis of biological materials for nickel
using acid extraction and atomic absorption spectrophotometry are:   (a) contam-
ination of the sample; (b) background absorbance;  and (c)  nonspecific absorbance
caused by the presence of inorganic salts  (Nomoto and Sunderman,  1970).
3.3  NICKEL IN AMBIENT AIR
     The discussion of  nickel  in ambient air is divided into two parts.   The
first part of  the  discussion concerns the determination of which species or
forms of nickel are being emitted into ambient air by stationary sources.  To
augment the  summarization in  Section 3.3.1,  a comprehensive  and  detailed
treatment of nickel species  in ambient air can be  found  in a recent report
prepared for  EPA's  Office of Air Quality  Planning  and  Standards by Radian
Corporation (Brooks et al.,  1984).   In the second part of  this section, avail-
able ambient air monitoring  data for nickel  are presented and characterized.

3.3.1  Nickel  Species  in Ambient Air
     The primary stationary  source  categories which emit  nickel into ambient
air  are  coal  and oil  combustion, nickel  ore mining/smelting, nickel  matte
refining, steel  manufacturing, nickel alloy  manufacturing,  iron and  steel
foundries,  secondary  nickel  smelting,  smelting of other secondary nonferrous
metals, co-product nickel recovery,  refuse incineration, sewage sludge incinera-
tion, electroplating,  nickel-cadmium  battery  manufacturing,  nickel  chemicals
manufacturing, cooling  towers, cement manufacturing,  coke ovens, asbestos
mining/ milling, and  nickel  catalyst manufacture and reclamation.  From these
19 individual   source  categories, five organizational  groupings exist that  .
generally describe the  major species of nickel emitted into  ambient air by
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anthropogenic sources.   These groups include primary nickel production sources,
combustion  sources,  high temperature  metallurgical  sources,  chemical  and
catalyst sources, and other miscellaneous sources.

3.3.1.1  Primary Nickel Production.   Primary nickel production sources include
nickel ore  mining/smelting  and  nickel  matte refining.  There  is  only one
source of each type  in the United States.  The only active nickel mine in the
U.S.   is located  near Riddle,  Oregon and is  currently  operated by the Hanna
Mining Company.  The Hanna  Nickel  Smelting Company, also  located in  Riddle,
processes  the mined  nickel ore to produce a  ferronickel containing 50 percent
nickel and  50 percent  iron.   At  the Hanna site, nickel air emissions are in
the form  of nickel  silicate as this is  the  form of nickel within the mined
mineral.   Because the  moisture content of the nickel  ore  is  relatively high
(about 20  percent),  dust generation during mining is minimized and any emissions
released tend to settle  quickly  in the  vicinity of the source  (Donaldson et
al.,   1978).   Very few  data  are available to  estimate  the  species of nickel
emitted to  air by the  nickel  ore smelting process.  Ore crushing, drying, and
calcining  operations should be emitting nickel in the silicate mineral lattice
because no  chemical  changes  are  occurring during  these processes. Emissions
from  the  high  temperature  ore roasting and  melting furnaces  used to  produce
ferronickel  would contain nickel  predominantly in the form of an oxide combined
with  iron  as a ferrite or spinel  (Warner, 1984a).   Total  nickel emissions from
the nickel ore mining/smelting operation have been estimated to be approximately
8.4 Mg (9.3 tons)/yr (Doyle, 1984;  Johnson, 1983; Oregon Department of Environ-
mental Quality, 1981).
     The AMAX Nickel Refining Company  in Braithwaite, Louisiana is the only
facility in the U.S. that is refining imported nickel  matte to produce nickel.
Nickel emissions to  ambient air  from the AMAX refining operation are  expected
to be in the forms  of nickel subsulfide, metallic nickel,  and to a much lesser
extent, nickel oxide.  Nickel subsulfide exists in particulate emissions asso-
ciated with matte  handling  and  preparation parts of  the  refining process
because the processed mattes are  sulfide in nature (Page,  1983; Warner, 1983).
Recent XRD  tests by the matte refining  plant have verified the existence of
nickel subsulfide emissions (Gordy, 1984).   Metallic nickel powder is generated
by the matte  refining  plant as a final product and is emitted during drying,
packaging,  and briquetting operations.   Nickel oxide can also be emitted from
the plant  sintering operation as  some metallic nickel  is likely to be oxidized
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in the high temperature sinter furnace (Warner,  1983).   Total  nickel  emissions
from the  matte  refining  facility  have been estimated  to  be  approximately
6.7 Mg (7.4 tons)/yr (Kucera,  1983; Radian Corporation,  1983).
3.3.1.2  Combustion and Incineration.   Combustion sources include coal and oil
burning units in utility, industrial, commercial, and residential use sectors
and incineration sources  such as municipal refuse and sewage sludge  incinera-
tors.   Ambient air monitoring samples taken near coal and oil  combustion sites
have not  been analyzed to speciate which  forms  of  nickel  they may contain.
However,  several studies  have  analyzed the fly ash samples which are emitted
into the  air from  combustion  sources for the purpose  of  speciating trace
elements.    In fly  ash samples collected  from the  stacks of five oil-fired
utility boilers, the  nickel  components were found  to  be 60 to  100  percent
water soluble (Henry  and  Knapp,  1980).   In the analysis of leachate from the
solubility  test, sulfate  anion was the only anion present at more than trace
levels.    With this  information,  it can be postulated that the form of nickel
in the fly ash emissions and ambient air from oil-fired combustion is predomi-
nantly nickel sulfate.  This theory was eventually confirmed after the fly ash
and the soluble  and insoluble fractions were analyzed  by  Fourier transform
infrared  spectroscopy  (Gendreau  et al., 1980).   In  another  study of  stack fly
ash and scale samples taken from  the reducing  and  oxidizing sections of an
oil-fired utility boiler,  nickel  was found to exist as nickel ammonium sulfate
[Ni(NH4)2 (S04)2'6H20] (Blaha et al. , 1979).
     In the insoluble fraction of  the  fly ash samples from  oil-fired boilers,
nickel was  determined by  XRD to potentially exist as nickel oxide (Henry and
Knapp, 1980).  However, with XRD patterns  it is frequently difficult to distin-
guish between pure  nickel oxide  and complex metal  oxides  involving nickel.
Potentially, the nickel component  of the  insoluble  fraction  could exist as
complex nickel oxides  such as ferrites, aluminates, and vanadates; a combination
of  complex  metal  oxides involving  nickel  and  nickel  oxide;  or purely nickel
oxide as  the XRD results  suggest.
     Tests  on five  oil-fired utility boilers by Dietz and Wieser  (1983) produced
results showing  that  water soluble metal  components of emitted  fly  ash exist
primarily as metal  sulfates.  The  portion  of the total amount  of  nickel present
in  the  fly ash  samples that was water soluble ranged from 15(+4)'to 93(+4)
percent,  with the average being  54(+9) percent.  Because the ion  chromatograph
sulfate  levels  of  the samples were on the  average less than the expected
sulfate levels based  on stoichiometric considerations, Dietz and Wieser (1983^
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postulated that some small part of the soluble nickel may have been present as
partially soluble  oxides  or very finely dispersed particles of metal oxides.
The insoluble  nickel components  of the oil  combustion  fly ash were  determined
to  be  metal  oxides.   Dietz  and  Wieser (1983) reported  nickel  oxide to be
present  in the emissions.  As no mention  was specifically made of  complex
oxides containing nickel and other metals, it is uncertain whether the authors
found such complexes.
     In summary, it appears that particles found in ambient air as a result of
oil combustion contain nickel predominantly in the form of nickel sulfate with
lesser amounts  as  nickel  oxide and complex metal  oxides containing nickel.
     Henry and  Knapp  (1980)  have performed solubility and component analysis
studies for  fly ash  from  coal  combustion  similar to  those discussed  above  for
oil combustion.  Samples  of fly  ash emitted  from  coal-fired utility boilers
were water leached and the  fraction of nickel found  to be soluble ranged from
20  to 80 percent.  As  in the  case of  oil  combustion,  sulfate was the major
anion present; therefore, in the  soluble fraction of fly ash from coal  combus-
tion,  nickel  probably  exists as  nickel sulfate.   Various metal  sulfates were
identified in  the  soluble fraction  of the coal  combustion fly ash by XRD and
FT-IR, but  specific  compounds were  not reported  (Henry and  Knapp, 1980).
Hansen and Fisher  (1980)  and Hansen et al.  (1984) conducted  experiments on
coal combustion fly  ash particles which indicated  that the majority  of  nickel
present was  soluble  and that this soluble  portion was  associated primarily
with sulfate anions,  and  to a much lesser extent,  fluoride  and phosphate
                                                            +2
anions.   Eatough et al. (1981) confirmed the existence of Ni    associated with
sulfate in the  soluble portion of emissions  from  an oil-fired  power plant.
     The. insoluble fractions of the coal  combustion fly ash were determined by
XRD to contain  metal oxides, although neither nickel oxide nor  complex  oxides
containing nickel  were specifically identified.   Hulett et al.  (1980) suggested
that nickel  in  the insoluble phase of coal  combustion  fly  ash exists  as  a
substituted spinel  of the form Fe»_  Ni 0..  Hansen et al. (1981) substantiated
                                 O /\  f\ i
the results of Hulett et al. (1980)  by demonstrating that the insoluble portion
of  coal combustion fly ash contains nickel as a  component  of complex metal
(primarily iron) oxides.
     The forms  of  nickel  emissions to ambient air  from coal combustion  appear
to  be essentially  the  same as those from oil combustion, i.e.,  predominantly
nickel  sulfate  with  less  as nickel  oxide  and complex  oxides  of nickel and
other metals.
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     National atmospheric nickel  emissions from coal  and oil  combustion dominate
releases from  all  other nickel  emission  source categories.   Recent studies
have estimated nationwide nickel emissions from coal and oil combustion to be
from 2,600  to  8,500 Mg  (2,860  to  9,350 tons)/yr.   Of the total  amount of
nickel  emissions from  coal  and  oil  combustion, oil  combustion has been esti-
mated to account for  60 to 98 percent  (Krishnan and  Hellwig,  1982; Systems
Applications Incorporated, 1982;  Baig et a!., 1981).
     The results of  one recent  study of  a  metropolitan area in  California
support the  possibility  that  oil  combustion contributes a  significant amount
of nickel  to ambient air particles,  particularly in the fine (less than 10 mm)
size fraction  (Cass and  McRae, 1983).   Routine air monitoring data  from sites
in the South Coast Air Basin were evaluated to reconcile the original source
of particular  trace  elements  found  in the samples.   Approximately 81 percent
of the nickel found was determined to be present as fly ash from residual  fuel
oil combustion (Cass and McRae, 1983).  In contrast, however, a similar study
was performed  on ambient air monitoring  samples taken  from  the Washington,
D.C. area,  and nickel  particles  could  not be  associated with any particular
source category,  combustion, or otherwise (Kowalczyk et al., 1982).
     Support for the  theory that the majority of  nickel  in ambient air  is
water soluble  and  is  in the form of  nickel  sulfate can be found in work by
Cawse (1974).  Cawse  (1974) measured the bulk deposition  of many elements,
including nickel,  at  seven  non-urban ambient air monitoring sites  in Great
Britain.  The  soluble  nickel  component as a percentage of total nickel depo-
sition ranged  from 47  to 80 percent,  with the  average  level  being 59  percent.
The major anion  measured in these samples was sulfate, implying the possible
existence and  predominance  of nickel  in  ambient air as  nickel  sulfate.   The
experiments  of Spengler  and Thurston  (1983) would lead to the speculation that
instead of  nickel  sulfate,  nickel  exists in ambient air to a large extent as
nickel ammonium sulfate.
     An absolute species characterization of potential nickel emissions from
refuse and  sludge  incinerators  is difficult  because the  compositions  of waste
streams vary so greatly  between units and may vary daily within the same unit.
Recent tests on the fly  ash emissions of  three refuse and three sludge incinera-
tors have shown that one-third to one-half of the emissions are water soluble.
The soluble  phase  of refuse incinerator emissions contained principally chloride
and sulfate ions,  thereby suggesting  that nickel can  be present in  this phase
as  nickel chloride or sulfate (Henry  et al., 1982).   The insoluble  portion of
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refuse incinerator emissions  contained  primarily oxide and silicate salts of
various metals.   Although not  specifically  identified, complex  oxides of
nickel and  other  metals (mainly iron)  are probably  the prevalent forms of
nickel that would exist (Henry et al., 1982).
     The water soluble  phase  of the sludge incinerator fly ash was found to
contain predominantly sulfate ions, although chloride, nitrates,  and phosphates
were present at much  lower levels.  The fraction  of total  nickel that was
water  soluble  in  sludge  incinerator  fly ash ranged  from 34  to  52 percent
(Henry et al.,  1982).   It is reasonable to expect that nickel  emissions present
in the water soluble  phase of sludge incinerator emissions are predominantly
nickel sulfate, with potentially much lower amounts of nickel  chloride, nitrate,
and phosphate.   The  insoluble phase of sludge incinerator fly ash emissions
was similar to that  of refuse incinerator emissions, and the probability is
great that  nickel exists  predominantly  as complex oxides of nickel and other
metals.  It is highly likely that nickel was combined  with  iron to form a
spinel; however,  such  a conclusion was not explicitly  determined (Henry  et
al., 1982).
3.3.1.3  Metallurgical Processes.  The  nickel  source categories   Included in
the  high  temperature metallurgical  grouping  include  steel  manufacturing,
nickel alloy manufacturing, secondary nickel  smelting, other secondary nonfer-
rous metals smelting,  and iron and steel foundries.   In the high temperature
processes occurring  in metallurgical furnaces,  the  majority  of  nickel in
emissions would be expected to be oxidized.   Data from the steelmaking industry
and from the related nickel alloy industry confirm that the majority of nickel
present in  emissions  from metallurgical melting furnaces is  in  the  form of
complex oxides of nickel  and  other metals (Page, 1983;  Koponen et al.,  1981).
In one test of nickel emissions from an electric arc furnace (EAF) producing
stainless steel,  only 5 percent  of the  total nickel  present was water  soluble
(Koponen et al.,  1981).   The nickel in the insoluble phase was determined to
exist as an alloyed  element in iron oxide particles.  Tests of the emissions
from an EAF producing carbon  steel  identified nickel  oxide to constitute from
0 to 3 percent of the total particulate emissions.   Similar work on the emissions
from  a  refining  vessel handling specialty steel  produced one sample  where
nickel oxide constituted  3.1  percent of total particulate emissions (Emission
Standards and  Engineering  Division,  1983;  Emission Standards and Engineering
Division, 1981;  Andolina, 1980; Sahagian et al.,  1977; Brough and Carter,
1972).
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     Several  dust samples have  been  collected during the manufacture of dif-
ferent nickel  alloys  and analyzed  using XRD, SEM, and  EDXA  (Page,  1983).
X-ray diffraction patterns of the dusts closely matched the reference patterns
for nickel oxide and a complex copper-nickel  oxide.  Dusts from the manufacture
of another variety of nickel alloy were  thought to contain nickel oxide and  a
complex iron-nickel oxide.   The presence of metallic  nickel  in nickel alloy
dusts emitted to the air has also been verified (Page, 1983).
     The  only  sulfur  compound  of nickel expected to  be  emitted  from high
temperature metallurgical processes  is nickel sulfate.  If sulfur is present
(usually as sulfur dioxide) in metallurgical  processes, sulfate and consequently
nickel sulfate  may be formed rather  than nickel sulfide  or nickel subsulfide.
Nickel sulfate  would  be formed because  it is  thermodynamically more stable
under these types of temperature conditions than either of the sulfide compounds
(Page, 1983).   When such emissions are  released into ambient air, any nickel
sulfides would be unstable relative to nickel sulfate.
     The  available  test  results  indicate that nickel  in high temperature
metallurgical environments  is  predominantly  oxidized and combined with other
metals present  (if stoichiometry permits) to form complex oxides of nickel and
other metals.   Nationwide nickel emissions from steelmaking and nickel alloy
manufacturing,  the  dominant emission categories of the  metallurgical  group,
have  been estimated  to  be 71 Mg  (79 tons)/yr and 66 Mg  (73 tons)/yr, respec-
tively (Young,  1983; McNamara et  a!.,  1981).
3.3.1.4   Nickel Chemicals and  Catalysts.  The nickel  chemical  and  catalysts
grouping  includes nickel  chemical manufacturing, nickel  electroplating, nickel-
cadmium battery manufacturing,  and nickel catalyst production,  use and reclama-
tion  source  categories.  These source categories  are grouped  together because
each  uses various nickel compounds  directly  as process input materials  and
this  chemically dictates  the  form  of nickel  air emissions.   Emissions  of
nickel from  the production  of  nickel chemicals are thought to  be  small (McNamara
et al., 1981).  Raw material handling  and product  drying, grinding,  and packaging
are  the operations which most  likely emit nickel.  Nickel  in  raw  material form
will  generally be metallic  nickel or  nickel  oxide, while nickel  as  a  product
can  exist as nickel sulfate  (the highest volume  chemical produced)  or any of
25 other  nickel  chemicals produced  in  the United  States.
      Nickel  emissions can potentially occur  from electroplating  shops during
the  handling of nickel  salts  used  to prepare plating  baths,  the plating of
nickel,  and grinding,  polishing, and  cutting operations performed on  the
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finished product and scrap metal.  Nickel emitted during preparation and from
misting during plating are in the form of the chemical used, generally  nickel
sulfate or chloride.   Emissions from grinding and polishing operations contain
metallic nickel particles (Radian Corporation, 1983).
     Nickel chemicals are used in nickel-cadmium battery manufacturing primarily
for battery plate construction.   The forms of nickel most likely to be emitted
by  a  battery plant are metallic nickel,  nickel  oxide, nickel  nitrate, and
nickel hydrate (Radian Corporation,  1983; Radakovich, 1978).  No specific data
are available  to indicate which form nickel  emissions may take during the
production, use, and reclamation of nickel catalysts.  During catalyst prepara-
tion,  nickel can be  emitted as fugitive  dusts  of  the raw  material such as
nickel  carbonate,  hydroxide, nitrate, or  acetate  (McNamara et al., 1981).
During the  recycling  of  nickel  catalysts, nickel may  be emitted as an  oxide
since the metal  is subjected to high temperatures required  for thermal decompo-
sition.  Based  on  limited source testing  data,  nickel  emissions from catalyst
recycling appear to be minimal (Veil el la, 1984).
3.3.1.5   Miscellaneous  Nickel  Sources.   Other  miscellaneous categories of
nickel air emission sources  include co-product nickel recovery, cement manufac-
turing, coke ovens,  asbestos mining/milling, and cooling towers.   Nickel can
be  emitted  during  cement manufacturing,  asbestos mining/milling,  and  coking
operations because nickel is a natural component of  the minerals used in these
sources.  During cement manufacturing, nickel is emitted either as a component
of  the  clays,  limestones, and shales used  as raw  materials or as  an  oxide
formed  in  the  high temperature process  kilns.   Nickel emitted to air  from
asbestos mining/milling is in the form of the silicate minerals from which the
majority  of asbestos is  obtained.   No specific data  are  available on the
species of  nickel  emitted from  coke  ovens;  however,  because the atmosphere of
a coke oven  is highly reducing, nickel emissions can be theorized to be in the
forms  of  nickel  sulfides (Ni'3S2 and NiS) and nickel metal  (Ni°).   When these
nickel-containing  particles  are released  into  ambient air, oxidation  takes
place.  The  extent of this  oxidation is governed by the temperature at which
the particles pass from the  reducing atmosphere into ambient air.
      Nickel  can  be emitted  from cooling towers because nickel salts are used
in  cooling  tower water as biocides.  The  exact form of nickel emitted with
tower drift  depends  on the  chemical characteristics of the cooling water and
the presence of ligands  which can bind  nickel ions  (Richter and Theis,  1980).
Potentially  nickel  could be released as  the hydroxide,  sulfate,  or chloride
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and as nickel ions.
     Co-product nickel recovery means the recovery of nickel compounds during
the electrolytic refinement of blister copper and platinum.   Nickel  sulfate is
emitted during  these processes from drying and packaging operations (McNamara
et al., 1981).

3.3.2  Ambient Air Nickel Levels
     The most  comprehensive assessment of nickel  levels in ambient air of  the
United  States  is  currently performed by  the U.S. Environmental Protection
Agency.  Nickel levels are assessed by EPA through its National Air Monitoring
Filter  Sites (NAMFS)  network  and  its  Inhalable Particulate (IP) network.   The
NAMFS  system was  known as the National  Air Surveillance Network (NASN) prior
to 1980.
     In the  NAMFS  network,  ambient air particulate  samples  are  taken using
high volume  (HiVol)  ambient  air samplers and are analyzed  for their nickel
content by ICAP spectrometry.   In the IP network both HiVol  samples and dichoto-
mous (dichot)  filter  samples  are taken.   Inhalable Particulate network HiVol
samples are  analyzed  using ICAP spectrometry, while XRF spectroscopy is used
on dichotomous  filter samples.  Routine NAA is not performed on any atmospheric
nickel  samples  because no suitable states exist in the nuclei of nickel isotopes.
Further elaborations  on  analytical procedures can be obtained  in Section 3.2.
     Data from the  NAMFS and  IP  networks  have been compiled  in Table  3-2 (see
Section 3.2.2).  Table 3-2 presents  the  cumulative  frequency distribution of
individual 24-hour ambient air nickel levels for the period 1977 to 1982.   For
the NASN (NAMFS) data there appears to be a general  downward trend as the  1977
mean of 0.012  ug/m3 fell to  0.008 ug/m3 in 1982.  In 1977, 99 percent of  the
NASN data points  were less than  0.062 ug/m  , but in 1982 the  level at which
                                                                      3
the 99th  percentile was gauged at being less than was only 0.030 ug/m .   The
IP  network  HiVol  data show a  similar  downward trend.  The mean IP  HiVol value
in  1979 was  0.021 ug/m3  but was only 0.007 ug/m3  in  1982.  The 99th percentile
value  for  the  IP network HiVols  had  an  even greater decrease than the NASN
data,  from 0.128 ug/m3 to 0.014 ug/m3.
     The  IP  network dichot data  also show  a decreasing trend for nickel  in
ambient air  with the  exception of the elevated values in 1981.  No information
is  available within the  IP system to  explain this  perturbation.  An examination
of  the raw nickel data for 1981 showed that the majority of  the values were  at
or  only slightly above the lower  limit of discrimination (0.001 ug/m  ).  There
                                    3-24

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were only a few elevated readings; however, these few were elevated to such an
extent  that  the averages in  Table 3-2  resulted.   Because the sampling  and
analysis took  place  on a year round  basis, seasonal  variations  could  not  be
listed  as the  cause  for the  higher values shown  for  IP  dichots  in  1981.   In
1982 the  IP  network  dichots reflect  a  significant  decline  in  ambient  nickel
levels.  Many  of the  data  were  below  the  lower limit  of  discrimination.
Inhalable Particulate  network dichot data for  1982 show a fairly  distinct
declining trend  for  ambient  air nickel levels when  compared  with similar
numbers for 1979 and 1980.
     A  large amount  of urban and nonurban site specific ambient nickel  data
are available  from the NAMFS  network.   These data,  which are too expansive to
present here,  are  a  part of  the  National Aerometric  Data Bank maintained  by
the U.S. EPA at  Research Triangle Park, North Carolina.   They  may be obtained
from the Monitoring  and Data Analysis Division of  the Office  of Air Quality
Planning and Standards at Research Triangle Park,  North Carolina.
3.4  NICKEL IN AMBIENT WATERS
     Nickel is found  in  ambient waters as a result of chemical and physical
degradation of rocks  and soils, deposition of atmospheric nickel-containing
particulate matter,  and  direct  (and  indirect) discharges  from industrial
processes.  The concentration of nickel in U.S. surface waters recorded in the
U.S. Environmental Protection Agency's STORET  data base ranges  from less than
5 ug/1 to greater than 1,000 ug/1 (STORET, 1984).   A mean nickel concentration
of 4.8 ug/1 was calculated for drinking water in the United States following a
survey of  969 water  supplies  covering eight metropolitan areas (NAS,  1975).
About 90  percent  of  the  samples taken in this survey contained  less than
10 Mg/l.
     The anthropogenic sources  of nickel  in waters are briefly discussed  in
this section.   Attempts  are  made to determine the species or form of  nickel
expected to be found  in  the effluents based on the nature of the process and
the  aqueous chemistry of nickel.  The concentrations  of  nickel in ambient
water are also reviewed and characterized.
                                    3-25

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3.4.1  Nickel  Species in Water
     The major anthropogenic  sources  of nickel  in water are associated with
primary nickel production, other metallurgical  processes,  fossil  fuel  combustion
and incineration, and the production and use of nickel  chemicals  and catalysts.
Other industrial processes,  such  as cement manufacture, asbestos mining and
milling, and  coke  production release  less significant amounts of  nickel  to
surface and groundwaters.
3.4.1.1  Primary Nickel  Production.   Domestic  primary  nickel  production  is
limited to  the  production of ferronickel by the Hanna Mining Company and the
Hanna Smelting  Company  in Riddle, Oregon  and the  refining of imported nickel-
containing matte by AMAX Nickel Division in Braithwaite, Louisiana.
     The chief  sources  of wastewater at Hanna include those associated with:

          conveyor belt washing
          scrubbers for ore dryers
          once-through cooling
          slag granulation
          ferronickel shot production

     No data  were  found which  identified  the  form or species of nickel  in
wastewater  from Hanna.   However,  by examining the  form of  nickel  associated
with each  wastewater source and applying  some concepts of nickel behavior  in
aqueous media,  some  general hypotheses may be  formed.   Any nickel found in
wastewaters associated  with belt washing  and scrubbers for ore dryers should
be  in  the  same  form as  in  the  ore  (a silicate mineral) since these processes
do  not  involve  significant  chemical changes in the ore.  Nickel in wastewaters
from  slag  granulation  and ferronickel  shot production may  be found as an
iron-nickel  oxide, condensed  and  oxidized from  molten ferronickel fumes.
     At AMAX, potential aqueous discharges include spent  electrolyte solution
and tailings  from pressure leaching vessels.   Although no  information  was
found which quantified  the  volume of  effluent  streams or their nickel content,
discharges  of nickel from the AMAX facility are probably  small.   Hoppe (1977)
reported  that  greater  than 99 percent  of the nickel  contained in  initial
feedstock  (matte)  is recovered.
                                                                     2+
     Nickel in  tailing  pond discharges  may be  present as the  ion,  Ni   , or  the
dissolved  sulfate  from  electrolyte  solutions.   A  small  amount  of the  insoluble
nickel  subsulfide  may be present  due  to dusts  from matte  handling  and  storage.
                                     3-26

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 Likewise,  small  amounts  of metallic  nickel  powder  may  be contained
 in  tailing ponds from floor washing and dust removal  in the powder production
 area.
 3.4.1.2   Metallurgical  Processes.   Approximately  75 percent  of the  nickel
 consumed  in the  U.S.  is  used to produce stainless  steel, cast iron, and alloys
 (Sibley,  1983).   In  general,  each of these  metals  is produced by melting
 nickel and other required materials, refining  the molten  metal,  and  pouring
 the  melt  into ingots or  slabs.  Hot working, cold working, and annealing are
 used to obtain the desired final product (coils, sheets, strips).  No definitive
 data were  found  which identified the species  of nickel discharged  in effluents
 from these processes.
     Based on analyses  of a high  alloy  nickel  plant by INCO (Page,  1983),
 nickel in  wastewater associated with air pollution  control  equipment may be
 present for  the  most part as an  oxide  of nickel and other metals  present in
 the alloy  (iron, copper,  chromium), as a soluble compound  (perhaps the sulfate),
 or  as  metallic nickel.   Although  its presence  was not substantiated  by XRD,
 some nickel oxide may be  contained in these effluents.
     Nickel  has  also been detected in  discharges  from hot or cold working
 processes  (mainly  cooling water)  and  in pickling  liquor.   Contact cooling
 water may contain particulate matter dislodged from nickel-containing slabs or
 billets.   Therefore, nickel could exist in these effluents as dissolved nickel
 or  as  nickel  alloy particles.   Pickling  or  scale removal uses hydrochloric or
 sulfuric acids to  remove oxidized film (scale) accumulated  on  slags  as they
 are hot-worked.  Although nickel oxide is insoluble in water, it is soluble in
 acids; iron  oxides  are  also acid  soluble.   Therefore,  if  the oxide film is
 nickel oxide  or  iron-nickel oxide, nickel discharged in pickling liquors could
 exist as dissolved nickel ion, or in an oxidized form.
 3.4.1.3  Combustion and Incineration.   Combustion of fossil fuels and inciner-
 ation of municipal  refuse and sewage sludge release nickel  into all environmen-
 tal  media  because  the  metal  is contained in materials  being burned.   The
 actual combustion process does not generate aqueous effluents, but the subsystems
 required for  boilers  and incinerators  such as  ash  disposal,  cooling  water,
waste ponds,  and certain types  of air pollution control  equipment generate
 significant volumes of wastewater with varying nickel  contents.
     No substantive  data  were  found in the  literature  which  identified  the
 form of nickel contained in boiler or incinerator effluents.   Based on analyses
of atmospheric emissions, the control  of which generates much of the wastewater,
                                    3-27

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and the chemistry of  nickel,  some speculation as to the speciation of nickel
in these effluents can  be made.   Based on analyses by Henry and Knapp (1980)
and Hulett et  al.  (1980), nickel  in fly ash from both utility and industrial
combustion of  fossil  fuel could  be  present as the dissolved  sulfate  or a
relatively insoluble oxide of nickel  and other metals.  These forms would also
be found in ash disposal wastewater streams.
     Boiler blowdown and metal cleaning streams contain products of corrosion,
scale buildup,  and various acids and alkalis (Baig et al., 1981).   This effluent
could contain  nickel  as the  dissolved ion, especially  if alkaline materials
are used to  neutralize  the effluent,  keeping  the pH between  7  and 9.  Overall
nickel discharged in  an effluent  from  fossil  fuel  combustion facilities  would
most  likely  be present  as the soluble sulfate, a complex oxide of nickel and
other metals (silicate,  spinel, ferrite) and the nickel ion.
     Wastewater sources  from  refuse  incinerators include  spray chamber water,
used to remove fly ash,  and bottom ash quench water.  Nickel found in inciner-
ator effluent may be present as it is in fly ash since most wastewater discharges
are associated with  ash disposal  or removal.   Henry et al.  (1982) found that
in refuse derived fly ash, the soluble portions were mostly sulfate and chloride
salts; solubles  from  sludge  fly ash  included  sulfate,  chloride, and phosphate
salts.  The  insoluble fractions  were oxides,  silicates,  and in sludge ash,
some  insoluble phosphates.   Therefore, in aqueous effluents associated  with
incinerator  ash disposal, nickel may be found as the dissolved sulfate, chloride,
or phosphate species.   Some  nickel may be  found associated  with silicates  and
oxides.
3.4.1.4   Nickel  Chemicals and Catalysts.   Nickel compounds  are consumed for
the most part  in electroplating and the production of nickel-cadmium batteries.
Because of  the close  relationship between  the primary producers and  consumers
of nickel  compounds,  the species of  nickel  in aqueous effluents associated
with  these industry segments  are  reviewed together in this  section.  Discharges
from  catalyst  manufacture and  use are  also  included here.
      Although  a wide  variety of nickel compounds are  produced  commercially in
the  U.S.  (the  halide  salts,  carbonate, hydroxide,  acetate), nickel  sulfate is
the  most  important  commercially.   Aqueous  discharges  of nickel during sulfate
production  apparently  are minimal.   Effluent  discharges  are  minimized by
extensive  recycling of  both  process  solids  and liquids.   The species of  nickel
discharged  would most  likely  be  nickel  sulfate,  either dissolved or as the
sulfate  compound.   Some unreacted metallic nickel powder or nickel oxide  may
                                     3-28

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be present  in effluent, but  extensive  recycling and material conservation
precludes the discharge of significant quantities of raw material.
     Discharges of nickel from the production of other nickel compounds could
contain dissolved nickel ion or the compound itself, depending on the solubil-
ity of the compound and the quality of the receiving waters.
     As mentioned previously,  several  nickel  chemicals are used to formulate
electroplating baths.   Although plant effluents are extensively recycled,  some
nickel may escape recovery during  in-plant wastewater treatment.  This nickel
                                    2+
is likely to be discharged as the Ni    ion or as dissolved nickel salt (sulfate,
chloride, etc.).
     Nickel  powder and nickel nitrate salts are the  raw materials used to
produce  sintered  plate nickel-cadmium  batteries.   Process wastewaters are
generated by  washing  and  rinsing of battery plates.   Based  on the forms  of
nickel used in the process,  including nickel nitrate, nickel  hydroxide, and a
nickel powder  (assumed to be  metallic nickel),  it  seems  reasonable to project
that these compounds would be present in wastewaters.  Depending on the pH of
the receiving waters   and  the presence of ligands,  nickel  discharged from
                                                2+
battery manufacturing could exist as divalent Ni   , metallic nickel,  or as the
hydroxide.  No data were found to conclusively substantiate these projections.
     Nickel  containing  catalysts  are used in hydrogenation of fats and oils,
hydrotreating of petroleum, and various ammonolysis and methanation reactions.
They are  also used in  catalytic  combustion of organic compounds  in automobile
exhausts.
     Wastewater sources were not  definitively  identified,  but may include
                           P
caustic  leachate  from  Raney   nickel  production,  filtrate  from the manufacture
of precipitated or supported catalysts, and water used in air pollution control
equipment.  The form  of nickel  present depends  on the type  of nickel in raw
materials, which may be an aluminum-nickel alloy, nickel  powder,  or a solution
of soluble salts such as the chloride, acetate, nitrate,  or sulfate (Antonsen,
1980).  Nickel in wastewaters may be the dissolved form  of  these compounds.
3.4.1.5   Other Sources of  Aqueous  Discharges of Nickel.   Because  nickel  is
contained in raw materials, the metal may be detected in effluents from proces-
ses such  as  the  production of cement and coke,  and from  asbestos mining and
milling.   Nickel  has also been detected in cooling tower  discharge at concen-
trations greater than that of intake water.   The species of nickel  potentially
emitted in effluents from these source categories are described below.
                                    3-29

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Cement Manufacture
     Nickel is contained in raw materials such as limestone, gypsum,  and shale
which are  used  in the production of Portland  cement.   The  major wastewater
stream associated with  cement production is that from filtration or flotation
of slurried feed materials to remove mica,  quartz,  and other impurities (Katari
et al.,  1974).   Any  nickel present would most likely be held in the mineral
lattice of the parent raw material (limestone, sand, etc.).
Coke Ovens
     By-product coke production requires thermal  distillation of coal.   Waste-
water sources associated  with  this source category  include quenching  water,
and water required for air pollution control  equipment.   Although no definitive
data were found which identified the form of nickel in such effluent, it seems
probable that nickel  may  be in an oxidized form because of the high tempera-
tures of the coking process.
Asbestos Mining
     No  wastewater  is generated during dry processing  of asbestos minerals.
At  the  single plant  using wet  processing,  approximately 68 percent of  the
water is recirculated and  4 percent becomes incorporated into the final product
(U.S. EPA,  1976).   Twenty percent is discharged  to a settling pond; 8  percent
is  lost  in tailings  disposal.   Tailing pile runoff may  contain  nickel  leached
from the mineral, especially under acidic conditions.  Nickel would be present
as  it  occurs  in the mineral,  substituted in the  magnesium-silicate  structure.
No data  were found to indicate  the magnitude of such discharges or to  identify
the form of nickel present.
Cooling  Towers
     Waslenchuk  (1982)  analyzed the intake and  discharge waters  of a power
plant  cooling  system which relied on  saline  intake water and  reported  that
discharge  waters contained 0.3 to 1.9  pg more dissolved nickel per  kilogram
than intake waters after  a 2-minute transit time through the system.   The form
of  nickel  in discharge  waters and the  persistence  and fate  of the metal  in the
receiving  water body depend on  the  aqueous  chemistry of the metal.   Nickel
could  be removed from  the water column by adsorption to sediments.   In the
Waslenchuk study, adsorption to sediments  apparently exerted  a significant
influence  on the fate of  dissolved nickel.  Therefore,  nickel in cooling tower
discharge  may enter  the receiving water body  as  a  cation and, depending  on the
presence of ligands,  suspended  particulate, water  pH and hardness, the ion may
form complexes,  be  adsorbed,  or precipitate out  of solution.

                                     3-30

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3.4.2  Concentrations of Nickel in Ambient Waters
     The concentrations of  nickel  in surface waters are generally low unless
impacted directly or indirectly by industrial processes.   The STORET data base
(STORET, 1984) compiles sampling data for surface water,  well water, and other
parameters for the  United  States.   The unremarked surface water data for the
15 major river basins  in  the continental U.S. were retrieved for 1980-1982.
As shown in Table 3-3, mean total nickel concentrations for these river basins
ranged from less than 5 ug/1 to greater than 700 ug/1  during the 3-year period.
Although differences in the number of samples taken per year limits the accuracy
of speculating upward  or  downward trends in  nickel concentration,  it can be
seen that  the Ohio River basin  consistently  shows  the highest mean nickel
concentration, ranging from 552 ug/1 in 1980 to 672 ug/1  in 1982.  The maximum
reported concentrations  for this basin were  between  7,800  and  10,900 ug/1.
     In 1980, 11 of the 15 basins had mean total nickel concentrations of less
than 50 ug/1.  During  that  year,  highest mean concentrations were observed in
the Ohio River, Northeast, Southeast, Western Gulf, and Tennessee River basins.
The Great Basin (the southern Nevada area) had the lowest mean.   For the 8,037
unremarked observations recorded  in  the STORET  system  that year, the mean for
all basins was 68.2 ug nickel/I.  Ten of the basins (66 percent) had concentra-
tions such that  85 percent  of the reported  values  were  less than 100 ug/1.
     For 1981, the  Ohio  River basin again showed the highest mean concentra-
tion, 742 ug/1; the South basin reported the second highest mean of 68.3 ug/1.
The remaining  13  basins  had mean nickel concentrations of less  than 50 ug/1.
In 1982, all  areas except the Ohio  River basin reported means  of less than
50 Mg/l.
     Figure 3-2  shows  the concentrations of  nickel  detected  in  surface waters
of counties  throughout the  continental  United States, documented by sampling
in 1982.  The  gradations  on the map are made as percent!les,  meaning that
85 percent of the values reported fall  into the ranges given on  each map.  The
darkest shadings  indicate that 85 percent  of the samples in that county are
greater than  26  ug/1   in  1982.   Although it is  somewhat  difficult  to make
comparisons between areas because of variations in the number of samples and
sampling location,  the map  indicates that greater  quantities of nickel  are
found in the Ohio-Pennsylvania area, some Rocky Mountain states  (Utah, Wyoming,
Colorado),  and  Oklahoma.    Similar geographic patterns in regard to nickel
concentrations have been  found over the past several  years  prior to 1982.
                                    3-31

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                     TABLE 3-3.   NICKEL CONCENTRATIONS  IN U.S.  AMBIENT SURFACE WATERS:   1980  -  1982  (|jg/1)
Major River Basin
Northeast
North Atlantic
Southeast
Tennessee River
Ohio River
Lake Erie
Upper
Mississippi
River
GO
co Lake Michigan
IN3
Missouri River
South Central
Lower
Mississippi
River
Colorado River
Western Gulf
Pacific
Northeast
California
Great Basin
TOTAL
OBSERVATIONS
MEAN (all basins)
UflTC. D~_._l 	 I _I_A .
n
628
518
862
56
1,921
155
350
126
749
831
362
570
783
94
32
8,037

mean
82.7
26.4
77.6
56.2
552.0
26.2
14.3
14.2
24.8
31.9
19.4
46.7
18.5
26.6
4.81

68.2
1980
max
9,140
920
900
780
10,900
200
500
120
1,300
1,110
300
251
480
200
12


85
percentlle
105.0
40.0
173.0
100.0
700.0
100.0
11.0
20.0
26.0
46.0
30.0
84.0
20.0
54.0
11.0


n
377
687
527
94
1,019
264
366
159
705
634
429
159
261
246
33
5,960

mean
9.50
35.0
68.3
48.6
742.0
26.2
18.3
10.1
13.5
20.4
19.8
11.1
23.1
45.0
3.21

72.9
1981
max
150
560
500
3,450
9,000
1,000
1,700
79.0
280.0
660.0
570.0
180.0
470.0
575.0
11.0


85
percentlle
17.0
50.0
190.0
20.0
100.0
50.0
13.0
10.0
20.0
27.0
25.0
17.0
30.0
88.0
5.0


n
232
455
647
232
882
185
386
120
513
487
295
144
155
352
17
5,102

mean
9.83
37.8
45.4
15.0
672.0
10.9
14.1
15.2
16.1
15.3
28.1
29.8
18.8
44.8
3.94

65.1
1982
max
190
1,210
480
985
7,800
260
1,000
700
270
300
910
540
280
538
10


85
percentlle
15.0
50.0
100.0
20.0
180.0
10.0
19.0
10.0
30.0
25.0
26.0
20.0
30.0
70.0
6.0

•''•'••-.._ - _-.-— i 	
Source:  STORET (1984).
                            N - number of observations.  85 percentlle means that 85 percent of all  recorded values are  less than the given value.

-------
I
CO
CO
                  NICKEL
                 1982  RMK-CXCLUDEO
                 85TH  PERCENTILES


                 @          <-     6.4000

                 E3   6.4000 TO    11.0000

                 89 11.0000 TO    26.0000

                 H         >     26.0000

           SCALE  •  1:12000000 OR 169.43 MILES PER INCH
                                         Figure 3-2.  Concentrations of nickel in surface waters, by county, 1982.

                                         Source:  STORET (1984).

-------
     Concentrations of nickel in groundwater, as shown in Table 3-4, are also
highly variable.   Fewer  river  basins  are represented in this  data base (as
compared to surface water  data)  and fewer samples  were  taken during the same
3-year period.  From Table 3-4 it is apparent that groundwaters from the Ohio
River basin show  substantially  higher  nickel concentrations for all 3 years
for which data were retrieved.  This trend is similar to that  seen  in surface
waters.   The  Southeast basin  reported  the second highest concentrations with
means ranging from 85.1 to 754 (jg/1.   The California basin  also has relatively
high concentrations of nickel  in  groundwater,  but these data  were obtained
from only three samples taken between  1981 and  1982.   The remaining basins all
had mean nickel concentrations in  groundwater of less than  50 ug/1.
     It must be noted that the extremely high concentrations found in the Ohio
River and Southeast basins may not truly reflect the extent of nickel  presence
in groundwaters for each  basin area because one or  two samples may have skewed
the data toward higher concentrations.  This is verified somewhat  by the data
for the Southeast basin in 1980 where  the maximum reported  value was 1,500 ug/1
but 85 percent of the remaining samples contained less than 130 ug/1.
3.5  NICKEL IN OTHER MEDIA
     The presence of  nickel  species in other media such as soil, plants, and
food constitutes a potential source of population exposure.  Nickel may  enter
these media through deposition on soils with a subsequent release in a soluble
form that  is  available  to plants, including those used as food  (NAS, 1975).
Significant factors determining the extent of release to plants  are:  (a) the
soil pH, decreases  in which generally result in  larger  releases to plants;
(b) the relative amount  of  soil  cation exchange  sites; and (c)  the relative
amounts of other cations in the soil (Hutchinson et al.,  1981).   The concentra-
tions of nickel  are  examined in this  section for three  interrelated media:
soils, plants, and food.   The measured levels are reported as elemental  nickel
owing to the fact that speciation data on nickel are unavailable in the litera-
ture.

3.5.1  Nickel in Soils
     The level of naturally occurring nickel in soils depends upon the elemen-
tal composition of rocks in the upper crust of the earth.   These rocks provide
                                    3-34

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                                    TABLE 3-4.    NICKEL CONCENTRATIONS IN  GROUNDWATER:   1980  - 1982
GO
1980
85
Major River Basin n mean max percentlle
North Atlantic 92 12.4 110 20.0
Southeast 123 85.1 2,500 130.0
Tennessee River
Ohio River 49 6,300.0 18,300 9,000.0
Upper 6 13.3 32 32.0
Mississippi
River
Western Gulf
Pacific 2 6.0 11 11.0
Northwest
California
TOTAL 272
OBSERVATIONS
1981 1982
85 85
n mean max percentlle n mean max percentlle
182 13.5 340 20.0 178 30.9 306
323 754.0 44,000 300.0 218 129.0 17,800
1 50.0 50 50.0 23 7.13 42
54 4,710.0 20,700 7,500.0 39 4,430.0 19,600
9, 3.38 9 6.0 6 2.95 5.90
5 18. 0 24

2 99.0 180 180.0 1 100.0 100
571 470
50.0
180.0
13.0
6,700.0
5.90
24.0

100.0

     NOTE:  Remarked data excluded, blanks Indicate data not available.  N = number  of observations.  85 percentlle means that 85 percent of all recorded
      values are less than the given value.

     Source:  STORET (1984).

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most of the  material  from which soils derive  their  inorganic constituents.
The crust of the earth  is composed of approximately 0.008 percent nickel with
the actual percentage composition varying according to the type of rock present
in the crust.   The  natural  concentration of nickel  in  soils  usually ranges
from 5 to 500  ppm,  but soils derived from serpentine rock may contain levels
as high as 6,000 ppm (NAS, 1975; Vaneslow, 1966).   Various researchers (Whitby
et al., 1978;  Dudas  and Pawluk, 1977; Frank et al.,  1976; Mills and Zwarich,
1975; Hutchinson et al., 1974) have measured natural  levels of nickel in soils
at concentrations ranging  from  1 ppm to 50 ppm.   The average level  of nickel
in soil is  estimated  at approximately 50 ppm (Bowen, 1979; Aubert and Pinta,
1977).   These data are presented in Table 3-5.
     Anthropogenic inputs of nickel to soils are hypothesized to occur through
several mechanisms:    (a) emissions from primary smelters and  metal  refineries
that are  deposited  on soils near the facility; (b) disposal of sewage sludge
on soils  or  application of sewage sludge as a fertilizer; (c) auto emissions
deposited on  soils  in the vicinity  of the  roadway;  and (d) emissions  from
electric power  utilities  deposited on soils downwind of  the  facility.   The
most significant anthropogenic nickel inputs to soil  result from metals smelt-
ing and refining operations and sewage sludge applications (Hutchinson et al.,
1981).
     Table 3-6 presents data  on  nickel concentrations in  soils  resulting from
anthropogenic  inputs.   The highest  levels  are  found  in soils  located  near
nickel  smelters and metal refineries.  Concentrations of nickel up to 4,860 ppm
have been  measured  in  the  surface litter of  forested  sites  near smelting
operations  (Hutchinson  et al.,  1981).   Frank et  al. (1982)  reported that
aerial  fallout  from  a nickel  smelter resulted  in  the accumulation  of  nickel
ranging from 600  to 6,455 ppm in the organic  soil of a farm.   At sites near
metal  refineries  recorded  levels of nickel have been as  high as 24,000 ppm.
Generally,  the  concentrations of  nickel  in soils  decrease with  increasing
distance  from  the emission point  (Hutchinson  et  al.,  1981;  Hutchinson and
Whitby, 1977;  Ragaini  et al., 1977; Beavington, 1975;  Burkitt  et al.,  1972;
Goodman and Roberts, 1971).
     Soils  in  agricultural  areas  can receive anthropogenic  enrichments of
nickel  when  sewage  sludge  is  applied to the land.  Nickel  has been  identified
as one of the trace metals found  in sewage sludge that  is  likely  to  cause
toxicity  problems  in plants (Webber, 1972).   In  sludge from more  than 300
                                    3-36

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            TABLE 3-5.  NATURAL LEVELS OF NICKEL IN SELECTED SOIL TYPES
      Soil Description
   Nickel Concentration
   (mg/kg, dry weight)
           Reference
Loams and clays
Temperate and boreal regions
Arid and semiarid regions
Tropical humid regions
Serpentine
Cultivated (various Canadian
sites)





Cultivated muck
Cultivated mineral
Virgin muck
Sandy agricultural
Clay agricultural
Organic agricultural
Cultivated, poorly-drained
Cultivated, well -drained
90 - 100
4 - 600
50
1 - 500
400 - 6,000
9 - 32

27 - 42
15 - 18
12 - 22
19 - 31
20 - 35
15
20
8 - 15
8
28
29
6 - 8
1-7
Aubert and Pinta (1977)
Aubert and Pinta (1977)
Aubert and Pinta (1977)
Aubert and Pinta (1977)
Vaneslow (1966)
Whitby et al. (1978)

Whitby et al. (1978)
Whitby et al. (1978)
Whitby et al . (1978)
Whitby et al. (1978)
Whitby et al. (1978)
Hutchinson et al. (1974)
Hutchinson et al. (1974)
Hutchinson et al. (1974)
Frank et al. (1976)
Dudas and Pawluk (1977)
Dudas and Pawluk (1977)
Dudas and Pawluk (1977)
Dudas and Pawluk (1977)
               TABLE 3-6.  NICKEL CONCENTRATIONS IN ENRICHED SOILS
   Enrichment Source
Nickel Concentration
 (mg/kg, dry weight)
         Reference
Nickel smelter emissions


Metal refinery emissions

Sewage sludge application


Auto emissions
      300 - 500
      to 4,860

      to 24,000

         129
        2-50

        1-8
Rutherford and Bray (1979)
Hutchinson et al. (1981)

Hutchinson et al. (1981)

Chaney et al. (1977)
Page (1974)

Lagerwerff and Specht
  (1970)
Hutchinson (1972)
                                     3-37

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sewage treatment plants  studied  by  Page (1974), the recorded nickel concen-
trations ranged  from 10 ppm  to  53,000 ppm for dried  sludge.   The typical
nickel concentrations in soils where sludge has been applied are significantly
lower than those levels in the sludge itself.   The amount of nickel in sludge-
mixed soil  is variable  and appears  to be dependent  upon the sludge source  and
amount  applied  (Wollan and Beckett, 1979).   Heavy metal  concentrations in
sewage  sludge  and in  soils from sites  where sludge was  applied  have been
studied by Chaney et al. (1977) for 43 treatment plants.   The mean concentration
of nickel  in  sludge-treated  soil was measured at 129 ppm with a median value
of 42 ppm.   Page (1974) measured nickel in sludge-amended soils at concentrations
ranging from 2 to 50 ppm.
     Auto emissions can result in the enrichment of soils with nickel.  Lagerwerff
and Specht  (1970)  studied the contamination of roadside soils near two major
highways.   Measured  nickel concentrations  were found  to  range  from  0.90 to
7.4 ppm.  These  concentrations  were lower at greater  distances from  traffic
and  at  greater  soil  profile  depths.   Hutchinson  (1972)  conducted similar
studies  of  nickel  enrichment  of soils  by  auto  emissions  and  found levels  of
nickel as high as 32 ppm.

3.5.2  Nickel in Plants
     The  primary route  for  nickel  accumulation in plants  is through root
uptake  from soil.   Nickel is present  in  vegetation usually below the 1 ppm
level,  except  for plants grown  in  nickel-rich  substrates such  as serpentine
soils.   Concentrations  ranging from 0.05 ppm to 5  ppm have been  reported  for
cultivated  crops and  natural  vegetation  (Vaneslow,  1966).   Connor et al.
(1975)  have reported mean values of approximately  0.20 to 4.5 ppm for nearly
2,000 samples of cultivated  crops and  natural  vegetation.  This  study showed
that  although  nickel levels  in  plants  rarely exceed 5 ppm, concentrations as
high  as  100 ppm  can  be  measured  in  plants  from  serpentine soils.
      Several  researchers have attempted to assess  the accumulations  of nickel
in  plants  grown in  soils  receiving anthropogenic  enrichments of  nickel  (see
Table 3-7).   For crops grown in  soils  where  sewage sludge was applied, the
concentration of nickel  was found to range from 0.3 to 1,150  ppm  (Giordano and
Mays,  1976; Schauer et  al.,  1980;  Mitchell et  al., 1978; Clapp et al.,  1976;
Anderson and  Nilsson,  1972; LeRiche, 1968).   Higher concentrations occurred in
soils with low  pH.   A  study by  Beavington  (1975) showed that  concentrations of
                                     3-38

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                                    TABLE 3-7.  ACCUMULATION OF NICKEL  IN PLANTS
GO
IO
Growth Environment
Background



Sludge enrichment
66 Mg/ha/yr
9 kg/ha

42 - 165 kg/ha
24 Mg/ha

20 Mg/ha
60 Mg/ha
20 Mg/ha
60 Mg/ha
Soil pH 5.7

Soil pH 7.5

Plant Species
Cultivated crops
Natural vegetation
Cultivated crops
Natural vegetation

Leeks, Beets
Rape

Corn
Various crops

Lettuce, Tomatoes
Lettuce, Tomatoes
Radishes, Carrots
Radishes, Carrots
Lettuce, Wheat grain



N1 Concentration
(mg/kg, dry weight)
0.05 -

0.20 -


7 -
9.2

0.3 -
0.8 -
1.8 -
6 -
3 -
5 -
11 -
1.7 -
119 -
1 -
5 -
5

4.5


16.5


3.0
76 1n fruit, root
6.2 1n leaves
10
7
11
18
241
1,150
23
166
Reference
Vanes low (1966)

Connor et al. (1975)


Le R1che (1968)
Anderson and
Nilsson (1972)
Clapp et al. (1976)
Giordano and Mays (1976)

Schauer et al. (1980)
Schauer et al. (1980)
Schauer et al. (1980)
Schauer et al. (1980)
Mitchell et al. (1978)



        Copper  smelter Inputs      Lettuce
2.7 - 6
Beavington (1975)

-------
nickel  in  lettuce  grown in soil near  a  copper smelter ranged  from  2.7  to
6 ppm.
     In a study  on  the uptake of nickel  by the edible portions of food crops
such as bush beans,  cabbage, onions, tomatoes,  and potatoes grown in test pots
in municipal sludge  from  Ithaca,  N.Y., Furr et al. (1976) observed:   (1) at
first-year harvest,  nickel levels in the above  food crops were increased 2- to
3-fold compared  to control  soil crops, the corresponding soil pH  levels being
7.1 for sludge-amended samples and 5.3 for control soils; (2) at second harvest,
the increases  seen  in the first harvest  did not  recur,  except for  about a
2-fold increase in onions and tomatoes.
     As discussed  previously (Frank  et  al., 1982),  aerial  fallout  from a
nickel  smelter resulted in accumulation of nickel  ranging from 600 to 6,455 mg/kg
in the organic soil  of a farm.  Vegetables have been grown commercially for 20
to 40 years  on this  farm located I km (0.6 miles)  from  the smelter and in
direct line  with the prevailing winds.   To evaluate  the possible impact of
nickel  contamination  on  the soil,  the nickel  content of the  edible  parts of
crops grown  on this  soil  was determined.  Nickel  levels (mg/kg,  dry weight)
ranged from  80 to 280 in  beet roots,  76  to 400  in cabbage  heads,  15  to 395 in
celery tops, 22 to 130 in lettuce tops and 24 to 140  in radish roots.

3.5.3  Nickel  in Food
     Nickel  may  be  ingested by  human  beings  through the  consumption  of nickel
which has accumulated  in plants used as foods.   Some  representative  values for
various foodstuffs, adapted from studies  by Schroeder  et al.  (1962)  and Vaneslow
(1966) are  given in  Table 3-8.   The level of nickel rarely exceeds  1 ppm,  but
in seafood it  has been measured as  high as 1.7 ppm.
     The  assessment  of average  daily  nickel intake in food can  be  done by
considering  the  aggregate nickel content  of average diets  in  the  population or
by  fecal  nickel  determinations.  Although fecal  nickel  levels would be  more
meaningful  than  diet analysis,  the lack  of literature in  this area  precludes
extensive treatment  in this  report.
     Schroeder et  al. (1962) calculated  an  average oral intake of  nickel  by
American  adults  to be about  300 to 600 ug/day; Louria and co-workers  (1972)
arrived  at  a value of  500  ug/day.  Murthy et  al.  (1973) calculated  the daily
food intake  of a study group  of children  to be  an average  of  450  ug/day.   In  a
related  study,  Myron  et al. (1978)  determined the nickel content  of nine
typical  institutional  diets in  the  United States  and  calculated  an average intake
                                    3-40

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     TABLE 3-8.   NICKEL CONTENT OF VARIOUS CLASSES OF FOODS IN U.S.  DIETS
Food Class and Examples
Nickel Content,
ppm, wet weight
Grains/grain products
     Wheat flour,  all-purpose
     Bread, whole-wheat
     Corn, fresh frozen
     Rice, polished American
     Rye flour
     Rye bread

Fruits and vegetables
     Potatoes, raw
     Peas, fresh frozen
     Peas, canned
     Beans, frozen
     Beans, canned
     Lettuce
     Cabbage, white
     Tomatoes, fresh
     Tomato juice
     Spinach, fresh
     Celery, fresh
     Apples
     Bananas
     Pears

Seafood
     Oysters, fresh
     Clams, fresh
     Shrimp
     Scallops
     Crabmeat, canned
     Sardines, canned
     Haddock, frozen
     Swordfish, frozen
     Salmon
Meats
     Pork (chops)
     Lamb (chops)
     Beef (chuck)
     Beef (round)
     0.54
     1.33
     0.70
     0.47
     0.23
     0.21
     0.56
     0.30
     0.46
     0.65
     0.17
     0.14
     0.32
     0.02
     0.05
     0.35
     0.37
     0.08
     0.34
     0.20
     1.50
     0.58
     0.03
     0.04
     0.03
     0.21
     0.05
     0.02
     1.70
     0.02
 Not detected
 Not detected
 Not detected
Source:  Adapted from NAS (1975).
                                    3-41

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of 165 |jg/day.
     Several studies have  reported  daily fecal  excretions of nickel.   Nodiya
(1972) in a  study  of Russian students reported a fecal excretion average of
258 |jg/day.   Horak and Sunderman (1973)  determined fecal  excretions of nickel
in 10 healthy subjects  and also arrived at a value of 258 ug/day.
     Food processing methods apparently  add  to the  nickel  levels  already
present  in  foodstuffs  via:   (1) leaching from  nickel-containing alloys in
food-processing equipment made from stainless steel,  (2) the milling of flour,
and (3) the catalytic hydrogenation of fats and  oils  by use of nickel  catalysts
(NAS, 1975).

3.5.4  Nickel in Cigarettes
     Cigarette smoking can contribute to  man's daily  nickel  intake by inhala-
tion.  However, recent studies  suggest that nickel  intake via this route of
exposure is considerably  less than  previously believed (Weast, 1980;  Gutenmann
et al., 1982; Hassler,  1983).  Therefore, the value  of 5 mg nickel  reported by
the National Academy of Sciences (1975) as the annual  nickel  intake  of individ-
uals smoking two packs  of cigarettes daily may be overestimated (see Chapter 4).
3.6  GLOBAL CYCLE OF NICKEL
     Nickel in all environmental compartments (air, water, and soil) is contin-
uously transferred between these media by natural chemical and physical processes
such  as  weathering, erosion, runoff, precipitation,  stream/river  flow,  and
leaching.  The ultimate  sink for nickel is  the  ocean.  The cycle  is contin-
uous, however,  because nickel  may  leave the ocean as  sea  spray aerosols,
burst, and release  minute particles containing nickel and other  elements  into
the atmosphere.   These particles can serve as nuclei  for the condensation of
rain  and  snow,  thereby reintroducing nickel into  the global  cycle.   Nickel
introduced into  the environment by anthropogenic means  is subject  to the  same
physical  and  chemical  properties which  affect nickel that occurs  naturally,
but  can  account  for  increased  ambient  concentrations in all environmental
media.
      In  the atmosphere,  nickel-containing particulates  are subject to  disper-
sion  and transport by winds and can be transferred from the atmosphere to soil
or water  by wet or dry deposition, impaction, or gravitational  settling.   In
                                    3-42

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water bodies, nickel is transported by stream flow and can be removed from the
water column by sedimentation, precipitation from solution, or adsorption onto
suspended solids.   In soils, nickel may be sorbed by clay or mineral fractions,
complexed with organic  material,  or leached through the soil column into the
groundwater.  Cross-media  transfer between soil  and water occurs via erosion
and  runoff.   Ultimately,   nickel  will  be  deposited  in  the world's oceans.
     This section briefly  examines the mechanisms by which  nickel  is cycled
through  all  environmental  media,  and  where  possible,  the amount of nickel
entering each compartment  from natural and anthropogenic sources is quantified.

3.6.1  Atmosphere
     Nickel  is introduced  into the atmosphere from both  natural  and anthropo-
genic sources as  shown  in Figure 3-3.  Estimates of the portion of the total
atmospheric burden of nickel attributed to either source category vary,  depending
on the choice of  emission  rate and nickel  concentration  of the material being
dispersed.   Nriagu  (1980) estimated that  2.6 x  104  Mg  (2.9 x 104  tons)  of
nickel are  released into  the atmosphere  per year,  worldwide  from natural
                                                                    4
sources,  and that anthropogenic  sources account  for  another  4.7  x  10  Mg  (5.2
x 104 tons).
     Galloway et  al.  (1982) estimated similar global emissions  from natural
                 4             4
sources,  2.8 x 10  Mg (3.1 x 10  tons)/year, but report emissions from anthro-
                            4          5
pogenic  sources of  9.8  x  10  (1.1 x 10  tons)/year,  an estimate nearly twice
that reported by  Nriagu.   The discrepancy  is most likely due to  the choice of
emission  factors.   The  proportion contributed to the atmosphere by natural
sources  varies with  local  meteorological  conditions, soil type, and physical
factors.   .Erosion by wind and volcanic action contributed an estimated 40 to
50 percent of the airborne nickel  from natural sources  (Nriagu,  1980).  Other
natural  sources  include forest  fires, sea salt spray,  meteoric dust,  and
vegetative exudates (Schmidt and Andren,  1980).   Up to 80 percent of anthropo-
genic emissions  of nickel  may  be generated by  fossil  fuel  combustion  and
nonferrous metals production (Nriagu, 1980).  Other researchers have estimated
that combustion of  oil  alone accounts for 83 percent of atmospheric  nickel
from anthropogenic  sources (Lee  and Duffield, 1979).  Although the  resolution
of differences in these worldwide  emissions is beyond the  scope  of  this docu-
ment, it  seems apparent that combustion and other high temperature processes
(metallurgical  furnaces)  account for  a significant  portion  of industrially
generated nickel   in  the atmosphere.  As discussed elsewhere in this chapter,
                                    3-43

-------
                                                        ATMOSPHERE
                                                          1.5x109g
                                                          (t = 7 days)
      KEY:
FLUX UNIT = 1010g/yr1
 t = Residence Time   I
00
Waste Disposal 1.3
LAND SURFACE
5.3x10'5g
(t = 3500 yrs)
^
Rivers 135
OCEAN
8.4x10"g
(t = 23000 yrs)
                                                          BIOSPHERE
                                                       Marine = 1.1 x10'°g
                                                           Terrestial =
                                                           1.4x10"g
                                                                                                                 SEDIMENTS
                                                                                                                  1.2x101«>g
                                                                                                                  (t = 10«yrs)
                                                              "Uplift" = Denudation = 150
                                    Figure 3-3. The global cycle of nickel on a 1-year frame.
                                    Source: Nriagu(1980)

-------
most anthropogenic nickel is likely to be present as the soluble sulfate with
additional amounts present as various oxides and silicates  of nickel.
     Once nickel enters the atmosphere, it may  remain suspended and available
for transport or it can be removed by wet or dry deposition.   A residence time
in the atmosphere  of  5.4  to 7.9 days has been  estimated for nickel (Schmidt
and Andren, 1980).  Based on mathematical  models, the  proportion  of  nickel
removed by wet  and dry deposition are about  equal  in  areas receiving 0.5 m
(19.7 in.) rain per year (Schmidt and Andren,  1980).
     The size of the particle influences the type of deposition by which it is
removed from the atmosphere.  Fine particulates and gases tend to move higher
into the  troposphere and  become  incorporated  into raindrops (Galloway et al.,
1982).   Larger  particles  are  more subject to gravitational  settling near the
emission source.
     Davidson (1980) applied three dry deposition models to ambient data from
six U.S.  cities and calculated a dry deposition flux for nickel of 1 to 2.7 ng/
  p
cm  per day,  with deposition velocities ranging from 0.19 to 0.49 cm/sec.   The
mass median diameter of particles used in these analyses was between 1.05 and
1.52 urn.   Galloway  et al.  (1982)  reported  wet deposition rates of 2.4  to
114 ug/1   nickel  in  urban  areas  (median 12 ug/1).   Their analyses showed that
dry deposition  accounted  for  30 to 60 percent of total  or  bulk deposition of
nickel, similar to the results of Schmidt and Andren (1980).
     Either method  of deposition can return atmospheric nickel-containing
particulate to the earth's surface.   Nriagu (1980) estimated a total  atmospheric
                   4             4
fallout of 2.2 x 10  Mg (2.4 x 10  tons) nickel per year are received  by ocean
                   4             4
waters and 5.1 x 10  Mg (5.6 x 10  tons) are deposited on land.  Of the material
deposited on land masses,  a fraction falls on surface waters,  thereby  subjecting
nickel  to additional fate and transport mechanisms of both  aquatic and soil/sediment
media.

3.6.2  Water
     Nickel is  introduced into  fresh waters  by  natural and  anthropogenic
means.   Natural sources include both wet and dry deposition of airborne nickel-
containing particulates,  erosion  (weathering),  and  runoff;  direct discharges
from industrial  facilities account for input  from anthropogenic sources.  The
distinct  definitions  of natural and  anthropogenic  sources  may become less
clear,  however, considering that natural  removal processes  such as rainout are
removing nickel-containing material  that was introduced into the atmosphere by
                                    3-45

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industrial activity.
     In areas  relatively free from man's  influence,  the concentrations of
nickel in surface  and  groundwaters  are low and are  usually  a result of the
weathering of parent rock  or soil  (Snodgrass,  1980;  NAS, 1975).   The ambient
data presented  in  this chapter show that most river basins have comparatively
low concentrations of nickel in surface and groundwater, with elevated concen-
trations seen in  heavily industrialized areas  such as  the Ohio River basin.
     Once in the aquatic environment,  nickel may be transported by bed traction
or water  flow  in  the dissolved or adsorbed form.   In the major rivers of the
world, Snodgrass  (1980)  noted  the  following distribution of  forms of nickel
transported:

          0.5 percent in solution
          3.1 percent adsorbed
          14.9 percent associated with organic  matter
          34.4 percent as crystalline material  (presumably weathered minerals)
          47 percent as a precipitated coating  on particles

This distribution  is determined  for each specific location by water pH, pE,
ionic strength, concentration of organic and inorganic ligands, and the presence
of surfaces  to  which nickel tends to sorb (hydrous iron oxides).   Sibley and
Morgan  (1975)  described a  fresh water  system  using  specific water quality
parameters and  ligand  concentrations  and entered  these  data into  a speciation
model.  Model output showed that the carbonate  complex was the major dissolved
species followed by the free ion and the hydroxide.  Adsorption was the second
most  significant  fate process.   Unfortunately,  the model did not include
organic ligands, known to substantially affect the mobility of nickel.  Never-
theless,  this model  provides an  indication  of the species of  nickel  likely  to
be found  in  fresh waters.
     Nickel  in  fresh water, either dissolved or adsorbed to sediments, eventual-
ly  is deposited in  the  oceans  which  are the ultimate  sink  for  the metal.
About 1.4 x  10  Mg (1.5 x 10  tons) nickel/year enter world oceans as riverine
suspended particulate  (Nriagu,  1980)  with an additional  1.1  x 10 Mg  (1.2  x
10  tons)/year  input from rivers as dissolved nickel.   Industrial and municipal
                                3             3
wastes  may   contribute  3.8  x 10  Mg  (4.2 x  10   tons)  nickel/year (Nriagu,
1980),  80 percent  of which are estimated to be  soluble forms of the  metal
(Snodgrass,  1980).
     The  transport of  nickel to the oceans depends on stream  velocity, channel

                                    3-46

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configuration, and stream  water  quality.   Although nickel tends to exist  in
the dissolved state, some  of the metal does sorb to suspended particulates  in
the stream.   The degree to which nickel is sorbed  is a function of pH and  the
presence or absence  of  ligands.   Depending on stream flow, the sorbed nickel
may settle in sediment beds,  impact on geologic channel  features,  or be trans-
ported  through  the river  system by bed traction,  eventually  reaching the
ocean.  Dissolved nickel is transported by stream flow.
     Nickel transported adsorbed to particles in river systems may be desorbed
when  entering estuarine and  subsequently  marine waters.    Using their model,
Sibley  and Morgan  (1975)  predicted that in seawater, the free ion was the
major species, followed by dissolved nickel chloride and hydroxide.   Adsorption
of nickel decreases with the increasing ionic strength of seawater.
     Not all  nickel  in  seawater remains suspended, as an estimated residence
time  for nickel  in the  deep ocean is 2.3 x 104 years (Nriagu, 1980).   Nickel
may be  taken  up  by marine flora and  fauna or deposited in oceanic muds and
sediments.   Accumulation of  the  metal  in these sediments, the ultimate sink
for nickel, is estimated to exceed 1.5 x 106 Mg (1.7 x 106 tons)/year (Nriagu,
                                                                           Q
1980).  The residence time for nickel in  sediments  is  on the order of 10
years (Nriagu, 1980).

3.6.3   Soil and Sediments
     Nickel is a  naturally occurring constituent  of several classes of rock
and may enter the  soil  by chemical and physical  degradation of parent rock
(Boyle,  1981).   Industrial activities are  additional  sources of nickel  in
soils through both direct  means (land spreading of sewage sludge) and indirect
pathways (deposition of airborne particulates containing nickel  generated  by
industrial operations).   Nriagu  (1980)  estimated that on  a  worldwide basis,
5.1 x 10   Mg  (5.6  x  10  tons)  of nickel are  introduced into  the soil environ-
ment each year by deposition of atmospheric nickel-containing particulates  and
that  waste disposal  (sewage  sludge, fly ash)  and fertilizers add 1.4 x 10   Mg
and 1 x 103 Mg (1.5 x 104  and 1.1 x 103 tons), respectively.   Litter fall  from
                                              5             5
vegetation may provide  an  additional  7.8 x 10  Mg (8.6 x 10  tons) of nickel
on an annual basis (Nriagu, 1980).
     Nickel added  to soils is subject to  transport by  erosion and runoff,
which carry nickel  through river systems and estuaries to the ultimate sink,
the ocean.  Nickel may  also  migrate through the soil column, concentrating in
a  given soil  layer depending on  the chemical  characteristics of the soil.   If
                                    3-47

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the  soil  is permeable and  no  sorbing matter is present,  nickel  can enter
groundwater supplies by leaching through the soil column.
     The extent to which nickel is held in the uppermost soil layers or migrates
through the soil depends on soil pH, amount of precipitation, and the presence
of  substances  which may sorb  nickel.   The form of nickel  input  into soil
(i.e., atmospheric deposition of a complex nickel-iron oxide or direct discharge
of nickel-containing mine wastes) affects nickel mobility as well.  Soils rich
in  organic  material and hydrous  iron and manganese  oxides  can immobilize
nickel as the  metal sorbs to these  materials.   However, below pH  6.5  the  iron
and  manganese  oxides  break  down,  thereby remobilizing any  nickel  present
(Rencz and  Shilts,  1980).   Hutchinson et al. (1981)  report  increased nickel
concentrations  in organic surface soil  layers in areas up  to 48 km  (30 miles)
from refineries and smelters,  presumably because of the high cation exchange
capacity of the organic  material.   The organo-nickel complexes can  serve  to
reduce the availability of nickel for further transport.
     Insoluble or less soluble nickel species may deposit and add to river bed
sediment loads as nickel  is transported in rivers and streams.   Soluble nickel
may  also be sorbed  to sediments, with fine sediments (clays) tending to sorb
more nickel than  coarse  fractions like sand (Hutchinson et  al.,  1981).   In
either form nickel is  ultimately deposited in the oceans.
                                    3-48

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3.7  REFERENCES
Akland, G.  (1981) [Memo to Donna Sivulka]. December 8. Available for inspection
     at:  U. S.  Environmental  Protection Agency, Research Triangle  Park,  NC;
     project file no. ECAO-HA-81-1.

American Society  for Testing  and Materials.  (1979)  Annual book of  ASTM stand-
     ards.  Part 31 — Water.  Available  from:  ASTM Publications,  Philadelphia,
     PA.

Anderson,  A.;  Nilsson,  K. (1972)  Enrichment of trace elements  from  sewage
     sludge fertilizer in soils and plants. Ambio 1: 176-179.

Andolina, A.  Y. (1980) [Letter and attachments to Mr. R. E.   Iverson].  August 20.
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                   4.   NICKEL METABOLISM IN MAN AND ANIMALS
4.1  ROUTES OF NICKEL ABSORPTION
     The major routes  of  nickel  absorption are inhalation and ingestion via
the diet,  with percutaneous  absorption  a less significant  factor  for the
systemic effects of nickel but important in the allergenic responses to nickel.
Parenteral administration  of nickel  is  mainly of interest to experimental
studies and particularly  helpful  in assessing the kinetics of nickel  trans-
port,  distribution, and excretion.  Transplacental transfer to the fetus is of
importance in  the  assessment  of i_n  utero  effects.  The relative magnitudes of
nickel  intake  and  absorption in humans are briefly  summarized  in the final
portion of this section.
     The amounts of  nickel  absorbed by organisms are determined  not  only  by
the quantities  inhaled or ingested, but  also  by  the chemical and  physical
forms of nickel.   A number of i_n vitro studies have described the relationship
of chemical composition and  such  properties as crystallinity of  nickel com-
pounds  to  their  relative  solubility in biologically relevant media.   In the
most  comprehensive study  of  this  type, Kuehn and Sunderman (1982) determined
dissolution half-times  of 17 nickel compounds in water,  rat  serum, and renal
cytosol.   The  potent  carcinogen,  nickel  subsulfide, had  a dissolution half-
time  of 34 and 21 days  in serum and kidney cytosol, respectively.   By  compari-
son,  elemental  nickel,  nickel oxide,  and  p-nickel  sulfide had corresponding
half-times of 1.4 to 11 years.  In  general, half-times were less  in biological
systems than in water.
      Solubilization  half-times  determined  in  this  fashion  can  be used to
predict J_n vivo elimination rates,  the biological dissolution being metabolical-
ly rate-limiting.  However,  examination  of the solubilization half-times  for
all 17  nickel  forms  in the Kuehn  and  Sunderman study indicates that solubili-
zation  cannot  be  the only factor operating in the careinogenicity of  various
nickel  compounds.
      In a  related  study,  Ung and Furst  (1983) reported  that dissolution  of
nickel  powder  in  human serum reached  a rate of approximately 23 mg Ni/1  serum
at 48 hours with shaking  of the suspension.  This rate of dissolution  was  much
greater than  that  in water,   saline,  or  ethylenediamine  tetraacetate chelant
solution.
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     A direct comparison of  the  Ung and Furst data  with  data for metallic
nickel described in the Kuehn and Sunderman (1982) study as a means of comparing
species-variable serum solubilization of metallic nickel  is, unfortunately,
not possible because  of  differences in  data presentation.   In addition, the
reliability of the analytical method used by Ung  and Furst is questionable in
that the serum blanks were  reported to contain 3  mg Ni/1,  which is approximate-
ly 1000-fold higher than generally accepted values.
     Lee and co-workers  (1983) found that 1- to 10-mM levels  (59-590 mg/1) of
nickel (II) in a biological solution were obtained after incubation of ornickel
subsulfide in a  mixture  of DNA,  rat liver microsomes,  and NADPH.   Nickel was
bound to DNA, with binding  mediated by microsomal  protein.  Suppression of the
dissolution rate by the reductant NADPH indicates that oxidation of the subsul-
fide  nickel  is   central  to solubilization, which supports earlier data of
Kasprzak and Sunderman (1977).
     In the more complex j_n vitro cellular test systems where the end point is
relative phagocytosis  of nickel  compounds  as a prelude  to cell  transforma-
tions,  Costa and Mollenhauer  (1980)  have furnished evidence to  show that
carcinogenicity  of particulate nickel  compounds   is directly  proportional to
the rate  of  cellular uptake.  Such uptake is clearly related to the relative
negative  charge  density on  particulate surfaces  (Heck  and  Costa,  1982).
Crystalline  NiS  has  a negative surface  charge, is actively taken  up  by  cells,
and is  a  potent  carcinogen.   The amorphous  form of  the  sulfide  has a positive
charge, is  not  sequestered,  and  is noncarcinogenic.  Chemical surface reduc-
tion of the  amorphous  form,  using a metal hydride, greatly enhances phagocytosis
and cell transformation  induction (Heck and Costa, 1982).
      Factors other  than  the  chemical and physical properties of nickel, such
as host organism nutritional and physiological status, may also play a role in
nickel  absorption, but they  have been little studied outside  of investigations
directed at  an essential role for nickel.

4.1.1   Nickel Absorption by  Inhalation
      Respiratory absorption  of various forms of  nickel is probably  the  major
route  of  nickel  entry into man under conditions  of occupational  exposure,  and
considerable attention has been  given  to  nickel  inhaled  as  either the  highly
toxic  nickel carbonyl  or nickel  particulate matter.
      Nickel  carbonyl, Ni(CO)4,  is  a  volatile, colorless  liquid (b.p.  43°C).
Armit (1908) found  its relative  toxicity to be 100-fold that of carbon  monoxide.
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Its presence and toxicological history as a workplace hazard followed closely
upon the development of the Mond process of nickel  purification in its process-
ing (Mond et al.,  1890).   A detailed discussion of the  toxicological  aspects
of nickel carbonyl  poisoning is included in the MAS report on nickel  (National
Academy of Sciences,  1975)  as  well  as a  recent  review  by Sunderman  (1977).
     Studies of nickel carbonyl metabolism by Sunderman  and co-workers (Sunder-
man and Selin,  1968; Sunderman et al., 1968) indicate that pulmonary  absorption
is both  rapid  and  extensive,  the agent passing the  alveolar  wall  intact.
Sunderman and Selin  (1968)  observed that rats exposed to nickel carbonyl at
100 mg Ni/£  air  for 15 minutes excreted 26 percent of the inhaled amount in
the urine by 4 days post-exposure.  On taking into  account the exhaled quantity,
as much  as  half  of the inhaled amount  could  have  been  initially absorbed.
     Few data exist  on the pulmonary absorption of  nickel  from particulate
matter deposited in  the  human  lung.  The International  Commission on Radio-
logical  Protection  (ICRP)  Task Group on  Lung  Dynamics  (1966) has advanced
detailed deposition and clearance models for inhaled dusts of whatever chemical
origin as a  function of particle size,  chemical  properties,  and compartment-
alization within the  pulmonary tract.   While these models have limitations,
they can be of some  value  in approximating deposition and clearance rates for
nickel compounds of  known particle  size.  For example, Natusch et al. (1974),
based on a detailed  study of eight  coal-fired power plants, found that nickel
is one of a number of elements emitted from these sources that is found in the
smallest particles  of  escaped  fly ash,  approximately 1  to  2  urn mass median
aerodynamic diameter  (MMAD), this being a size that penetrates deepest into
the pulmonary tract.  According to the approaches of the ICRP model,  particles
of 1  urn  undergo  a  total deposition percentage of 63 percent,  with 30 percent
in the nasopharyngeal  tract,  8 percent in the tracheobronchial part, and 25
percent in the pulmonary compartment.   The clearance rate of deposited particu-
late matter in the ICRP model  is based on chemical  homogeneity of the particu-
lates, however, and  one  can only approximate such  clearance if heterogeneous
particles are considered.   According to Natusch et  al.  (1974), nickel-enriched
particles in fly ash  have much of the nickel on the particle surface.  If one
approximates the clearance  rate by  assuming that particles enriched in nickel
in the outer  portions of the  particle  are  handled by the model  lung  in  a
fashion similar to a homogeneous particle, then one obtains a total  absorption
(clearance) of  approximately  6 percent,  with major  clearance,  5 percent,
calculated as taking place from the pulmonary compartment.
                                    4-3

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     Further complicating the  issue  of pulmonary absorption from particulate
matter  is  the  finding of Hayes  et a "I.  (1978) that trace  elements  such as
nickel are  not  uniformly  distributed among particles of similar size.  From
scanning electron microscope  studies,  the authors found that some particles
carry much  of  the  element for a given  concentration  determined by ordinary
chemical analysis.   Therefore, theories relating lung clearance to estimates
of toxicity, based  on  bulk  analysis rather than on single-particle analysis,
must be carefully considered.
     Quantitative data for  the actual  uptake of  particulate nickel from the
various compartments of  the human  respiratory tract  are meager.  Kalliomaki
and  co-workers  (1981)  observed  very little  increase over time in urinary
nickel  in  stainless  steel welders  even when  the  nickel content of  inhalable
welding fumes  approached  1  percent and the nickel concentration ranged up to
           3
30 ug Ni/m .   The  author's  observations indicated that very little nickel  is
absorbed from the respiratory tract.
     Torjussen  and  Andersen (1979) found that  nickel  accumulation  in nasal
mucosa of  nickel workers was highest with inhalation of particulate subsulfide
and  oxide  forms as compared to inhalation of  nickel chloride/sulfate aerosols.
This  finding would  be  expected on  the  basis  of  the relative solubility  of  the
respective  compounds.   Nasal  mucosal  nickel  underwent  very slow clearance,
having a half-life of around 3.5 years.
     Animal studies have provided more  quantitative information on the deposi-
tion and absorption rates of various forms of nickel  in the lung.
     Wehner and  Craig  (1972), in their studies of the effect of nickel oxide
aerosols on the golden hamster, observed that inhalation  by these animals of
nickel  oxide particles in a concentration of 2 to 160 jjg/£ (2-160 mg/m ) and
particle size  of 1.0 to 2.5 urn MMAD led to a deposition of 20  percent of the
total  amount  inhaled.   After 6 days post-exposure,  70  percent  of the nickel
oxide  remained in  the lungs,  and  even after 45 days approximately half the
original deposition was  still present.  Since no  material  increase in nickel
levels  of  other tissues  had  occurred,  it appeared that absorption  in  this
interval was  negligible.   In a  later,  related  study (Wehner et al. , 1975),
co-inhalation  of cigarette smoke  showed  no effect on either deposition  or
clearance.
      Kodama and co-workers  (1985)  exposed adult  rats to nickel  oxide aerosol
                                                                o
(MMAD  range, 0.6 to 4.0  u)  at  a  concentration of  0.4  to 70 mg/m  for  a maximum
                                     4-4

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period of 90 days (6-7 h/day, 5 d/week).   In addition to a dose-lung deposition
relationship, deposition  was observed to be  inversely  related to particle
diameter, from 24  to  2.3  percent.   No significant absorption of nickel into
the blood stream occurred as evidenced by the absence of nickel  elevation in
blood and soft tissues  across the dosing groups.  The  authors  estimated an
annual clearance rate of  the element from  lungs  of  these animals at about
100 ug Ni/year.
     Wehner et al.  (1979) exposed Syrian hamsters to nickel-enriched fly ash
aerosol   (respirable  concentration,  approximately 185-200  ug  fly ash/liter)
for either  6 hours or 60  days and found that, in  the  short exposure, about 90
percent of  80 ug deposited  in the deep tract  remained 30 days after exposure,
indicating  very  slow clearance.   In the two-month study, the deep tract depo-
sition was approximately 5.7 mg enriched fly ash, or 510 ug nickel.   Thus, nickel
leaching from the  nickel-enriched fly ash in  the  hamster's lung  did not occur
to any extent over the experimental  time frame.
     In a more recent study, Wehner et al.  (1981) exposed hamsters to approxi-
mately 70 ug/1 respirable nickel-enriched fly ash (NEFA)  aerosol (6 percent
nickel), 17  ug/1Her NEFA (6  percent nickel), or  70 ug/1 fly ash (0.3 percent
nickel) for up to 20 months.  The authors observed a difference in nickel  lung
concentrations and suggested  that the  apparent increased retention of nickel
in the  high-NEFA group  (731 ug after 20 months  exposure compared to 91,  42,
and 6 ug  for the low-NEFA, FA, and control groups, respectively) was due to
reduced pulmonary clearance.
     Leslie and  co-workers  (1976) have described their results from exposing
rats to  nickel and other  elements contained in welding fumes.   In this case,
the particle size  versus  nickel  content was  known precisely, highest nickel
levels being determined in particles 0.5 to 1.0 pm in diameter at an air  level
              3
of 8.4 ug Ni/m .   While the authors did not determine the total  nickel deposi-
tion in the lungs of these animals, they observed that essentially no clearance
of the  element from  the  lung had occurred  within 24 hours,  nor were there
elevations  in blood nickel, suggesting negligible absorption.
     In a related  study of Kalliomaki et al.  (1983a), the authors observed a
rough linear relationship of lung nickel levels  with inhalation exposure in
rats  exposed to  a stainless  steel welding  fume.   When  the relative  nickel
content of  fume was 0.4 percent, the measured nickel retention rate was 0.3 ug
                                    4-5

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Ni/g dried  lung  tissue/hour  of inhalation and the maximum  level  was 7.1 ug
Ni/g dried  lung  tissue.   The half-time of nickel  clearance from the lungs of
these animals was 30 ± 10 days.
     Kalliomaki  and  co-workers (1983b)  also  demonstrated, in experimental
animals, that  the deposition and clearance rate for nickel  from welding  fumes
is  highly  dependent  on the type of  welding  process.   Fumes from stainless
steel welding, in which  the  metal  inert gas method is used, were compared to
fumes generated  from  manual  metal  arc systems.  The nickel retention rate in
the  lung was  increased 20-fold when animals were  exposed to fumes from the
former  process.   A  corresponding  maximum lung  nickel  level  (6.1  versus
0.3 (jg/g/h) of 20:1 was obtained and a corresponding 3-fold increase in nickel
half-time clearance (86 versus 30 days) was observed.
     From this study,  it would appear that the  inert gas method of welding
poses a  greater  nickel exposure risk than does  the  conventional  technique.
Since the authors did  not characterize particle size profiles or nickel content
versus  size,  it  is  not possible to  define  the basis  of  these differences.
     Srivastava  et al. (1984)  reported that exposure of adult rats (6 h/day, 15
days) to  fly ash generated at  a coal-fired power plant  (0.2-0.4 mg/liter,  400
mesh) was  associated  with a steady  rise  in  nickel  content of lung,  liver,
heart,  kidney, small  intestine, and serum.  The relative rates  of decay of
nickel  levels  in these tissues were  measured  up  to 30 days  following the last
day  of exposure.  The biological half-time for  nickel  in the lung was calculated
to  be  21 days. The corresponding  values  for  the extrapulmonary  organs  were:
26  (liver),  5.5  (heart), 8 (kidney), 30  (small intestine),  and 57 days (serum).
While  the  extent of  nickel  leaching from fine-particle  fly ash cannot be
estimated from this study, it  nevertheless serves to  indicate that the element
in  this  material was  sufficiently bioavaiTable in the  lung to lead  to marked
elevations  of  nickel  in  various vital tissues.
     In  contrast to these studies with  particulates,  Graham et al.  (1978),
                                                                      3
using  mice  and nickel chloride aerosol  (< 3 urn diameter, 110 mg Ni/m )  found
about 75 percent clearance by  day  4  post-exposure.  The rapid clearance  of  the
nickel  halide was probably due to its  solubility  relative to the oxides  or
other  insoluble  nickel forms in welding  fumes.
     The  implications of  these studies in determining the relationship of
pathogenic  effects  to respiratory absorption  is somewhat unclear.   While  the
above  studies appear to demonstrate that differences  in compound solubilities
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relate to pulmonary  clearance,  with inert compounds having relatively slower
clearance,  the  relationship of  clearance to toxic  manifestations  is less
certain.   For  example,  in the Wehner et  al.  (1981)  study on hamsters, the
authors concluded that  the  quantity of dust, rather than its nickel content,
appeared to be the major  factor  in  determining tissue  response.  The  severity
of pathological  findings  was significantly  higher  (p  <0.01)  in the FA and
high-NEFA group  (70  ug/1  each)  than in the low-NEFA group (17 ug/1), whereas
the pathologic differences  between  the  FA group (0.3 percent nickel) and the
high-NEFA group (6 percent nickel) were insignificant despite the large differ-
ences  in  lung  retention (vide supra).  (For  further discussion, see  Chapter
8).
     Several studies  have examined  the  lung clearance rate  for nickel  when
various compounds of  the  element were administered  intratracheally  to rats or
mice.
                                                                  CO
     Corvalho and Ziemer (1982)  administered microgram amounts of   Ni-labeled
nickel chloride  intratracheally  to  adult  rats and observed that 71  percent of
the administered  amount was removed from  the lungs  by 24 hours,  with only
0.1 percent remaining by day 21.   This indicated a lung clearance half-time of
soluble nickel of <  24  hours in  the rat,  with the rate of urinary elimination
of nickel  paralleling that of nickel removal from lung.
     Williams et al.   (1980) also instilled 63Ni-labeled  nickel  chloride solu-
tion  in rats at  levels  of 1, 10, and 127  nmol nickel.  Removal  of nickel from
rat lung was  independent  of instillation concentration with a nickel removal
rate  (percent) of  0.2/minute, corresponding to  a calculated  clearance half-
time  of  approximately 4.5 hours.   Williams  et al.  (1980) also studied the
behavior of the perfused and ventilated rat lung using the same test protocol.
In this case, clearance rate half-time was dose-dependent, being around 20 hours
at the 1 nmol dose and decreasing to 4.6 hours at the 127 nmol dose.
     Moderately soluble nickel  carbonate  was instilled  intratracheally into
mice at a loading of 50 ug in a  study by Furst and Al-Mahraq (1981).  From the
authors'  tabulated daily nickel  urinary excretion rates (erroneously indicated
in the report  in mg/ml  instead  of  ug/ml),  a lung clearance rate of roughly
72 hours for  the carbonate can  be calculated.   This  assumes that  urinary
excretion parallels  that  of instilled nickel absorption  from lung, which is
clearly the case in the Corvalho and Ziemer (1982) report on rats.
                                    4-7

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                                                                rn
     In the study of  English  and co-workers (1981), where both   Ni-labeled
nickel  chloride solution and nickel  oxide suspension were administered to rats
via intratracheal instillation,  the  rather  slow clearance of the  oxide,  also
described in other studies,  was associated with accumulation of the element in
both mediastinal lymph nodes and lung.   Raised lymph node levels indicate that
lymphatic clearance is  one  route in the slow removal of oxide from the lung.
     The pulmonary clearance of  particulate   Ni-labeled  nickel subsulfide in
mice (1.7 urn,  MMD) has been described by Valentine and Fisher (1984).   Following
intratracheal   instillation,  clearance  was  observed in two distinct phases
having biological half-times of  1.2 and 12.4 days,  respectively.   The label
was detected  in blood,  liver,  and other tissues by 4 hours postinstillation.
In these experiments,  approximately 57 percent of the total label  was excreted
after 3 days,  and excretion was 100 percent after 35 days.  The faster clearance
rate (1.2 days) could be attributed to retro-ciliary removal of the material
with translocation to the gastrointestinal tract, consistent with  a significant
level of  label  in feces during  the  first  12-hour period.  Approximately 60
percent of  the total  label  excreted  was  lost  in  urine,  demonstrating a signi-
ficant degree  of solubilization  of particulate subsulfide by the  mouse lung.
The data  of Kuehn and Sunderman  (1982),  described earlier,  showed  dissolution
half-times  for the  subsulfide  of 34 and 21 days  in serum and tissue cytosol,
respectively,  which is  roughly consistent with a clearance half-time of 12.4
days from mouse lung  (Valentine and Fisher, 1984).  Hence, both jm vitro and
iji vivo bioavailability data suggest that there is a higher level  of mobiliza-
tion of the element in this form into the blood.
     In addition to  nickel  exposure in  man  due  to inhalation of  ambient and
workplace air,  cigarette smoking constitutes  a  possible exposure  source  among
heavy  smokers.   Early  studies  by Stahly (1973),  Szadkowski  and  co-workers
(1970), and Sunderman and Sunderman (1961)  indicated that 10 to 20 percent of
cigarette nickel was  carried in  mainstream smoke, with better than 80  percent
of this amount being  in  gaseous, rather  than particulate,  form.  It was claimed
that nickel carbonyl  constituted the gaseous fraction  (Sunderman and Sunderman,
1961),  suggesting that the  relative absorption  of nickel  from cigarette  smoke
was  proportionately  greater than from airborne  nickel  particulates and  with
heavy  smokers may have been the main  source of  inhalatory  nickel absorbed.
     Recent data indicate,  however,  that tobacco  nickel  in mainstream smoke is
not  in  the  form of the  carbonyl.  Using  Fourier-transform infrared  spectrometry
                                     4-8

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and testing of  representative  commercial  cigarette samples via the "vacuum-
smoking" method, Alexander  et  al.  (1983)  reported that no measurable amounts
of Ni(CO)4 could be detected at a detection level of 0.1 pi carbonyl/1 smoke.
Furthermore,  recent  studies have also  shown  that the amount of  nickel  in
mainstream smoke  from cigarettes with  a high  nickel  content  is  minimal
(Gutenmann et al., 1982;  Hassler,  1983) and that the transfer of nickel  from
cigarettes to the  lung  is likely negligible because of the very high boiling
point of nickel  (2730°C) compared to the temperature in the glow of a cigarette
(900°C) (Weast, 1980; Hassler, 1983).   Therefore, the  value of  5 mg of nickel
reported  by  the National  Academy  of Sciences (1975)  as  the  annual  nickel
intake of individuals smoking two packs of cigarettes daily is likely overesti-
mated.
     In summary, available  human and animal data  permit the following conclu-
sions about respiratory absorption of nickel:
     (1)  Insoluble particulate  nickel,  e.g.,  the oxide and the subsulfide,
deposited  in  the  various  respiratory  compartments  in both occupationally
exposed subjects  and the  general  population is  very  slowly  absorbed with
accumulation over  time;  nickel in the  nasal mucosa  of nickel  workers has a
clearance half-time  of  approximately 3.5 years.   Workers who inhale  nickel-
containing welding  fumes do not show  increased  systemic  levels, indicating
extremely low absorption of nickel from the lung.
     (2)  Experimental animal  data using various  species show very slow clear-
ance  of deposited and  insoluble nickel oxide  from  the  respiratory tract,
moderate  clearance of the carbonate with a half-time  of  around 3 days, and
rapid  clearance of soluble nickel salts with a half-time of hours to several
days.   In the  case of nickel  oxide, clearance from  lung involves both direct
absorption  into the  blood  stream and  clearance  via the  lymphatic system.

4.1.2   Gastrointestinal  Absorption of Nickel
     Gastrointestinal  intake  of  nickel  by man is surprisingly  high, relative
to other  toxic  elements, which  is at least partly accounted for by contribu-
tions  of  nickel from  utensils  and equipment in processing and home preparation
of food.
     Total daily dietary intake  values  may range  up  to 900 ug nickel, depending
on the nature  of  the diet, with average values  of 300 to 500 ug daily  (NAS,
1975).  Collectively,  the data of Horak and Sunderman (1973),  Nodiya (1972),
                                    4-9

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Nomoto and Sunderman (1970),  Perry and Perry (1959),  and Tedeschi and Sunderman
(1957) indicate that  1  to 10 percent of dietary nickel is absorbed.   In the
more recent study  of  Christensen and Lagesson (1981), adult human volunteers
ingested, without  fasting,  a single dose of  5.6 mg  nickel  as the  sulfate.
Over the  three days after ingestion,  urinary  nickel  levels rose  to  a peak  and
then decreased towards normal.   The cumulative excretion over this time period
was 176 ug, indicating  a  minimal gastrointestinal  absorption rate of roughly
3 percent.
     Fecal analysis more  accurately  reflects  dietary  intake where the  rate of
absorption is  known and  the existence  and extent of  biliary excretion is
known.  Diet profiles  tend  to  be different than fecal analysis data owing to
the obvious inherent difficulty of arriving at "true" diets for human subjects.
In  the case of  nickel,  where absorption is  assumed  to be small, the  fecal
analysis  data approximate the  low end of dietary profile estimates, and one
can say that daily GI intake is probably 250 to 300 |ug Ni/day.
     One  question that arises in considering the dietary intake and absorption
of  toxic  elements  has to do with  the bioavailability of the agent in solid
foodstuffs versus  water and beverages.   Ho  and Furst (1973) observed  that
intubation of   Ni  in dilute acid  solution  leads to  3  to 6 percent  absorption
of  the radio-labeled nickel   regardless of the dosing level.   A more systematic
and directly  relevant study concerning  nickel bioavailability in human diets
is  that   of Solomons  and co-workers  (1982),  who  showed bioavailability of
nickel to be  quite dependent on dietary composition.  Adult human  volunteers
ingested  5.0 mg of nickel as the  soluble  sulfate  in water and  the  resulting
serum  nickel  profiles were  compared to  those obtained when the  same amount of
nickel was  given  in beverages and two test meals, including a North American
breakfast.  All beverages except soft drink  suppressed nickel absorption, as
did the  two  test  diets.  The chelating  agent,  EDTA, added to the  diet sup-
pressed  nickel in  serum to a point below even fasting  baseline levels.

4.1.3  Percutaneous Absorption of  Nickel
      Percutaneous  absorption of  nickel  is mainly  viewed  as  important  in  the
dermatopathologic  effects of this agent,  such  as contact dermatitis, and
absorption  viewed  this  way  is restricted  to the passage of  nickel past the
outermost layers of skin  deep enough to bind  with  apoantigenic factors.
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     Wells  (1956)  demonstrated  that divalent nickel penetrates  the  skin at
sweat-duct and hair-follicle ostia  and binds to keratin.  Using  cadaver  skin,
Kolpakov (1963) found  that  nickel  (II) accumulated in the Malpighian  layer,
sweat glands and walls of blood vessels.   Spruitt  et  al.  (1965) have shown
that nickel penetrates to the dermis.
     Values for the  amounts  of  nickel passing through outer  layers  of skin
relative to amounts  applied  have not been determined.  Samitz and Pomerantz
(1958) have reported that the relative extent of nickel penetration is enhanced
by sweat and detergents.
     Mathur and co-workers  (1977)  have reported the  systemic  absorption of
nickel  from the  skin using nickel   sulfate at  very high application rates.
After 30 days  of exposure to nickel at doses of 60  and 100 mg Ni/kg, a number
of testicular  lesions  were  observed in rats, while hepatic effects were seen
by 15 days  at  these exposure levels.  It  is  not  possible to calculate  any
absorption data from this study.

4.1.4  Transplacental Transfer of Nickel
     Evidence   for  the  transplacental  transfer of nickel to the fetus dates to
the study  of Phatak and Patwardhan (1950) who found that newborn of rats fed
nickel in various chemical forms had whole-body levels up to 22 to 30 ppm when
mothers received 1000 ppm nickel in the diet.
     Pregnant   mice  given  nickel  chloride  intraperitoneally as one dose  (3.5
mg/kg) at  16 days  of gestation showed transfer to placental  tissue with peak
accumulation having  occurred by  eight  hours post-exposure (Lu and co-workers,
1976).
     Jacobsen   et al.  (1978),  using   Ni-labeled nickel  chloride and single
intraperitoneal injections into  pregnant  mice at day 18 of gestation, showed
rapid passage  from mother to  fetus, with fetal tissues  generally showing
higher concentrations than that of the mothers.   Kidney levels were highest in
the fetus  with lowest levels being seen  in  brain.   Furthermore, 01 sen  and
                    CO
Jonsen  (1979)  used    Ni  whole  body radiography in mice  to  determine that
placental transfer occurs throughout gestation.
     A  similar study is that of Sunderman et  al.  (1978), who administered
CO
  Ni-labeled solution  to  pregnant  rats intramuscularly.   Embryo  and embryonic
membrane showed measurable  label  by day eight of gestation,  while autoradio-
grams demonstrated label in yolk sacs of placentae one day post-injection (day
18 of gestation).
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     Several reports indicate transplacental passage of nickel also occurs in
man.   Stack et al.  (1976) showed levels of 11 to 19 ppm in dentition from four
fetuses as  well  as  a mean element concentration  of  23 ppm in teeth from 25
cases of stillbirth and neonatal death.
     Casey  and  Robinson  (1978)  found detectable  levels of  nickel  in  tissue
samples from 40  fetuses  of 22 to 43 weeks  gestation,  with levels in liver,
heart  and  muscle being  comparable  to  those seen  in adult  humans.   Values
ranged from 0.04 to 2.8 ppm (ug Ni/g dry weight).  This study suggests ready
movement of nickel  into  fetal  tissues, given the similarity  in fetal  versus
adult human levels.
     Creason et  al. (1976) studied  the  maternal-fetal  tissue levels  of 16
trace  elements  in   eight  selected U.S.  communities.   The authors reported
geometric mean nickel levels of 3.8 ug/100 m£ in maternal  blood, 4.5 ug/100 ml
in cord blood and 2.2  ug/100 g  in placenta.   In order  to  examine  the  relative
levels of  maternal  and cord blood trace  elements, ratios  of these values were
computed and a  standard  t-test was applied to the logs of these ratios.  The
geometric  mean  of  the  ratio for  nickel was 1.15  based upon 166 observations.
This ratio  was  not  significantly different from  1 at  the  .05 level.   While
statistical significance  was  not shown,  this study, nevertheless,  indicated
possible transplacental passage of nickel in humans.
4.2  TRANSPORT AND DEPOSITION OF NICKEL IN MAN AND EXPERIMENTAL ANIMALS
     The  kinetic  processes  governing the  transport and  distribution  of nickel
in  various  organisms are dependent upon the  modes of absorption,  the rate  and
level  of  nickel  exposure, the chemical form of  nickel  and the physiological
status of the organism.

4.2.1  Nickel in  Blood
     Blood  is  the main vehicle  for transport of  absorbed nickel.   While it is
difficult  to determine from the literature  the  exact partitioning of nickel
between  erythrocytes and plasma  or serum for unexposed  individuals,  serum
levels  are  useful indicators of blood burden and,  to a more limited extent,
exposure  status  (NAS, 1975).  Regarding  the latter, it is important here  to
note  that serum nickel would not  reflect amounts of insoluble and unabsorbed
nickel  deposited  in lungs.   In  unexposed  individuals, serum nickel values  are
approximately 0.2 to 0.3 ug/dl.
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     The study of  Christensen  and Lagesson (1981) is particularly helpful  in
addressing the issue of nickel  partitioning between plasma and erythrocytes in
human subjects.  Baseline  serum and whole blood  nickel  values,  as well as
changes  in  these media over time, were measured  in adult human volunteers
(N=8) ingesting a  single quantity of 5.6 mg nickel.  Mean baseline values  for
serum and whole blood were 1.6 and 3.0 ug/1,  respectively, with large variance,
indicating that under  steady-state  conditions  of low nickel  absorption there
is no statistically  significant enrichment in  either fraction and that it is
difficult to  obtain  any  correlation.   Analytical  variance in baseline values
is often due  to contamination.   Partitioning of nickel into the two  fractions
was not significantly  different after  ingestion of  the nickel  salt.   Further-
more, nickel levels in serum and whole blood,  being much  higher after ingestion
of the  nickel, were  strongly correlated (r=0.99, p <0.001)  over  the entire
study period.
     The kinetics of nickel removal  from serum  in these same  subjects showed a
single clearance half-time of 11 hours over the 51-hour study period.  Whether
the serum half-time  in humans   is dose dependent  cannot be determined.  In a
study of  nickel-exposed workers, Tossavainen  and co-workers (1980)   used  a
linear one-compartment  kinetic  modelling  approach to estimate that the half-
time of nickel  in  plasma of four electroplaters  ranged from 20 to 34 hours.
     The results of  Onkelinx et al.  (1973) indicate that clearance of nickel
from plasma or serum in experimental animals is characterized by a two-compart-
ment distribution, with  corresponding  half-times  which can be calculated  at
several  hours and several days, respectively.
     Distribution  of  serum-borne  nickel among  the various biomolecular compo-
nents has been discussed  in  some  detail in recent reviews (MAS, 1975;  Mushak,
1984), and it will  mainly be noted here that serum albumin is the main carrier
protein in sera of man, rabbit, rat, and bovine.   Furthermore, there exists in
sera of man and rabbits a nickel-rich metal loprotein  identified as  an a,-
macroglobulin (nickeloplasmin)  in rabbits  and  as a 9.5 S ot,-g1ycoprotein  in
man.   Sunderman (1977)  has suggested that nickeloplasmin may be a complex of
the ot,-glycoprotein with serum a-,-macrog1obulin.
     In vitro study of nickel (II) binding in  human serum (Lucassen and Sarkar,
1979) shows  histidine to be a  major  micromolecular binding  species  and an
equilibrium between albumin and histidine may  be the factor in blood to tissue
transfer of nickel.
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     Glennon and Sarkar (1982) studied, in some detail, the binding of nickel
(II) to human  serum  albumin (HSA) and found,  using  equilibrium dialysis of
HSA, that:  (1) both  nickel  and  copper bind HSA  at  the same site; (2)  the
binding site involves the a-amino group of aspartate, two deprotonated peptide-
N groups, the  imidazole  N atom of histidine,  and the carboxyl  of aspartate;
and (3) a ternary complex of histidine, HSA and nickel  exists under equilibrium
conditions,  suggesting that nickel transfer from HSA to histidine may serve to
transport nickel into  tissue.  Using nuclear magnetic  resonance techniques,
Laussac and Sarkar (1984) confirmed that nickel binding in human serum albumin
takes  place  at peptide 1-24,  the N-terminal  tripeptide segment containing
alanine, histidine, and aspartate.
     Using two-dimensional immunoelectrophoretic techniques and autoradiography,
Scott  and Bradwell  (1984) determined that labeled nickel  in human serum was
bound mainly to two proteins: albumin and an alpha-2-protein, possibly alpha-2-
nickeloplasmin.  The  relative  i_n  vitro partitioning of the metal between the
two proteins was approximately 2  to 1, respectively.   The relative high amount
of  nickel in  the  human alpha-2-protein may indicate a more important role of
this protein in nickel homeostasis than had been previously assumed.
     While the  relative  amounts  of protein-bound nickel  in  sera of  various
species have  a considerable range (Hendel and Sunderman, 1972) which reflect
relative binding strengths  of  albumins,  the total nickel levels are  markedly
similar, as may be seen in Table  4-1.

4.2.2  Tissue Distribution of Nickel
4.2.2.1  Human  Studies.   The distribution  of nickel  in  tissues  of human  popu-
lations has been reviewed by Mushak (1984).
     Generally, nickel content in human tissue has been studied through autopsy
specimens.  The problems  attending the use of  such  specimens  determine  the
reliability of  such  measures.   Furthermore,  it appears that earlier data are
subject to questionable analytical reliability and sensitivity.
     The  studies  of Schroeder and Tipton  and  co-workers (Schroeder  et a!.,
1962;  Tipton  and  Cook, 1963; Tipton et al., 1965) indicate that many autopsy
tissues evaluated  in  the respective  laboratories of these workers were below
the detection  limits  available to them at that time.  Therefore, information
on  relative  nickel content  could  only be  gained by examining  the relative
frequency of  nickel  detection  across tissues.   By  using this  method, these
                                    4-14

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         TABLE 4-1.  SERUM NICKEL IN HEALTHY ADULTS OF SEVERAL SPECIES

                                                      Nickel concentration,
         Species (N)                                           ug/£
  Domestic horse (4)                                      2.0 (1.3-2.5)
  Man (47)                                                2.6 (1.1-4.6)
  Jersey cattle (4)                                       2.6 (1.7-4.4)
  Beagle dog (4)                                          2.7 (1.8-4.2)
  Fischer rat (11)                                        2.7 (0.9-4.1)
  British goat (3)                                        3.5 (2.7-4.4)
  New Hampshire chicken (4)                               3.6 (3.3-3.8)
  Domestic cat (3)                                        3.7 (1.5-6.4)
  Guinea pig (3)                                          4.1 (2.4-7.1)
  Syrian hamster (3)                                      5.0 (4.2-5.6)
  Yorkshire pig (7)                                       5.3 (3.5-8.3)
  New Zealand rabbit (24)                                 9.3 (6.5-14.0)
  Maine lobster (4)                                      12.4 (8.3-20.1)

 Mean (and range)
Source:   Sunderman et al. (1972).

workers noted a greater uptake of nickel in lung, kidney, liver,  heart, trachea,
aorta, spleen,  skin,  and intestine.   Overall, levels adjusted to wet weight
indicated less than 0.05 ug/g in most cases.   Higher levels in skin, intestine,
and lung  reflected some  fraction of  the unabsorbed element.  Of importance to
nickel pharmacokinetics was the demonstration by these workers that the element
does not  accumulate  with age except in the lung.  Lung accumulation reflects
the deposition  of  insoluble  nickel  particulates.  Other studies support the
observation of  nickel  accumulation in  lung.   Sunderman et al. (1971) reported
that lung  from  accidental death  victims had the  highest  levels (0.016 pg Ni/g
wet weight) of  all tissues.   Andersen and Hogetveit  (1984)  have  found that
autopsied  lung  samples from former  nickel refinery  workers in  Norway have
nickel contents ranging  from 2 to 1350 ppm,   depending on worksite  classifi-
cation within a nickel operation.
     Bernstein and co-workers (1974)  reported that mean nickel  content of lung
and lymph  node  samples from  the autopsies of 25 New York City residents were
0.23 and 0.81 pg Ni/g wet weight, respectively.   The relatively  high values in
lymph nodes indicated that lymphatic  clearance of particulate nickel lodged in
lung also  occurs in  humans,  such clearance being demonstrated in experimental
animals (vide supra).

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     Sumino et al.  (1975) analyzed nickel  in autopsy samples from 30 non-exposed
Japanese and also found highest levels in lung (0.16 ug/g wet weight),  followed
by liver (0.08) and kidney (0.1 ug/g wet weight).
     Various studies of  individuals  accidentally  exposed to nickel carbonyl
have indicated that  lung has the highest uptake, followed  by kidney, liver,
and brain (MAS, 1975).   The carbonyl  differs from other forms of nickel  in its
penetration of the blood-brain barrier, as  evidenced by brain nickel content.
     Age-dependent accumulation  of  nickel  in tissues appears to occur in the
case of the lung, other soft tissues showing no accumulation.  The question of
accumulation  in  mineralizing tissue has been  addressed  in  several  reports.
Knuuttila et al.  (1982)  studied  the content of nickel, along with other ele-
ments,  in human  cancellous bone  in 88 subjects having normal mineral  status.
The authors found  a  mean concentration (±  1 S.D.)  of  1.29  (± 0.83) ug/Ni/g.
Bone nickel did  not  vary with age.   Lappalainen and Knuuttila (1981) observed
no accumulation in dentition with age.  Extracted permanent teeth were obtained
from 89 subjects,  8  to 67 years of  age.  Mean nickel  levels were higher in
enamel (43.8 ug/g) than  in dentine (31.4 ng/g).
4.2.2.2  Animal Studies.  A number of studies of the distribution of nickel in
experimental  animals exposed to  nickel  carbonyl  have been  described (NAS,
1975).
     Armit (1908) exposed dogs, cats, and rabbits to nickel  carbonyl vapor and
was able to measure  elevated nickel levels  in lung, brain,  kidney, and adrenal
glands.  Later investigators have observed  elevated, rapidly cleared levels of
nickel  in lungs, brain,  kidney, and liver of various animal  species (Mikheyev,
1971;  Sunderman  and  Selin,  1968;  Ghiringhelli  and  Agamennone, 1957; Sunderman
et al., 1957; Barnes and  Denz, 1951).
     Sunderman and Selin (1968) have shown that  one day after  exposure  to
inhaled    Ni-labeled nickel carbonyl,  viscera contained about  half of  the
total  absorbed  label with one-third  in muscle  and fat.   Bone and connective
tissue  accounted  for about one-sixth of the total.  Spleen  and  pancreas also
appear  to take up  an appreciable amount of  nickel.   Presumably,  nickel carbonyl
crosses the alveolar membrane intact  from either route, inhalation or injection,
suggesting that  its  stability is greater than  has usually been assumed (Kasprzak
and  Sunderman,  1969;  Sunderman  et al., 1968;  Sunderman  and Selin, 1968).
Retained  nickel  carbonyl undergoes decomposition  to carbon  monoxide and zero-
valent  nickel  in the erythrocyte and  tissues,  followed by intracellular oxida-
tion  of the element to  the  divalent form  and subsequent  release into  serum.
                                    4-16

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     A number of reports in the literature describe the tissue distribution of
divalent nickel  following  parenteral  administration of nickel salts.  These
studies have been  of  two types:   tissue nickel  content assessment or studies
measuring the  kinetics  of  nickel  deposition and clearance within a modeling
framework.   These data are summarized in Table 4-2.
     It can be  generally stated  that nickel administered this way  leads to
highest accumulation in kidney, endocrine glands, lung, and liver.   Relatively
little nickel  is  lodged in neural tissue,  consistent  with  the  observed low
neurotoxic potential of divalent nickel  salts.   Similarly,  there  is  relatively
slight uptake  into  bone, consistent with other evidence that  nickel is rather
rapidly and extensively cleared from organisms, with little retention in soft
or mineral  tissue.
     Sunderman and Fraser (1983)  examined the ability of soluble  nickel  (NiCl?)
to  induce  the  metal transport protein,  metallothionein  (MT), in liver and
kidney of Fischer  rats.  Nickel (II) was moderately  active  as an inducer at
dosing levels of 0.10 and 0.75 mmol/kg (i.p.),  being more effective  for hepatic
MT.   Since actinomycin  did not prevent MT  induction, the mechanism for nickel
induction of MT  is  apparently unrelated to enhanced Cu/Zn uptake.  However,
nickel may induce MT synthesis through either hormonal  disturbances  or stimulated
translation of mRNA in  liver and kidney ribosomes.
     Absorption and tissue distribution  of nickel  in  animals orally exposed
appear to  be dependent  upon  the relative  amounts  of  the  agent employed.
Schroeder et al.  (1974) could find no uptake of  nickel  in rats  chronically
exposed to nickel  in drinking  water (5 ppm) over the lifetime of the animals.
Phatak and Patwardhan  (1950)  reported the effects on  tissue  accumulation  of
different nickel compounds given  orally to rats.  Among the  three  chemical
forms  of  nickel  used,  i.e.,  carbonate, nickel  soaps, and  metallic  nickel
catalyst, tissue levels were greatest in the groups fed the carbonate.   O'Dell
and co-workers  (1971) fed  calves  supplemental nickel in the diet at levels  of
62.5, 250, and  1000 ppm.   While  levels  of  nickel  were somewhat  elevated in
pancreas, testis, and bone at 250 ppm,  pronounced increases in these tissues
were seen at 1000 ppm.   Whanger (1973) exposed weanling rats to nickel  (acetate)
in  the  diet  at levels  up  to  1000 ppm.   As nickel  exposure was  increased,
nickel content of  kidney,  liver,  heart, and testis  was  also  elevated,  with
greatest accumulation  in the  kidneys.   Spears et  al.  (1978)  observed that
                              CO
lambs given tracer  levels  of    Ni orally with or without supplemental  nickel
                                    4-17

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                         TABLE 4-2.   TISSUE DISTRIBUTION  OF  NICKEL (II)  AFTER PARENTERAL ADMINISTRATION
     Species
              Dosage
            Relative distribution of 63N1
             Reference
   Mouse
   Rat
   Guinea pig
   Rabbit
I
t—'
oo
   Rabbit
   Mouse
8      6.2 mg/kg
         (one 1ntraper1toneal
         Injection)

4      617 ug/kg
         (one Intravenous
         Injection)
       1 mg/kg
         (subcutaneously
         for 5 days)

       240 ug/kg
         (one Intravenous
         Injection)
       4.5 ug/kg
         (Intravenously for
         34-38 days)
12     38.3 ug - or 76.6
         ug/kg (10-20 uC163N1
         given Intravenously
         1n one dose)
Kidney > lung > plasma > liver > erythrocyte
  spleen > bladder > heart > brain > carcass
  (muscle, bone, and fat)

Kidney > lung > adrenal > ovary > heart > gastro-
  intestinal tract > skin > eye > pancreas >
  spleen = liver > muscle > teeth > bone >
  brain = fat
           Wase et al.
             (1954)
           Smith and
             Hackley
             (1968)
Kidney > pituitary > lung > liver > spleen >
  adrenal > testls > pancreas > medulla
  oblongata = cerebrum = cerebellum
heart >    Clary (1975)
Kidney > pituitary > serum > whole blood > skin >
  lung > heart > testls > pancreas > adrenal >
  duodenum > bone > spleen > liver > muscle >
  spinal cord > cerebellum > medulla oblongata =
  hypothaiamus

Kidney > pituitary > spleen > lung > skin > testls >
  serum = pancreas = adrenal > sclerae > duodenum =
  liver > whole blood > heart > bone > 1r1s > muscle >
  cornea = cerebellum = hypothalamus > medulla
  oblongata > spinal cord > retina > lens > vitreous
  humor

Kidney > lung > sternal cartilage > pancreas
           Parker and
             Sunderman
             (1974)
           Parker and
             Sunderman
             (1974)
           Oskarsson and
             Tjalve (1979)
   Source:   Adapted from NAS (1975).

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in diet had the highest levels of the label in kidney; the relative levels in
kidney, lung and liver being less for the low-nickel  group.
     Comparison of  the  above studies suggests that  a  homeostatic  mechanism
exists to regulate  low  levels of nickel  intake, e.g., 5 ppm, but such regula-
tion is overwhelmed in the face of large levels of nickel  challenge.

4.2.3  Subcellular Distribution of Nickel
     Nickel  toxicity  to organelles  is associated with specific  patterns  of
subcellular distribution, particularly with respect to carcinogenicity.
     Earlier studies suggest that:   (1)  70 to 90 percent  of cellular nickel  is
lodged in the  nucleus in rhabdomyosarcoma induced by nickel  subsulfide (Webb
et al., 1972)  and  is  distributed between nucleolus and sap + chromatin frac-
tions; (2) nuclear  binding  involves  both R.NA and DNA (Heath and Webb, 1967);
(3) similar nuclear accumulation is obtained with intrarenal  administration of
the subsulfide  in  rats  (Jasmin and Riopelle,  1976);  and (4)  lung and  liver of
rats exposed to nickel  carbonyl  exhibit  highest nickel accumulation in micro-
somal and supernatant fractions (Sunderman and Sunderman,  1963).
     The  binding  of nickel  to chromatin,  nuclei,  and nuclear proteins was
studied by Ciccarelli and Wetterhahn (1984) in rats given nickel  carbonate (40
mg/kg,  i.p.,  single  dose).   The relative amount of  nickel  bound  to  whole
chromatin was  greater for kidney than for  liver and was  directly  related to
nuclear nickel  content.   In  addition, much  higher  levels  of  nickel were found
in the  DNA-histone complex from kidney  as  compared  to liver.  Other  binding
sites where significant nickel levels were found included non-histone proteins
from both  kidney  and liver  nuclei and  histone octamer proteins  from  kidney.
     A  number  of  recent  studies  indicate that subcellular  partitioning of
nickel j_n vivo or J£j vitro is markedly different between insoluble nickel  com-
pounds and  soluble nickel salts.   Her!ant-Peers et  al. (1983) reported that
intraperitoneal injection of   Ni-labeled nickel  chloride solution into mice
was associated with a pattern of label incorporation into subcellular fractions
over short  time  periods.   This pattern  was characterized by generally lower
accumulation in nuclei than  in cytosol,  mitochondria, or microsomes.
     In vitro  cell  studies of Costa et al. (1981) indicate  that carcinogenic
nickel  subsulfide,  crystalline  nickel  sulfide, and crystalline nickel subse-
lenide are all actively phagocytized and enter Syrian hamster embryo or Chinese
hamster ovary  cells with  subsequent transfer of nickel to cell nuclei.  Harnett
                                    4-19

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et al.   (1982)  compared the differential  binding of labeled nickel  as  the
insoluble crystalline  nickel  sulfide  and soluble nickel  chloride solution in
cultured Chinese hamster ovary cells.   RNA and DNA binding of nickel  following
sulfide exposure was 300 to 2000 times greater than with the soluble divalent
nickel.  In describing the possible mechanistic basis for selective uptake of
nickel   by nuclei  from  phagocytized insoluble nickel  particles,  consideration
must be given to  the  observation that  endocytosis delivers  the particles
adjacent to the  nucleus.   Eventual dissolution permits nickel  ion uptake by
the nuclear membrane.
     As noted  above, administration  of soluble or volatile nickel to animals
shows  a sizable fraction remaining  in cell  supernatant.   Sunderman et al.
(1981)   characterized the biomolecular  distribution of nickel in  renal cytosol
in  rats given injected nickel  (II).   The greatest fraction, approximately
68 percent, was  bound  to low-weight components, <2000 daltons.   The  remainder
was partitioned  among  molecules of 10,000 to <130,000 molecular weight, with
molecules in  the higher weight  range  comprising the most prominent portion of
this fraction.  This pattern was confirmed in a later study using high-perfor-
mance  size-exclusion chromatography  (Sunderman et al., 1983).   Abdulwajid and
Sarkar  (1983),  on  the  other hand,  have claimed that their method of  purifica-
tion of renal  cytosolic binding proteins results in most of the nickel  being
bound  to  a  glycoprotein (derived  from renal  basement  protein)  of 15,000 to
16,000  molecular weight.
4.3  RETENTION AND EXCRETION OF NICKEL IN MAN AND ANIMALS
     When  studying  the systemic  retention  of  an  element  such  as  nickel,  it  is
necessary  to  differentiate between relatively short-term retention  associated
with  replacement in tissue of optimal  levels of an essential element  (see
Chapter 9)  versus  accumulation  with organism age,  such  as  is exhibited with
lead in mineralizing tissue or cadmium in  kidney cortex.
     The  ICRP (International  Commission  on Radiological  Protection, 1981)  has
estimated  that  the human adult  body contains  about 10  mg nickel  for unexposed
subjects.   The   ICRP has  also  estimated  a retention half-time of  1200  days
(approximately 3.3 years)  based upon a daily  retention rate of around 30 percent
from  a rather high daily  intake  of 400  ug nickel.   Bennett (1982), however,
reported  a body  burden of  500 ug  nickel, many-fold  lower than the ICRP  values,
based  upon calculations of a body nickel retention  time  (not  half-time)  of  200  days
                                    4-20

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under steady-state conditions of  exposure.   Bennett's figure is an estimate
from average nickel  levels of 7  ng/g tissue.
     The data for teeth and bone nickel  levels described above (1.3 (jg/g bone,
30-40 pg/g dentition) lead to a  body nickel  burden closer to the ICRP estimate.
If it is  assumed that the current daily  nickel  intake  is closer to 200 ug
(Myron et al., 1978;  Clemente et  al.,  1980) than the ICRP  value of 400 (jg,
then the  biological  half-time  is  increased, being  entirely  determined by
mineral  tissue burden.  Since nickel in bone  is relatively constant with age,
it presumably is constantly being resorbed and deposited in the mineral matrix.
The daily intake retention figure of 30 percent for nickel as estimated by the
ICRP for normal human intake may or may not apply to excessive intake.
     The excretory routes  for nickel in man  and animals depend  in part  on the
chemical forms of nickel  and the mode of nickel  intake.  Unabsorbed dietary
nickel is simply lost in the feces.   Given the relatively low extent of gastro-
intestinal absorption (vide supra), fecal  levels of nickel roughly approximate
daily dietary intake of 300-500 ug/day in man.
     Urinary excretion in man and animals is usually the major clearance route
for absorbed nickel.   Reported normal levels in urine vary considerably in the
literature, and  earlier value variance probably reflects  methodological limi-
tations.  More recent studies  suggest values of  2-4 ug/£ (Andersen et al.,
1978; McNeely et al., 1972).
     Biliary excretion  is  also  a  possible clearance  route for absorbed  nickel
and  is  known  to  occur in the rat (Smith and Hackley, 1968), the calf (O'Dell
et al.,  1971),  and  the rabbit  (Onkelinx  et  al.,  1973). However, Marzouk and
Sunderman (1985, in press), employing relatively accurate methodology, observed
that  biliary  excretion of  nickel  in the rat, when  administered in single
subcutaneous doses,  only  amounted to approximately  0.3 percent of  the  total
dose  over a 24-hour period, thereby  constituting a rather minor route for
clearance.  Whether biliary excretion occurs  in man  is unknown.
     Sweat  can constitute  a major route  of  nickel  excretion.  Hohnadel and
co-workers  (1973) determined nickel  levels  in the  sweat  of  healthy subjects
sauna bathing  for brief periods at 93°C to be 52 ±  36 ug/£ for men and 131 ±
65 pg/£ for women.
     The  role  of nickel  deposition in hair  as  an excretory  mechanism  in man
has  prompted  a number of  studies.   The  use  of hair nickel levels in assessing
overall nickel body burdens remains to be widely  accepted.  Schroeder and Nason
                                    4-21

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(1969) have reported  sex-related  differences  in nickel levels of human hair
samples,  female subjects  having  nickel  levels (3.96 M9/9,  S.E.M. = ± 1.06)
about fourfold those  of men (0.97 fjg/g, S.E.M. = ± 0.15).   Such a difference,
however,  was not  encountered  by  Nechay and Sunderman  (1973)  nor  were their
average sample values as  high.  The differences in these two  studies  serve  to
point out  some of the difficulties in establishing quantitative relationships
for the role of hair levels in nickel  metabolism.
     In experimental  animals,  urinary  excretion is the main  clearance route
for nickel compounds introduced parenterally.
                                                              CO
     Onkelinx et  al.  (1973)  studied  the kinetics of injected   Ni metabolism
in rats and  rabbits.   In both species, a  two-compartment model of  clearance
could be  discerned,  consisting of fast and slow components.   In  the  rabbit,
better than 75 percent  of the dose was excreted within 24  hours, while com-
parable clearance in  the  rat required 3 days.   In  a later study,  Onkelinx
                                         CO
(1977) reported  whole body  kinetics  of    Ni  in rats.  The time  course  of
plasma nickel  levels  entailed first-order  kinetics analyzable  in terms of  a
two-compartment model.  The  major portion  of nickel clearance was  accounted
for by renal excretion.
                                                                        CO
     Chausmer  (1976)  has  measured exchangeable nickel in the rat using   Ni
given intravenously.   Tissue exchangeable pools were directly estimated and
compartmental analysis performed by computer evaluation of  the relative isotope
retention  versus  time.   Within 16 hours,  kidney had the  largest  labile pool
with two  intracellular compartments.   Liver, lung,  and spleen pools could also
be characterized  by two  compartments, while bone fit a one-compartment model.
Corresponding  half-times  for  the fast and slow components  were several hours
and several days, respectively.
     Animals exposed  to  nickel carbonyl  via  inhalation  exhale a  part of  the
respiratory burden  of this agent within 2 to 4 hours, while the balance is
slowly degraded  i_n  vivo to divalent  nickel and carbon monoxide with nickel
eventually undergoing urinary excretion  (Mikheyev,  1971;  Sunderman  and Selin,
1968).
     The  pattern  of labeled-nickel  urinary excretion  in  rats given a single
                               63
injection  (4  mg/kg, 12.5 u Ci  Ni/mg  cold Ni,  as  chloride)  was  studied  by
Vertna  et  al.  (1980) who  reported nickel  to be excreted  as  a mixture of  com-
plexes within  24 hours of dosing, the  ligating moieties having  a  molecular
weight of 200  to  250.
                                     4-22

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4.4  FACTORS AFFECTING NICKEL METABOLISM
     A number of disease  states and other physiological  stresses are  reported
to alter the  movement and tissue distribution of  nickel  in man as well  as
experimental animals.   Furthermore, i_n vivo movement of nickel may be deliber-
ately altered to enhance nickel removal from the organism to minimize toxicity
in cases of  excessive exposure,  specifically via the use of nickel chelating
agents in the clinical management of nickel  poisoning.
     In man,  increased levels of  serum nickel  are seen  in  cases  of acute
myocardial  infarction  (Sunderman et al., 1972; McNeely et al.,  1971;  D'Alonzo
and Pell,  1963),  such alterations  presently being considered as secondary to
leukocytosis and leukocytolysis (Sunderman,  1977).   Leach et al. (1985) compared
the serum  nickel  levels  of healthy adults  (N=33)  with patients having  acute
myocardial   infarction (AMI,  N=37)  and with patients  having unstable angina
pectoris (N=24).   Patients were monitored periodically after hospitalization,
every 8 hours on day 1 and daily for the second and third days.   Hypernickelemia
was seen in  65  percent of those patients with AMI and in 54 percent of those
with  unstable  angina pectoris.  There  was  no relationship  of  serum  nickel
level to age,  sex, medication, or cigarette  smoking.  The  authors concluded
that  elevated  nickel  may  be associated with the  pathogenesis  of ischemic
myocardial  injury.
     Serum nickel  levels  are also  elevated  in acute  stroke  and  extensive  burn
injury (McNeely et al., 1971), while reduction is  seen in hepatic  cirrhosis or
uremia, possibly secondary to hypoalbuminemia.
     Rubanyi et al.  (1983)  have  claimed a role for endogenous nickel release
in the myocardial  injury and vasoconstriction attending  acute burn injury in
rats.  Thermal  burn  injury in rats was  seen  to  induce a rise  up  to  5-fold
(p <0.001)  in serum  nickel.   Nickel ion was seen to  be released directly  from
myocardial  cells  by  cytochemical  techniques.   Nickel sensitivity  of coronary
vessels in  perfused  hearts  from burn-injured  rats, measured in  terms  of total
coronary resistance,  was also significantly  enhanced.   One difficulty with
this report lies in the serum nickel value reported for the control group.  At
100 ug/1,  this  value  is  approximately  50-fold over levels generally observed.
While the  control  value  indicates  a large systematic  contamination error,  the
relative and  huge  fivefold  increase to 500  ug/1  in the test group  is  inexpli-
cable.
     Several  recent  studies  demonstrate an association  of  serum  nickel with
chronic renal failure and hemodialysis.  According to Drazniowsky  and co-workers
                                    4-23

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(1985),  serum  nickel  levels were  elevated  in hemodialysis patients  (N=16,
median 7.6 ug/1,  p <0.01) compared to normal subjects (N=71, median 1.0 ug/1).
Similarly, Savory et al.  (1985) have observed that nickel in serum (3.7 versus
0.4 ug/1)  is  significantly elevated (p <0.00005)  in hemodialysis patients.
Hopfer et  al.  (1985)  have determined that  the  hemodialysis hypernickelemia
seen by them and other researchers (vide supra)  is based on nickel-contaminated
dialysis solution.  As evidence,  the authors note that reduction of solution
nickel by  about  30 percent  results  in  a concomitant  decrease  of the same
amount in serum nickel of dialysis subjects.
     Palo  and  Savolainen (1973) reported that  hepatic  nickel  was increased
tenfold  over normal values in  a deceased patient with  aspartylglycosaminuria,
a metabolic disorder characterized by reduced activity of aspartyl-p-glucosami-
nidase.
     Other stresses appear to  have an effect on  nickel  metabolism.   Signi-
ficant reduction  in  serum nickel  has been  seen in mill  workers  exposed  to
extremes of  heat  (Szadkowski  et al., 1970), probably due to excessive nickel
loss through sweating, as was noted earlier.
     Tissue  nickel  levels  have been reported to be  elevated in  rats during
pregnancy  (Spoerl  and Kirchgessner, 1977).   In a  study on  humans,  Rubanyi
et al. (1982)  showed  a 60  percent  decrease  in serum  nickel  in pregnant women,
which  rose to  normal  at parturition.  Most striking was the observation of a
20-fold,  transitory  rise in  serum nickel at  5  minutes postparturition.   By
60 minutes,  serum  values were  normal.   Such a  transitory rise may indicate a
physiological  role  of the  element  in controlling atonic  bleeding or  promoting
placental  separation  through  effects on uterine vasoconstriction and uterine
smooth muscle.
     Use  of  various  classes  of chelating  agents  employed  to  expedite the
removal  of nickel  from man and animals  has  been reported.   The  data  have  been
reviewed  (Sunderman,  1977; NAS, 1975) and  will only be summarized  in this
section.
     On  the  basis  of reported  clinical experience,  sodium  diethyldithiocar-
bamate  (dithiocarb)  is  presently  the  drug of  choice  in the management of
nickel carbonyl poisoning, being preferable overall  to EDTA  salts, 2, 3-dimer-
captopropanol  (BAL),  and penicillamine.   While it has been  assumed  that such
agents work  to accelerate the  urinary excretion of absorbed amounts  of nickel
before extensive  tissue  injury can  result, recent evidence  from experimental
animals  would  suggest that the dithiocarbamates may serve  to  markedly alter
                                     4-24

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the distribution of  nickel  as well as  its  retention  HI vivo (Oskarsson and
Tjalve, 1980).   Similar results have been reported using alkyl thiuram sulfides,
agents which undergo  ready  j_n vivo reduction to  the dithlocarbamates  (Jasim
and Tjalve, 1984).   The  chemotherapeutic function of the dithiocarbamates in
nickel intoxication,  therefore,  may be to divert  nickel  (II) from  sensitive
physiological  binding sites  via  formation  of inert, lipophilic  complexes,
rather than to enhance the lowering of body nickel burdens.
                                     4-25

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Alexander, A.  J.; Goggin, P. L.; Cooke, M. (1983) A Fourier-transform  infrared
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Andersen,  I.;  Hogetveit, A. C.  (1984)  Atmospheric monitoring of  nickel  at
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Andersen,  I.;  Torjussen,  W.;  Zachariasen, H.  (1978)  Analysis for nickel  in
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Armit,  H.  W.  (1908)  The  toxicology of nickel  carbonyl.   Part II.   J.  Hyg.  8:
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Bennett,  B. E.  (1982) Exposure of  man  to environmental nickel--an exposure
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Bernstein,  D.  M.;  Kneip, T. J.;  Kleinman,  M.  T.; Riddick,  R.;  Eisenbud,  M.
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Casey,  C.  E. ;  Robinson,  M.  F.  (1978)  Copper,  manganese, zinc,  nickel,  cadmium,
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Chausmer,  A.  B.  (1976) Measurement  of  exchangeable nickel  in the rat. Nutr.
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Christensen,  0.  B. ;  Lagesson, V.  (1981) Nickel concentration  of  blood and
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Ciccarelli, R.  B.; Wetterhahn, K.  E.  (1984) Nickel-bound chromatin,  nucleic
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Clary,  J.  J.  (1975)  Nickel chloride-induced metabolic changes in  the rat and
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Clemente,  E.  F. ; Rossi,  L. G. ;  Santaroni,  G.  P.  (1980)  Nickel  in foods and
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     New York, NY:  John  Wiley  and Sons; pp.  493-498.

Corvalho,  S.  M.  M.;  Ziemer, P.  L.  (1982) Distribution and clearance of 63NiCl2
      in the rat:  intratracheal study.  Arch.  Environ.  Contam. Toxicol.  11:  245-
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Costa, M. ;  Mollenhauer, H.  H.  (1980) Carcinogenic activity  of  participate
     nickel  compounds  is  proportional  to  their  cellular uptake.  Science
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Costa, M. ;  Simmons-Hansen, J. ; Bedrosian,  J. ;  Bonura, J. ; Caprioli,  R.  M.
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Creason,  J. ; Svendsgaard, D.; Bumgarner, J. ; Pinkerton, C. ; Hinners, T. (1976)
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D'Alonzo,  C.  A.; Pell,  S.  (1963)  A study  of  trace elements  in  myocardial
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Drazniowsky, M.; Channon,  S.  M.; Parkinson,  I.  S.;  Ward,  M. K.;  Poon,  T.  F-H;
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English,  J.  C. ;  Parker,  R. D. R.;  Sharma, R. P.; Oberg,  S. G. (1981)  Toxico-
     kinetics of nickel  in rats  after intratracheal administration of  soluble
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Furst, A.; Al-Mahraq,  H.  (1981) Excretion  of  nickel  following  intratracheal
     administration of the carbonate. Proc. West. Pharmacol.  Soc.  24:  119-121.

Ghiringhelli, L. ;  Agamennone,  M.   (1957) II metabolismo del nichel  in  animali
     sperimentalmente avielenati con nichelcarbonile.  Med. Lav.  48: 187-194.

Glennon,  J.  D. ;  Sarkar,  B.  (1982)  Nickel  (II)  transport  in human blood serum.
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                           5.   NICKEL TOXICOLOGY
     Both acute and  chronic  effects of exposure to various nickel compounds
have been extensively  documented  over the years.   The following chapter dis-
cusses these non-mutagenic/carcinogenic effects of exposure to various nickel
compounds.   Because of the large volume of information available regarding the
mutagenic and carcinogenic effects,  as well  as the reproductive  effects of
nickel exposure,  these topics  have  been discussed in  following  chapters.
5.1  ACUTE EFFECTS OF NICKEL EXPOSURE IN MAN AND ANIMALS
5.1.1  Human Studies
     In terms of  human health effects, probably the most acutely toxic nickel
compound is nickel carbonyl, Ni(CO)., a volatile,  colorless liquid formed when
finely divided nickel comes  into contact with carbon monoxide, as  in the Mond
process for purification  of  nickel  (Mond et al. ,  1890).   A sizable body of
literature  has  developed over the years dealing  with  the acute inhalation
exposure of  nickel-processing workers to nickel  carbonyl  (Sunderman,  1977;
National Institute  for Occupational  Safety  and  Health,  1977; National Academy
of Sciences,  1975).   Since much of  this information  is relevant mainly to
industrial  accidents and occupational medicine rather than general  environmental
health, it is not appropriate to accord it detailed discussion in this document.
     According to Sunderman (1970)  and Vuopala et  al.  (1970), who have studied
the clinical  course  of  acute nickel  carbonyl poisoning in workmen, clinical
manifestations include  both immediate  and  delayed symptomatology.  In the
former, frontal  headache, vertigo,  nausea,  vomiting, insomnia,  and irritability
are commonly  seen,  followed  by an  asymptomatic interval before the onset of
insidious,  more persistent symptoms.  These  include constrictive chest pains,
dry  coughing,  hyperpnea,  cyanosis,  occasional gastrointestinal  symptoms,
sweating,  visual  disturbances,  and  severe  weakness.  Aside from the weakness
and hyperpnea, the  symptomatology strongly  resembles that of viral pneumonia.
     The lung is  the target organ  in nickel  carbonyl  poisoning in man and
animals.  Pathological  pulmonary lesions observed in  acute human exposure
include pulmonary hemorrhage and edema accompanied by derangement  of alveolar
cells, degeneration of bronchial epithelium, and formation of fibrinous intra-
alveolar exudate.   Roentgenological  follow-up  on patients surviving acute
episodes of exposure frequently indicates pulmonary fibrosis.
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     In man, nephrotoxic  effects  of nickel  have been clinically detected in
some cases of  accidental  industrial  exposure to nickel  carbonyl  (Carmichael,
1953; Brandes, 1934).   This  takes the form of renal  edema with hyperemia and
parenchymatous degeneration.

5.1.2  Animal Studies
     The pronounced  pulmonary  tract  lesion  formation seen in animals acutely
exposed to nickel carbonyl vapor  strongly overlaps that reported for cases of
acute industrial  poisoning (Armit, 1908; Barnes and Denz,  1951; Kincaid et al.,
1953; Sunderman et al., 1961; Hackett and Sunderman,  1967, 1969).   The lung is
the target organ  for effects of nickel carbonyl in animals regardless of the
route of  administration.   The response of  pulmonary tissue is very rapid,
interstitial edema developing  within  1  hour of  exposure.  There is subsequent
proliferation  and  hyperplasia of  bronchial  epithelium  and alveolar lining
cells.   By several days post-exposure,  severe  intra-alveolar edema with  focal
hemorrhage and alveolar cell  degeneration has  occurred.  In animals that do
not survive  acute  exposures,  death usually occurs by the fifth day.   Animals
surviving the  acute  responses show  regression of cytological  changes with
fibroblastic proliferation within alveolar interstitium.
     Acute renal  injury with proteinuria and hyaline casts were observed by
Azary (1879)  in  cats and  dogs given nickel  nitrate.   Pathological  lesions of
renal tubules  and glomeruli  have  been  seen  in  rats exposed  to  nickel carbonyl
(Hackett and  Sunderman, 1967;  Sunderman et al., 1961; Kincaid et al., 1953).
Gitlitz et al.  (1975)  observed aminoaciduria and proteinuria  in  rats after
single  intraperitoneal  injection  of nickel  chloride, the extent of the renal
dysfunction  being dose-dependent.   Proteinuria was observed at a  dose of 2
mg/kg,  while  higher  dosing occasioned aminoaciduria.  Ultrastructurally, the
site of the effect within the kidney appears to be glomerular epithelium.
These renal  effects  were  seen to  be  transitory,  abating  by the fifth day.
5.2  CHRONIC EFFECTS OF NICKEL EXPOSURE IN MAN AND ANIMALS
5.2.1  Nickel Allergenicity
     Nickel  dermatitis  and other dermatological effects of  nickel  have  been
documented  in  both nickel  worker populations and  populations  at large (NAS,
1975).   Originally considered to be a problem  in  occupational  medicine,  the
                                   5-2

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more recent clinical and epidemiological picture of nickel sensitivity offers
proof that it may be more of a problem in individuals not having occupational
exposure to nickel but encountering an increasing number of nickel-containing
commodities in their everyday environment.
5.2.1.1  Clinical  Aspects of Nickel  Hypersensitivity.   Occupational  sources of
nickel   that  have  been associated  with nickel  sensitivity  include  mining,
extraction, and refining of the element as well  as such operations as plating,
casting, grinding, polishing,  and  preparation of nickel alloys (NAS, 1975).
Although the  frequency of  nickel  dermatitis has considerably abated owing to
advances in  both  control technology and  industrial  medicine,  it may still
persist in electroplating shops (NAS,  1975).
     Nonoccupational exposure to nickel leading to dermatitis includes nickel-
containing jewelry,  coinage, tools,  cooking utensils, stainless steel kitchens,
prostheses, and clothing  fasteners.   Women  appear to be particularly at risk
for  dermatitis of the  hands, which has been  attributed to  their continuous
contact with many of the nickel-containing commodities noted above (Maiten and
Spruit, 1969).
     Nickel dermatitis usually  begins  as  itching or burning papular erythema
in  the  web of  fingers  and  spreads to  the  fingers,  wrists, and  forearms.
Clinically, the condition is usually manifested as a papular or papulovesicular
dermatitis with a tendency  toward lichenification, having the  characteristics
of atopic, rather than eczematous, dermatitis.
     According to Calnan  (1956),  on the basis  of  a  large number of  cases,
nickel  dermatitis has a unique topographical distribution pattern:  (1) primary:
areas  in direct  contact  with the element;  (2)  secondary:   spreading of the
dermatitis  in a symmetrical  fashion;  and (3) associated:  afflicted areas
having  no  relation  to contact  areas.   Furthermore, the  affliction may persist
some time after removal  of obvious sources of exposure.
     A  clear  relationship  between  atopic dermatitis  and  that elicited by
nickel  has  been precluded  by conflicting  reports  in  the literature.   Watt  and
Baumann (1968)  showed that atopy was present in 15 of 17 young patients with
earlobe nickel  dermatitis,  but other workers (Caron,  1964;  Marcussen,  1957;
Calnan, 1956;  Wilson, 1956) have  failed to  demonstrate  any  connection between
the  two disorders.   Juhlin  et  al.  (1969)  demonstrated elevated immunoglobulin
(IgE) levels  in atopy patients, while Wahlberg and Skog (1971) saw no signifi-
cant increases of IgE in patients having nickel and atopic dermatitis histories.
                                   5-3

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     The occurrence of  pustular  patch test reactions to  nickel  sulfate  has
been considered significant in connecting nickel  and atopic dermatitis (Becker
and O'Brien, 1959).   Uehara  et al.  (1975) have reported  that pustular patch
test reactions to 5 percent nickel  sulfate were regularly produced in patients
with atopic dermatitis,  but  only when applied to areas of papulae, erythema,
lichenification, and  minimal  trauma;  such  response  seldom occurred on normal-
appearing skin  surface.  Furthermore, traumatizing  the test areas  in control,
as well  as  dermatitic subjects,  furnished positive responses.   These authors
suggest  that pustular patch  testing is primarily a  primary irritant reaction.
     Christensen and Moller (1975a) found that of 66 female patients with hand
eczema and  nickel  allergy,  51 had an eczema  of  the pompholyx type; i.e., a
recurring itching  eruption with  deeply  seated fresh vesicles and little ery-
thema  localized  on the  palms,  volar aspects,  and sides of fingers.  Of these,
41 had pompholyx only,  while the remainder had at least one of the following
additional  diagnoses:   allergic  contact  eczema,  irritant  dermatitis,  nummular
eczema,  or atopic dermatitis.  These workers also found that the condition was
not influenced by any steps taken to minimize external exposure.  Subsequently,
these workers (Christensen and Moller, 1975b) discovered that oral administra-
tion of  nickel  in 9  of  12 of the earlier  subjects  aggravated the  condition,
while  intense  handling  of  nickel-containing objects was without effect.   The
level  of nickel  ingested was approximately 5  mg.   Although this  level seems
excessively high in light of commonly reported dietary levels of 300 to 600 ug
Ni/day,  the authors noted that the value was at the high end of dietary intake
of a comparison  population from a community near the clinic where the patients
reported (mean:  0.76  mg; range: 0.20  - 4.46 mg).
     The role  of oral nickel  in  dermatitic responses  was  also demonstrated  by
Kaaber et  al.  (1978), who investigated  the  effect  of a  low nickel  diet  in
patients with chronic nickel dermatitis presenting as hand eczemas of dyshidro-
tic morphology.  Of 17  subjects  in the clinical trial, nine showed significant
improvement during a period of 6 weeks  on a low nickel  diet.   Of these  nine
showing  improvement,  seven had a flare-up  in their  condition when placed  on a
normal diet.  Furthermore, there was  no correlation apparent between the  level
of  urinary  nickel  and  the degree of  improvement following the diet.  These
authors  recommended limitation in dietary nickel as  a help in  the management
of  nickel  dermatitis.  In  this connection, Rudzki  and Grzywa (1977) described
an  individual  having chronic flare-ups  in nickel dermatitis whose chronicity
                                    5-4

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of condition was  traced  to the nickel content of margarine,  Polish margarine
having a rather high nickel content, up to 0.2 mg Ni/kg.
     More recent  studies  have  confirmed that dietary nickel is definitely a
factor in nickel  dermatitis  flare-ups in a  sizable  fraction  of the nickel-
sensitive population  (Jordan and King,  1979; Cronin  et al., 1980; Christensen
et al., 1981; Veien  et al.,  1983a).   The data of Jordan and King (1979) and
Cronin et al. (1980)  indicate  a dose-response relationship between flare-ups
of hand  eczema  in  nickel-sensitive  patients and level of dietary  nickel.
     Sjoborg et al.  (1984),  using  light and electron microscopy,  studied the
morphological changes of  Langerhans cells in nickel  dermatitis patients. Both
normal skin  and healed patch test areas were examined in subjects who experi-
enced flare-up reactions  induced by oral nickel  administration.   The authors
found that,  following oral  administration of nickel, the  cellular  reactions
took place  in the topmost portion  of  the epidermis  and  were accompanied by
formations of lipid-like  inclusions  in the Langerhans cells.  Keratinocytes
adjacent to the Langerhans cells had membrane and cytoplasmic changes.
     As might  be  expected  from the above  discussions, control  of  dietary
nickel ameliorates  the frequency and  severity of the allergenic response.  In
the study of Veien et al.  (1983a),  23 of 33 patients who  had flare-ups follow-
ing oral challenge with nickel  and  other salts and were subsequently placed on
low-metal allergen diets  showed clearing or improvement of the condition after
approximately 4 weeks.
     The  association  between endogenous  nickel  and nickel sensitivity  has
prompted study of the known nickel  chelant diethyldithiocarbamate, in the form
                                               p
of the dimer commercially available as Antabuse , for the management of flare-
ups.   In  the double-blind,  placebo-controlled study of Kaaber et al. (1983),
24 subjects  with  hand eczema and nickel  allergy were given graduated doses of
the agent (up to  200  mg)  for a  period  of  6  weeks.  The treatment  group  showed
a significant reduction  in the number  of flare-ups  and  the  extent  of  skin
scaling (p <0.05) compared to controls.  In the similar but uncontrolled study
                                                                D
of Christensen and Kristensen (1982), 11 patients given Antabuse  (200 mg/day,
8 weeks) showed healing  in 2 cases  and improvement  in 8 patients.   Relapses
were observed in all patients 2 to  16 weeks after discontinuation of the drug.
In both studies,  hepatotoxicity was observed in some patients as a side effect
of treatment.
                                   5-5

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     While Kaaber et al.  (1978) found little correlation between nickel excre-
tion and  the status of dermatitis in their patients, Menne and Thorboe (1976)
reported elevated urinary nickel levels during dermatitis flare-ups.   deJongh
et al.  (1978)  found  limited correlation between plasma nickel  level, urinary
excretion of nickel,  and  the clinical  activity of the condition in a patient
followed during two periods of 5 and 6 weeks  each.   More recent reports of
Kaaber et al.   (1979)  and  Christensen and Lagesson (1981), however,  indicate
that urinary nickel is  a  more reliable indicator of nickel intake,  at least
under conditions  of challenge  involving  a sizable amount of  the element.
     Internal   exposures to  nickel   associated  with nickel  sensitivity and
arising from prosthesis alloys have been reviewed (Fisher, 1977; MAS, 1975;
Samitz and Katz, 1975),  and many of these data will  only be summarized in this
section.
     The most  common prosthesis alloys are stainless steel or cobalt-chromium
(Vitallum), which may contain nickel in amounts up to 35 percent, but gener-
ally range between 10-14 percent (Samitz and Katz, 1975).
     Instances  of allergic  reactions,  as well as urticarial  and eczematous
dermatitis, have been attributed to implanted prostheses with resolution of
the condition after removal  of the  devices (NAS, 1975;  Samitz and Katz, 1975).
Apparently, sufficient solubilization of nickel from the surface of the material
appears to  trigger  an  increase in  dermatitis  activity.   In support  of this,
Samitz and  Katz (1975)  have shown  the release of nickel from stainless steel
prosthesis by the action of blood,  sweat, and saline.
     Fisher (1977), in  his  review,  has counseled caution in interpreting the
reports and has recommended specific criteria for proof of nickel dermatitis
from a  foreign body to  include evidence  of surface corrosion and sufficient
corrosion to give a positive nickel  spot test.
     Nickel dermatitis  has  recently been described in  a patient undergoing
hemodialysis (Olerud et al., 1984).   Exposure occurred through blood contamin-
ated by nickel which had leached from a stainless steel fitting.   Since nickel
exposure  can occur  by various  means  for hemodialysis patients  (Savory  et al.,
1985; Hopfer et al. , 1985), as noted earlier in Chapter 4, allergenic responses
may be a potential problem  in these  individuals.
     Determination of nickel  dermatitis  classically involves the use  of the
patch  test and site response  to a  nickel salt solution  or  contact with a
nickel-containing object.   The optimal  nickel concentration in patch test
                                   5-6

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solution is set at 2.5 percent (nickel sulfate).  Patch test reactions may be
ambiguous in that they  can  reflect a primary  irritation  rather  than a pre-
existing sensitivity (Uehara et al., 1975).  Intradermal testing as described
by Epstein (1956) has  also  been  employed,  but  the procedure appears to offer
no overall  advantage to the  conventional  method (NAS,  1975).
     The effect of nickel  on lymphocyte transformation and the utility of this
phenomenon as an j_n  vitro alternative to conventional patch testing with its
attendant ambiguity and dermatological  hazards  merit discussion.
     Transformation of cultured human peripheral lymphocytes as a sensitive i_n
vitro screening  technique for nickel hypersensitivity  versus  the  classical
patch testing has been  studied in a number of  laboratories, and the earlier
conflicting studies  have  been  reviewed (NAS, 1975).   The studies of Svejgaard
et al.  (1978), Gimenez-Camarasa et al. (1975),  Millikan et al. (1973), Forman
and Alexander (1972), and Hutchinson et  al. (1972)  have, however, established
the reliability of the technique.
     Nordlind and Henze (1984) found that nickel (II)  (7.6 to 76 uM) stimulated
both immunologically immature thymocytes and immunocompetent peripheral lympho-
cytes in children of different ages.  Nickel-stimulated DNA  synthesis  in both
these systems occurred  at a lower rate  than did  synthesis stimulated  by the
lectinic mitogens phytohaemagglutinin,  concanavalin A,  and pokeweed mitogen.
DNA synthesis appeared  to decrease with age in children ranging from 6 to 13
years of age.
     The comparable  value of the leukocyte migration inhibition test as an
alternative technique remains to be demonstrated conclusively (MacLeod et al.,
1976; Jordan and Dvorak,  1976; Thulin, 1976).
     The induction of nickel sensitivity in human subjects has been claimed by
Haxthausen (1936) and Burckhardt (1935).  In their subjects, prior sensitivity
was not ruled out.   Furthermore,  the concentration of the sensitizing solution,
25 percent, may  easily have induced an  irritation  response.   More  recently,
Vandenberg and Epstein (1963)  successfully sensitized 9 percent (16 of 172) of
their clinical subjects.
     One area of  controversy with regard to nickel dermatitis involves the
question of hypersensitivity to groups of metals, i.e., cross sensitivity, and
various  sides  of the issue  have  been  reviewed (NAS,  1975).  Of particular
concern is the existence  of hypersensitivity to both  nickel and cobalt, as the
elements occur  together  in  most  of  the commodities with which  susceptible
                                   5-7

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individuals may come  in  contact.   In a study by Veien et al. (1983b), 55 of
202 patients with  hand  eczema  showed sensitivity to oral  challenge of either
nickel, chromium,  or cobalt salt.   The authors found that  reaction sensitivity
was no greater for ingestion of mixtures of the metals than that for individual
salts, suggesting  that  cross  sensitivity  was not common  in  this  particular
patient group.
     The underlying mechanisms  of  nickel  sensitivity presumably include:  (1)
diffusion  of nickel  through the skin, (2) subsequent  binding  of  nickel  ion
with protein(s) and  other  skin components, and (3) immunological  response to
the nickel-macromolecule complex (MAS, 1975).   In the  section on  nickel meta-
bolism, it was  noted  that  penetration  of  the  outer  skin layers  by  nickel does
occur.  Jansen  et  al.  (1964) found that nickel in complex with an amino acid
(D,L-alaline) was  a  better sensitizer than nickel alone,  while Thulin (1976)
observed that  inhibition of leukocyte migration  in  10 patients with nickel
contact dermatitis  could be elicited with nickel bound to bovine and human
serum  albumin  or  human  epidermal  protein, but not  with  nickel ion alone.
Hutchinson et al.   (1975) noted  nickel binding to lymphocyte surfaces from both
sensitive  and  control  subjects; thus, nickel binding, per se,  is not the key
part  of  the immunological  response (lymphocyte  transformation).   Braathen and
co-workers (1983)  investigated HLA-antigen profiles in patients  with  nickel
dermatitis and  found  no  association between HLA-A,B,C, or OR and active nickel
allergenicity.  Similar  results have been noted  by  Karvonen et al. (1984).
5.2.1.2   Epidemiological Studies of  Nickel Dermatitis.  There  are no studies
of  general populations  which relate  nickel  exposures or levels  in tissues and
fluids to  physiological, subclinical or clinical  changes.   The  studies previous-
ly  cited  do not cover properly designed  and  executed  samples of  either total
populations or selected population segments  which would  permit projection  of
findings  to the total population from  which  subjects were  selected.  Only some
industrially-exposed  worker populations have  been surveyed or monitored in  any
statistically  adequate  manner, and these  studies will be reported  later in
connection with nickel  carcinogenesis.   The  literature  on adverse  health
effects  in relation to  nickel  exposure for  the general population is  limited
to  the investigation of nickel dermatitis  and nickel sensitivity, with only
occasional reports related to other diseases or conditions.   These latter are
 so fragmentary that they will  not  be considered.
                                    5-8

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5.2.1.2.1   Nickel  sensitivity and contact dermatitis.   Nickel  dermatitis and
other dermatological  effects  of  nickel  have been documented  in  both nickel
worker populations and populations at large (MAS, 1975).  Originally considered
to be a problem in occupational  medicine, the more recent clinical and epidemi-
ological picture of nickel sensitivity offers ample proof that it is a problem
among individuals  not having occupational exposure to nickel but  encountering
an  increasing  number  of  nickel-containing  commodities  in  their every-day
environment.
     There  has  been  only  one population survey using a probability sample to
determine  the  incidence or  prevalence  of this  allergic  condition  and its
clinical manifestation, contact dermatitis.  The  literature is mostly  limited
to studies  of  patient populations,  and this provides an unreliable basis for
projection to the general  population.   Patient populations in specialty clinics
are either self-selected and represent individuals who have decided that their
condition  is  severe  enough  to require  medical  care or  are those who have
access  to  medical care and  have  been referred  to  specialty  clinics.   The
perception of need for medical care for specific health problems varies signi-
ficantly by socio-demographic characteristics.   For example, a hairdresser  or
manicurist with dermatitis of the hands will seek medical care, while a factory
worker or clerical worker with the same condition may not do so simply because
there are  no  clients who  object.   The data presented here, therefore, are of
limited  value  in assessing the distribution  of sensitivity in the  general
population.
     Large-scale  surveys  (Table 5-1)  of  patient populations were  conducted  by
the International  Contact  Dermatitis  Group  (Fregert et al., 1969), The North
American Contact  Dermatitis  Group  (1973),  and  Brun in  Geneva  (Brun, 1975).
Veien et al.  (1982)  reported on  all pediatric  patients  in their clinic, 14
years or younger,  who presented  with contact dermatitis  within  a five-year
period.   Peltonen  (1979)  and Prystowsky  et  al.  (1979) departed from  the  prac-
tice of surveying patient samples  to surveying subjects more representative of
the general population.
     All of these studies found  that nickel sensitivity  is  one  of the more
common ones when  standard test  kits covering large numbers of substances are
used, or when  selected smaller numbers of allergens are  used.  Females always
show a higher positive reaction  rate than do males,  and elicitation of contact
history reveals universal  exposure  to the ubiquitous metal and its compounds.
                                   5-9

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             TABLE 5-1.   RATES OF POSITIVE REACTORS IN LARGE PATIENT AND POPULATION STUDIES
All subjects
Study and location
Fregert et al . , Europe (1969)
North American Contact
Dermatitis Group, USA and
Canada (1973)
Brun, Geneva (1975)
Peltonen, Finland (1979)
Prystowsky et al. ,
San Francisco (1979)
Veien et al., Denmark (1982)
number
4825
1200
1000
980
1158
168
percent
reactors
6.
11.
12.
4.
5.
19.
7
2
2
5
8
0
Females
number
NS*
691
NS
502
698
NS
percent
reactors number
9.9 NS
14.9 509
NS** NS
8. 0 478
9.0 460
NS NS
Males
percent
reactors
1.8
5.5
NS
0.8
0.9
NS



Percent
nickel sulfate
5.
2.
3.
5.
2.
2.
NS
0
5
0
0
5
5




adults
children


*NS - not stated
**"h1gher than men"

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     The North  American study  permits  examination of race as  a  factor in
positive reaction rates.   As  Table 5-2 shows, blacks have a higher rate than
whites, and the  females in either racial group  have higher reaction rates.
     A history of eczema is common in persons with positive reactions.  Table
5-1 shows a summary  of findings from large  scale  studies.   The finding of
particular interest is that nickel  sensitivity appears as frequent in "general"
population studies  as in patient population  studies,  and it provides  more
certainty to the finding that large segments of the population,  and females in
particular,  are at risk for this condition.
     Table 5-3 shows,  for  a range of studies, the  proportion of nickel  sensi-
tives who have a history of eczema of  the  hand and who  reacted in  kind to
testing.   This suggests  that  nickel  sensitivity is  by no means a  negligible
problem for a large proportion of those who exhibit the sensitivity.
     Spruit and  Bongaarts  (1977a) investigated the relationship  of  nickel
sensitivity to nickel  concentrations  in plasma, urine, and hair and found no
association.   The role of atopy, either personal or familial,  in nickel-sensi-
tive and nonsensitive  dermatitis  cases  was examined by Wahlberg (1975).   No
differences of rates  of personal  or familial atopy  were found for  nickel-
sensitive and nonsensitive patients with hand eczema.  All  cases were  ladies'
hairdressers;  they showed  a  positive  reaction rate  of 40 percent  to nickel
sulfate (5 percent) solution.   Wahlberg1s finding for atopy are in accord with
the earlier work by Caron (1964).
     Spruit and  Bongaarts  (1977b)  and  Wahlberg (1975) reported that positive
reaction to nickel  sulfate occurs  at very  low  dilution  levels  in  some  indi-
viduals.   Wahlberg found 5 of 14 positive reactors sensitive to <0.039 percent
nickel sulfate solution.  Spruit and Bongaarts (1977b) found one female patient
with a positive reaction when the solution was 10 ug Ni  /£.
     Edman and Mbller  (1982)  reported on a  University  of  Lund patient  popula-
tion of 8933 who had been patch tested at the University clinic over a 12-year
period.  The  authors  found  that  nickel sensitivity increased  during that
period for both male and female patients and that females had a higher rate of
positive reactions than males.
     Menne et al. (1982) reported on a stratified sample of the female popula-
tion of Denmark  surveyed by interview  in 1978.   The response  rate was 77.4
percent.   Of  those responding, 14.5  percent reported a  history  of nickel
allergy.   The authors found that the prevalence rate was highest in the younger
age groups and declined after the age of 50 (range: 16 to 99 years).   Although
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    TABLE 5-2.   NORTH AMERICAN CONTACT DERMATITIS GROUP PATCH TEST RESULTS
                  FOR 2.5 PERCENT NICKEL SULFATE IN 10 CITIES
Subjects
Black


White


All

Total
Females
Males
Total
Females
Males
Total
Females
Males

Total No.
79
64
143
612
445
1057
691
509
1200
Positive Reactions
No.
14
6
20
89
22
111
103
28
131
Percent
17.7
9.3
14.0
12.7
4.4
10.5
14.9
5.5
11.2
Source:   North American Contact Dermatitis Group (1973).
            TABLE 5-3.   HAND ECZEMA IN PERSONS SENSITIVE TO NICKEL
Author
Bonnevie (1939)
Wilson (1956)
Calnan (1956)
Fisher and Shapiro (1956)
Wagmann (1959)
Marcussen (1960)
Wahlberg and Skog (1971)
Cronin (1972)
Christensen and Moller (1975a,b)
Peltonen (1979)
Nickel
sensitive
63
85
400
40
62
621
53
84
185
44
Hand
No.
32
14
81
16
22
272
41
50
96
9
eczema
Percent
50.2
16.5
20.0
40.0
35.0
43.2
77.3
60.0
52.0
20.5
Source:  Adapted from Peltonen (1979).
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the  authors  noted that use of the interview as an investigative technique had
certain  limitations,  they believed it was  the only realistic way to obtain
data  on a  large  and  geographically  widespread population and  noted  that
their  results  were in agreement with data  obtained through more conventional
testing  (e.g., patch  testing) methods.
     The avoidance of contact with nickel  suggests itself as an obvious  pre-
ventive measure.   Kaaber  et al. (1978) reported encouraging results  in attempts
to  manage  chronic  dermatitis  by reduction of  nickel  intake  via the diet.
However, total  avoidance  of contact with nickel would be  extremely  difficult,
as  it  is commonly found  in articles  and substances found in  the home  and in
metals  used for  jewelry,  metal  fasteners of clothing, coinage, etc.   Some
preparations used  in  hairdressing contain nickel, and consequently hairdressers
exhibit  nickel  dermatitis.  The  consequences of nickel  contact  dermatitis
seems  to vary with  the  surrounding  social  factors.   Male factory workers
appear  not  to  be  handicapped  by  it  (Spruit  and Bongaarts,  1977b)  and continue
in their work; hairdressers leave their  occupation when they develop dermatitis
(Wahlberg, 1975).
     The impact of nickel dermatitis  on  the health of the total U.S. popula-
tion cannot be assessed at this time since  the prevalence of this condition in
the population  is not established.   Also,  there  are  no data  on  the  range of
severity, the consequences, and the costs of the condition.
5.2.1.2.2   Sensitivity to nickel  in prostheses.   Stainless steel, chrome,  and
other metal  alloys used  in prostheses and  other  surgical  devices frequently
contain proportions  of nickel  that  have  proved to cause reactions in patients
ranging  from  itching to dermatitis to tissue breakdown requiring replacement
of  the  device.    The  National  Academy of Sciences  report  (1975) lists the
following devices  and prostheses reported in the literature as associated with
adverse reactions  to their nickel contents:  wire suture materials, metallic
mesh for nasal  prostheses, heart valves, intrauterine contraceptive devices,
batteries for  implanted pacemakers,  alloys  for dental castings and fillings,
and orthopedic implants.
     The alloys, contrary to general assumption, appear not to be biologically
inert and produce adverse reactions in  some of the individuals  sensitive  to
nickel.   Two cases of cancer in humans at the site of steel plate implantation
were reported.  These cancers  developed  30 years after implantation in both
cases.   In both cases the alloys of the plates and screws  differed and  possibly
electrolysis and metallic corrosion may have occurred.
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     Deutman and colleagues  (1977)  reported  on metal sensitivity before and
after total hip  arthroplasty in  212 cases from their  orthopedic  service in
Groningen, The Netherlands.   They  instituted their study because they noted
that the  recent  literature  contained reports of reactions to orthopedic im-
plants which included loosening of total  joint prostheses.   The authors studied
the preoperative sensitivity  status  of 212 patients scheduled for total hip
replacement and followed up these patients to ascertain if sensitivity developed
after the insertion.   Fourteen patients were  sensitive  to one or more of three
metals tested  and  eleven  of these were sensitive  to nickel.   The allergens
used were  those  recommended by the  International  Contact  Dermatitis Group,
that is,  for  nickel  sensitivity,  a 2.5 percent nickel  sulfate solution was
employed  in the  patch test.   The past  experience with metallic appliances for
bone surgery was found  to be 173 cases without previous experience,  17 cases
with less  than total  joint replacement,  16 with total   joint replacement and
subsequent loosening and  reoperations, and six with stable McKee-Farrar pros-
theses.   Of the eleven nickel-sensitive patients,  three had previous  implants.
Histories of nickel  sensitivity showed five cases  of eczema due to jewelry  or
garters and two  cases with previous implants where the eczema appeared over
the scar  tissue  of the  site  of the  implant.   Four individuals with  positive
reaction to the nickel  allergen did not have  a previous history of eczema.   In
addition, there were five patients with a history of sensitivity but  no positive
reaction to the patch test.
     A second phase of the study consisted of 6 postoperative patch-testing of
66  of  the 198 patients  that  had  not exhibited preoperative sensitivity to
patch tests.   There were 55 women and 11 men  with an average age of 69.5 years
in this group.   Four of  these 66 showed metal sensitivity, three to nickel  and
one to cobalt.   This included one woman with  a  negative preoperative patch
test but  who had a history  of eczema from  garters  and who was positive on the
postoperative  patch  test.   None  of the 66, regardless  of sensitivity status,
had  shown pain,  loosening  of the prosthesis, infection,  or  skin symptoms
during the  postoperative period  of the study which was  approximately two
years.  This  represented  a postoperative conversion rate of 6 percent within
approximately  two years.  A sensitivity rate  of 4.6 percent to nickel by patch
test was found in  the 173 patients without previous bone surgery.
     Since the publication  of the National Academy of Sciences report, addi-
tional reports have  appeared augmenting the  list  of items which have created
sensitization  and  symptoms.
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     This special  area of exposure via nickel  in prostheses is of grave concern
to the medical  specialties  and the patients involved,  and  is manageable to
some extent by preoperative testing for sensitivity and routine elimination of
nickel alloys.
5.2.1.3   Animal Studies  of  Nickel  Sensitivity.   Useful experimental  animal
models of  nickel sensitivity have  only slowly been forthcoming and only  under
very specialized conditions.
     Nilzen and Wikstrom  (1955)  reported the  sensitization of guinea pigs to
nickel via repeated topical  application of nickel sulfate  in detergent solution.
Samitz and Pomerantz (1958), however,  have attributed this to local  irritation
rather than true allergenic response.   Samitz  et al.  (1975)  were unable to
induce sensitization in guinea pigs using any  nickel  compound from complexation
of nickel ion with  amino acids or guinea pig skin extracts.
     Wahlberg  (1976)  employed intradermal  injection  of  nickel  sulfate  in
highly sensitive guinea  pigs.   The reactions  to the  challenge  were  statis-
tically greater than  with control  animals.   Turk and  Parker  (1977) reported
sensitization  to  nickel  manifested  as allergic-type  granuloma  formation.
Sensitization  required  the  use of a split-adjuvant treatment consisting of
Freund's complete adjuvant  followed by weekly intradermal injections of  25  ug
of the salt  after  2 weeks.   Delayed hypersensitivity  reactions  developed  in
two of five  animals at 5 weeks.   Interestingly, these  workers also observed
suppression of  the  delayed  hypersensitivity when intratracheal intubation of
nickel sulfate  was  also  performed on these animals (Parker and  Turk,  1978).
     Various  attempts  to  sensitize mice to nickel have also  been described.
Moller (1984) found that, while mice could easily be sensitized to such potent
antigens  as  picryl  chloride,  response to nickel  could only be achieved by
repeated epicutaneous application of a strong  (20 percent) nickel salt solution
for a 3-week  interval.  The resulting dermatitis was moderate, as indicated by
a weak wet weight increase in inflamed skin tissue.

5.2.2  Respiratory  Effects of Nickel
     Effects of nickel in the human respiratory tract, other than carcinogeni-
city,  mainly  derive from  studies  of nickel workers  in various  production
categories who  have  been exposed to various forms  of the element.   In  the
aggregate, assessment  of  available  clinical and  animal  data show two areas  of
concern for  humans:   (1)  direct  respiratory effects such  as asthma manifested
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as either a  primary  irritation  or an allergenic response; and (2) increased
risk for  chronic respiratory tract  infections secondary to  the  effect of
nickel  on the respiratory immune system.
     The acute effects of Ni(CO). on the lung  in man and experimental animals
were summarized  earlier  (Section  5.1).  Few data are available on the chronic
respiratory effects of this  agent except for one case described by Sunderman
and Sunderman  (1961)  in  which a subject exposed to low levels of the carbonyl
developed asthma and  Loffler's  syndrome,  a condition characterized by fever,
cough,  breathlessness, anorexia,  weight loss and associated with eosinophilia
and granulomatous tissue.
     Available data on chronic noncarcinogenic effects of nickel  compounds are
mainly concerned with  the  soluble nickel  (II) sulfate employed  in electro-
plating operations and present as aerosols.  Under heavy exposure conditions,
anosmia and  severe nasal injury such as septal perforation have been commonly
observed, as well as chronic rhinitis and sinusitis (Tatarskaya,  1960;  Kucharin,
1970; Sushenko and Rafikova, 1972).
     Asthmatic lung disease in nickel-plating workers has also been documented
(To!at  et al.,  1956;  McConnell  et al., 1973;  Malo  et al. ,  1982;  Block and
Yeung,  1982;  Cirla  et al. ,  1985).  In an occupational survey report of Cirla
et al.  (1985), 14 workers studied in the nickel-plating industry had rhinitis
and/or  asthma.   Six  subjects who showed a typical  allergic  response  were
workers in  particular stages  of the plating process.  Dolovich et al.  (1984)
documented that occupational asthma in a nickel worker, as established by skin
test and  inhalation  challenge,  was  associated with  an antigenic determinant
comprised of  divalent nickel  bound to human serum at a specific copper/nickel
transport  site.   Similarly,  Novey and  co-workers  (1983)  evaluated a metal
plater exposed to nickel  sulfate who developed a biphasic asthma-like response.
Specific IgE antibodies  to nickel were also observed in the worker, leading the
authors to  believe  that  an  IgE Type  1 immunopathogenic mechanism was involved
in mediating the bronchial response.
     While  asthma  appears to  be most  recognized  in  nickel plating  operations,
asthma  has  also  been documented  in welders.   Keskinen et al. (1980) examined
seven  stainless  steel welders suffering  from  respiratory distress  during  work
and  established  that  their  distress was due  to  IgE-mediated chromium and
nickel sensitivity.
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     Numerous studies of noncarcinogenic respiratory responses in experimental
animals inhaling various  forms  of nickel have been reported.   Bingham et al.
(1972) exposed rats to aerosols of both soluble (as the chloride) and insoluble
(as the oxide)  nickel  at levels in the  region of  those acceptable for human
industrial exposure.   Hyperplasia of bronchiolar and bronchial epithelium with
peribronchial lymphocytic infiltrates was seen.   Port et al.  (1975) noted that
intratracheal injection  of  a  suspension of nickel oxide (5 mg,  < 5 |jm)  into
Syrian hamsters first treated with influenza A/PR/8 virus 48 hours previously,
significantly increased  mortality versus controls.  Surviving animals at this
dosing and lesser doses showed mild to severe acute interstitial infiltrate of
polymorphonuclear  cells  and macrophages  several  weeks  later.   Additional
pathological changes included bronchial epithelial hyperplasia,  focal  prolifera-
tive pleuritis and adenomatosis.
     Wehner and co-workers (1981) studied hamsters inhaling nickel-enriched fly
ash (aerosol, 17 or  70 ug/1)  for up  to  20 months.  Lung weights and volumes
were significantly increased in the higher (70 ug/1) fly ash  exposure groups.
The severity  of  anthracosis,  interstitial  reaction,  and bronchiolization was
dose-dependent.
                                                         3
     Rabbits  inhaling  nickel  chloride  aerosol  (0.3 mg/m  Ni)  for 30 days
showed changes  (doubling)  in  cell  number and volume of  alveolar epithelial
cells, as well as nodular accumulation of macrophages and laminated structures
(Johansson et al., 1983).   This effect pattern strongly resembled pulmonary
alveolar proteinosis.  These same workers (Johansson et al.,  1981) investigated
                                                                  3
the lung  response  in rabbits inhaling metallic nickel  dust (1 mg/m  Ni)  for 3
and 6  months.  In addition  to  responses similar  to those noted above  for
soluble nickel aerosol, the 6-month group showed pneumonia.
     A number of studies have involved the cellular toxicity of nickel  compounds
as they relate to the incidence of infections in the respiratory tract,  parti-
cularly the  impairment  of alveolar macrophage activity (Murthy et al.,  1983;
Wiernik et al. , 1983;  Lundborg  and Camner, 1982;  Casarett-Bruce  et al.,  1981;
Castranova et al.,  1980; Johansson et al., 1980;  Aranyi  et al., 1979;  Adkins
et al., 1979; Graham et al., 1975a; Waters et al., 1975).
     At 1.1  mM  nickel  ion,  rabbit alveolar macrophages show no morphological
evidence of injury but apparently lose the ability for phagocytosis (Graham et
al., 1975a).  At 4.0 mM, cell viability is reduced to approximately 50 percent
of controls (Waters et al., 1975).
     Sprigelberg .and co-workers (1984) exposed adult  Wistar  rats  to  nickel
oxide aerosols for either 4 weeks or 4 months.  Exposure levels for the short-
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term study were  50,  100,  200, 400, and 800 ug Ni /m3, while exposure levels
for the long-term study were either 25 or 150 ug Ni/m3.   Short-term effects on
alveolar macrophages Included altered size at the 100 ug Ni/m3 level, increased
phagocytic activity  (elevated to 141 percent of controls) at the 400 ug Ni/m3
level, and increased numbers of polynucleated cells, also at the 400 ug Ni/m3
level.   After 4 months of exposure, the number of macrophages was significantly
increased at 25  ug  Ni/m3,  but slowly decreased at 150 ug Ni/m3.   Increase in
size and  number  of  polynucleated  macrophages was observed at both the 25 and
           2
150 ug Ni/m   levels  and phagocytic activity increased to 130 and 230 percent
of controls,  respectively.
     Several  studies have  examined the composition of lung fluid in animals
inhaling various nickel compounds.   Pulmonary lipid composition has been shown
to be significantly altered in rabbits inhaling nickel  dust (1.7 mg/m3,  40 per-
cent respirable) resulting in a 3-fold increase in phosphatidyl choline  (Casarett-
Bruce et  al.,  1981).   Lundborg  and Camner (1982) reported  that  significant
decreases of lysozyme  had  occurred in rabbits inhaling nickel  dust or nickel
chloride after exposures to 0.1 mg/m3 of metallic nickel  and 0.3 mg/m3 chloride
salt for as little as 3 months.   Hydrolytic enzymes  in macrophages were  signi-
ficantly  reduced  in  content,  whereas  the opposite occurred in macrophages of
rats inhaling  nickel oxide (120 ug/m3) or nickel  chloride (109 ug/m3 (Murthy
et al.,  1983).
     Aranyi et  al.  (1979) demonstrated that alveolar macrophage viability,
total protein, and lactate dehydrogenase activity were significantly affected
when nickel oxide was  adsorbed  into fly ash ranging in size from less than 2
um to 8  urn.   The effect increased with increased particle loading of nickel
oxide and decreased particle size.
     As recently  discussed by Lundborg and Camner (1984), the  overall effects
of exposure to various  forms of nickel on respiratory cellular defense mecha-
nisms appear  to resemble the pathological picture  presented  by both human
pulmonary alveolar proteinosis and animals inhaling quartz dust.
     Respiratory tract  cytotoxicity of nickel  species jji vitro has also been
examined.  Dubreuil  et al. (1984) found that  treatment  of human pulmonary
epithelial cells  (line  A  549)  with nickel chloride, at levels up to 1.0 mM,
produced  a dose-dependent  decrease in  cell  growth rate,  decreased content of
ATP and  diminished viability.  The levels of nickel employed were 0.1, 0.2,
and 1.0 mM.
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5.2.3  Endocrine Effects of Nickel
     In different experimental animal species, nickel (II) ion has been shown
to affect carbohydrate  metabolism.   Bertrand and Macheboeuf (1926) reported
that the parenteral  administration of nickel  salts antagonized the hypoglycemic
action of  insulin.   Later workers  (Horak and Sunderman,  1975a  and  1975b;
Freeman and Langslow, 1973; Clary and Vignati, 1973; Kadota and  Kurita, 1955)
observed a rapid, transitory hyperglycemia after parenteral exposure  of rabbits,
rats, and domestic  fowl  to nickel  (II)  salts.   In several  reports,  Horak and
Sunderman (1975a; 1975b) noted the effects of nickel (II) on normal,  adrenalec-
tomized,  and hypophysectomized rats.   Injection  of nickel  chloride (2  or 4
fflg/kg) produced prompt elevations in plasma glucose and glucagon levels with a
return to normal  2-4  hours afterwards,  suggesting that hyperglucagonemia may
be responsible  for  the  acute hyperglycemic response to divalent  nickel (Horak
and Sunderman,  1975a).   Nickel  had  the most pronounced  hyperglycemic effect
when this element was studied in conjunction with other ions given in  equimolar
amounts (Horak  and  Sunderman,  1975b).   Concurrent administration of insulin
antagonized this  hyperglycemic effect.    Kadota  and Kurita (1955) observed
marked damage to  alpha  cells and some degranulation and  vacuolization of  beta
cells in the pancreatic islets of Langerhans.  Ashrof and Sybers (1974) observed
lysis of pancreas exocrine cells in rats  fed  nickel  acetate  (0.1 percent).
     Human endocrine responses to  nickel  have been poorly studied, although
Tseretili and Mandzhavidze (1969)  found pronounced hyperglycemia in workmen
accidentally exposed to nickel  carbonyl.
     Nickel  apparently  has an  effect on the hypothalamic  tract  in  animals,
enhancing the release of prolactin-inhibiting  factor (PIF) thereby decreasing
the release of  prolactin  from bovine and  rat  pituitary  glands  (La Bella et
al. ,  1973a).   Furthermore, intravenous administration  of  small amounts  of
nickel to urethane-anesthetized,  chlorpromazine-treated rats produces  signifi-
cant depression  of  serum  prolactin  without any  affect on  growth hormone or
thyroid-stimulating hormone.   The jm vitro release of pituitary hormones other
than PIF have been demonstrated for bovine and rat pituitary (La Bella et al.,
1973b).  In a more recent  study,  subcutaneous injection of nickel chloride (10
or 20 mg/kg) into rats first produced a drop in serum prolactin over the short
term, but resulted in a sustained elevation of the hormone  after 1 day, lasting
up to  4 days (demons and  Garcia, 1981).   Elevation was  due to  reduced levels
of prolactin-inhibiting factor.  A recent study by Carlson  (1984), demonstrating
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that nickel  (II)  antagonizes the stimulation of  both  prolactin and growth
hormone by barium (II), suggests that the basis  of antagonism may be competitive
inhibition of calcium uptake.
     Dormer and coworkers  (1973;  1974)  have studied the In vitro effects of
nickel  on secretory systems,  particularly the release of amylase, insulin,  and
growth hormone.   Nickel (II)  was seen to be a potent inhibitor of secretion in
all three  glands:   parotid (amylase),  islets of  Langerhans (insulin), and
pituitary (growth hormone).   Inhibition  of growth hormone release at nickel
levels comparable to  those which  La Bella et al.  (1973b) observed to enhance
release,  may reflect differences in  tissue handling prior to assay.   Dormer et
al. (1973)  suggested that nickel  may block exocytosis  by interfering with
either secretory-granule migration or membrane fusion and microvillus formation.
     Effects of nickel on thyroid  function have  been noted by Lestrovoi  et  al.
(1974).  Nickel chloride  given  orally to rats (0.5-5.0 mg/kg/day, 2-4 weeks)
or by inhalation (0.05-0.5 mg/m )  significantly  decreased iodine uptake by  the
thyroid,  such an effect being more pronounced for  inhaled nickel.

5.2.4  Cardiovascular Effects of Nickel
     Recent studies,  mainly  involving experimental  animal  models,  indicate
that exogenous nickel (II) ion,  under j_n vivo, ex  vivo,  and HI vitro conditions,
has a  number  of  effects on the heart,  including  coronary  vasoconstriction,
myocardial depression, and subcellular injury.
     Ligeti and co-workers (1980) reported  that administration of nickel (II)
ion at rather low levels (20  ug/kg body weight)  to anesthetized dogs induced a
significant decrease  of  coronary  vascular conductance.   Higher nickel  dosing
(200,  2000, and 20,000 ug/kg b.w.) caused  further  reduction of coronary blood
flow and depression of heart  rate  and left ventricular  contractility.  Reduction
of coronary blood flow was determined as arising from local action on coronary
vessels.
     Rubanyi and Kovach  (1980)  observed that low  levels of nickel (II) (0.01
to 1.0 uM) in the perfusate of the isolated rat  heart increased coronary tone,
while higher doses of the element  depressed myocardial  contractile performance.
In related work, Rubanyi  et al. (1981) found that:   (1) endogenous nickel was
released  from  ischemic myocardium of dogs  and  rats using a nickel-complex
cytochemical method, (2) exogenous nickel in amounts equivalent to that released
endogenously induced  coronary vasoconstriction in  both  the rat and dog heart,
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and (3) the cytochemical  method  was  not affected by  tissue  autolysis.   The
basis of this vasoconstrictive activity appeared to involve a calcium-dependent
mechanism (Keller et a!.,  1982).   As  a follow-up to  their earlier studies,
Rubanyi and co-workers  (1984)  evaluated the effect of nickel on the j_n situ
heart of anesthetized open-chest dogs.   Soluble nickel (NiCl») was administered
either intravenously (20 ug Ni/kg bolus injection) or via intracoronary infusion
(40 pg Ni/min/kg).  Rubanyi and  co-workers  found  that exogenous nickel at the
reported levels of administration  induced coronary vasoconstriction by direct
action on coronary  vessels.   This  vasoconstriction was  induced when coronary
arteries were dilated by  low flow  ischemia, arterial  hypoxemia, and adenosine
infusion.    In  addition,  nickel  inhibited  vasorelaxation and postocclusion
reactive hyperemia  in  response to arterial hypoxemia or infused  adenosine.
The authors postulated  that vasoactivity might be related  to  the existence  of
positive feedback  loops  triggered by  alterations in the  level of nickel.
     The release of endogenous nickel  from damaged tissue and its  implications
for ischemic heart disease as  described above have been  examined in regard  to
the pathology  of  acute  carbon monoxide poisoning  and  acute burn  injury.
According to Balogh et al. (1983),  significant amounts of nickel were detected
in autopsied heart  muscle of  human carbon monoxide poisoning victims or rats
and dogs experimentally intoxicated with  the agent when  the  Co-Hb fraction
exceeded 30 percent.  Rubanyi  et al.  (1983) demonstrated that acutely burned
rats showed significant accumulation  of nickel  in myocardium.  In  addition,
focal myopathy, as characterized by intracellular edema,  ruptured sarcoplasmic
reticulum,  and  swelling/vacuolization  of  mitochondria with ruptured cristae,
was also seen  in  this  tissue.    Isolated, perfused heart  from burned animals
showed significantly greater  total coronary vascular resistance in terms of
exogenous perfused nickel concentration when compared to controls  at levels as
low as 0.01 |jM.
     Human data relating  nickel  to the pathogenesis of cardiovascular disease
states are  meager.  As  noted above, Balogh  et al. (1983)  observed  significant
nickel accumulation  in  postmortem myocardium  of carbon  monoxide victims,
paralleling the observation in experimental animals.   Leach et al.  (1985) have
noted  that  elevated  serum nickel in  patients with myocardial infarction does
not relate  to  nickel  exposure differences  or to  the  biochemical indicators,
serum CK or LDH activities, suggesting that hypernickelemia may be involved in
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the pathogenesis of ischemia myocardial injury.   The existence of hypernickel-
emia in burn patients (see Chapter 4) and other traumatic states parallels the
experimental data of  Rubanyi  et al.  (1983), who studied acutely burned rats.
     The above  experimental  and clinical  observations suggest that exogenous
nickel  (II) ion, and possibly endogenous nickel  (II), has a marked vasoconstric-
tive action on  coronary  vessels which could synergize the adverse effects of
the primary ischemic  lesion.   Vasoconstrictive  action of nickel may be more
broadly operative in  humans.  As  noted  in Chapter 4, the  huge transitory  rise
in serum nickel attending childbirth may likely be  related to a minimizing of
atonic bleeding.  Whether excessive  nickel  exposure in occupational or non-
occupational populations exacerbates  ischemic  heart disease or enhances  the
risk of  myocardial  infarction  in subjects  with  coronary artery disease  is
unknown.    The presently  available literature on mortality and  morbidity  of
nickel  workers  for  noncarcinogenic  end points,  specifically coronary artery
disease,  does not permit any conclusions on the matter, but the issue merits
further study.   Such study  should  also include populations  living  in  the
proximity of nickel  operations.
     Nickel subsulfide administered intrarenally in rats (5 mg/animal) induced
arteriosclerotic lesions which  were  determined  by inspecting hematoporphyrin
derivative-injected arteries  under  ultraviolet  light (Hopfer et al. , 1984).
Based upon  various  measurements of the  chemical constituents of serum, it was
determined that the observed arteriosclerosis  was not associated with hyper-
tension and hyperlipidemia.

5.2.5  Renal Effects of Nickel
     Nickel-induced nephropathy in man or animals has not been widely documen-
ted.   Acute renal  injury with proteinuria and hyaline  casts was observed by
Azary (1879)  in cats and dogs given nickel  nitrate.  Pathological lesions of
renal tubules and glomeruli  have  been  seen  in rats  exposed to nickel carbonyl
(Hackett and  Sunderman,  1967; Sunderman et al., 1961; Kincaid et al., 1953).
Gitlitz et  al.  (1975) observed aminoaciduria and proteinuria  in  rats after
single intraperitoneal injection  of  nickel  chloride, the extent of the renal
dysfunction being dose-dependent.   Proteinuria  was observed at a  dose  of 2
mg/kg, while  higher dosing  occasioned aminoaciduria.  Ultrastructurally,  the
site of  the effect within the  kidney  appears  to be glomerular epithelium.
These renal effects were seen to  be  transitory, abating by the  fifth day.   In
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rabbits,  Foulkes and Blanck (1984)  found that the nephrotoxic action of injected
nickel  salt (NiCK,  20  umol/kg)  was selective,  being associated with reduced
reabsorption of aspartate and having no effect on either glucose or cycloleucine
reabsorption.
     In man, nephrotoxic  effects of nickel  have been clinically detected in
some cases of  accidental  industrial  exposure to nickel  carbonyl (Carmichael,
1953; Brandes,  1934).  These effects are manifested as renal  edema with hyper-
emia and parenchymatous degeneration.

5.2.6  Other Toxic Effects of Nickel
     Nickel compounds  appear to possess  low neurotoxic potential  save for
fatal acute exposures  to nickel  carbonyl (NIOSH,  1977;  NAS,  1975).   Neural
tissue lesion  formation in the  latter  case  is  profound, including  diffuse
punctate hemorrhages in cerebral, cerebellar, and brain stem regions, degener-
ation of neural fibers, and marked  edema.
     Intrarenal injection  of  nickel  subsulfide  in rats  elicits a  pronounced
erythrocytosis (Hopfer et al., 1980; Hopfer and Sunderman, 1978; Morse et al.,
1977; Jasmin and Riopelle, 1976).  Morse et al.  (1977) showed that the erythro-
cytosis is dose-dependent, is not elicited by intramuscular administration and
is associated  with  marked erythroid hyperplasia of  bone marrow.   Hopfer and
Sunderman  (1978) observed a marked inhibition of erythrocytosis when manganese
dust was co-administered.  Sunderman et al.  (1984) surveyed the erythrocytogenic
potential  of 17  nickel  compounds given  intrarenally  to  rats (7 mg/animal).
Erythrocytosis was induced by nine of the agents: NiS, p-NiS, orNioSp, Ni^FeS^,
NiSe,  Ni'3Se2,  NiAsS, NiO,  and Ni  dust.  Rank  correlation  (p <0.0001) was
obtained between erythrocytosis and renal cancers.
     The effects of  nickel chloride on the cellular and  humoral immune responses
of mice have been studied (Smialowicz et al., 1984; Smialowicz, 1985).  Natural
killer (NK) cells, lymphocytes thought to be one of the  first lines  of nonspe-
cific  defense  against  certain types of  infection and tumors, were seen to be
significantly  suppressed  in activity within 24 hours of  a single intramuscular
injection  of NiCl2  (18.3 mg/kg)  into mice.   Nickel  chloride  was also shown to
significantly  decrease the percentage of T lymphocytes observed in the spleens
of treated mice (P  < 0.05).   The results confirmed the  works of others on the
immunosuppressive effects of  nickel on circulatory antibody titers to T! phage
(Figoni and Treagan, 1975), on antibody  response to sheep erythrocytes (Graham
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et al., 1975b), on  interferon  response  of cells treated i_n vivo (Treagan and
Furst, 1970),  and on the  susceptibility  to  pulmonary infections following
inhalation (Adkins et al., 1979).   Of  particular importance were the effects
on NK cells in light of their possible  relation to tumor development.
5.3  INTERACTIVE RELATIONSHIPS OF NICKEL WITH OTHER FACTORS
     Both antagonistic  and synergistic  interactive  relationships  have been
demonstrated for both nutritional factors and other toxicants.
     Co-administration of  high  doses  of vitamin C to the weanling rat offset
the effects of oral nickel exposure on growth rate, as well as the activity of
certain enzymes, such  as  liver and kidney succinic  dehydrogenase  and liver
glutamic-oxaloacetic transaminase  (Chatterjee et  al.,  1980).   According to
Hill (1979),  dietary protein  antagonizes the  effect  of  dietary  nickel  (as  the
chloride, 400  or 800  ppm) on retarding  growth  in chicks over the range of
10-30 percent protein.
     Ling and Leach (1979) studied element interaction  in diets containing 300
mg/kg of  nickel  and 100 mg/kg of iron, copper, zinc, and cobalt.   Indices of
toxicity  were growth rate, mortality,  and anemia.  The lack of interaction
among  these elements and  nickel  is  in contrast  to  a protective  effect of
nickel  for  the adverse effects  of  copper  deficiency (Spears and  Hatfield,
1977).   Presumably,  the existence  of  any interactive mechanism  is  overwhelmed
at  large  levels of agents  employed in the  former  study.
     Using  lethality  of  injected  NiCl2 (95 or 115  umol/kg)  in rats as an
effect  index, Waalkes et al.  (1985) demonstrated  that co-administration of zinc
(II)  (multiple  doses,  300 umol/kg)  at different times significantly  increased
the 14-day  survival rate.   Administration of  zinc  (II) offset the extent
of  renal  damage and hyperglycemia seen  in animals exposed solely to  nickel
(II).   This protective action did not  appear to  be  associated with  induction
of  metallothionein, nor did it  alter  the excretion/distribution of the element.
     According  to  Nielsen (1980),  there is a nutritional  interaction  between
iron  and nickel in the rat which depends  on  the  state  (valence) and level of
iron  in the diet.   Nickel supplementation  offset reduced hemoglobin  and hema-
tocrit  values in iron-deprived  rats when the  ferric  ion was employed,  but  less
so  when divalent-trivalent iron mixtures  were  used.   It is possible that  the
enhanced absorption of the  trivalent iron was directly  related  to  nickel.
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     Divalent nickel appears  to  antagonize  the digoxin-induced arrythmias in
intact and  isolated  hearts  of rats,  rabbits, and  guinea  pigs,  doing so by
either binding competition with calcium ion at cell membranes or provoking an
increase in malic and oxaloacetic acid activity (Prasad et al.,  1980).
     Pretreatment of rats with nickel  (6 mg  Ni/kg,  i.p.,  3 daily doses)  reduced
the  level  of enzymuria, proteinuria, and aminoaciduria  in rats exposed to
cadmium  ion  (6  mg Cd/kg,  i.m.,  single  dose) (Tandon et  al.,  1984).   This
protection  occurred  without altering cadmium  excretion  or accumulation in
liver and kidney.
     In a study on  the effect of nickel chloride on natural  killer (NK) cell
activity (Smialowicz, 1985), the authors also tested for  the  effects of  manga-
nese chloride.   Unlike nickel  chloride,  manganese chloride was  found to  enhance
NK cell activity,  and this enhancement was associated with increased levels of
circulating  interferon.  The authors reported that the manganese chloride had
an antagonistic effect  on NiCl2-induced suppression of NK cell  activity which
might provide important clues  to understanding the  antagonism of manganese for
nickel-induced carcinogensis.
     Nickel  ion combined with  benzo(a)pyrene enhanced the morphological  trans-
formation frequency  in  hamster  embryo  cells over that seen with either  agent
used alone  (10.7  percent,  verses  0.5 percent and 0.6 percent for nickel and
benzo(a)pyrene,  respectively)  at levels of 5 ug/ml nickel salt and 0.78 ug/ml
benzo(a)pyrene.    Futhermore,  in  a mutagenesis  system using  hamster embryo
cells, as described  by  Barrett  et al.   (1978), a co-mutagenic effect between
nickel sulfate and benzo(a)pyrene has also been observed  (Rivedal and Sanner,
1980; 1981).  These observations,  supported  by co-carcinogenic  effects  between
nickel compounds  and certain  organic  carcinogens (Toda,  1962;  Maenza et al.,
1971; Kasprzak et al.,  1973),  are of  considerable importance  in evaluating the
enhancing effect  of cigarette smoke on the incidence of lung cancer in nickel
refinery workers (Kreyberg, 1978).
                                   5-25

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5.4  REFERENCES
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Balogh, I.; Somogyi,  E. ;  Sdtonyi,  P.; Pogatsa, G. ; Rubanyi,  G. ; Bell us, E.
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Brun, R.  (1975) Statistique des tests epicutanes positifs de 1,000 cas d1eczema
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Burckhardt, W. ; Beitrage  zur  ekzemfrage  III.  (1935)  Mitteilung.  Die  Rolle  der
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Calnan, C.  D.  (1956) Nickel dermatitis.  Br. J. Dermatol. 68: 229-236.

Carlson,  H. E. (1984)  Inhibition  of prolactin and growth  hormone secretion by
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Carmichael, J. L.  (1953)  Nickel  carbonyl poisoning.  Report of a case. Arch.
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Castranova, V.; Bowman,  L. ;  Reasor, M.   J. ;  Miles,  P.  R.  (1980)  Effects  of
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Chatterjee, K. ; Chakarborty,  D. ;  Majumdar,  K. ;  Bhattacharyya,  A.; Chatterjee,
     G. (1980) Biochemical studies  on nickel  toxicity in weanling rats: influ-
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Christensen, 0. B.; Moller, H. (1975a) Nickel allergy and hand eczema. Contact
     Dermatitis 1:  129-135.

Christensen, 0. B. ;  Holler,  H.  (1975b)  External  and internal  exposure to  the
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Christensen,  0.  B.; Lagesson, V.  (1981) Nickel concentration of blood  and
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Christensen, 0. B.; Kristensen, M.  (1982) Treatment with disulfuram  in chronic
     nickel hand dermatitis. Contact Dermatitis 8: 59-63.

Christensen, 0. B.; Lindstrom, C.;  Lofburg, H.; Moller, H.  (1981) Micromorpho-
     logy  and  specificity of  orally induced flare-up reactions  in  nickel-
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Cirla, A.  M.; Bernabeo,  F. ;  Ottoboni,  F. ; Ratti, R.  (1985) Nickel-induced
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Clary, J.  J.;  Vignati, I. (1973)  Nickel  chloride-induced changes in glucose
     metabolism in the rat. Toxicol. Appl. Pharmacol. 25: 467-468. Abstr.  #75.

demons,  G. K. ;  Garcia, J. F. (1981) Neuroendocrine effects of acute nickel
     chloride  administration  in  rats.  Toxicol. Appl. Pharmacol.  61:  343-348.


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Cronin, E.  (1972) Clinical prediction on patch test results. Trans. St. John's
     Hosp.  Dermatol.  Soc. 58: 153-162.

Cronin, E.  ; DiMichiel,  A.  D. ;  Brown, S.  S.  (1980)  Oral  challenge in  nickel-
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     Jr.,   eds. Nickel  Toxicology.  New York, NY:  Academic Press;  pp. 149-152.

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     influencing nickel dermatitis. I. Contact Dermatitis 4: 142-148.

Deutman, R. ;  Mulder, T.  J. ;  Brian, R. ; Water, J. P. (1977) Metal sensitivity
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Dormer, R.  L. ; Ashcroft,  J.  H.  (1974) Studies on the  role of calcium ions  in
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Dormer, R.  L. ; Kerbey,  A.  L.;  McPherson, M.; Manley,  S.; Ashcroft, S. J. H.;
     Schofield, J. G. ;  Randle, P.  J.  (1973)  The  effect of  nickel  on secretory
     systems.   Studies  on the release of amylase, insulin, and growth hormone.
     Biochem.  J.  140:  135-142.

Dubreuil,  A.;  Bouley,  G.; Duret,  S.; Mestre, J.-C.; Boudene, C. (1984) In vitro
     cytotoxicity of  nickel  chloride  on  a human pulmonary  epithelial  cell
     line  (A 549).  Arch. Toxicol. Suppl. 7: 391-393.

Edman, B. ; Mb'ller, H.  (1982) Trends  and  forecasts  for  standard  allergens  in a
     12-year patch test material.  Contact Dermatitis 8: 95-104.

Epstein, S. (1956) Contact dermatitis due to nickel and chromate. Arch. Dermatol.
     73: 236-255.

Figoni, R.  ; Treagan, L.  (1975)  Inhibition effect of nickel and chromium upon
     antibody response  of  rats  to immunization with Tt  phage.  Res. Commun.
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Fisher, A.  A.  (1977) Allergenic dermatitis  presumably  due  to metallic foreign
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Fisher, A.  A.; Shapiro,  A.  (1956) Allergic  eczematous contact dermatitis due
     to metallic nickel. JAMA J.  Am. Med. Assoc.  161:  717-721.

Forman,  L.;   Alexander,  S.  (1972)  Nickel  antibodies.   Brit.  J.   Dermatol.
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Foulkes, E. C.; Blanck, S. (1984) The selective action of nickel  on tubule  function
     in rabbit kidneys.  Toxicology 33: 245-249.

Freeman, B. M.; Langslow, D.  R.  (1973) Responses of plasma glucose, free fatty
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     Comp.  Biochem.  Physio!.  A46:  427-436.

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Fregert, S.;  Jharth, N.; Magnusson, B.; Bandmann, H. -J.; Calnan, C. D. ; Cronin,
     E.; Malten,  K.;   Menghin,  C.  L. ;  Pin'a,  V.;  Wilkenson, D.  A.  (1969)
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Gimenez-Camarasa,  J. M.;  Garcia-Calderon,  P.; Asensio,  J. ;  deMoragas,  J,  M.
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     titis. Br.  J. Dermatol. 92: 9-15.

Gitlitz, P.  H.;  Sunderman,  F.  W. , Jr.; Goldblatt,  P. J. (1975) Aminoaciduria
     and proteinuria in  rats after a single  intraperitoneal  injection of  Ni
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Graham,  J. A.; Gardner,  D.  E. ;  Miller,  F.  J.;  Daniels,  M.  J.;  Coffin,  D.  L.
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Horak,  E. ; Sunderman,  F.  W., Jr. (1975a) Effects  of Ni  (II),  other divalent
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Hutchinson, F.;  Raffle, F. J.; MacLeod, T. M. (1972) The specificity of  lympho-
     cyte transformation j_n vitro by nickel salts in nickel sensitive subjects.
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Hutchinson, F.; MacLeod,  J.  M.;  Raffle,  E.  J.  (1975)  Nickel  hypersensitivity.
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Jordan, W. P., Jr.;  Dvorak, J.  (1976)  Leukocyte  migration inhibition assay
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Jordan, W. P.; King, S. E.  (1979) Nickel  feeding  in  nickel-sensitive patients
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Keskinen, H. ;  Kalliomaki,  P.  L. ,  Alanko,  K.  (1980)  Occupational  asthma due to
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     secretion is  specifically inhibited  by  nickel. Nature (London)  245: 331-332.

LaBella, F. ;  Dular,   R. ;  Vivian,  S.;  Queen, G.  (1973b)  Pituitary hormone
     releasing or  inhibiting  activity of metal  ions  present in  hypothalamic
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Leach, C. N. Jr.;  Linden, J.; Hopfer, S.  M.; Crisostomo, C.;  Sunderman,  F. W.,
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Lestrovoi,  A.  P.;  Itskova, A.  I.;  Eliseev,  I.  N.  (1974) Effect  of nickel  on
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Ligeti,  L. ;  Rubanyi,  G.;  Kaller,  A.;  Kovach, A.  G.  B.  (1980) Effect  of nickel
     ions on  hemodynamics, cardiac  performance  and coronary  blood  flow in
     anesthetized  dogs.  In: Anke,  M. ;  Schneider,  H.-J.;  Bruckner, C.;  eds. 3.
     Spurenelement-Symposium:  Nickel. Pp. 117-122.

Ling, J. R.; Leach, R. M. (1979) Studies  on  nickel metabolism interaction  with
     other mineral elements. Poult. Sci.  58: 591-596.

Lundborg, M.;  Camner,  P.  (1982) Decreased level  of  lysozyme  in  rabbit  lung
     lavage fluid  after inhalation of low nickel  concentrations.  Toxicology
     22: 353-358.

Lundborg, M.; Camner, P. (1984) Lysozyme  levels in rabbit lung after inhalation
     of nickel, cadmium, cobalt and copper chlorides.  Environ. Res. 34: 335-342.

MacLeod, T. M.;  Hutchinson,  F. ; Raffle,  E.  J.  (1976)  The leukocyte  migration
     inhibition test  in allergic  nickel  contact dermatitis.  Br. J.  Dermatol.
     94: 63-64.
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Maenza, R. M.; Pradhan, A. M.; Sunderman, F. W. , Jr. (1971) Rapid induction  of
     sarcomas in  rats  by  combination of nickel  sulfide  and 3,4-benzypyrene.
     Cancer Res.  31: 2067-2071.

Malo, J.-L;  Cartier,  A.; Doepner, N. ;  Niebohr,  E.;  Evans, S.;  Dolovich,  J.
     (1982)  Occupational  asthma caused  by  nickel  sulfate.  J.  Allergy Clin.
     Immunol. 69: 55-59.

Malten, K.  E. ;  Spruit, D. (1969) The relative  importance of various environ-
     mental  exposures  to nickel  in causing contact  hypersensitivity.  Acta
     Derm. Venereol. 49:  14-19.

Marcussen, P. V.  (1957) Spread of nickel dermatitis. Dermatologica  115:  596-607.

Marcussen, P. V.  (1960) Ecological considerations  on nickel dermatitis.  Br.  J.
     Ind.  Med. 17:  65-68.

McConnell,  L. H.;  Fink,  J.  N.;  Schlueter,  D.  P.;  Schmidt,  M.  G.  (1973) Asthma
     caused by nickel  sensitivity. Ann.  Intern. Med. 78: 888-890.

Menne, T.;  Thorboe, A. (1976) Nickel dermatitis  - nickel  excretion.  Contact
     Dermatitis 2:  353-354.

Menne, T. ;  Borgan,  0. ; Green,  A.  (1982) Nickel allergy and hand dermatitis in
     a stratified  sample  of the Danish  female population:  an epidemiological
     study  including a statistic  appendix.  Acta Derm. Venereol. 62:  35-41.

Millikan,  L.  E.;  Conway,  F.;  Foote,  J.  E.  (1973)  In  vitro  studies  of  contact
     hypersensitivity:  lymphocyte transformation  Tn  nickel sensitivity.  J.
     Invest. Dermatol. 60: 88-90.

Moller, H.  (1984) Attempts  to  induce contact  allergy  to nickel  in  the mouse.
     Contact Dermatitis 10:  65-68.

Mond,  L.;  Langer, C.;  Quincke, F.  (1890) Action of carbon monoxide on nickel.
     J. Chem. Soc.  57: 749-753.

Morse, E.  E. ;  Lee, T.  Y.; Reiss, R.  F.; Sunderman, F. W.,  Jr.  (1977) Dose-re-
     sponse  and  time-response  study  of  erythrocytosis  in rats  after intrarenal
     injection of  nickel  subsulfide.  Ann.  Clin.  Lab.  Sci.  7:  17-24.

Murthy,  R.  C.;  Barkley,  W.;  Hollingsworth,  L.; Bingham, E. (1983) Enzymatic
     changes  in  alveolar macrophages of rats  exposed to lead  and  nickel  by
     inhalation.  J.  Am. Col.  Toxicol. 2:  193-199.

National  Academy of Sciences  (1975)  Nickel.  Washington, DC:  National  Academy
     of Sciences.

National  Institute for Occupational Safety and Health. (1977) Special occupa-
     tional  hazard review for  nickel  carbonyl.  Cincinnati, OH:  Department of
     Health,  Education and  Welfare,  National  Institute for Occupational  Safety
     and  Health;  publication no.  DHEW (NIOSH) 77-184.

Nielsen,  F.  H.  (1980)  Effect of form of iron on the interaction between nickel
     and  iron in  rats:  growth and blood parameters.  J. Nutr.  110: 965-973.

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Nilzen, A.; Wikstrom, K. (1955) The influence of lauryl sulphate on the  sensi-
     tization of  guinea pigs  to  chrome  and  nickel. Acta  Derm.  Venereol.
     35:  292-299.

Nordlind, K. ; Henze,  A.  (1984) Stimulating effect  of mercuric chloride and
     nickel sulfate on DNA synthesis of thymocytes and peripheral blood  lymphocytes
     in children.   Int. Arch. Allergy Appl. Immunol.  73: 162-165.

North American Contact Dermatitis Group.  (1973) Epidemiology of contact  derma-
     titis in North America:  1972. Arch.  Dermatol. 108: 537-540.

Novey, H. S.; Habib, M.; Wells, I. D. (1983) Asthma  and IgE antibodies induced
     by  chromium  and  nickel  salts.   J.  Allergy  Clin.  Immunol. 72:  407-412.

Olerud, J. E.; Lee, M. Y.; Uvelli, D. A.; Goble, G.  J.; Babb,  A.  L. (1984)  Pre-
     sumptive  nickel  dermatitis  from  hemodialysis.   Arch.  Dermatol. 120:
     1066-1068.

Parker, D.; Turk, J. L. (1978) Delay in the development of  the allergic  response
     to  metals  following  intratracheal  instillation. Int.  Arch.  Allergy  Appl.
     Immunol. 57:  289-293.

Peltonen,  L.  (1979) Nickel  sensitivity in the general population.  Contact
     Dermatitis 5: 27-32.

Port,  C.  D. ;  Renters,  J.  D.  ;  Ehrlich,  R. ;  Coffin,  D.  L.;  Gardner,  D. (1975)
     Interaction  of nickel   oxide  and   influenza  infection in  the  hamster
     (abstract). EHP Environ. Health Perspect. 10: 268.

Prasad,  C.  M. ;  Nair,  K. C. ; Sheth,  U.  K. (1980)  Reversal  of digoxin induced
     cardiac  arrhythmias by  nickel  chloride. Res.  Commun. Chem.  Pathol.
     Pharmacol.  27: 405-408.

Prystowsky,  S.  D.;  Allen,  A. M. ; Smith,  R. W.; Nonomura, J. H.;  Odom, R.  B.;
     Akers, W. A.  (1979) Allergic contact hypersensitivity  to  nickel, neomycin,
     ethylenediamine, and benzocaine. Arch. Dermatol.  115:  959-962.

Rivedal,  E. ;  Sanner,  T.  (1980) Synergistic  effects  on morphological  transfor-
     mation  of  hamster embryo  cells by  nickel sulfate and benzo(a)pyrene.
     Cancer  Lett.  8: 203-208.

Rivedal,  E. ; Sanner, T. (1981) Metal salts as promoters of  i_n  vitro morphologi-
     cal  transformation of  hamster embryo cells  indicated  by  benzo(a)pyrene.
     Cancer  Res. 41: 2950-2953.

Rubanyi,  G.;  Kovach,  A. G.   B.  (1980) The effect of  nickel  ions  on cardiac
     contractility, metabolism and  coronary flow in the  isolated rat heart.
     In:  3.  Anke,  M.;  Schneider,  H.-J.;  Bruckner, C., eds. 3.  Spurenelement-
     Symposium:  Nickel. Pp.   111-115.

Rubanyi,  G.; Ligeti, L.; Koller, A.  (1981) Nickel is released  from the ischemic
     myocardium and contracts coronary  vessels by a  Ca-dependent  mechanism.  J.
     Mol. Cell.  Cardiol. 13:  1023-1026.
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Rubanyi, G.; Szabo,  K.;  Balogh,  I.; Bakos, M. ; Gergely, A.; Kovach, A. G. B.
     (1983) Endogenous nickel release as a possible cause of coronary vasocon-
     striction and myocardial  injury in acute burn of rats. Circ. Shock 10:
     361-370.

Rubanyi, G.; Ligeti,  L.;  Keller, A.;  Kovach,  A. G.  B.  (1984)  Possible  role of
     nickel ions  in  the pathogenesis  of  ischemic  coronary  vasoconstriction in
     the dog heart.   J. Mol. Cell.  Cardiol. 16: 533-546.

Rudzki, E.; Grzywa,  Z.  (1977)  Exacerbation of nickel  dermatitis by margarine.
     Contact Dermatitis 3: 344.

Samitz, M. H.;  Pomerantz, H. (1958)  Studies  of  the effects on  the  skin  of
     nickel and chromium  salts. Arch. Ind. Health 18: 473-479.

Samitz, M. H.;  Katz, S.   A.  (1975) Nickel  dermatitis hazards from  prostheses.
     Jjn vivo and  i_n  vitro solubilization  studies.  Br.  J.  Dermatol.  92:  287.

Samitz, M. H. ;  Katz,  S. A.;  Schneiner,  D.  M.; Lewis,  J.  E.  (1975) Attempts to
     induce sensitization in guinea pigs  with nickel  complexes. Acta Derm.
     Venereol.  (Stockholm) 55: 475-480.

Sjbborg, S.; Andersson, A.;  Christensen,  0.  B. (1984)  The  Langerhans cells in
     healed patch test reactions,  before and after oral  administration  of
     nickel.  Acta Dermatol.  Venereol. Suppl.  Ill: 1-23.

Smialowicz, R.  J. (1985)  The effect of nickel and manganese on natural  killer
     cell  activity.  In: Brown, S.  S.; Sunderman,  F.  W.,  Jr.,  eds.  Progress in
     nickel toxicity. Oxford, England: Blackwells Ltd.; pp. 161-164.

Smialowicz, R.  J.;  Rogers,  R. R. ;  Riddle, M. M.; Stott, G. A.  (1984)  Immuno-
     logic effects of  nickel: I.  Suppression  of cellular and humoral immunity.
     Environ.  Res. 33: 413-427.

Spears, J. W. ;  Hatfield,  E. E.  (1977)  Role of nickel  in  animal nutrition.
     Feedstuffs 49:   24-28.

Spiegelberg, Th. ; Kordel, W. ; Hochrainer, D.  (1984)  Effects of  NiO inhala-
     tion  on  alveolar macrophages  and the humoral immune  systems of  rats.
     Ecotoxicol.  Environ.  Saf. 8:  516-525.

Spruit, D.; Bongaarts, P. J. M.  (1977a)  Nickel  content of plasma, urine and
     hair  in contact  dermatitis.  Dermatologica 154: 291-300.

Spruit, D.; Bongaarts, P. J. M.  (1977b)  Nickel  content of plasma, urine and
     hair  in  contact dermatitis.  In:  Brown,  S.S.,  ed.  Clinical  chemistry and
     chemical toxicology  of metals. Amsrerdam, The Netherlands: Elsevies; pp.
     261-264.

Sunderman, F. W.  (1970) Nickel poisoning. In: Sunderman, F. W.; Sunderman, F.
     W.,  Jr.,  eds.  Laboratory diagnosis  of  diseases caused by toxic agents.
     St.  Louis, MO:  Warren H.  Green;  pp.  387-396.

Sunderman,  F.  W.; Sunderman, F.  W. ,  Jr.  (1961)  Loffler's  syndrome associated
     with  nickel  sensitivity.  Arch.  Intern.  Med.  107:  405-408.

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Sunderman,  F.  W.;  Range,  C.  L.; Sunderman,  F.  W.,  Jr.; Donnelly,  A.  J.;
     Lucyszyn, G. W.  (1961) Nickel  poisoning. XII.  Metabolic and pathologic
     changes  in acute  pneumonitis from nickel carbonyl. Am.  J. Clin. Pathol.
     36: 477-491.

Sunderman,  F.  W. ,  Jr.  (1977) The metabolism  and toxicology  of nickel.  In:
     Brown, S.S., ed.  Clinical  chemistry and  chemical  toxicology of metals.
     Amsterdam, The Netherlands: Elsevier; pp. 231-259.

Sunderman,  F.W., Jr.;  McCully,  K.S.; Hopfer,  S.M. (1984) Association between
     erythrocytosis and  renal  cancers in rats following intrarenal  injection
     of nickel compounds.  Carcinogenesis 5: 1511-1517.

Sushenko, 0.  V.;  Rafikova, K.  E.  (1972)  Questions of  work  hygiene in hydro-
     metallurgy of copper,  nickel and cobalt  in  a sulfide ore.  Gig.  Tr.  Prof.
     Zabol. 16: 42-45.

Svejgaard,  E.;  Morling,  N. ; Svejgaard, A.;  Veien,  N.  K. (1978)  Lymphocyte
     transformation induced  by  nickel  sulphate:  an HI  vitro study of subjects
     with  and without a  positive nickel patch  test.  Acta  Derm.   Venereol.
     58: 245-250.

Tandon, S.  K. ;  Khandelwal, S. ;  Mathur, A.  K. ; Ashquin,  M.  (1984) Preventive
     effects  of  nickel on  cadmium  hepatotoxicity and  nephrotoxicity.  Ann.
     Clin.  Lab. Sci.  14:  390-396.

Tatarskaya, A. A.  (1960) Occupational disease of upper  respiratory tract in
     persons  employed  in  electrolytic nickel   refining departments.  Gig.  Tr.
     Prof. Zabol.  6:  35-38.

Thulin, H.  (1976)  The  leukocyte migration test  in nickel contact dermatitis.
     Acta Derm. Venereol. 56: 377-380.

Toda, M.  (1962) Experimental studies  of occupational lung cancer. Bull.  Tokyo
     Med. Dent. Univ.  9:  440-441.

Tolat,  F. ;  Broden,  P.; Neulat,  G.  (1956) Asthmatic  forms of lung disease in
     workers  exposed to  chromium,  nickel  and  aniline  inhalation. Arch.  Mai.
     Prof. Med. Trav.  Secur. Soc.  18: 288-293.

Treagan,  L. ;  Furst, A. (1970) Inhibition  of interferon synthesis  in mammalian
     cell cultures after nickel  treatment. Res.  Commun. Chem. Pathol. Pharmacol
     1: 395-401.

Tseretili,  M.  N.; Mandzhavidze,  R.  P. (1969)  Clinical  observations of  acute
     nickel carbonyl  poisoning.  Gig. Tr.  Prof. Zabol. 13: 46-47.

Turk, J.  L.;  Parker,  D.  (1977) Sensitization  with Cr, Ni,  and Zr salts and
     allergic type granuloma formation in the  guinea pig. J.  Invest. Dermatol.
     68: 341-345.

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     atopic dermatitis. Arch. Dermatol. Ill: 1154-1157.
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Vandenberg, J. J. ; Epstein, W.  L.  (1963)  Experimental  nickel  contact sensiti-
     zation in man.  J.  Invest. Dermatol. 41: 413-416.

Veien, N.  K. ; Mattel, T.; Justesen, 0.; Nrfrholm,  A.  (1982)  Contact dermatitis
          in children.  Contact Dermatitis 8: 373-375.

Veien, N.  K. ; Mattel,  T. ;  Justesen, 0.;  Nrfrholm,  A.  (1983a) Oral challenge
     with metal  salts.  (I).  Vesicular patch-test-negative hand eczema. Contact
     Dermatitis  9: 402-406.

Veien, N.  K. ; Mattel,  T. ;  Justesen, 0.;  Ndrholm,  A.  (1983b) Oral challenge
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     9:  407-410.

Vuopala, U.; Huhti,  E.; Takkunen, J.;  Huikko, M.  (1970) Nickel carbonyl poison-
     ing. Report of 25 cases.  Ann. Clin. Res. 2:  214-222.

Waalkes, M. P.;  Kasprzak, K. S.; Ohshima, M.; Poirier, L. A.  (1985)  Protective
     effects of zinc acetate toward the toxicity of nickelous acetate in rats.
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Wagmann,  B.   (1959)  Beitrag zus  Klinik des Nickel  Ekzems.   Dermatologica
     119: 197-210.

Wahlberg,  J.  E.   (1975)  Nickel  allergy and  atopy in hairdressers.  Contact
     Dermatitis  1: 161-165.

Wahlberg, J.  E.  (1976)  Sensitization  and testing  of guinea pigs  with nickel
     sulfate. Dermatologica 152: 321.

Wahlberg, J. E.;  Skog,  E. (1971) Nickel allergy and atopy. Threshold  of nickel
     sensitivity  and  immunoglobulin  E  determination.   Br.  J.   Dermatol.
     85: 97-104.

Waters,  M.  D.;  Gardner, D.  E.; Coffin, D.   L. (1975)  Toxicity of metallic
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Watt, T.  L. ;  Baumann,  R. R.  (1968)  Nickel earlobe dermatitis. Arch.  Dermatol.
     98: 155-158.

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     of hamsters to nickel-enriched fly ash. Environ. Res. 26: 195-216.

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     inhalation of soluble  nickel. I.  Effects on alveolar macrophages. Environ.
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             6.   REPRODUCTIVE AND DEVELOPMENTAL TOXICITY OF NICKEL
     Various nickel  compounds have been assessed for their effects on reproduc-
tion and the  developing  embryo/fetus.   This chapter summarizes the pertinent
literature related to  the  reproductive and developmental toxicity of nickel.
6.1  REPRODUCTIVE FUNCTION/FERTILITY EFFECTS
     Ambrose et al.  (1976)  examined the effects of dietary administration of
nickel sulfate hexahydrate  in  a three-generation reproduction study in rats.
Males and females  of the parent (FQ) generation were exposed to levels of 0,
250, 500, and 1000 ppm nickel,  starting at 28 days of age.   Mating within dose
groups was initiated after 11 weeks of feeding.   The first generation consisted
of two groups of offspring,  F,   and F-., , derived from the single FQ generation.
For the second and third generations, breeding pairs from dams and sires exposed
to  nickel  in F...  or  Fp, , respectively,  were placed on  the  same  diet; and
progeny from these  matings  were carried through the same protocol as  the  F-^
generation.   Consequently,  all  generations  comprised two groups of offspring.
     Exposure to 250  or 500 ppm diets had  no effect  on body weight of the
parents when measured before  mating and at  weaning.   Body  weight was lower
following exposure  to 1000  ppm  (<8  percent  in females,  <13 percent in  males).
No other signs of toxicity in the parental animals were  reported.   In a concur-
rent two-year chronic feeding study, rats exposed to 1000 ppm and above showed
changes in organ-to-body weight ratios for liver and heart.
     As regards reproductive  function and fertility, the authors reported no
effect on fertility,  pregnancy  maintenance,  or  postnatal survival of the off-
spring throughout  the three generations.  There was a  consistent  reduction in
offspring body weight at weaning in the 1000 ppm group in all three generations,
although the authors  note that the animals  "recovered considerably"  by the
time they were mated.   Unfortunately, statistical analysis  of  this  and the
other reproduction  data is  lacking.  Furthermore, the body weight reductions
and "recovery" are  not distinguished by sex; thus, sex  differences in growth
may obscure  the significance of these observations.  Considering  these points
and the reduced parental body weight at this dose, the effect of nickel exposure
on postnatal growth cannot be assessed.  Other observations included an increase
in  fetal death  in  both groups  of the first generation  (but not  subsequent
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generations) and a possible  decrease  in litter size and postnatal survival.
However, the authors do not discuss these data relative to reproductive toxi-
city, and with  the  lack of statistical analysis, the significance cannot be
determined.
     Schroeder and Mitchener (1971) also exposed three generations of rats  to
drinking water which contained nickel  (5 ppm) as an unspecified soluble salt.
In each of  the three generations, the  animals exposed to nickel gave birth  to
litters which  exhibited a significantly increased perinatal  mortality,  and
there was a significantly increased number of "runts"  in the first and third
generations.  There also  appeared to be a generation-related  decrease in both
litter size and male:female ratios.
     Phatak and  Patwardhan (1950) added nickel at levels of 250,  500, or 1000
ppm  in  the  diets of male and female albino rats.   Nickel was supplied either
as metallic  nickel, as  nickel  carbonate,  or  as a  "nickel  soap" (a material
derived by  mixing  nickel  carbonate  with a mixed fatty acid solution obtained
from refined groundnut  oil).  There appeared  to be an effect  on growth in the
parental animals during eight weeks  exposure prior to mating at 1000 ppm.   Due
to deficiencies  in the experimental  design relative to sample size and statis-
tical analysis,  it  is difficult  to  discriminate potential differences between
treated and control groups.   However,  the limited data  do  suggest that the
litter  size from rats  treated with 1000 ppm  nickel  may  be smaller than in
controls.
6.2  MALE REPRODUCTIVE SYSTEM EFFECTS
     Hoey (1966)  examined  the effects of a  number  of metallic salts on the
testis  and  epididymis  of male rats.   The  lack  of  appropriate  controls  and  the
incomplete description of the methods make analysis of the experiment difficult;
however,  the  resultant histology demonstrated an effect of nickel.  In acute
studies,  male  rats received a single, subcutaneous injection of 0.04 mmol/kg
nickel  sulfate, 18 hours to 12 days before sacrifice.  By 18 hours postexposure,
there  was marked  damage to the  seminiferous  tubules, but no effect on  the
interstitial  tissue.   Within  the epididymis,  there  was  some  shrinkage  and  the
spermatozoa were  completely degenerated.   By day  12 postexposure,  most of  the
histopathological  changes  were  no  longer evident;  however, spermatogenesis
remained  very  limited.   Under multiple exposure conditions, the exposure level
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and types of effects relative to time of exposure are unclear from the descrip-
tion.   However, in  general,  degenerative  changes similar to those following
acute exposure were reported.
     Mathur et al.  (1977)  examined dermal exposure  of  male  rats to  nickel
sulfate,  applying concentrations of 40, 60, and 100  mg Ni/kg daily, for up to
30 days.   There were no clinical  signs of general  toxicity  or  mortality.
There were no macroscopic changes in skin, liver, kidney, or  testis.   Histolog-
ically, the testis  exhibited  tubular damage and sperm degeneration following
exposure  to 60 mg  Ni/kg  for 30 days, and these effects were  more dramatic at
the 100 mg  Ni/kg  level.   The  liver  also  showed signs of toxicity  at this
exposure  level/duration.   There was no effect on the testis  at 40 mg Ni/kg for
30 days or  at  any  exposure  level when  applied  only  for 15  days.  Thus, the
toxic  effects  appear related to both  level  and duration of  exposure.  The
authors note  the  similarity of their results with  those of  Hoey (1966) and
von Waltschewa et al. (1972)  .   Mathur and co-workers (1971) point out that
dermal exposure (as  assessed  in their  study) appears  to permit  appreciable
absorption of  nickel, and therefore may be a significant route of exposure in
specific  occupational settings.
     Other studies have also provided evidence to support nickel's toxicity in
the reproductive system of male mice.  Jacquet and Mayence (1982) intraperitone-
ally injected male BALB/c mice with 40 or 56 mg/kg of nickel  nitrate in saline
and then mated  the treated  males or control males (treated with  saline only)
to superovulated females for a five-week period.  Pregnant females were sacri-
ficed, and  isolated, viable  embryos  (which  were undergoing cleavage) were
cultured in Brinster's medium for a total of  three  days.   The embryos were
scored for  their  ability to  develop to the  blastocyst  stage.  The results
indicated that a dose of 40 mg/kg did not affect the fertilization capacity of
the spermatozoa or the ability of the fertilized eggs to cleave.   However, the
dose  of  56 mg/kg  yielded a significant  proportion  (p <0.01)  of uncleaved
(unfertilized)  eggs  which  were  incapable of developing into blastocysts.
Cleaved eggs from this same dose group were capable  of developing into blasto-
cysts.   Because treatment  with nickel  did  not  affect the ability of  those
embryos which  were  fertilized to  develop  to  the blastocyst stage, the authors
suggested that treatment with 56 mg/kg  nickel had a  toxic effect on the process
of spermatogenesis.
 Original manuscript not available during this review.
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     Deknudt and Leonard  (1982)  performed  a dominant lethal test for nickel
chloride and nickel nitrate in BALB/c mice.  Neither nickel compound produced
an increase in  postimplantation  death;  however,  both were associated with a
decreased rate  of  pregnancy and  an increase in the  preimplantation  loss of
embryos.  The data  suggest  that  these nickel-containing compounds may either
affect the male reproductive tract or may have an  effect on early preimplanta-
tion embryos.   (For further discussion  of these  studies  in regard  to  the
induction of chromosomal aberrations, see Chapter  7.)
6.3  FEMALE REPRODUCTIVE SYSTEM EFFECTS
     Studies on  nickel-induced  effects  on the reproductive system of female
animals are  limited, but have demonstrated that the effects of nickel are not
only seen in male animals.   The effects of intrauterine devices on the viability
of embryos  or  implantation  of embryos into the endometrium have been tested.
Chang  et  al.   (1970) evaluated  the ability of several  metals  within these
devices to  produce  effects  in rats  and  hamsters.  Nickel was found to inhibit
the fertility of rats as evidenced by a decrease in the number of implantations
and an increase  in the number of resorption sites in those uterine horns which
had intrauterine devices made of nickel.  These data suggest that nickel can
affect both  the  ability of embryos to  implant and the  viability  of  recently
implanted embryos.
6.4  DEVELOPMENTAL EFFECTS
     Sunderman  et  al.  (1978a)  studied the  effects  of  intramuscularly injected
nickel chloride in Fischer 344 rats.  A single acute injection was administered
on  gestational  day 8 in doses  of either  8,  12,  or  16  mg/kg body  weight.   In a
preliminary  study, an  LDrn of 22 mg/kg was established for treatment on gesta-
tion day 8,  and the  authors reported  an LDr of 17 mg/kg.  However, none of  the
three  doses  in the  developmental toxicity study  led  to maternal death or
altered  gestation  length.   No  other signs  of  maternal  toxicity were  reported.
Treatment  resulted in fetal  effects  at the two higher dosages which included
decreased  numbers  of live pups  per dam with  increased ratios  of  dead  fetuses
to  implantation sites.  In addition,  the mean fetal weights of  the  high dose
group  were statistically  lighter than controls.  When allowed  to  survive until
                                     6-4

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8 weeks  of  age,  the nickel-treated pups  remained  statistically  lighter  than
controls.  In a separate experiment, Sunderman et al. (1978a) investigated the
effect of repeated  doses of 1.5 or 2.0  mg/kg of nickel chloride per day on
gestational   days  6 through  10.   Control dams were  injected  with an equal
volume (0.4 ml) of sterile saline.   Under this treatment regimen the high dose
group (2 mg/kg per day) exhibited a decrease in the mean number of live fetuses
per dam,  and an  increase in the ratio of dead fetuses to implantation sites;
however, the mean body weights of the fetuses were not decreased.
     Lu et al. (1979) administered a single acute intraperitoneal injection of
nickel chloride to pregnant CD-I mice on one of gestational days 7 through 11.
On each of the gestational days, 7 experimental groups of animals were treated,
including 6  nickel  groups (1.2, 2.3,  3.5, 4.6,  5.7,  or  6.9 mg/kg of  nickel)
and a  vehicle control.   Maternal  death was  associated  with  the 6.9 mg/kg
exposure level on all treatment days,  and with 4.6 mg/kg or above on gestation
days 9,  10,  or 11.  No other  signs  of maternal toxicity  were  reported.   There
was a dose-related increase in fetal death on all treatment days, with apparent
increases occurring even  at the lowest dose tested (1.2 mg/kg).   On all  days
of treatment, exposure to 4.6 mg/kg or higher resulted in a significant reduc-
tion in fetal weight and placental  weight; similar reductions also occurred at
3.5 mg/kg on days 10 and 11.  The authors also reported a dose-related increase
in structural abnormalities,  encompassing both the skeleton and soft tissue.
The significance of  this finding is obscured, however,  since the percent  or
number of abnormal fetuses  at each  dose  level  and  treatment time  is not  indi-
cated.    In addition,  abnormalities  occurred only at  dose  levels where fetal
death occurred, and  thus may be related to general fetotoxicity and not to a
specific teratogenic action.
     Other studies have also provided evidence to support the potential devel-
opmental toxicity of  the aqueous nickel  salts.  Berman  and  Rehnberg (1983)
administered 500 or  1000 ppm  nickel chloride  in drinking  water  to  pregnant
CD-I mice during the period of gestational days 2 through 17.   No effects were
seen at  the  500-ppm  dose level; however, 1000 ppm nickel  caused a loss in
maternal weight, reduced  mean  birth weights of pups, and increased incidence
of spontaneous abortions.   Using a  short-term, J_n vivo  screen, Chernoff and
Kavlock  (1982) treated pregnant CD-I  mice with  30 mg/kg of  nickel  chloride
intraperitoneally on gestational day 8.   They concluded that nickel chloride
was fetotoxic based on a  decreased  mean  number of pups per litter compared to
                                    6-5

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controls.   In addition,  the pregnancy rate for nickel-treated dams was signifi-
cantly reduced (43 percent  treated  versus 53 percent controls).   The authors
did not report the presence of any malformations or variations in pups at day
20 of gestation.   Finally,  Perm  (1972) reported that intravenous administra-
tion of 30 mg/kg of nickel  acetate to  hamsters on day 8 of gestation  produced
fetal  death  and  "general  malformations,"  although the malformations were not
described.
     The  potential developmental toxicity of  aqueous soluble nickel  salts has
also been studied in the avian species.   Nickel chloride  hexahydrate was
injected  into fertile chicken eggs on either day 4 of incubation, via the yolk
sac, or day  8 of incubation, via the  chorioallantoic  membrane (Ridgway and
Karnofsky, 1952).  The  doses  used were 2.0 mg per egg on day 4 or 1.4 mg per
egg on  day 8.   Nickel  chloride was found to be embryolethal, but not terato-
genic.   The time of administration in this study was relatively late, however.
In studies by Gilani  and Marano (1980, 1982),  nickel  chloride was injected
into fertile  chicken eggs at  doses of  0.02 to 0.7 mg per egg on  either day  of
incubation 0,  1,  2, 3,  or 4.  Control  eggs were  injected with  an  equal volume
(0.1 ml)  of  sterile  saline per egg.   The embryos were sacrificed on day 8 of
incubation and  examined grossly  for malformations.   Under  these  conditions,
nickel  chloride   was  found to induce  a  series  of malformations which were
dose-dependent; the highest incidence  of  malformations occurred  on  day two  of
incubation.
     Storeng  and  Jonsen (1980,  1981) studied the effects of nickel  on early
embryogenesis  in  NMRI/Bom  mice.   Using   an in  vitro  approach  (Storeng and
Jonsen, 1980),  mouse  embryos from the 2- to  8-cell  stage were  cultured  in
media which  contained  nickel chloride at concentrations of 10  to  1000  uM.
Control media did not  contain nickel.  There was a dose-related effect  on
development  to  the morula stage of embryos exposed at the 2-cell stage, with
effects observed at the  lowest dose tested (10 (jM NiCl2  • 6H20).  When exposure
was not initiated until  the  4- to  8-cell stage, higher  concentrations (200-
300 uM) were  required to  cause an effect  on development; no effect was observed
at 100  uM.   In a  subsequent jn vivo study (Storeng and Jonsen, 1981), a single
intraperitoneal  injection of  nickel chloride  hexahydrate (20 mg/kg body weight)
was administered  to pregnant  mice on one  of gestational days 1 through 6.   The
dams were sacrificed  on gestational  day  19 and gestationai  and embryotoxicity
data were ascertained.   The data  presentation and statistical  approach do not
                                     6-6

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permit a  clear interpretation  of  dose-  and  time-related  effects.   However,  it
does  appear  that  i_n vivo exposure during this period of gestation may result
in increased resorptions and gross structural defects.
      The potential embryotoxicity and fetotoxicity of nickel subsulfide (Ni~S?)
were  examined  by Sunderman et al.  (1978a).  Nickel subsulfide dust with a mean
particle diameter of less than 2 urn was suspended in a volume of 0.2 ml penicil-
lin G.  The  suspension  of  nickel  subsulfide was  injected intramuscularly  at a
dosage of  80 mg of nickel per  kg  of body weight on  gestational  day  6  into
Fischer 344  rats.   Control  dams received 0.2 of  penicillin G vehicle only.
The nickel subsulfide  treatment was determined to be embryotoxic to the rats
based upon a reduction  of the number of live fetuses per dam and an increase
in the ratio of dead and  resorbed  fetuses to the  total number of  implantation
sites.  No skeletal  or  visceral anomalies were observed in the pups at term.
      Sunderman  et  al.  (1983)  have also used intrarenal  injection of nickel
subsulfide in  rats prior to mating in order to assess the potential effects of
nickel subsulfide-induced  maternal  polycythemia  on  the offspring.   Virgin
female Fischer 344  rats were  each given  an intrarenal injection  of 10 mg of
nickel subsulfide  suspended in  saline.  Seven days post  injection  the females
were  caged with virile  males to mate.   The  dams were  allowed to give  birth  to
their young, which  were examined  on postnatal day three for possible gross
malformations.  Pups were allowed to survive until four  weeks after birth,  at
which time they were  weighed  and blood samples were collected for evaluation
of the hematocrit.  Evaluation  of the maternal data suggested that the intra-
renal  injection of  nickel subsulfide did  successfully induce maternal polycy-
themia and erythrocytosis in the dams but not in the offspring.   These findings
indicate that  the  release of maternal erythropoietin  by  the maternal  kidneys,
caused by  nickel  subsulfide,  did  not stimulate erythropoiesis  in the pups.
The postnatal  hematocrits  of  the  nickel-treated pups tended to be lower than
those of the control pups during the first two weeks,  although they did approach
controls by  the end of  the experiment.  Nickel subsulfide was associated with
a decrease in mean pup weights of both male  and female pups, both at birth and
throughout the first postnatal  month.
     Finally,  in a  series  of  experiments, Sunderman and co-workers (1978b,c;
1979;  1980;  1983)  exposed pregnant rodents (rats  and hamsters) to varying
levels of nickel carbonyl  via  inhalation or  intravenous  injection and observed
both teratogenic and fetotoxic effects.   In  rats,  a single exposure by inhala-
tion  on gestation day 7 to 0.16 mg/liter for 15 minutes  resulted  in decreased
                                    6-7

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fetal viability  and  fetal  weight,  and an  increased  number of litters with
malformations.   Similar effects were seen at 0.30 mg/liter, but this level was
also associated with significant maternal death.   Lower exposure levels on day
7 were  not  evaluated.   On  gestation day 8,  fetal  viability was reduced  at
0.08 mg/liter/15 minutes (lowest level  tested), and fetal viability and weight
were reduced and malformations increased at 0.16 mg/liter.   On day 9, 0.16 mg/
liter/15 minutes caused reduced fetal viability and weight, but did not result
in any  malformations.   In  hamsters,  inhalation exposure to 0.06 mg/liter for
15 minutes  on  gestation  day  4 or 5  led  to  decreased  fetal  viability  and  in-
creased number  of  litters  (and  fetuses)  with malformations.   Exposure on  days
6, 7, or  8  did not have  a  significant effect on  development.   Among the tera-
togenic effects  noted  were anophthalmia and microphthalmia in rats and exen-
cephaly and cystic lungs in hamsters.
6.5  SUMMARY
     The  studies  that  have  been  reviewed  indicate  that  exposure  to  nickel  has
the  potential  to cause  reproductive  and  developmental  toxicity  in  various
experimental animals.   In  contrast to these studies, it should also be noted
that the  experiments  of Nielsen  et al.  (1975,  1979)  demonstrated that  a defi-
ciency  of dietary nickel can also  be  associated with reproductive effects.
     With respect to  specific reproductive effects, exposure of  male  rats to
nickel  salts  results  in degenerative  changes  in the  testis  and  epididymis  and
in  effects on  spermatogenesis.   Limited  studies  in  female  rats  and hamsters
suggest an effect on embryo viability  and the  implantation process.  In general,
the  studies reviewed  provide sufficient  data  to indicate  the potential for
effects on the reproductive process.   However,  studies should be designed to
cover  a  wider  range  of exposure  levels  and  durations,  in  order to better
define  the exposure-response relationship for various reproductive endpoints.
In  addition,  studies  that focus on the  female reproductive system should be
carried out to  expand the limited data  base that is currently  available.
     With respect to  developmental toxicity,  nickel  exposure of animals prior
to  implantation  has been associated  with delayed embryonic development and
possibly  with  increased resorptions.   Exposure following implantation  has  been
associated with  increased fetal  lethality and resorptions  and decreased fetal
weight.  Several  studies using nickel  salts reported an increase in structural
                                     6-8

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malformations in the mammal or chick.  However,  in the mammalian studies, the
manner of data reporting and lack of detail make it difficult to determine the
significance of these findings.   There is a teratogenic effect associated with
exposure to  nickel  carbonyl,  which Sunderman and co-workers have reported in
two  species  by  two routes of exposure.   Studies designed to establish  the
no-observed or lowest-observed effect level would aid in assessing the risk to
the  human  relative  to effects on embryo/fetal development,  following  exposure
to this form of nickel.
                                    6-9

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6.6  REFERENCES
Ambrose, A. M. ;  Larson,  P.  S.;  Borzelleca,  J.  F.;  Hennigar,  G.  R.,  Jr.  (1976)
     Long term toxicologic assessment of nickel in rats and dogs. J.  Food  Sci.
     Technol.  13: 181-187.

Berman, E.; Rehnberg,  B.  (1983)  Fetotoxic  effects  of nickel  in drinking water
     in mice.  Available from: NTIS, Springfield, VA.

Chang, C.  C. ;  Tatum,  H.  J. ; Kind,  F.  A.  (1970) The effect of  intrauterine
     copper and  other  metals on implantation  in  rats and hamsters.   Fertil.
     Steril. 22:  274-278.

Chernoff, N. ;  Kavlock,  R.  J. (1982) An  i_n  vivo teratology screen utilizing
     pregnant mice. J.  Toxicol.  Environ. Health 10:  541-550.

Deknudt, G. H.; Leonard, A.  (1982) Mutagenicity tests with nickel salts  in the
     male mouse.  Toxicology  25:  289-292.

Ferm, V.  H.  (1972) The teratogenic effects  of metals on mammalian  embryos.
     Adv. Teratol. 5:  51-75.

Gilani, S.  H.  (1982)  The effect of  nickel  upon chick embryo  cardiogenesis.
     Teratology 25: 44A.

Gilani, S.  H. ; Marano,  M.  (1980) Congenital  abnormalities in nickel  poisoning
     in chick embryos.  Arch. Environ. Contam.  and Toxicol. 9:  17-22.

Hoey, M.  J.  (1966) The effects of  metallic salts  on the  histology  and func-
     tioning of the rat testis.  J.  Reprod. Fertil. 12: 461-471.

Jacquet,  P.; Mayence,  A.  (1982)  Application of the i_n vitro  embryo  culture to
     the study of the mutagenic effects of nickel  in male germ cells. Toxicol.
     Lett. 11:  193-197.

Lu,  C..-C.;  Matsumoto,  N. ;  lijima,  S.  (1979) Teratogenic effects of nickel
     chloride on embryonic mice and its transfer to  embryonic  mice.  Teratology
     19: 137-142.

Mathur, A. K.; Datta, K. K. ; Tandon, S. K.  (1977)  Effect  of  nickel sulphate on
     male rats. Bull.  Environ. Contam. Toxicol. 17:  241-248.

Nielsen, F. H.; Myron, D. R.; Givand, S. H.; Zimmerman, T. J. ; Ollerich,  D. A.
     (1975) Nickel deficiency in rats. J. Nutr. 105:  1620-1630.

Nielsen,  F. H. ;  Zimmerman,  T. J.;  Ceilings,  M. E.; Myron, D.  R.  (1979) Nickel
     deprivation  in rats:  nickel-iron interactions.  J. Nutr.  109: 1623-1632.

Phatak,  S.  S.; Patwardhan,  V. N.  (1950)  Toxicity of nickel.  J. Sci.  Ind.  Res.
     Sect. B 9: 70-76.
                                    6-10

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Ridgway, L.  P.;  Karnofsky,  D.  A. (1952)  The  effects of metals on  the  chick
     embryo:  toxiclty  and production of  abnormalities  in development.  Ann.
     N.Y.  Acad.  Sci. 55: 203-215.

Schroeder,   H. A. ; Mitchener, M.  (1971)  Toxic  effects of trace elements on the
     reproduction of mice and rats.  Arch. Environ. Health 23:  102.

Storeng, R. ;  Jonsen, J.  (1980) Effect of nickel chloride and  cadmium  acetate
     on the  development  of preimplantation  mouse  embryos J_n  vitro.  Toxicology
     17: 183-187.

Storeng, R.; Jonsen, J. (1981) Nickel toxicity in early  embryogenesis  in mice.
     Toxicology 20:  45-51.

Sunderman,   F. W. ; Shen,  S.  K. ; Mitchell, J. M.; Allpass, P.   R.; Damjanov,  I..
     (1978a)  Embryotoxicity  and  fetal toxicity in  nickel  in  rats. Toxicol.
     Appl.  Pharmacol.  43: 381-390.

Sunderman,   F. W. ; Allpass,  P.;  Mitchell, J. (1978b) Ophthalmic malformations
     in rats  following prenatal  exposure to  inhalation of nickel  carbonyl.
     Ann.  Clin.  Lab. Sci. 8:  499-500.

Sunderman,  F. W.; Mitchell,  J.; Allpass, P.; Baselt, R.   (1978c) Embryotoxicity
     and teratogenicity  of nickel carbonyl  in  rats.  Toxicol.  Appl.  Pharmacol.
     45: 345.

Sunderman,   F. W. ; Allpass,  P.  R. ; Mitchell,  J. M. ;  Baselt,  R. C.  (1979) Eye
     malformations in rats:  induction by prenatal  exposure to  nickel carbonyl.
     Science (Washington, DC) 203: 550.

Sunderman,  W. F. ; Shen,  S.K.;  Reid, M.  C.; Allpass, P.   R. (1980) Teratogeni-
     city and embryo toxicity  of  nickel  <-arbonyl in  Syrian hamsters. Teratog.
     Carcinog. Mutagen. 1: 223-233.

Sunderman,  F. W.; Reid, M. C.; Shen, S.  K.; Kevorkian, C. B.   (1983) Embryotoxi-
     city and teratogenicity of  nickel  compounds.  In: Nordberg,  G.; Clarkson,
     T.; Sager,  P., eds.  Developmental  and reproductive toxicity  of metals.
     New York, NY: Plenum Publishing Co.

von Waltschewa, W.; Slatewa,  M. ; Michailow, I. (1972) Hodenveranderungen bei
     weissen Ratten  durch chronische Verabreichung von Nickel  sulfat [Testicu-
     lar changes  due to  long-term administration  of  nickel sulphate in rats.]
     Exp.  Pathol. 6: 116-120.
                                    6-11

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                        7.   MUTAGENIC EFFECTS OF NICKEL
     Various inorganic compounds of  nickel  have been tested for mutagenicity
and other genotoxic  effects  indicative of mutagenicity in a variety of test
systems ranging from microorganisms to human cells.  This chapter includes an
analysis of the pertinent literature pertaining to the mutagenicity and geno-
toxicity of these nickel  compounds.   For further information on the mutagenicity
and genotoxicity  of  nickel   compounds,  the extensive  reviews  by Sunderman
(1981, 1983) and Christie and Costa (1983) should be consulted.
7.1  GENE MUTATION STUDIES
7.1.1  Prokaryotic Test Systems (Bacteria)
     Gene mutation studies  of  nickel  compounds in bacterial  systems are sum-
marized in Table 7-1.
     LaVelle and Witmer  (1981),  in an abstract of  a  paper presented at the
Twelfth Annual  Meeting of  the  Environmental  Mutagen  Society, claimed that
nickel chloride  (NiCU)  was mutagenic in the Salmonella typhimurium TA 1535.
They used a fluctuation test and a concentration range of 0.01 to 0.1 mg/ml of
the test  chemical.  According to these authors, dose-related  increases in  the
mutation  frequency were  noted.   Ethylmethane sulfonate and dimethylsulfoxide
(DMSO) were used  as  positive and solvent controls,  respectively.  Details of
experimental data are not available in this abstract;  hence,  a critical evalua-
tion of this study is not possible.
     Green et al. (1976) investigated the mutagenic  potential  of nickel chloride
using the Escherichia coli WP2 trp-fluctuation test.  In the fluctuation test,
where a reversion from auxotrophy  to  prototrophy  takes place  in  culture tubes
treated with the  test  compound, multiplication  of the prototrophic  revertants
results in  an  increase of turbidity of the medium.  The  frequency of mutation
can be determined by  counting the number of  turbid tubes.   After treatment
with  nickel  chloride  at concentrations of 5  ug/ml, 10  ug/ml,  and 25 ug/ml,
mutation  frequencies were similar  to  those of control groups.   In the  experi-
mental groups  there were 51, 42,  and 27  turbid tubes,  respectively, for  the
above doses.   Controls showed 44,  44, and 51  turbid tubes.  Two  hundred tubes
were scored for each concentration with 200 concurrent control tubes.
                                    7-1

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TABLE 7-1.   MUTAGENICITY  EVALUATION  OF  NICKEL:   GENE  MUTATIONS  IN PROKARYOTES
Indicator
Organisms
Salmonella
typhimurium
Escherichia
coli
Corne-
bacterium

Strain
TA1535
Homo-
serine-
dependent
Assay
System
Fluctuation
test
Fluctuation
test
Fluctuation
test
Test
Compound
Nickel
chloride
Nickel
chloride
Nickel
chloride
Reported
Concentration Response
0.01-0.1 mg/ml +
5,10,25 ug/ml
0.031, 0.062, +
0.125, 0.25, 0.5,
1, 5, 10 pg/ml
Comments
Meeting
abstract;
no details
Preliminary
study needs
confirmation;
Reference
LaVelle and
Witmer
(1981)
Green et al .
(1976)
Pikalek and
Necasek
(1983)
                                                                     dose-related
                                                                     increases  in
                                                                     revertants
                                                                     only seen
                                                                     at levels  ^
                                                                     0.5 pg/ml

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     Pikalek and Necasek  (1983)  demonstrated the mutagenic effect of nickel
chloride using  the simplified fluctuation  test and  the clone  test,  in a
homoserine-dependent strain of Cornebacterium.  Nickel chloride  at concentra-
tions of  0.031,  0.062, 0.125,  and 0.25 ug/ml  did not induce revertants.
However, at  concentrations of 0.5, 1.0,  5.0,  and 10.0 ug/ml, dose-related
increases in the number  of revertants were  obtained  as  shown in Table 7-2.
     In the  clone  method  the  cells  were treated with nickel  chloride  and
incubated for 41 hours at 29°C on a  reciprocal shaker.  The  cell suspension
was diluted and  spread  on complete agar medium and  minimal  agar medium to
select  revertants.   In the  clone  test, the nickel chloride caused a decline in
the revertant frequency up to  a concentration of 28 ug/ml.   However,  concen-
trations of  36  ug/ml  and  above yielded  increased  frequencies of revertants
with a decrease in  cell  survival  as shown in Figure 7-1.
     Mutagenicity  of  nickel  compounds  in  bacterial  systems are considered
inconclusive because of a lack of adequate  data in the Salmonella assay and
because the  Cornebacterium assay  requires  further confirmation.  However,
these studies point out that variation in the sensitivity of bacterial strains
plays an important  role in testing metal compounds.

7.1.2  Eukaryotic Microorganisms (Yeast)
     Gene mutation studies of nickel  compounds in  eukaryotic  systems  and
cultured mammalian  cells are summarized in Table 7-3.
     Singh (1983)  reported nickel  sulfate (NiS04)-induced gene conversion and
reverse mutations  in the yeast Saccharomyces cerevisiae D7.   Aliquots  of cells
were spread on complete growth medium.  After the aliquots had dried,  a center
well was made  in the agar medium  and the  well  was filled with 0.1 M nickel
sulfate.  Plates were incubated  overnight  at 30°C.  As  the  test  compound
diffused into the  medium,  a concentration gradient was produced  and a zone of
cell killing in the vicinity of the well demonstrated the toxicity of the test
compound.  The plates were replica plated onto medium lacking tryptophan and
medium  lacking  isoleucine and valine.   Gene  conversion  at  trp  and reverse
mutation at ilv were indicated by a ring of colonies on the agar plates lacking
tryptophan and  isoleucine, respectively.  Nickel sulfate showed a  positive
reaction to gene conversion  and  weak response to reverse mutation.   However,
this study was  generally  lacking in details and data were  not presented to
support the author's conclusion.
                                    7-3

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           TABLE  7-2.   THE MUTAGENIC  EFFECT OF NICKEL CHLORIDE ON A
                 HOMOSERINE-DEPENDENT STRAIN OF CORNEBACTERIUM

NiCl2, mg/1
0.031
0.062
0.125
0.25
0.5
1
5
10
P
3
5
5
5
6
2
5
3
N
99
165
165
165
198
66
165
99
C
11
25
25
25
27
10
43
29
T
10
30
25
30
50
21
158
99
T%
10.1
18.1
15.1
18.1
25.2
31.8
96.3
100
X2
-
-
-
0.54
8.52
5.10
172
108
P = number of experiments,  N = total  number of test-tube  cultures  in  the
control  or test series,  C = number of positive test-tube  cultures  in  the
control  series, T = number of positive test-tube cultures in  test  series.

Source:   Adapted from Pikalek and Necasek (1983).
                                    7-4

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logN,
                                     -  3
                                     - 2
log N
                                                m
                                   50
           Figure 7-1. The relationship
           between the lethal and muta-
           genic effect of IMi2+ (//g/ml) by
           means of the clone method:
           Nc, number of surviving cells
           (open symbols); Nm mm
           (closed symbols) in 1 ml of
           culture.

           Source: Pikalek and Necasek
           (1983).
                    7-5

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              TABLE 7-3.  MUTAGENICITY EVALUATION OF NICKEL:   GENE MUTATIONS IN YEAST AND CULTURED MAMMALIAN CELLS
CD
Test System
Saccharomyces
cerevi siae
Chinese hamster
Cell
Line
D7
V79
Test
Compound
Nickel
sulfate
Nickel
chloride
Concentration
0.1 M
0.4 mM (5 ug/ml),
0.8 mM (10 ug/ml)
Reported Response
+ gene conversion
+ reverse mutation
+ HGPRTase
Comments
Data are lacking.
Only one concen-
tration used, no
dose-response.
At lower concen-
trations results
Reference
Singh (1983)
Mlyaki et al.
(1980)
    Chinese hamster    CHO
    ovary cells

    Mouse lymphoma     L5178Y
Nickel
chloride

Nickel
chloride
Not reported
40, 52,
71, 95,
127 ug/ml
+ HRPRTase
  TK Locus
are similar to
controls.  At
higher concen-
trations the cell
survival was too
low to get a
realistic estima-
tion of mutation
rate.

Data not reported.
Dose-response
relationship
was noted.
Hs1e et al.
(1979)

Amacher and
Palllet (1980)

-------
7.1.3.  Mammalian Cells In Vitro
     Miyaki et  al.  (1980)  investigated  the mutagenic  potential  of nickel
chloride in cultured  V79  Chinese hamster cells, at the hypoxanthine-guanine
phosphoribosyl  transferase  (HGPRTase)  locus.   The authors used  a test that
involves selection of  presumed  mutations that are resistant to 8-azaguanine.
Normally,  the  wild type  cells  contain HGPRTase enzyme,  which converts 8-
azaguanine to toxic metabolites, resulting in cell  death.   However,  spontaneous
mutants and mutants induced by  test chemicals do not contain active HGPRTase,
and therefore grow in the presence of 8-azaguanine.  Nickel chloride at concen-
trations of  0.4 mM (5 |jg/ml) and  0.8 mM (10 ug/ml)  induced  7.1 ±  0.2 and
15.6 ±2.0 mutants per 10  survivors,  respectively.   The control mutation rate
was 5.8 ±  0.8 per  10   survivors.   The cell survival  rate was  55 percent at
0.4 mM and 0.4  percent  at 0.8 mM,  respectively.  At the higher survival rate
(55 percent), the mutation frequency (7.1 ±0.2 per 10  survivors) was  almost
similar to that of  the control  rate (5.8 ± 0.8 per  10  survivors).   At the
lower cell survival rate  (0.4 percent) the concentration  of nickel (0.8 mM)
was too  toxic  to result in a realistic  estimate of mutants.   In  the absence
of data  between concentrations  of 0.4 mM and 0.8 mM,  this report cannot be
regarded as an  indication of a positive mutagenic response of nickel chloride.
     Hsie et al. (1979) studied  the mutagenicity of nickel chloride in cultured
Chinese hamster ovary  cells,  CHO,  at the HGPRTase locus,  using 6-thioguanine
as another purine analog  selective agent.  According to these  authors,  nickel
chloride was mutagenic.   However, the  authors did not provide  data to  support
their conclusion.  The authors indicated that the results  were preliminary and
needed further  confirmation.
     Amacher and Pail let (1980)  reported that nickel  chloride was mutagenic in
mouse  lymphoma  L5178Y cells.   Nickel  chloride  at  concentrations of 1.69  x
10"4 M (40 ug/ml),  2.25 x 10"4  M (52 ug/ml), 3.00 x  10"4 M (71 ug/ml), 4 x
10"4 M  (95 ug/ml),  and  5.34 x  10"4 M  (127 ug/ml)  induced 0.95 ± 0.17,
1.00 ± 0.25,  0.88 ± 0.06,  1.00  ± 0.08, and  1.38 ± 0.24 trifluorothymidine-
                        4
resistant mutants per 10  survivors.   The cell  survival at these concentrations
ranged from 32  ± 2 to 22 ± 3 percent.   These results demonstrate a dose-related
response and translate  into a 4- to 5-fold increase in  the mutation frequency
over  the control  level  (0.38 ±  0.06).  Cultures treated with 1 percent  saline
served as controls.
     The studies of Miyaki et al. (1980) and Hsie et al. (1979) are lacking in
data; the study of Amacher and Pail let (1980) is the only  study that indicates
                                    7-7

-------
that nickel is mutagenic  in  cultured mammalian cells.  Confirmation of this
study by independent  investigators  in  other laboratories  is desirable  before
concluding that nickel is mutagenic in  cultured mammalian  cells.
7.2.  CHROMOSOMAL ABERRATION STUDIES
     The ability  of nickel compounds  to  induce  chromosomal  aberrations in
cultured mammalian cells has been investigated, and these studies are summarized
in Table 7-4.   Additional  studies  on j_n vivo induction of chromosomal aberra-
tions are summarized in Table 7-5.

7.2.1  Chromosomal Aberrations In Vitro
     Umeda and  Nishimura  (1979)  exposed FM3A mammary carcinoma cells derived
from C3H mice  to  various  concentrations of nickel chloride, nickel  acetate,
potassium cyanonickelate,  and  nickel  sulfide,  and analyzed air-dried chromo-
somal preparations for aberrations.  Nickel chloride and nickel acetate induced
                                             -3          -4              -4
no aberrations  at concentrations of 1.0 x 10  ,  6.4 x 10  ,  and 3.2 x 10   M
when cells were exposed for 24 and 48 hours.  Potassium cyanonickelate at the
same concentrations  induced 4- to 18-fold increases  in  aberrations  over the
control value  (2  percent)  following 48 hours of  treatment. Potassium cyanide,
which was used  as a positive control, induced aberrations similar to potassium
cyanonickelate,  indicating that the  cyanide moiety may be responsible  for
aberration  induction.   The aberrations  induced  by the test compounds were
mainly  in  the  form of gaps.   The  same concentrations of nickel  sulfide  also
induced many-fold (6 to 14) increases  in  aberrations over the control value
                                                                      -3
(2 percent)  at  48 hours of treatment.  The  concentration of 1.0 x 10 M was
cytotoxic for all the test  compounds.  No  statistical analysis was provided in
this report.
     Nishimura  and  Umeda  (1979),  in a  continuation  of their experiments de-
scribed  above,  detected chromosomal aberrations  in  FM3A cells recovered  in
normal  growth  medium following exposures  to nickel chloride,  nickel  acetate,
potassium cyanonickelate,  and  nickel  sulfide.  These  investigators exposed 1.0
x 10  cells/ml  to various  concentrations  of  nickel  compounds  for 6, 24,  or
48  hours,  washed the  cells with Hanks'  balanced  salt  solution  (HBSS),  and
reincubated  the cells in the control  growth medium for another 24, 48,  72, or
96  hours.   Chromosome preparations  were  made at the end of  each  recovery
                                     7-8

-------
                        TABLE 7-4.   MUTAGENICITY  EVALUATION OF  NICKEL:   IN VITRO CHROMOSOMAL ABERRATIONS
I
uo

Indicator
Cells
Mouse
mammary
carcinoma
cells FM3A
Duration
of Treatment
24h, 48h
48h
Test Compound
Nickel chloride,
nickel acetate
Potassium
cyanonickelate,
Concentration Reported Response Comments
1.0 x W~l
6.4 x 10 7
3.2 x 10 ^M
Same as + Effects of
above potassium
Reference
Umeda and
Nishimura
(1979)
    Mouse
    mammary
    carcinoma
    cells FM3A
    Human
    lymphocytes
    Syrian
    hamster
    embryo cells
6, 24,
48h
in the
test
compound,
recovered
in normal
medium after
24, 48, 72,
and 96h
culture
48h


24h
                                   nickel  sulflde
Nickel  chloride,
nickel  acetate,
potassium
cyanonickelate,
nickel  sulfide
Nickel  sulfate


Nickel  sulfate
1.0 x I0
6.4 x 10
3.2 x 10
        ~l
1.9 x 10"5M
(5 ug/ml)

1.9 x 10"5M
(5 ug/ml)
cyanonickelate
may be due to
cyanide moiety.
No statistical
analysis of
data.

Delayed
effects.
No statistical
data.
                                      No dose-
                                      response.

                                      No statistical
                                      analysis.
Nishimura and
Umeda (1979)
                  Larramendy
                  et al. (1981)

-------
                        TABLE 7-5.   MUTAGENICITY EVALUATION OF NICKEL:   IN VIVO  CHROMOSOMAL  ABERRATIONS
I
I—>
o

Species
Human
Rat
Mouse
Mouse
Mouse
Cell Source
Lymphocytes
(chromosomal
aberrations)
Bone marrow
and sperma-
togonlal cells
Bone marrow
cells
(mlcronucleus
test)
Dominant
lethal test
Embryonic
cells derived
Test
Compound
N1
Nickel
sulfate
Nickel
chloride
and
nickel
nitrate
Nickel
chloride
and
nickel
acetate
Nickel
nitrate
Dosage
and Route
0.5 mg N1/m3
(range 0.1-1.0
mg N1/m3)
3 and 6 mg/kg
for 7 and
14 days
25 mg/kg
(50% LD50)
56 mg/kg
(50% LD50)
IP
25 mg/kg
(50% LD50)
56 mg/kg
(50% LD50)
IP
40 mg/kg
56 mg/kg
Treatment
Duration
7-29 years
45-57 years
Subchronic
30 hours
30 hours
Acute
Acute
Response Comments

No data. No
rationale for
dosage
selection.
Dose response
not studied.
Dose response
not studied.
Not clastogenlc
but Induced
preimplantatlon
failure.
Not clastogenlc
but reduced
Reference
Waksvik and
Boysen (1982)
Mathur et al.
(1978)
Deknudt and
Leonard (1982)
Deknudt and
Leonard (1982)
Jacquet and
Mayence
              from treated
              male germ
              cells
fertilizing
capacity
of sperm.
(1982)

-------
period using the  flame-drying  method,  and 100 metaphases  for  each interval
were analyzed for chromosomal  aberrations.  Nickel acetate at a concentration
           -3
of 1.0 x  10   M induced no chromosomal aberrations after 6 hours of treatment
and 24, 48, and 72 hours of recovery.   After 24 hours of treatment and reincu-
bation periods of 24,  48,  and 72 hours,  the same concentration induced 5 to
10 percent aberrations  (breaks,  exchanges and  fragments);  after 48 hours of
treatment and 24, 48,  72,  and 96 hours of  reincubation,  no  metaphases were
                                                     -4
noted.   Nickel acetate  at  a  concentration of 8  x  10   M after 48 hours of
treatment induced 20 percent aberrations  only after  48  hours of reincubation,
after  which  aberrations were  observed  to the  extent of 20  percent.   At  a
                        -4
concentration of  6 x 10   M, aberrations  were also observed  after  24  hours of
reincubation. Nickel chloride,  nickel  sulfide,  and potassium cyanonickelate
induced similar clastogenic responses.   The authors speculated that the nickel
compounds induced damage to DNA  in the cells but required periods  of  recovery
for the cells to express the  genetic damage in  the form of chromosomal aberra-
tions.   This was probably due to a delay in cell  cycle.
     Larramendy et al.  (1981)  investigated the clastogenic  effect of nickel
sulfate in human  lymphocyte cultures.  Nickel sulfate (hydrated) at a concen-
                    -5
tration of 1.9  x  10   M (5.0 ug/ml) induced 14  aberrations  in 125 metaphase
cells  (11.20 percent)  or 0.07 ± 0.02 aberrations per  metaphase  following  a
48-hour treatment. The background frequency was 3 aberrations in 200 metaphases
(1.5 percent).   The aberrations included gaps,  chromatid breaks,  and chromosome
breaks, including rings and minutes.   Nickel sulfate also induced 33 aberrations
in 200 metaphases  (16.5 percent)  or 0.16 ± 0.03 aberrations  per metaphase  in
Syrian hamster cells exposed to the same concentration (5.0 ug/ml) for 24 hours.
The majority of the  aberrations were of  chromatid type.  The aberrations in
both these cell types  were many-fold higher than the control values.   Unfor-
tunately, this  study  is limited because only one concentration was tested  by
these investigators.
     Clearly, well  designed  ui  vitro  chromosomal  aberration studies  using
nickel  compounds are necessary before concluding that nickel  is clastogenic in
cultured mammalian cells.   Emphasis should be given to dose-response relation-
ships and statistical analyses of the data.

7.2.2  Chromosomal Aberrations In Vivo
     Mathur  et al.  (1978)  failed to detect chromosomal  aberrations  in bone.
marrow and spermatogonial  cells  of albino rats  treated with nickel sulfate.
                                    7-11

-------
Male albino rats were intraperitoneally injected with 3 and 6 mg nickel sulfate/
kg in saline  daily  for periods of 7 and 14 days.   After a period of 45 hours
rest, the  animals were sacrificed and chromosome preparations were made from
bone marrow and  spermatogonial  cells.   Fifty metaphases per dose group were
scored for chromosomal  aberrations.   Acccording to these authors,  the number
of aberrations  in experimental  animals was not significantly different from
that of  the  control value.   However,  the authors did  not  provide  data to
support their conclusion.   No rationale, such as LD    was provided for dosage
selection.
     Waksvik  and  Boysen (1982)  analyzed  blood lymphocytes for  chromosomal
abnormalities and sister chromatid exchanges from workers exposed to nickel in
a refinery.  Three groups of workers were studied.  According to these investi-
gators,  the  subjects were  nonsmokers  and  nonalcohol  users  and did not use
drugs regularly.  The workers had not received any form of therapeutic irradia-
tion. Of  the  3  groups,  2 served  as  experimental and  the third as control.  In
the  experimental  groups, the first group of 9 workers was exposed to a range
of 0.1 to 1.0 mg Ni/m  (0.5 mg Ni/m ) from 7 to 29 years, with an average of
21.2 years.   The  plasma concentration of  nickel  in  blood  ranged from  1 to 7
(ug/1).   Cytogenetic analysis  revealed an  average  of 11.9 percent chromosomal
gaps and 0.9 percent chromosomal breaks compared  to control  frequencies   of
3.7  percent  gaps  and  0.6 percent  breaks.  The  average  frequency of sister
chromatid  exchange per metaphase was 4.8 compared to the control level of  5.1.
The  second experimental  group of 10 workers was exposed to an average nickel
concentration of  0.2 mg/m   air, a  range  of  0.1 to 0.5  mg  Ni/m  .  The  age  of
the  workers  ranged  from 45 to 57  years,  with an average exposure period  of
25.2 years.   The  average plasma concentration of nickel in these workers  was
5.2  ug/1  of  blood.   Chromosomal analysis  revealed 18.3 percent gaps and 1.3
percent  chromosomal  breaks.   This study is  inconclusive  because chromosomal
gaps, which may restitute to normal chromosomes, do  not represent true chromo-
somal  aberrations,  and the frequency  of  chromosomal  breaks reported in the
paper  was not significantly different  from  the control value.  Furthermore,
these workers did not  exhibit  increased incidence  of  sister chromatid exchanges
over the  control  level.
     Deknudt  and  Leonard (1982) investigated  the  ability  of nickel  chloride
and  nickel nitrate  to induce  chromosomal  aberrations using the micronucleus
test and the  dominant  lethal assay  in  mice.   Toxic dosage was determined to be
50 mg/kg for  nickel  chloride and  112 mg/kg for nickel nitrate.
                                    7-12

-------
     In the micronucleus test, nickel chloride at a concentration of 25 mg/kg
(50 percent LD5Q) and nickel nitrate at a concentration of 56 mg/kg (50 percent
ID™) were  used.   One thousand polychromatic erythrocytes  from  bone marrow
cells of 5 male mice were scored for each test compound.   The yields of micro-
nucleated cells  were 2.60 ± 0.51 and 3.20 ± 0.58,  respectively,  for nickel
chloride and nickel  nitrate.  These yields were well within the control level
of 2.60 ± 0.24.  Cyclophosphamide was used as a positive control.
     In the dominant  lethal  test,  male mice were intraperitoneally  injected
with 25 mg/kg  of nickel  chloride and 56  mg/kg  of nickel nitrate.  Treated
males were  bred  with  untreated females weekly for 4 weeks covering the entire
spermatogenic cycle.  Pregnant mice were  sacrificed and  the incidence of pre-
and  postimplantation  losses in  treated  and control  groups was  recorded.
Nickel  salts did not increase the postimplantation loss significantly over the
control level.   However,  these nickel compounds reduced the number of implanta-
tions,  indicating  the toxicity  of  the metal  for the preimplantation zygotes.
The authors indicated that  since dominant lethals are generally  a result of
chromosomal  aberrations  induced  in  germ  cells,  the lack of dominant lethal
effects in these experiments suggested that nickel was not clastogenic in male
germ cells.   Since  only  a  single dose was tested in both of these studies,  a
positive result at other doses cannot be  excluded.
     Jacquet and Mayence (1982)  studied the effects of nickel nitrate in male
germ cells of mice using embryonic  cell  cultures (see Chapter 6 for discussion
of study).   The authors  concluded that nickel  nitrate induced toxicity in germ
cells but  did  not  induce  chromosomal aberrations as  evidenced  by  reduced
numbers of  viable  embryos,  but  normal development in those that were viable.
     The above chromosomal  aberration studies  suggest a  lack of  clastogenic
activity of nickel  in j_n vivo systems.    However, some of these studies have
also indicated that  nickel  is toxic to male germ cells,  resulting in reduced
numbers of  fertilized eggs.   Studies on  the effects of  nickel have not been
performed in female germ cells.  This is  important because many metals,  such as
cadmium and mercury, have been found to  induce chromosomal nondisjunction lead-
ing to aneuploidy  in female germ cells of mammals  (Watanabe  et a!., 1979;
Mailhes,  1983).   Consequently,  studies  on the effects  of nickel  in female
mammalian germ cells  and additional studies in male  germ cells are needed
before concluding  that nickel is not  a germ cell mutagen.  Nickel should also
be tested for its ability to cause  nondisjunction in somatic cells.
                                    7-13

-------
7.3  SISTER CHROMATID EXCHANGE (SCE) STUDIES IN VITRO
     Nickel compounds have  been  tested for the induction of SCE in a variety
of i_n vitro systems (Table 7-6).
     Wulf  (1980)  investigated SCE  in  human lymphocytes  exposed  to nickel
sulfate  for  72 hours at various  concentrations.   There  was a dose-related
                                                  -4
increase in SCE.  At  a concentration of 2.33 x  10  M/l  (55 ug/ml), the SCE
frequency was 9.5 ± 0.84 per metaphase (p <0.0005); at a concentration of 2.33
x  10  M/l  (5.5 ug/ml),  the  SCE  frequency was  8.50 ± 0.51 per metaphase
(p <0.0025);  and  at  a concentration of 2.33 x 10"6M/1 (0.55 ug/ml),  the  SCE
frequency was  7.24 ± 0.38 per metaphase  (p <0.05),  compared  to the control
frequency of 6.24 ±  0.42 SCE  per  metaphase.  The  study was  well conducted  and
the data were statistically analyzed (student t-test).
     Ohno et al.  (1982)  investigated the induction  of SCE  by nickel  sulfate
and nickel  chloride in the Chinese hamster Don cells.  These authors determined
the TCIDgQ (50  percent  inhibition dose of tissue  culture cells)  as 50 ug/ml
for  nickel  sulfate and  32  ug/ml  for nickel chloride.   Nickel  sulfate and
nickel  chloride at these concentrations  resulted in 7.2 and 6.2  SCE/cell,
respectively.  The  spontaneous SCE level  was 3.90  ±  0.82/cell.   The authors
indicated that  these  results  were statistically significant at the 95 percent
confidence limit  compared  to the spontaneous  level  (p <0.05).   Although no
attempts were made to study the dose response, the statistical analysis of the
data  supports  the fact  that  nickel induces SCEs in Chinese hamster cell  cul-
tures.
      In a preliminary SCE study,  Anderson (1983) noted a weak mutagenic effect
of nickel  sulfate on lymphocytes of one  human  donor without apparent dose-
response relationship and no  effect of nickel  on  lymphocytes  of another  human
donor. Data were  not presented in this report.
      Saxholm et al.  (1981)  investigated  the ability of  nickel  subsulfide to
induce SCE in human lymphocytes.   Lymphocyte cultures were  treated at a concen-
tration  range  of  1 to 100 ug/ml   for  24  hours  and 48 hours, and analysis of
chromosomes for SCEs  was performed.  In the 24-hour treatment group, the SCE
frequency was  similar to that of the  control  group, whereas in the 48-hour
treatment  group the  results were significantly higher than controls (t-test,
p  <0.001).  The toxic concentration  level was  1000 ug/ml,  and there was  no
dose-related response in the  increase of SCE frequencies.
      Newman et  al. (1982) detected a significant  increase  in  the  incidence of
SCEs  over background  in human lymphocytes exposed to nickelous chloride.   At a
                                    7-14

-------
TABLE 7-6.   MUTAGENICITY EVALUATION OF NICKEL:   IN VITRO SISTER CHROMATID EXCHANGES
Sources of
Cell
Culture
Human
lymphocytes



Chinese
hamster Don
cells



vj Human
>L lymphocytes
en
Human
lymphocytes
Human
lymphocytes


Human
lymphocytes




Syrian
hamster
cells



Duration
of Test
Cultures Compound
72h Nickel
sulfate



72h Nickel
sulfate
Nickel
chloride


Nickel
sulflde

Not Nickel
reported sulflde
64h Nlckelous
chloride


72h Nickel
sulfate




72h Nickel
sulfate




Concentration
2.33 x 10"5mol/l
2.33 x 10 ?mol/l
2.33 x 10 Dmol/l


50 ug/ml

32 ug/ml



Not reported




1.0 x 10" ^M
9.88 x 10 cM
5.45 x 10'r.M
1.19 x 10 *M
9.5 x 10"6M
(2.5 ug/ml),
1.9 x 10 3M
(5 ug/ml)



3.8 x 10"6M
(1 ug/ml )«
9.5 x 10 °M
(2.5 pg/ml),
1.9 x 10"5M
(5 ug/ml)
Treatment Reported
Time Response Comments
72h + Dose
response
reported
with student
t-test.
72h + No dose
response
studied.
Data
analyzed
statistically.
Not reported + No data were
presented.

24h, 48h + No dose
response.
64h + Data analyzed
with a student
t-test.

24h, 48h + Low concentra-
tion used. The
results would
probably be
more dramatic
at higher
concentration.
24h, 48h +





Reference
Wulf (1980)




Ohno et al.
(1982)




Anderson
(1983)

Saxholm
et al. (1981)
Newman et al.
(1982)


Larramendy
et al.
(1981)











-------
                           -4
concentration of  1.19  x  10  M (28 pg/ml), nickel approximately  doubled  the
baseline SCE incidence to  yield  a mean value of  8.52  ± 0.33 SCEs per cell.
Control cells produced a  mean background incidence of  3.92  ±0.7 SCEs per
cell.    Nickel concentrations  lower than 1 x 10   M  yielded  mean SCE values
between 8.52 and  the control  value of 3.92 ±0.7  exchanges per cell.  Concen-
                                     ~4
trations of  nickel at or above 5 x 10  M were toxic to  lymphocytes. Data were
analyzed with a student t-test.
     Larramendy et al.  (1981) investigated the  effect of nickel  sulfate on SCE
frequencies  in human lymphocytes.   Nickel  sulfate at concentrations of 9.5 x
10"6M (2.5 ug/ml) and 1.9 x 10~5M (5.0 ug/ml) induced 17.20  ± 0.90 and 18.95 ±
1.52 SCEs  per cell,  respectively.   The control  value was 11.30  ± .60 SCE per
cell.    The  range  of  SCE  per cell in control  cultures was 5  to 18 and 7 to 20
in human and hamster samples, respectively.  In the metal-treated  samples  the
SCE range was from 10 to 35.
     In Syrian hamster cells  exposed to 3.8 x 10  M  (1 ug/ml),  9.5 x 10  M
(2.5 ug/ml), and 1.9 x 10"5M (5.0 ug/ml), nickel  sulfate induced 15.95 ± 0.92,
17.25 ± 1.44, and 21.25  ±  1.13  SCEs, respectively.  The background level  of
SCEs in control  cultures was  11.55 ± 0.84 per metaphase.  The authors claimed
that the increases  in  SCE were dose-related.  Toxic doses and cell survival
data were not indicated in this paper.   The rationale for dosage selection was
given  on  the basis of morphologic  cell  transformation.  Compared to other
studies on  SCE induction,  this study employed relatively lower concentrations
of the  test  compound.
     The weight  of  evidence,  based on the above  studies,  demonstrates that
nickel  compounds  (nickel   sulfate,  nickel  subsulfide,  and nickel  chloride)
induce  SCEs in cultured  mammalian cells and  cultured human lymphocytes.
However, in the  only ui vivo study reported (Waksvik and Boysen, 1982) where
workers were exposed to  nickel  in a refinery,  a  negative response for SCE in
lymphocytes  was noted (see  Section 7.2.2).
7.4  OTHER STUDIES INDICATIVE OF MUTAGENIC DAMAGE
7.4.1  Rec Assay in Bacteria
     Nishioka  (1975)  and Kanematsu et al. (1980)  found nickel  monoxide and
nickel trioxide to be nonmutagenic in the rec assay, which measures inhibition
of growth in Bacillus subtil is.
                                    7-16

-------
     Kanematsu et al. (1980) exposed Bacillus subtil Is strains H17  (rec+) and
M75 (rec-) to 0.05 ml of 0.005 to 0.5M nickel monoxide and nickel trioxide  in
agar petri plates.   The  treated  plates were first  cold  incubated (4°C) for
24 hours and then incubated  at 37°C overnight.    Inhibition of growth due to
DNA damage was measured  in both  the wild  type  H17  (rec+) and the sensitive
type (rec-) strains.  The  difference  in growth  inhibition between  the wild-
type strain and the  sensitive  strain was less than  4 mm, which was  considered
to indicate a negative response.
     Nishioka (1975)  detected  no rec effect  in Bacillus  subtil is  using nickel
chloride.

7.4.2  S-Phase-Specific Cell  Cycle Block
     Costa et al. (1982a)  investigated the ability  of water-insoluble nickel,
crystalline nickel subsulfide  (Ni3$2),  crystalline  nickel monosulfide (NiS),
crystalline nickel selenate  (Ni-Se,,),  and  crystalline nickel oxide  (NiO) to
induce cell cycle block  in Chinese hamster ovary (CHO) cells, using the flow
cytometric technique.  All  these  compounds  induced S-phase-specific cell  cycle
block.    At  higher concentrations,  nickel  subsulfide (10 ug/ml)  and nickel
selenate (5 ug/ml) also caused accumulation of cells in mitosis.   This appears
to indicate that nickel  subsulfide and nickel selenate, in addition to blocking
cells in the S-phase, also inhibit mitosis.

7.4.3  Mammalian Cell Transformation Assay
     Sunderman (1983) has  published an extensive review  of morphologic  cell
transformation induced by nickel  compounds
     DiPaolo and  Casto (1979)  evaluated nickel along with 44  other  metals for
its  ability  to induce morphologic  transformation in Syrian  hamster embryo
cells  ijn vitro.   Nickel  subsulfide (Ni-S,,)  induced a positive response in
these studies, whereas amorphous NiS gave  negative  results in the transforma-
tion assay.
     DiPaolo and Casto (1979) also found that when divalent nickel was adminis-
tered to pregnant Syrian hamsters on day 11 of gestation, morphologic transfor-
mation was observed  in cell cultures derived from 13-day-old embryos. Costa et
al. (1979) showed that morphologic transformation induced by nickel subsulfide
in Syrian  hamster embryo cells was dose-dependent.   These transformed cells
induced  fibrosarcomas when implanted  subcutaneously into "nude"  mice.   Costa
                                    7-17

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et al.  (1982b) found that soluble nickel chloride (NiCK) induced morphologic
transformation of Syrian hamster  embryo cells.   Saxholm et al . (1981) found
that nickel subsulfide (Ni-S?) induced morphologic transformation in C3H/10T1/2
cells.  Hansen and  Stern  (1982)  studied the activity of nickel dust, Ni^Sp,
nickel  trioxide  (Ni203),  nickel  oxide  (NiO), and  Ni(C2H302)2 for iji vitro
transformation of  Syrian  hamster BHK-21 cells.   These  compounds varied  in
their potency to  transform  the cells but produced the same number of trans-
formed colonies at the same degree of toxicity (50 percent survival).
     The synergistic effects  of  nickel  compounds with benzo(a)pyrene (BP) to
induce  morphologic  transformation in  Syrian  hamster embryo cells were studied
by Costa and  Mollenhauer  (1980)  and  Rivedal and Sanner (1980, 1981).  Costa
and Mollenhauer  found  that  pretreatment of  cells with BP  enhances  cellular
uptake  of Ni,Sp particles.   Rivedal  and Sanner found that a combined treatment
of NiSO, and BP results in a transformation  frequency of 10.7 percent, compared
to 0.5  percent and 0.6 percent for the  individual substances.
     Nickel-induced morphologic  cell transformation  may  be due to  somatic
mutations, because there is suggestive  evidence of nickel-induced gene mutations
(Amacher and  Paillet,  1980) and chromosomal aberrations (Larramendy et  al.,
1981) in cultured mammalian cells.

7.4.4   Biochemical Genotoxicity
      Sunderman  (1983)  has  reviewed  the biochemical  genotoxicity of nickel
compounds.  Sigee  and  Kearns  (1982)  demonstrated  that nickel  in  the  chromatin
of  dinoflagellates  associated with  high-molecular-weight proteins and nucleic
acids.   Kovacs  and Darvas  (1982) demonstrated the  localization  of  nickel in
centric! es  of  HeLa cell  cultures.  Hui and  Sunderman (1980)  found 0.2 to 2.2
     CO
mol   Ni/mol  of DNA nucleotides  in  DMA  isolated  from  liver  and kidney of rats
treated with  63NiCl2  or 63Ni(CO)4.    Ciccarelli  and Wetterhahn (1983) demon-
 strated  nickel-nucleic  acid-histone complexes in  liver  and  kidney of
 treated  rats.   They proposed that nickel  may initiate DNA damage by forming a
 covalent nickel-DNA  complex.
      Ciccarelli  and Watterhahn (1982) demonstrated DNA-protein crosslinks and
 DNA  strand  breaks  in kidney  cells  of  rats  exposed  to  NiCO-j.   In  Chinese  hamster
 ovary cells,  crystalline NiS was  found to induce  DNA strand  breaks  (Robinson
 and  Costa,  1982).   However, DNA  strand breaks  should not be accepted as the
 principal  evidence  of  direct  DNA  damage  by metal compounds, since  strand
                                     7-18

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breaks can also be  produced by indirect, nonspecific effects, such as intra-
cellular release of lysosomal nucleases (Levis and Bianchi, 1982).
     Zakour et al.  (1981)  studied the effect of nickel  in the DNA infidelity
assay and found that cations of nickel increase misincorporation of nucleotide
bases in the daughter strand of DNA that is synthesized i_n vitro from synthetic
polynucleotide templates by microbial polymerases.
     The effects of  nickel  cations on transcription of  calf  thymus DNA and
phage t.  DNA  by RNA polymerase from  E.  coli  B were studied  by Niyogi  and
Feldman (1981) under  carefully controlled conditions.   These studies demon-
strated that  nickel  ion concentrations which inhibited overall  transcription
increased RNA chain initiation.
     The  studies  cited demonstrate  that nickel compounds induce  genotoxic
effects. The  translation  of these effects into actual  mutations, however, is
still not clearly understood.
                                    7-19

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7.5  REFERENCES
Amacher, D. E.;  Paillet, S. C. (1980) Induction of trifluorothymidine-resistant
     mutants  by  metal   ions  in L5178/TK /"cells.  Mutat.  Res. 78: 279-288.

Anderson, 0. (1983) Effects of coal combustion products and metal compounds on
     sister chromatid  exchange (SCE)  in a macrophage cell line.  EHP Environ.
     Health Perspect.  47: 239-253.

Christie, N. T.; Costa, M. (1983) Iri vitro assessment of the  toxicity of metal
     compounds.  Biol.  Trace Elem. Res. 5: 55-71.

Ciccarelli, R. B.; Wetterhahn, K. E. (1982) Nickel distribution and DNA lesions
     induced  in  rat tissues  by the carcinogen  nickel  carbonate.  Cancer Res.
     42: 3544-3549.

Ciccarelli, R.  B. ; Wetterhahn, K.  E.  (1983)  Isolation  of  nickel-nucleic acid-
     protein  complexes  from  rat tissues (abstract). Proc.  Am.  Assoc.  Cancer
     Res. 24:  45.

Costa, M. ; Mollenhauer, H. H.  (1980) Phagocytosis  of nickel subsulfide particles
     during the  early  stage  of neoplastic transformation  in  tissue  culture.
     Cancer Res. 40:  2688-2694..

Costa,  M.;  Nye, J. S.;  Sunderman,  F.  W., Jr.;  Allpass,  P.  R.;  Gondos, B.
     (1979) Induction  of  sarcomas  in nude mice  by implantation of Syrian
     hamster  fetal  cells  exposed  iji vitro to  nickel  sulfide.  Cancer  Res.
     19: 3591-3596.

Costa, M.; Cantoni, 0.; deMars, M.; Swartzendruber, D. E.  (1982a) Toxic metals
     produce  an  S-phase-specific cell.cycle  block. Res.  Commun.  Chem.  Pathol.
     Pharmacol.  38: 405-419.

Costa,  M. ;  Heck, J.  0.;  Robinson,  S.  H. (1982b)  Selective phagocytosis  of
     crystalline metal  sulfide particles and  DNA strand  breaks  as a  mechanism
     for the  induction of cellular transformation. Cancer Res.  42:  2757-2763.

Deknudt, G. H.;  Leonard, A.  (1982) Mutagenicity  tests with nickel salts  in the
     male mouse. Toxicology  25:  289-292.

DiPaolo, J. A.; Casto,  B.  C.   (1979) Quantitative  studies of iji  vitro morphologi-
     cal  transformation of  Syrian  hamster cells  by inorganic  metal  salts.
     Cancer Res. 39: 1008-1013.

Green,  M.  H.  L.; Muriel,  W.   J.;  Bridges,  B.  A.  (1976)  Use of a simplified
     fluctuation test  to detect  low  levels of mutagens. Mutat.  Res.  38:  33-42.

Hansen,  K. ;  Stern, R.  M.  (1982) Iri vitro and transformation potency of nickel
     compounds.  Danish Welding Institute,  Copenhagen,  Report  No.  82/22;  pp.  1-10.
                                     7-20

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Hsie, A. W.; Johnson, N.  P.; Couch,  D.  B.;  San  Sebastian,  J.;  O'Neill,  J.  P.;
     Hoeschele, J.  D.;  Rahn, R. 0.; Forbes, N. L. (1979) Quantitative mammalian
     cell mutagenesis and a preliminary study of the  mutagenic potential  of
     metallic  compounds.  In:  Kharasch, N., ed.  Trace  metals  in  health and
     disease. New York,  NY: Raven Press; pp. 55-69.

Hui, G.; Sunderman, F.  W., Jr.  (1980) Effects of nickel compounds on incorpora-
     tion of thymidine-3H into DNA in  rat  liver and kidney.  Carcinogenesis
     1:  297-304.

Jacquet, P.; Mayence, A.  (1982)  Application of  the  i_n  vitro  embryo  culture to
     the study of the mutagenic effects of  nickel in male germ  cells. Toxicol.
     Lett.  11:  193-197.

Kanematsu,  N.;  Hara, M.;  Kada,  T. (1980) Rec assay and mutagenicity studies  on
     metal  compounds.  Mutat. Res. 77: 109-116.

Kovacs,  P.; Darvas, Z.  (1982) Studies on the Ni content of the  centriole.  Acta
     Histochem. 71: 169-173.

Larramendy, M.  L.; Popescu, N.  C.; DiPaolo, J. A. (1981) Induction by inorganic
     metal  salts of  sister chromatid exchanges and chromosome  aberrations in
     human  and Syrian  hamster  cell  strains.  Environ.  Mutagen.  3:  597-606.

LaVelle, J. M.; Witmer,  C. M. (1981) Mutagenicity of N1C1, and  the analysis  of
     mutagenicity  of metal  ions in a bacterial  fluctuation  test (abstract).
     Mutat. Res.  3: 320.

Levis, A. G.; Bianchi,  V.  (1982) Mutagenic  and cytogenetic effects of chromium
     compounds.  In: Langard, S. , ed. Biological and environmental aspects of
     chromium.    Amsterdam,  The Netherlands:  Elsevier  Biomedical  Press;
     pp. 171-208.

Mailhes, J.  B.  (1983)  Methyl mercury effects  on Syrian  hamster metaphase II
     oocyte chromosomes.  Environ. Mutagen.  5:  679-686.

Mathur,  A.  K.;  Dikshith,  T. S.  S. ; Lai, M.  M.; Tandon, S. K. (1978) Distribution
     of nickel  and cytogenetic changes  in poisoned rats. Toxicology 10:  105-113.

Miyaki,  M. ;  Akamatsu,  N.  ; Suzuki, K. ;  Araki, M.; Ono, T. (1980)  Quantitative
     and qualitative changes  induced in DNA  polymerase  by carcinogens.  In:
     Gelboin,  H.  V.  Genetic and environmental  factors in environmental and
     human cancer. Tokoyo, Japan: Science Society Press; pp. 201-213.

Newman,  S.  M.;  Summitt, R.  L.;  Nunez, L. J. (1982) Incidence of nickel-induced
     sister chromatid exchange. Mutat.  Res. 101: 67-74.

Nishimura, M.;  Umeda, M.  (1979)  Induction of chromosomal aberrations in cultured
     mammalian cells by nickel  compounds. Mutat. Res.  68: 337-349.

Nishioka,  H.  (1975) Mutagenic  activities  of  metal  compounds  in bacteria.
     Mutat. Res.  31: 185-190.
                                    7-21

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Niyogi, S. K. ; Feldman, R. P. (1981) Effect of several metal  ions on mis-incor-
     poration during transcription. Nucleic Acids Res. 22: 9-21.

Ohno,  H. ;  Hanaoka, F. ; Yamada,  M.  (1982) Inducibility of sister  chromatid
     exchanges by heavy metal ions.  Mutat. Res. 104: 141-145.

Pikalek,  P.; Necasek,  J.  (1983)  The  mutagenic activity  of nickel  in
     Cornebacterium sp_.   Folia Microbiol. (Prague) 26: 17-21.

Rivedal, E.;  Sanner, T. (1980) Synergistic effect on morphological transforma-
     tion  of  hamster  embryo  cells  by  nickel  sulfate  and  benz(a)pyrene.  Cancer
     Lett. 8: 203-208.

Rivedal, E.;  Sanner, T. (1981) Metal salts as promoters of i_n vitro morphological
     transformation of  hamster embryo  cells  induced  by benzo(a)pyrene.  Cancer
     Res. 41: 2950-2953.

Robinson,  S.   H. ;  Costa, M.  (1982) The  induction of  DNA strand  breakage by
     nickel  compounds  in  cultured Chinese hamster ovary  cells.  Cancer Lett.
     15: 35-40.

Robinson, S.  H. ; Cantoni, 0.; Heck, J. D. ; Costa, M.  (1983) Soluble and  insolu-
     ble nickel compounds induce DNA repair  synthesis in  cultured  mammalian
     cells. Cancer Lett.  17: 273-279.

Saxholm, H.  J.  K. ;  Reith, A.; Brogger,  A.  (1981) Oncogenic transformation and
     cell lysis in C3H/10T1/2 cells and  increased sister chromatid exchange  in
     human lymphocytes by nickel  sulfide. Cancer Res. 41: 4136-4139.

Sigee,  D.  C. ;  Kearns,  L.  P.  (1982)  Differential retention of proteins  and
     bound divalent  cations in  dinoflagellate  chromatin  fixed under varied
     conditions: an x-ray microanalytical study. Cytobios 33: 51-64.

Singh,  I.  (1983)  Induction  of reverse  mutation  and mitotic gene  conversion by
     some metal compounds in Saccharomyces cerevisiae. Mutat. Res. 117:  149-152.

Sunderman, F. W. ,  Jr.  (1981) Recent research on nickel  carcinogenesis.  EHP
     Environ. Health Perspect. 40: 131-141.

Sunderman, F.  W. , Jr.  (1983) Recent  advances in metal carcinogenesis.  Ann
     Clin. Lab.  Sci. 13:  489-495.

Umeda,  M. ; Nishimura,  M.  (1979)  Inducibility of chromosomal  aberrations  by
     metal compounds  in  cultured  mammalian  cells.  Mutat.  Res. 67: 221-229.

Waksvik, H.;  Boysen, M. (1982) Cytogenetic analysis of lymphocytes from  workers
     in a nickel refinery. Mutat.  Res. 103: 185-190.

Watanabe,  T.  ; Shimada,  T. ;  Endo,  A. (1979)  Mutagenic  effects of cadmium on
     mammalian oocyte chromosomes. Mutat. Res. 67: 349-356.

Wulf,  H.  C.  (1980)  Sister chromatid exchanges in human lymphocytes  exposed to
     nickel and lead.  Dan. Med.   Bull.  27: 40-42.
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Zakour, R.  A.;  Tkeshelashvi'11,  L.  K. ;  Sherman, C. W.; Koplitz, R. M. ;  Loeb,
     L. A.  (1981)  Metal-induced infidelity of  DMA synthesis. J.  Cancer Res.
     Clin. Oncol. 99: 187-196.
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                     8.   CARCINOGENIC EFFECTS OF NICKEL
     A large number of experimental, clinical, and epidemiologic studies have
been conducted over the years to determine the role of various nickel compounds
in occupational and experimental carcinogenesis.  These studies have been the
subject of a  number  of reviews (Mastromatteo, 1983;  Sunderman, 1981; Wong et
al.,  1983;  National  Institute  for  Occupational  Safety and  Health,  1977a,
1977b; International  Agency for Research on Cancer, 1972,  1976, 1979; National
Academy of Sciences,  1975).

8.1  EPIDEMIOLOGIC STUDIES
     The  epidemiologic  evidence on  nickel  carcinogenesis in  humans,  with
particular regard to specific  nickel  species, is reviewed in  this section.
The epidemiologic studies reviewed are organized on the basis of the worksites
involved.  The  study  designs,  results,  and conclusions are  summarized and
critiqued.  An attempt  is  made to delineate the actual nickel  exposures that
occurred  at each worksite  as the result of the processes  in use at that work-
site during the  time periods studied,  based  on information contained  in the
reports reviewed.

8.1.1  Clydach Nickel  Refinery (Clydach, Wales)
     The  Clydach  Nickel  Refinery opened  in 1902 in the  County  Borough of
Swansea,  South Wales, Britain.  Nickel was refined at  Clydach  by the carbonyl
process,  and a number  of changes in the  production  process  have been made
since the plant was opened.  Nickel  ore used by the plant  was mined and partial-
ly refined in Canada.   The first epidemiologic investigation  of cancer risk  at
the Clydach plant was  reported in 1939 (Hill, 1939, unpublished).  This was
followed by a series  of studies between 1958 and 1984.
     Morgan (1958) has  provided the  most detailed description of the production
process and related exposures  at the Clydach plant.   There were essentially
six steps in the refining  of nickel at Clydach:  (1) crushing  and grinding of
the matte; (2) calcination (oxidation  by heating)  of the  matte,  resulting in
the production of mixed  oxides  of copper  and  nickel; (3)  copper extraction of
the matte using sulfuric acid;  (4) reduction of the nickel oxides to  produce
impure nickel powder;  (5)  volatilization  of the reduced  nickel using  carbon
monoxide  gas to produce  nickel  carbonyl;  and (6) decomposition,  in which the
                                    8-1

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nickel  carbonyl  is  precipitated onto  nickel  pellets to form  pure  nickel,
releasing carbon monoxide in the process.
     Arsenic was a contaminant of the sulfuric acid used to remove copper from
the matte.   The amount of arsenic in the acid  peaked between 1917 and 1919 and
declined significantly after 1921.   In  1924, all of the remaining "old stock"
of acid which contained arsenic was used.   Since 1926,  the  acid was  practical-
ly free of arsenic.
     After the  decomposition  step,  the residue was sent to  a  concentration
plant where  it  was  calcined and copper and nickel were extracted using  sul-
furic acid.  This resulted  in a matte which had a relatively high concentra-
tion of  precious metals.  In the reduction and  volatilization process and the
decomposition step, the  matte  had a very low concentration of copper due to
prior extraction with sulfuric acid.
     The  following  changes  occurred  between  1902 and  1957 with regard  to
worker exposures.   The  use  of sulfuric acid with a high  concentration  of
arsenic  was  discontinued after 1924.  A plow type  of  calciner was employed
from 1902  to 1911.   It was changed  to  "double  deckers with rotary rakes in
1910 which,  although  very dusty, constituted an  improvement over the first
type" (in  terms of  decreasing  exposure) (Morgan,  1958).  In 1922, cotton nose
and mouth  respirator  pads were issued; in 1924, calciners  were shortened and
improved,  although  it is not stated how the  improvements  affected  exposure;
in 1929, the copper sulfate plant was closed down; in 1934, the composition of
the matte was changed to  include only 2 percent copper as compared to 35 percent
and 2 percent sulfur compared to 20  percent; in 1935, electrostatic precipitators
were added which diminished the amount of  dust emitted from the stacks.   In
addition,  the  crushing and  grinding operations were centralized in a single
plant.   The  author  notes  that the plant was "virtually dust free" (Morgan, 1958).
Prior to this  time, crushing and  grinding  had  been  done separately,  and the
operations  were characterized as "very dusty."   In  1936,  new  calciners  were
installed.   The old type had  led  to underground  flues which needed frequent
cleaning.   The  author  stated,  "It  is significant that most of the nasal  cancers
occurred amongst men  who were  engaged  in cleaning those flues.    The new  calciners
are  in well-ventilated rooms and the flue gases from these calciners  are taken to
two  large  electrostatic  precipitators"  (Morgan, 1958).
     The exposures  to nickel species and other substances  varied according to
the  type of work performed  and by calendar time at the Clydach plant.   In
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addition,  since  the residue  from the  carbonylation  extraction was passed
through  the  complete refining process  several  times,  the concentrations of
other  metals,  such  as  cobalt,  selenium,  and  precious metals,  increased.
Table 8-1  provides  some  descriptive  information on exposures associated with
different work areas (Morgan, 1958; INCO, 1976).
     Five  different populations  at  risk (PAR) from  the  Clydach plant are
described  in the seven reports which were issued between 1939 and 1983 and that
are reviewed  here.   Hill  (1939) defined an approximate  PAR employed at the
plant from 1929 to 1938 in order to obtain a rough estimate of the standardized
mortality  ratio (SMR) for lung and nasal cancer.  The analysis is presented as a
cohort investigation, but is more likely a proportionate mortality ratio (PMR)
study.   Hill's investigation is described by Morgan (1958) in some detail.   In
addition, Morgan also provides the only complete description of the cohort and
total  PAR  from  the Clydach plant.  Between 1902  and  1957,  there were 9,340
"new entrants" to  the  plant.   Morgan (1958) identified  2,094 who worked at
least one  year.   His study gives important background  information  which is
useful  in  interpreting reports  issued between  1970 and 1984.  A  third  PAR was
defined by Doll  (1958),  who published  a PMR study  of lung and nasal cancer
occurring  in  four  "local  authority districts"  in South Wales.  The study was
initiated  to  investigate  risks  in the nickel industry, which  by  definition  in
South Wales was the Clydach plant.
     The fourth  PAR is  a less definitive  subset  of  the  cohort described by
Morgan (1958).   It  includes  those likely to have been  employed at least 5
years between 1902  and  1944,  and who were  employed  as of 1939 (1934 in two
reports).  The definition  of  this PAR,  with regard to exposure  and calendar
time of  employment,  must  be given careful  consideration when  interpreting the
risk estimates.
     A fifth PAR was described by Cuckle et al. (1980), who studied workers in
the Wet Treatment Plant and the Chemical Products Department.   Details on each
of the PARs,  results, and methodologic issues  pertaining to the interpretation
of results are discussed below.
8.1.1.1  Hill (1939, unpublished).  This was the first epidemiologic study of
the Clydach plant workers, and was summarized  by Morgan (1958).  The study is
noteworthy because  it identifies  the  risks associated with the  nickel refi-
nery.   It provides no risk estimates  by  species of nickel.
                                    8-3

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     The population at  risk  was  not defined per se,  but the age distribution
and number  of employees over  time  was estimated from  pension  records  and
employee lists for two  different  dates,  1931 and 1937.  Sixteen lung and 11
nasal   cancer  deaths were  identified,  but  the  follow-up method  was not
described and it is not known exactly  how the deaths corresponded to the PAR.
Nonetheless, measures  of  risk were  derived  by  applying age-specific death
rates  for England and  Wales  to the  age-specific groups of the "approximate"
PAR.   The observed-to-expected ratio was  16 (16/1)  for lung  cancer and greater
than 11  (11/<1)  for  nasal  cancer.   The excess  lung  and nasal  sinus cancer
deaths were  almost  exclusive  to  process workers;  no  nasal  cancer deaths
occurred among non-process  workers.
               TABLE 8-1.   EXPOSURES BY WORK AREA (CLYDACH,  WALES)
     Work area
      Exposures
Level
Changes
Crushing, grinding
and calcining shed
Dust, nickel, oxides,     Very high
S02, copper, sulfur
Copper extraction
Copper sulfate,
arsenic (contaminant)
Reduction, volatil-
ization,
decomposition
Nickel powder, nickel
carbonyl, CO
            Greatly reduced
            after 1930 from
            separation of
            crushing and
            grinding oper-
            ations and
            improvements
            in production.

            The arsenic
            levels in the
            sulfuric acid
            used for copper
            extraction
            peaked between
            1917 and 1919.
            The levels de-
            clined dramati-
            cally after 1921.
            Since 1926, the
            acid was prac-
            tically free of
            arsenic.
                                    8-4

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     This  study  documents  the fact of excess  risks  in the nickel refining
plant at Clydach.  The PAR was not well defined, nor was the identification of
deaths well described.   The  risks for lung and nasal sinus cancer among pro-
cess workers  were very  high,  and it is unlikely that  they were spurious.
8.1.1.2  Morgan  (1958).  This  was a  study of workers employed at  least 1 year
at the Clydach  refinery  between 1902 and 1957-  The paper  provides the only
detailed description of the total cohort entering the plant, and the most com-
plete description of the nickel refining process and changes in the plant over
its 55 years of operation.
     No analysis of risks was presented.   Descriptive statistics were reported
on the number of employees and the number of deaths  from lung and  nasal sinus
cancer by  calendar period of first employment, length of  employment,  and
department.  The  investigation suffers from a  lack of detail on the method of
follow-up.   The  report contains detailed reference information on the occur-
rence of deaths,  the  size  of the cohort, and possible risks by calendar time
and department.   It does not appear that this data set has  been fully exploited,
since information  on  the jobs held  and  length of employment appear  to  be
available on all employees.
     The total number of new entrants into the plant between 1902 and 1957 was
9,340.   The company had a pension plan involving annual visits  which enabled it
to keep  records  of all pensioners wherever their  place of residence.  The
author did  not  state,  however, how many years one had to work  to be eligible
for a pension.   When  a pensioner died,  it was necessary  for dependents to
furnish a  death  certificate  in order to obtain death benefits.   The cause of
death was therefore recorded in every case.
     Exposure was  defined  in  terms  of category of work or  process,  and in
terms of total  length  of employment.  These factors were considered indepen-
dently,  and no measure of exposure which incorporated both  department or type
of process  and length of employment was provided.
     The report  provides information  on  the number of  workers  and cases  of
lung cancer by year of entry  and  number of years of service.  Out  of approxi-
mately 2,100 workers entering  the plant between 1902 and 1929,  1,240 worked 1
to 10 years, 79  worked  11  to 20 years, and 780 worked over 20  years.   Fifty-
three employees  entered the plant between 1900 and 1904, 178 between 1905 and
1909, 269  between  1910  and  1914, 667 between 1915 and 1919, 602 between  1920
                                    8-5

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and 1924, and  326  between  1925 and 1929.  Table 8-2 shows the percentage of
workers diagnosed with  nasal  or  lung cancer by year of entry and length of
employment.   The risk of  nasal  cancer appears  to  have  been highest for those
first employed between  1905  and  1914.   The rate of nasal cancer among those
first employed between  1900 and 1904 is  low in comparison with other periods.
However, only  53 employees  worked more than 1 year  and were first employed
during this time period.   The pattern for lung cancer  is somewhat different
than that for nasal cancer by year of entry and length  of employment.   Workers
starting between 1900 and  1904 had a  rate similar  to  those first employed
between 1905 and 1914.   Individuals entering between 1900 and 1904 and working
less than 10 years  had  the highest rate,  20 percent,  as compared to those
entering during other periods and working  less than 10  years.  All subsequent
cohorts, defined by  year  of entry and working for 1 to 10 years,  had a  lung
cancer rate of close to zero.  The rates for both nasal and lung cancer were
high for those first employed between  1900 and 1924.  The risk for both  types
of cancer dropped  dramatically  among those first employed  between 1925  and
1929.
     The study  shows the  distribution of cases of  lung and nasal cancer by
department or  process.  The calcination  and copper sulfate departments appear
to have  had the highest risks of  lung  cancer of the eight departments  listed.
The  rate of  nasal  cancer  was highest  in the calcination department (14/58),
followed by the furnace (5/36) and copper  sulfate (8/87) processes.  However,
it is difficult to interpret these rates, since the denominator is not clearly
defined.  To estimate  rates,  an average annual population  size was derived,
but the means  used to derive this average are not clear.  It could be an average
number of person-years  or an average number of persons.
8.1.1.3  Doll  (1958).   This was a community-based study  of four local  authority
areas  in South Wales,   in  which nickel  industry workers, i.e., Clydach plant
employees, were  compared  to  workers  in other  occupations,  excluding  steel
industry workers, coal  miners, and selected industrial   occupations such as oil
refinery workers, aluminum workers, and copper smelter  workers.
     Cases were  identified  from death records, and were divided into three
groups:  lung  cancer,  nasal  cancer,  and all other  causes  of death.  Between
1938 and  1956, 48  lung  cancer cases  and 13 nasal  cancer cases  were identified
and  categorized  by the occupation listed on the death  certificate.  Analyses
were presented for nickel  industry workers as a whole,  compared to all  other
                                    8-6

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           TABLE  8-2.   PERCENT OF  LUNG  AND  NASAL  CANCER  DEATHS  AMONG
        WORKERS BY YEAR OF ENTRY AND  LENGTH OF  EMPLOYMENT  (CLYDACH, WALES)
Year of
entry
1900-1904


1905-1909


1910-1914


1915-1919


1920-1924


1925-1929


Length of
employment
1-10
11-20
20+
1-10
11-20
20+
1-10
11-20
20+
1-10
11-20
20+
1-10
11-20
20+
1-10
11-20
20+
Percent
Nasal
-
-
2
0
100
9
2
28
19
0
13
4
1
5
2
0
0
0
of workers
Lung
20
14
15
0
16
23
0
22
21
0-2
20
6
1
21
13
0.5
0
0
Source:   Adapted from Table 9 of Morgan (1958).

occupations, and process  and nonprocess  nickel  workers compared to all  other
occupations.
     Analysis by calendar  time  in two of the local authority areas showed a
decline in  the  PMR  for lung cancer from 1,379 for the period 1938 to 1947 to
666 for the period 1948 to 1956.  The author suggests that the decline in the
PMR between these two  periods does not necessarily reflect a decline in the
risk of lung cancer among  nickel workers.  He suggested that the decline can,
in part, be accounted for by a dramatic rise in the national  lung cancer rate,
which was due largely to the increased prevalence of smoking.   The excess lung
cancer risk, i.e., the difference between the observed and expected risk, for
the two time periods noted above is constant,  supporting the idea of no declining
                                    8-7

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risk in the  industry.   The  PMR overall for nasal cancer was extremely high,
ranging from 19,600 to 24,200,  depending upon  the local  areas which were  included
and the time period of coverage.   The PMR for  lung and nasal  cancer was higher for
process (defined as "processman"  or "process worker"  on the death certificate) vs.
nonprocess workers. The lung cancer PMR for process workers was 700 vs.  340 for
nonprocess workers.  The  nasal cancer PMR was 30,000 for process workers vs.
12,000 for nonprocess workers.
8.1.1.4  Doll et al. (1970).  This  is  the first of a series of three papers
on the mortality  risks  among a select group  of  Clydach plant workers.   The
definition of the  cohort  was different from  that used by Morgan (1958), who
described the complete  cohort,  i.e., all workers  entering  the plant up to
1958.   The cohort  studied by Doll et al.  was  defined as men "likely" to  have
been employed for at least 5 years, who started between 1902 and 1944, and who
were alive and  employed as  of April, 1934.   Workers  listed on at least  two
consecutive  paysheets  5 years  apart, i.e., April  of  1934,  1939, 1944, and
1949,  were  included in  the cohort.  Given this  definition,  workers first
employed before 1934  must have been employed  longer than 5 years to meet the
cohort criteria.   For  example, a worker who  started  in  1924 must have been
employed 15  years  to  be included in the cohort, since, by definition, he was
working in April  of 1939.  Length of employment  and extent  of exposure were
thus highly  correlated with year of first employment,  and therefore any
inference regarding risks by calendar time of first employment is  necessarily
confounded by length of employment.
     Of a total  of 845 men who met the cohort  criteria, 563 began their employ-
ment before  1925,  77  between 1925 and 1929,  and  the remaining 205  during or
after 1930.  The  follow-up  period was 28 years,  from  1939 to 1967,  during
which  113  lung  and  39 nasal cancer cases were  identified.  Twenty-seven
workers were lost to follow-up.  Analyses were presented by age at first expo-
sure,   calendar  time of  first  exposure, and  calendar  time  of observation.
Expected  values  for the  analysis  by time of   first exposure  were  based  on
general population  rates  from  England and South  Wales, while  values  for the
analysis by  age of first  exposure  and calendar time of  observation  were  based
on an internal  reference group.
     The report noted the observed to expected values by year of first employ-
ment for  nasal  cancer,  lung cancer, other neoplasms, and all other causes of
                                    8-8

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death.   All 39 nasal sinus cancer cases occurred among those starting employ-
ment before 1925.   The  overall  SMR was 364 for workers starting before 1925,
and ranged from a low of 116 among those starting between 1920 and 1924, to  a
high of 870 for  those  starting between 1910 and  1914.   The SMR for workers
starting before 1910 or  after  1914,  although still extremely high, was less
than half that for the  group starting between 1910 and 1914.
     Only eight of  the  113  lung cancer cases occurred among those starting
employment on or  after  1925.   The SMR for workers  starting before 1925 was
750.  The SMR for those starting before 1915 ranged  from 950 to 1,005 and
dropped to 570 to 630 among workers entering during or after 1915.   This trend
may have  been somewhat  confounded  by length of  employment,  since workers
starting before 1915 were  probably employed for  longer periods of time than
those starting during or after 1925.
     The overall  SMR for lung  cancer for those starting during or after 1925
was 130, which was  considerably less than the SMR  for those starting before
1925.   However,  the length of the follow-up period was not as long for workers
starting after 1924.  In addition, because of the way  the cohort was defined,
the average length  of  employment was not as long for workers starting after
1924.  The  analysis  by age  at  first exposure,  which is  limited  to workers
starting before 1925,  shows  a  direct relationship  between the risk of nasal
cancer and the age  at first exposure.  In contrast, and except for the young-
est age group,  i.e.,  less  than 20 years of  age,  there was a slight inverse
relationship between the risk of lung cancer and age at first exposure.
     Analyses in  the Doll et al.  (1970) study were  also presented by calendar
time of observation.  The statistics given are difficult  to  interpret because
of  the  long  interval during which subjects entered the cohort,  i.e., 1902 to
1924.   Nonetheless, the  risk  for nasal cancer appears to have declined with
time since exposure, or, as the authors state,  "after the disappearance of the
carcinogen after 1924."
     In this  study, the  risk for  lung  cancer is clearly seen to have declined
with calendar time.  Again,  however, the interpretation could have been more
straightforward  if  the analysis  had been carried  out by time  since first
exposure.   The authors  suggested  that  the pattern of risk for lung cancer  and
age at first exposure may have been due to the differences in smoking patterns
among different cohorts.   In  essence,  even if the  risk  of lung cancer from
                                    8-9

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nickel  exposure were constant over time,  the attributable risk for lung cancer
from nickel exposure would  decline  with  time because of a higher risk due to
the increasing prevalence of  smoking.  This constitutes a plausible explana-
tion for the pattern  noted  in the Doll et al.  (1970) study (which assumes an
additive effect for nickel  and smoking).
     The virtual  absence of  nasal  cancer among those  starting  employment
during or after 1925, and the dramatic decline in the risk of lung cancer for
those starting  during  or after  1925,  suggest that  significant  changes  in
exposure to various species  of  nickel  and possibly other substances, such as
arsenic, may  account  for these  declines.    In addition,  the  significantly
elevated SMR for nasal cancer noted among those workers starting between 1910
and 1914 suggests  that  some change may have occurred during that time.   Some
notable process changes  are:  (1)  Before 1932, the partially refined ore imported
from Canada  contained  a high proportion  of copper and sulfur,  as  well  as
precious metals, in the  nickel sulfide  matte.  After that time,  the copper and
sulfur content of the ore from Canada was significantly reduced.   (2) In 1924,
a new type of  calciner  was  used, and sometime between  1922 and  1924, cotton
respirators were  introduced.   These may  have reduced  exposures  to larger
particles,  which would  normally  deposit  in  the  nasal  sinus  area.   (3) The
level of arsenic  in  the  sulfuric acid used  to  leach copper from the nickel
matte reached a peak  between 1917 and 1919, and declined dramatically after
1921.  These changes, however, are  not seen as having  any direct correspon-
dence to the changes in  lung cancer risk.
8.1.1.5  Doll et al. (1977).  This  is an update of the  study reported in 1970
by Doll et al.   The follow-up period was extended to 37 years,  from 1934 to
1971.  The definition of the cohort was  changed slightly to include all men
likely  to  have  worked  at least 5 years  as  of 1929  or  later.   This change
increased the number of  workers  meeting  the cohort  criteria who entered the
plant before 1925  and decreased  the overall average length of employment for
this group.  However,  the group starting  before 1925 was still  highly selected
in that it was composed  of workers employed for more than 5 years.
     Nine hundred thirty-seven workers  met the cohort criteria,  in contrast to
845 in the previous report.   Thirty-seven were lost to follow-up, and 145 lung
cancer and 56  nasal  cancer  cases were  identified.   A slightly larger propor-
tion of the  cohort started  their employment before  1925  (68  percent vs.  66
percent) due to the change  in the cohort definition  between this and the 1970
(Doll) report.
                                    8-10

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     Expected values  for  lung and nasal cancer were derived by applying age-
and time-specific rates for England and Wales to the number of person-years of
follow-up.  Extremely  high  risks  were reported for nasal sinus cancer.  Even
with the extended follow-up to 1971, no new cases of nasal cancer were identi-
fied among  those workers  who  started  employment after  1924.  The  nasal cancer
SMRs by  starting  date were:  38,900 (<1910);  64,900 (1910 to 1914);  44,000
(1915 to  1919); and 9,900 (1920 to 1924).   The  peak SMR was among workers
starting between 1910  to  1914.   However, the difference  between  the  1910  to
1914 cohort and other groups defined by start date was not as great as was
noted in  the  1970 report  by Doll et al.  The  change may in part be due to  the
revised cohort definition.
     The magnitude  of  SMRs  and the pattern  for lung cancer by start date were
essentially the same  as  that reported in 1970, with one  exception.   The SMR
for those  first employed  between  1925 and 1929 was 360, more than twice that
reported previously.
     The authors suggested  that the use  of  respirators, which were introduced
in 1922  or  1923,  could account for the virtual  absence of nasal  sinus cancer
among workers starting employment after 1924.   It would be of interest to know
the extent of respirator use, and whether respirators were used throughout the
plant or only in selected  departments.   Such documentation  could provide
valuable information on species-specific risks.
8.1.1.6  Cuckle et  al. (1980, unpublished).    This  was  a cohort study  of 297
men who  had been employed for at least 12 months between  1937 and 1960 in  the
Wet Treatment Department  (WTD)  or Chemical  Products Department (CPD)  of the
Clydach  plant.  The WTD  and CPD opened  between 1937  and 1939.   None of the
cohort were employed  at  the Clydach plant  prior to 1933, when, according  to
the authors,  the  lung and nasal  cancer hazards  were "eliminated."  Follow-up
was from 1938 to 1980, during which 13 deaths from lung cancer,  13 deaths from
other cancers, and  79 deaths  from other causes occurred.   No  deaths due to
nasal sinus or  laryngeal  cancer  were identified.   Four subjects  were lost to
follow-up.
     Feed material  for the  WTD  originated  in the  nickel  carbonyl extraction
plant and was very high in nickel  content,  relatively low in copper and sulfur,
and high  in precious metals.  Products from the WTD operation included ferric
hydroxide, cobaltic  hydroxide, precious metal  residues, and copper sulfate and
                                    8-11

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nickel sulfate crystals.  The  CPD,  built in 1939, manufactured compounds and
salts of nickel,  cobalt, and selenium.   The raw materials used included nickel
oxide and black cobalt oxide from Canada, nickel sulfate and cobaltic hydroxide
from the WTD,  nickel powder and metal, cobalt metal, and selenium, as well as
a range  of  acids  and alkalies.  The end products included, in addition  to a
number of other substances,  salts  and hydrates of nickel and cobalt, nickel
cyanide, and cobalt ammonium sulfate.
     Personal  sampling  values  of total airborne nickel were obtained from the
WTD and  CPD  for  the period 1974 to 1978.  These  data showed that the nickel
levels for the mean, median, and maximum were two to three times higher in the
WTD than in  the  CPD.   It should be noted,  however,  that these measurements
were made 35  years  after the plant opened,  and may not be relevant to  the
exposures incurred earlier in the plant's history.
     SMRs were calculated by  multiplying  age-  and time-specific mortality
rates  for  England and Wales by the age-  and time-specific distribution of
person-years  for  the  study  cohort.   The SMR was  highest for those with  less
than 20  years since first exposure (SMR = 178), as compared to an SMR of 107
for those with more than 20 years' exposure.   Overall, those employed for 6
years  or more in  the plant had lower risks (SMR = 128 vs.  142).   The authors
indicate that the workers who were employed only in the WTD and the CPD had
the highest  risk  of lung cancer, with an  SMR  equal  to 207, as compared to
those who spent ^ 1 year of their working time in other departments.
     Overall,  this  study showed low risks for lung cancer, a small  number of
cases, and  very complex exposure circumstances.   Given these factors, and the
virtual absence of nasal sinus cancers in the cohort, this study is noteworthy
for its  contrast  to other studies with cohorts  of similar  size.  It  should be
kept  in  mind, however,  that for the Clydach  Plant  during this period,  the
relative risks for  lung cancer were declining and approaching unity, and that
no  nasal cancer  cases were identified among workers  whose employment began
after  1924.   The  patterns noted in the  WPD  and the CPD are thus consistent
with the pattern  of risk  for the plant overall.
8.1.1.7  Peto et  al.  (1984).   This was the  third  of  three  papers reporting on
the mortality risks among selected Clydach plant workers.  Peto et al. provide
the most extensive  analysis to date, using  regression methods  to adjust for
the  possible  confounding variables  noted earlier.   In  addition,  detailed
                                    8-12

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employment records were compiled to improve the precision of studying risks by
duration of employment in different work settings.   The risks of cancer of the
larynx, kidney, prostate, and stomach, as well as circulatory and respiratory
disease, were investigated,  in addition to cancer of the lung and nasal sinus.
The definition of  the  cohort remained the same  as  that reported in Doll  et
al., 1977; however, follow-up was extended to 1981.   There were 968 workers in
the cohort, 18 of which were lost to follow-up—a decline from the 37 that had
been reported in 1977 as being lost to follow-up.  One hundred fifty-nine  lung
cancer and 58  nasal  sinus cancer cases were  identified.  Much of the analysis
was restricted to workers first employed before  1925.   Both external (England
and Wales) and  internal  comparisons were used.  Exposure groups were defined
by occupation  and,  in  a separate analysis,  by  length  of employment in the
furnace and copper sulfate areas.
     Four occupations showed a statistically significant association with  lung
cancer, nasal  cancer,  or lung and nasal  cancer combined, after adjusting  for
age and calendar  time  of first exposure and testing for an association with
duration  in  job.   The  four  job categories, as defined by work area or opera-
tion, were:  the calcining furnace area,  the calcining crushing operation, the
copper  sulfate  area, and the Orford furnace  area.  A nested case-control
design was used in which individuals were identified with lung or nasal cancer
from the  nickel worker cohort,  and the controls comprised  all  of the other
workers.   In the  reduction  area of the plant, where the ambient nickel car-
bonyl  level  was  stated to be highest, no significant association was evident
for either lung  or nasal cancer, nor was there evidence of an association in
10 other  job categories.   Peto et al., however, found an excess risk of lung
or nasal  cancer  for the job categories in the furnaces and copper  sulfate
areas  of  the plant.   "Low"  and "high" exposure were therefore defined on  the
basis of duration of employment in these two areas  of the plant.  A worker was
considered to  have  had  "low  exposure"  if he  had  never  worked  in the  furnaces,
and had spent less than 5 years working in the copper sulfate areas.   A worker
had  "high exposure"  if he had  spent  any  time in the  furnace  area,  or had
worked for 5 or more years in the copper sulfate area.   The low-exposure group
was further  divided  into two ordinal categories, and the high-exposure group
was divided into four ordinal categories.
                                    8-13

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     The SMRs for  lung  cancer  ranged from 340 to  510  for those in the low-
exposure groups  and from 1,390  to 18,800 for those in the high-exposure groups.
These SMRs were  found  to increase with increasing duration of time spent in
the furnaces.  In  the  case  of  nasal  cancer, the  SMR was 14,700 to 22,000 for
those with low exposures and was 58,800 to 177,200 for those with high exposures.
The highest risk occurred for those workers who had spent more than 5  years  in
both the  furnaces  and the copper  sulfate areas.  For the workers  in the  high-
exposure group,   the lowest  risks  occurred among those who had spent less than
2 years  in the  furnaces and 5  or more years in the copper sulfate areas.
Although the  higher exposure groups, as defined,  showed an excessively  high
risk of lung and nasal  cancer,  the risks for these two tumors were not confined
to the furnaces  and the copper sulfate areas.
     Using the same definitions for low and high  exposures,  Peto et al. showed
statistically significant excess  risks  of death from circulatory  disease (p <
0.05 for  all  of  the workers between 1902 and 1944), bladder cancer (p < 0.05
for  the  high-exposure  group),  cerebrovascular diseases (p <  0.05 for the
high-exposure group), and respiratory  disease  (p <  0.05  for the  high-exposure
group).   The authors  noted  that  the death  rate  for circulatory  disease in
South Wales  was  the highest in  Britain, and  that  if  the  SMR for  cerebrovascu-
lar  disease  is  adjusted for local rates,  the  excess risk completely disap-
pears.
     In  addition to  the job categories of  calcining, Orford  Furnace,  copper
sulfate,  and crushing,   a fifth  group  labeled "absence" was significantly
associated with  nasal cancer (p < 0.01).  "Absence" was defined as "the number
of years  prior  to 1925  between  first and  last  employment in the  refinery when
a man worked  elsewhere."  The meaning of this variable in terms of exposure is
unclear.   It could reflect the  earlier workers'  movement  from process to
non-process  jobs,  or  it could  reflect  loss  of work days due to illness among
the  older workers. Additional  information on  these workers would be  required
in order  to  interpret the meaning of this variable.
     The  authors  presented  a  table (adapted  herein  as Table 8-3) showing
"simultaneous"  estimates of the dependence of  incidence on  age at first expo-
sure,  period of first exposure,  duration  in high risk  areas  up to 1924, and
time since first exposure.   These analyses were  based on internal comparisons
using  as the "standard  category" men  with  the lowest exposures who had been
first  employed  before  age  25 between  1902  and 1910  and  who had  been  observed
more than 50 years after first  exposure.  Nasal cancer showed  a  strong positive
                                     8-14

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                  TABLE 8-3.   CLYDACH, WALES NICKEL REFINERS:
              RELATIVE RISKS FOR LUNG AND NASAL CANCER MORTALITY IN
               PRE-1925 COHORT, ADJUSTING FOR CONCOMITANT FACTORS
                                  ,   Significance                  .   Significance
Risk factor            Lung cancer   level p          Nasal cancer    level p
Age first exposed (A)
<25
25-34
35+
Period first
<1910
1910-1914
1915-1919
1920-1924
Time since fi
<20
20-29
30-39
40-49
50+
Job category
Time in
copper sul-
1.00
1.27 NS
1.26
exposed (P)
1.00
1.33 NS
0.89
1.70
rst exposure (T) (years)
0.21
0.61
1.15 <0.001
1.25
1.00
(J):
Time in
furnaces
1.00
2.96
10.03

1.00
1.81
1.31
0.60

0.06
0.28
0.37
0.75
1.00




<0.001



<0.05





<0.01





fate (years) (years)
0
<5
5+
-

0 1.00
0 1.59
0 3.23 <0.001
<5 3.16
5+ 4.18
1.00
1.27
2.68
2.67
7.18


<0.01


Estimated by fitting the equation:   Annual death rate=Constant x A x P x T x J.

 Value of constant 0.0048.
/*
 For improvement in fit, based on change in log likelihood when each factor
 is removed from the full (Poisson)  model.

 Value of constant: 0.0026.

Source:   Table 6 from Peto et al. (1984).
                                    8-15

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relationship with age at  first  exposure,  whereas lung cancer showed no such
relationship.   Both lung  and  nasal  cancer showed an increasing  risk with  in-
creasing duration of work in  high-exposure areas.   The risk for nasal  cancer
peaked for  the 1910  to  1915 cohort and declined thereafter, whereas the risk
for lung cancer  was  highest for the 1920 to 1924 cohort.  The risks of both
lung and nasal cancer were low within 20 years  of  first exposure,  and in-
creased up  to 40 years after  first exposure for  lung cancer and 50+ years for
nasal  cancer.
     The results displayed  in Table  8-3 can, in part, be an artifact of the
cohort definition.   Table 8-4 shows  that each cohort  at Clydach  defined by
year of first employment  differs in both the minimum number of years employed
and the minimum  number of years between first employment and the beginning of
follow-up.   As a result,  the year of first employment may be highly correlated
with duration of exposure and the interval to follow-up, and possibly age at
first employment.  Given  these  constraints,  any one variable shown  in Table
8-3 may not be  adequately adjusted for the other three  variables.   In addi-
tion, only  individuals  first hired during or after 1915 contribute to the
adjusted estimate  for risks less than 20 years  since  first exposure.  Given
the cohort  definition, there  are no individuals who were first hired before
1915 and who  were  followed or diagnosed within  20  years of first exposure.
Similar problems may  exist in estimating adjusted  relative  risks  for other
variables shown  in Table  8-3.
     Finally, Table 8-4  indicates  that for the  cohort starting before  1910,
all lung and  nasal  cancer cases dying  within 25 years since first exposure
were not ascertained.  As such,  the  cases  ascertained  for this  cohort are, by
definition, late onset  cases.  This affects the risk estimates for all vari-
ables shown in  Table 8-3 unless one  assumes  a  constant relative  risk by  age
and/or  time since first  exposure.   In contrast, cases  from the 1920-1924
cohort  who  died  within  10 to 14 years after first exposure were not ascer-
tained.  As such,  the cases ascertained in the  cohort  cover the  spectrum  from
early to  late onset cases. If  the  latency periods  for lung and  nasal  cancer
are  different and  if the  relative risk is not constant  by age or latency, it
is  possible that the pattern of risk shown in Table 8-3 is  an artifact  of the
cohort  definition.
                                    8-16

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         TABLE 8-4.   MINIMUM NUMBER OF  YEARS  OF  EMPLOYMENT  AND  YEARS
            BETWEEN  FIRST EMPLOYMENT AND THE  BEGINNING OF FOLLOW-UP
   FOR COHORTS FROM  THE CLYDACH PLANT,  DEFINED BY  YEAR OF FIRST EMPLOYMENT

                                     ——                     Minimum
                                                            number of years
                                 Minimum                         between
   Year of                   number of  years                 first employment
first employment              of employment                   and follow-up
<1910
1910-1914
1915-1919
1920-1924
20+
15-19
10-14
5-9
25+
20-24
15-19
10-14
8.1.1.8  Summary of Studies on the Clydach Nickel Refinery.   Changes  in the
nature and extent  of  lung and nasal cancer  risks are  important markers of

probable changes in exposures.  However,  given the variety of modifications in

production and  control  measures,  the studies of the Clydach workers to date

are limited  insofar as  assessing  these risks with regard to specific nickel

species.  Other disease risks were also identified in these studies, including

circulatory disease, cerebrovascular disease, respiratory disease, and bladder

cancer.  Additional  studies are necessary to  determine  if these risks are

real,  and  if so,  with what work  areas  or exposures they are  likely  to be

associated.
     The studies of workers at the Clydach Nickel Refinery reveal the follow-

ing noteworthy patterns of risk in lung and nasal cancer:


     (1)  The risk  of  nasal  cancer was found  to  be  highest for workers who
          began their employment between 1910 and 1914.  The risk declined for
          workers  starting  after  1914,  and  no cases occurred  among workers
          starting after 1924.

     (2)  The highest risk of nasal cancer was found for workers who had spent
          5  or  more years  in  the  copper sulfate  area and/or  the  furnace area.
          The calcining  furnace and crushing areas were also associated with
          an excess risk.   In contrast,  no  excess risk  was  associated with
          working  in  the reduction area,  where  nickel  carbonyl  levels were
          highest.

     (3)  The risk  of  lung cancer, in contrast to nasal cancer, was found to
          be high among workers starting before 1920, and peaked among workers
          starting between 1920 and 1924.   Doll et al.  (1977) showed that lung
          cancer risk was  still  in excess and appeared  to be  increasing  for
          workers starting between 1925 and 1929.

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     (4)  The highest risks of  lung  cancer were found to  parallel  those of
          nasal  cancer, with regard  to  work area,  and were  associated with
          work in the copper sulfate  and Orford furnace areas.

     The use of  gauze  masks,  which were introduced around 1922-23,  was the
predominant explanation suggested  to account for a decline  in the risk of
nasal cancer.  Experimental studies  with the masks showed that they reduced
the total dust exposure and altered  the size distribution of particles pene-
trating the respiratory system.  A single gauze pad was  found to have  a fil-
tering efficiency of 60 to 85 percent,  while two in tandem had 85 to 95 per-
cent efficiency.   Particles most effectively screened were  those ranging in
size from 5  to  15 pm (INCO, 1976).  (Typically,  particles  ranging from 5 to
30 pm are intercepted  in  the  nasopharyngeal region.)  If  the  masks had  been
used on a continuous  basis in the areas  of highest risk, workers probably
would have received  effective  protection from exposures to  the nasopharynx.
No cases of  nasal  cancer  occurred among workers starting after 1924, shortly
after the introduction of  masks.   The risk  of  nasal cancer,  however, seems to
have been declining before the  introduction of  the masks  (Peto et al.,  1984).
In part, this decline could be an artifact of the cohort definition.   That is,
to meet the  cohort  definition,  workers who started earlier, e.g., 1900-1904,
had to  be employed  longer  and therefore  would  have  had a  higher exposure. The
cohort  definition  forces   an inverse relationship  between calendar year of
first employment and length of employment.  As a result,  the cumulative exposure
for workers defined by calendar year of first employment declined independently
of any changes in workplace exposure.

8.1.2   International Nickel Company, Inc.  (INCO) Work Force  (Ontario,  Canada)
     Several epidemiologic studies have been done on workers at INCO's nickel-
producing operations in Ontario, where sulfide nickel ore  is mined and refined
at several locations by different processes.  The refining processes and expo-
sures are  described in greatest detail  in  the review of the paper by Roberts
et al,  (1982, unpublished).  For additional descriptive background information,
the  reader  is referred  to INCO's 1976  supplementary submission to NIOSH.
     Some  important information on  processes and facilities  is  summarized
below,  while  salient points as disclosed in the individual  studies are  cited
in the  sections  pertaining to those  studies.  Any discrepancies between  reports
of  dates,  etc.,  should be resolved by industrial  hygienists  familiar with the
INCO history.
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     The nickel sulfide  ores  are mined in the Sudbury area of Ontario,  from
the same nickel deposit as that which is mined by Falconbridge,  Ltd.  (Epidemio-
logic findings  regarding the  cancer mortality experience  of Falconbridge
workers are discussed  following  this section on studies  of  INCO workers in
Ontario.)
     According to  INCO (1976), most  of  the nickel present in  the  sulfide ores
is found in pentlandite (NiFeSp) with smaller amounts of nickeliferous pyrrhotite
(Fe-,S0).  Copper  is also  present, as are precious metals.  Primary processing
   / o
of the  ore  is  carried out at  INCO's Copper  Cliff  Smelter;  until 1972,  the
Coniston Smelter also conducted some primary processing (Roberts et a!., 1983,
unpublished).   The resulting metallic "matte" contains primarily nickel subsulfide
(Ni3S2) and  copper sulfide (Cu2S).   Before  1948  (Dr.  Stuart Warner,  INCO,
personal communication),  this matte was sent  to  INCO's  refineries in  Port
Colborne, in southern  Ontario,  and  to refineries in Clydach,  Wales.   At each
of these refineries, the matte was reheated in the  presence  of oxygen to yield
both nickel and copper oxides (Roberts et al., 1983, unpublished).  Studies of
Clydach workers are  reviewed  in a separate  section  of  this  document, while
studies of Port Colborne workers are reviewed in this section on INCO's Ontario
operations.
     At Port  Colborne,  nickel was  oxidized  in calciners supplemented  with
traveling grate sintering machines,  using an open hearth with very high tempera-
tures of approximately 1650°C.  This sintering of impure nickel  sulfide required
the  use of fine  coke  (INCO,  1976).  The calcining/sintering area  of Port
Colborne as well as the calcining area at Clydach "were considered the dustiest
parts of  the  respective  refineries"  (Roberts et al.,  1983,  unpublished).
     At Port Colborne,  sintering was carried out from the  late 1920s until
1958, while calcining  was carried out  from  1921 to  1973.   A new sintering
plant was opened  in  1948 at Copper  Cliff, the  Sudbury area,  and continued
production until  1964  (Roberts  et al., 1983, unpublished) or February 1963
(Sutherland, 1971).  "Around  this time the oxidation process  was being taken
over by fluid bed roasters,"  according  to Roberts et al.  (1983, unpublished).
     The matte processing using fluid-bed roasters  produces  nickel oxide which
is sent to Port Colborne and to Clydach, Wales for  further processing (Roberts
et al., 1982,  unpublished).   The work at the  Port  Colborne  Nickel  Refinery
includes leaching, calcining  and sintering,  electrolytic, anode furnace, and
other occupational subgroups (Roberts et al., 1982,  unpublished).
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     INCO operated a  third  sinter plant facility in Ontario, at the Coniston
smelter.   At  this  plant, finely  crushed  nickel  ores were agglomerated and
pre-heated prior to  entering  the blast furnace,  using a lower temperature of
approximately 600°C.   This low-temperature sintering was carried out from 1914
to 1972  (Roberts et  al., 1983, unpublished).  This  process  was the same as
that used by Falconbridge, Ltd. until 1978 (Shannon et al.,  1983, unpublished).
8.1.2.1.   Early Studies.   Studies of  Ontario  INCO  workers  carried out by
Sutherland (1959,  1969) had an important impact on the recognition and quanti-
fication of cancer risks among nickel-exposed workers.   Additional follow-up
of the cohorts  of  Sutherland's studies was  reported by  Mastromatteo  (1967),
Sutherland (1971), INCO  (1976),  and  Chovil et al.  (1981).  These  reports  have
been reviewed extensively by NIOSH (1977a) and Wong et al.  (1983, unpublished).
The designs of these  studies,  and their most salient findings,  are  summarized
below.
8.1.2.1.1   Sutherland (1959),  Mastromatteo  (1967),  and  INCO  (1976).   Because
these three reports  discussed  the same study cohort, they  will be reviewed
together in this section.  The study cohort comprised 2,355 men on the payroll
at Port  Colborne,  Ontario,  as of January 1, 1930.   Sutherland  described  the
cohort as:  "All employees with 5 years or more of  service who were  on payroll
on 1 January  1930  or who subsequently acquired this length of service."  All
of the men  in the  cohort therefore had survived  at  least 5 years  of exposure.
Mortality from  1930  through 1957 was ascertained through group  life insurance
records  for refinery  employees and pensioners, and  through municipal  registry
offices  in and near Port Colborne for employees who  had  left the plant.   Thus,
under-ascertainment of  deaths  would  be expected to  occur  among men who had
left the immediate geographic  area.   Sutherland expected  such under-ascer-
tainment to be  minimal, "since the  study was  restricted to 'term-long1 em-
ployees  . . .  who might  reasonably be expected to be fairly permanent residents
of the local community."  Death certificates were obtained from local municipal
registry offices for deaths occurring from  1930 to 1948.   For  1949 to  1957,
other records were used, except when deficiencies were found in the information,
or more  importantly,  when cancer was mentioned  in the  municipal or  company
records.  Various  revisions  of the  ICDA were  used to code  primary causes of
death.   The calculation of person-years was not uniform for all workers; men
beginning employment  after  1930 were counted from  the  time  of  hiring,  while
others were counted from 1930.
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     Ontario male  death  rates  specific for age and 5-year calendar time were
used to  calculate  expected numbers of deaths.   An  exception is that sinus
cancer death rates  were  available only for the period 1950 to 1957; if sinus
cancer death risks  in Ontario were actually lower from 1930  to  1949, then the
use of the  1950  to  1957  rates would overestimate the expected number of sinus
cancer deaths from 1930 to 1949, and would underestimate the SMR.
     Men were classified  into  8 exposure groups, according  to  their occupa-
tions since  1930.   Five  of the exposure groups were restricted to men with a
single exposure,  i.e.,  with a "pure"  exposure  history:   furnace  (including
cupola, calciners,  sinter,  and  anode  furnace workers);  other dust (including
men with a  variety  of exposures who had worked  for 5 or more years within the
plant,  other than  in  the furnace group, the electrolytic department, or the
office staff, in positions  such as sinter conveyormen, sulfide  unloaders, and
weighers, as well  as painters,  electricians,  welders,  etc.);  electrolytic
(presumably having exposure to mists of nickel  salts and hydrides); other non-
exposure (composed  of men in a variety of occupations but not working in the
plant); and, lastly,  a  category, for office workers.  Three  "mixed" exposure
groups were created to include men whose employment included work in more than
one of the  exposure groups;  the reasons for changing jobs were  not considered
in the classification scheme but might have included health problems.
     Of the  total  of 245  deaths  ascertained  from 1930 to  1957,  19 deaths
occurred as  the  result  of lung cancer, while  only  8.45  were expected (p <
0.001).   All of the known lung cancer deaths occurred after 1944,  probably due
to the fact  that the  cohort was too young to have experienced lung cancer in
the 1930s.   Sutherland stated that 76 percent of the person-years  were accumu-
lated in employment (rather than retirement) years,  and  that 65 percent of the
person-years were  at  ages younger than 45.  The excess  of pulmonary cancer
deaths seen  after  1944  appeared most strongly  in the furnace exposure group
(SMR = 380)  and the mixed  exposure group  with 3 or more years in furnace
occupations  (SMR  = 360), while the "Other  Dust"  group  had  an  SMR  of  220.
Reconsideration  of  the  exposure  group of  the  19 lung cancer deaths  and  3
additional  cases  in order  to  include occupational  history prior to 1930
resulted in  reclassification of several  cases  into  the  "dusty" categories,
which does  not  change the interpretation of the results.
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     Nasal sinus  cancer was  also  found in excess among  the  Port Col borne
workers, with 7  deaths  observed and 0.19  expected (p  <  0.0001).   The risk
appeared to be concentrated among men in the furnace occupations.  However, a
subsequent update  of  Sutherland's  study with follow-up  through  1974 (INCO,
1976) indicated that the nasal cancer risk was  not limited to furnace workers.
     It should be  noted that  while many of the methods  used  in Sutherland's
study have been  criticized  in the 1980s,  this  study  was carried out in the
1950s and  used  techniques that were acceptable at  the time.   Although the
potential  biases  must  be kept  in  mind  when evaluating  the  results  of the
study,  it  is  clear that Sutherland's work catalyzed  much of the subsequent
interest in the risks of nickel exposure.
     A brief summary of the results of Sutherland's extension of the follow-up
period, reported  by  Mastromatteo  (1967), continued to show excess risk.   Ac-
cording  to Mastromatteo,  major process  changes as well  as the transfer  of
sintering  operations  from Port  Colborne  to Copper Cliff,  Ontario  were  made as
a result of Sutherland's findings.
     INCO  (1976, unpublished) continued follow-up on 2,328 of the 2,355 workers
in Sutherland's 1959 report.  Nasal cancer deaths through 1974 increased to 24
(SMR =  5,106, p  <  0.01) and pulmonary cancer deaths through 1974  increased to
76  (SMR = 1,861, p < 0.01).   Four  laryngeal  cancer deaths were ascertained
(SMR =  187,  p > 0.05).    Detailed  occupational  histories of all  known cases
(not only  deaths)  of  nasal  cancer  (36)  and lung cancer (90) were  presented  in
the  1976  report  to address  the  question as to which exposures were  associated
with the  excess  cancer  risk.    INCO concluded that tankhouse exposure was not
associated with  lung cancer,  contrary to the findings  of  Pedersen et al.  (1973)
in  a study of ostensibly similar tankhouse  exposure  in  a nickel  refinery in
Norway.   INCO  also observed  that since  three cases  of nasal cancer at Port
Colborne  occurred to  men without a known  occupational history of exposure to
any  furnace  occupation  or other dusty  job, a year's exposure to  sintering or
calcining  at Port  Colborne  was  not necessary to put a  worker  at increased risk
of  nasal  cancer.   These preliminary observations and conclusions  were  based on
a  data set which had  the  same epidemiologic problems as previously  noted
regarding  the Sutherland  (1959) report.
8.1.2.1.2  Sutherland (1969).  The sintering operation  at  Port  Colborne was
transferred  to INCO's  Copper Cliff  plant, apparently with process  changes.
For example,  no  cupola  exposure was described at Copper  Cliff.  The  transition
                                     8-22

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began  in  1948 and  was  complete by 1958  (Sutherland,  1971).   Sintering of
nickel sulfide concentrate to nickel oxide at Copper Cliff was discontinued in
February 1963.  The Ontario  Department of Health carried out  a cohort mortal-
ity study of Copper Cliff sinter workers who appeared on at least two lists of
workers in  1952,  1956,  and 1961.  Thus,  the  cohort  comprised men with 5 or
more  years  of experience  at  Copper Cliff from 1948 to  February  1963,  but
excluded long-term workers in 1952  who did not continue to work through  1956,
and also excluded short-term workers between the listed years.  The cohort was
required to  have  had  at least 6 months  in the sinter  plant.  Deaths through
June  1968 were  ascertained through the company's pension records, which may
have  caused  a  possible  under-ascertainment  of deaths.   Causes of  death were
gathered from death certificates and company records.
     A total of 483  men were identified who  had served at least 6 months  in
the sinter  plant.   By June 30,  1968, 21 were  known  to have died, 297 were
known to be  alive,  and a strikingly high proportion were lost to  follow-up,
i.e., 165/483, or 34 percent.  Men who were  lost to follow-up because they had
left the company contributed person-years until their dates of separation from
the company.
     Of the 21 deaths, 7 were due to pulmonary cancer,  although only 0.78 were
expected (p  < 0.05).   The only  other  cancer death was due  to  nasal  sinus
cancer; this was  not  a  statistically significant excess in this small sample,
but the length  of follow-up  was short.   Nonetheless,  the results did suggest
an excess of pulmonary  cancer deaths among  sinter workers  at Copper Cliff.
8.1.2.1.3  Sutherland (1971).  To address the  hypothesis that the  lung cancer
risk among nickel  workers was related to the levels of  airborne sulfur dioxide
generated in the work areas,  Sutherland studied workers at INCO's Copper Cliff
smelter.   A  sample  was  selected by INCO (using an unspecified method) of men
who had had  at  least  5 years of  experience in  their respective exposure  areas
by the end  of  1950.   The exposure areas and the numbers of men in the sample
were as follows:
       I.   Smelter Converters (n = 246), with  the highest exposures to
           sulfur dioxide and furnace  fumes.   Exposures included nickel
           sulfide and nickel oxide.
      II.   Mill and Separation  (n =  172),  with low exposures to sulfur
           dioxide and metallic fumes, except  for the exposures incurred
           by  being close  to the converter building.   Until  1948,  the
           separation  process was the Orford process, with nickel  sulfide
           exposure in the  cupola  furnaces.   Since approximately 1948,
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           controlled slow cooling has  been  used instead of the Orford
           process,  but  this  process  also involves exposure to  nickel
           sulfide.   The men  in  the  study may have been exposed  to both
           processes.
     III.   Tankhouse,  Mechanical  and Yard and Transport (Copper Refining
           Division) (n = 199),  with  virtually  no  exposure to sulfur
           dioxide or metallic fumes.
      IV.   Frood Mine  (n =  225),  with  no  exposure to sulfur dioxide.
       V.   Eleven of 842  men  in  the study could not  be classified by
           exposure to sulfur  dioxide.

     The methods used in this  study were similar to those used  for the earlier
Sutherland reports.   Morbidity experience was also followed.
     By 1967, 157 men were reported to have died of various causes.  Eleven of
these deaths were  due  to pulmonary cancer (SMR  = 122).   The nonsignificant
excess of pulmonary cancer deaths did not appear to be concentrated in any one
exposure group,  although  there were  3 such  deaths  among  tankhouse workers,
compared to  0.94  expected.  No mention of nasal  cancer deaths  could be found
in this report.
     Although this study gave  no  evidence of increased risks, several  methodo-
logical problems may  have decreased its ability  to demonstrate an increase.
These problems  include  the  lack  of a clearly defined cohort, the  lack  of  an
extensive vital  status  follow-up (deaths were ascertained  through the  group
life  insurance  plan), and the influence  on the calculation  of person-years  at
risk of past employees whose deaths were not discovered.
8.1.2.1.4   Chovil  et al.  (1981).   Chovil et al.  (1981)  followed  522  Copper
Cliff sinter workers,  including  workers who had not  been identified  in the
original cohort  of  483  men in the study by Sutherland (1969).   Excluded were
10 men  who  had died before 1963, one of whom had died of lung cancer, and 17
men who were known to have emigrated out of Canada.  Thus, the cohort was com-
posed of  495 men who had survived to  1963,  who  were  known  not to  be  lost  to
follow-up,  and who had been exposed at some time  between 1948 and  1962.
     The cohort  was  followed  for mortality through 1977 in  Canada  and 1978 in
Ontario.  Incident cases  of lung cancer were identified through the records of
the Workmen's  Compensation Board of Ontario; this may have  led to  under-ascer-
tainment of cases who were not in the files  of the Compensation Board.
      Only  75 percent of 495  men were  followed  successfully through  1977  or
1978.   This poor  follow-up rate  raises questions regarding  the representative-
                                    s' 24

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ness of the  study  subjects.   Either one of  the  two major problems with the
cohort (definition of  cohort  or follow-up rate) would  be  cause for concern
with regard to the interpretation of the results of this study; both together,
when combined with other methodologic problems, suggest that this study cannot
provide reliable information on cancer risks.
     The authors attempted  to estimate incidence rates, but used a question-
able method in which numbers of deaths were multiplied by 1.5 to obtain expected
numbers of cases.
     The results of  the study do suggest  an excess risk of lung  and  sinus
cancer.  However,  the  many  analyses  of more  sophisticated  questions  regarding
dose response,  latency,  etc., cannot be interpreted  because of  the  problems
with the data set and the method of analysis.
8.1.2.2  Recent Studies.  A large cohort mortality study was commissioned as a
result of  the  1975  Collective  Bargaining  Agreement between INCO's  Ontario
Division and the United Steelworkers of America, and was carried out by McMas-
ter University.  Several  reports on the results of this study have  been  re-
viewed here  (Roberts and Julian, 1982;  Roberts  et al., 1982,  unpublished,
1983, unpublished, 1984).
     These reports will be discussed  together to  describe the  basic  study
design, the  overall  cohort, and the method  of follow-up and analysis.  The
results will  be discussed relative to  each group of workers or set of analyses.
     The cohort was  defined as  all  men who had worked at least six months  for
INCO in Ontario,  and who were  known to be alive on or after January 1, 1950.
An  exception  was that men who  had  worked  in the sinter plant were  included
regardless of the duration of  employment.   Men employed exclusively  in  an
office environment away from  production facilities were excluded.   For this
cohort, the  earliest and most  recent  dates  of employment were not specified.
Presumably the  earliest dates could  have been  as early as the  founding  of  INCO
in  1902,  or  earlier in the companies  which  joined  to form INCO.  The men who
were alive in 1950 after having been  exposed to earlier methods  of mining
would  comprise  a selective  sample  of survivors who  might have  mortality risks
very different  from those of other  workers.   In the case  of the most recent
dates of employment, if they  were within six months of the end of the  follow-up
period in 1976,  then the most recently hired men would not have  had  a  sufficiently
long latent period for  cancer death.   This problem  is partially  addressed  in  a
subgroup analysis  by number of  years since first exposure.
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     A cohort of  54,724  men  was identified,  of whom 50,436 had worked in the
Sudbury, Ontario  area and 4,288 had worked in the Port Colborne Nickel Refin-
ery in  southern Ontario.   The  men were classified  into 14 occupational sub-
groups.   Mortality  through December 31,  1976  was  ascertained  through the
Canadian National  Mortality Data Base (described in Smith and Newcombe, 1982),
and underlying causes of death from the  death certificates were coded using
the ICDA,  Eighth  Revision.  SMRs  were calculated  using  age-  and  calendar
year-specific mortality rates for Ontario males.
8.1.2.2.1   Roberts  and Julian  (1982).   This  report focused on approximately
30,000 men  with some  mining  experience,  and an unspecified number of men  in
"the  entire Sudbury group excluding those men with some experience in the
sinter plants, because of their known increased cancer mortality."   The miners
had been exposed  to nickel/iron sulfide, copper/iron sulfide, iron sulfide,
and small amounts  of precious metals.   The authors stated that the  Sudbury ore
contained no  asbestos-type material,  and that levels of  radon daughters had
been found  to be  low in the mines.
     Results  for  the  entire  Sudbury cohort showed a nonsignificant excess of
total  mortality (SMR = 104), which decreased when  deaths  from accidental  or
violent causes were removed  (SMR for all other causes  = 96).   Among miners
with  at least 15  years  since  first  exposure,  cause-specific SMRs  were  in-
creased but were  not  statistically significant (p  >  0.05) for nasal  cancer
deaths, SMR = 166 (0/E = 2/1.20)  or  kidney  cancer deaths, SMR = 137 (0/E =
14/10.22);  the  SMRs were not  increased  for  laryngeal  cancer (SMR  = 102) or
lung  cancer (SMR  =  105).   In the  main  cohort of Sudbury  workers with  at  least
15 years since  first  exposure, nonsignificant (p >  0.05) excesses  of nasal,
kidney, and laryngeal  cancer deaths were seen  (SMRs  of 144, 124,  and 118,
respectively), while a slight  excess of lung cancer deaths was observed (SMR =
108,  95 percent confidence interval  of 95 to 124).   Further  analysis  by  dura-
tion  of exposure  did not suggest  that  the slightly increased  risks occurred
only  among  men with many years of  exposure.   In  fact, the laryngeal cancer
excess  was  seen among workers  with less than 5 years  of exposure,  both in  the
group  of  miners  (SMR =  125 among those with less than 5  years compared to 93
among those with  5  or more years), and  among all  Sudbury  workers combined  (SMR
=  248 among those with  less than 5 years of exposure compared to 100 among
those with  5 or more years).
      Two other cancer sites  showed  interesting results among men with  at least
15  years  since first exposure.   There  was  some  evidence  for an increase  in
                                    8-26

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pancreatic cancer  deaths  among miners  (SMR = 142, p < 0.05).  Prostate cancer
deaths were  also  significantly  Increased among miners (SMR = 167, p < 0.01),
and showed a gradient of excess with  Increasing duration of exposure with a
very small p value for the SMR among the men with 15 or more years of exposure
(SMR = 192,  p = 0.0004).  This finding is consistent with the observations of
Enterline and Marsh  (1982)  and  of Shannon et  al.  (1984) of an increase in
cancer of the prostate.
8.1.2.2.2  Roberts et. al. (1982, unpublished).  This was  a study of Sudbury
workers and  Port  Colborne workers, in  which each group was  analyzed  separate-
ly. Sinter plant  workers  were considered as a separate subgroup in each geo-
graphical location.  In the Sudbury area, sinter workers were employed at either
the Coniston smelter or the Copper Cliff plant.
     The report provides  informative  diagrams  of the INCO operations and de-
scriptions of  the occupational  subgroups.  In a subsequent paper (Roberts
et al., 1983,  unpublished;  1984), additional  information  on processes and
dates was presented.
     At the  Coniston  plant  in the Sudbury area, sintering  was  part of the
smelting process.   Sintering  machines  were used to prepare  the finely crushed
ore for blast  furnaces by preheating it to the relatively low temperature  of
600°C.   This smelting process produced  a  metallic  matte containing nickel
subsulfide (Ni-Sp).  The process was  used at Coniston from 1914 until mid-1972
(Roberts et  al.,  1982, unpublished), and at Falconbridge Nickel Mines Ltd.  of
Ontario until 1978 (Roberts et al., 1982, unpublished; Shannon et al., 1984).
The sintering at  Copper  Cliff was part of matte processing.  It had been in
operation from  1948  to 1964  when  the  oxidation process was taken  over  by
fluid-bed roasters (Roberts et al., 1984).
     At Port Colborne, located  in southern Ontario  near Lake Erie, nickel
copper matte  is processed.  From 1921  to 1973, nickel subsulfide was oxidized
in enclosed  calciners.   From  the  late 1920s to 1958,  sintering was used with
calcining to oxidize  the  ignited  sulfur charge,  using traveling grate sinter
machines on  an open  hearth  at 1,650°C.  The calcining/sintering process was
dusty,  and is said to  have caused exposures similar to those in the calcining
sheds at Clydach,  Wales.   It  should  be noted  that Port Colborne workers who
were classified as sintering  plant workers included men exposed to leaching
and calcining, both of which  were carried out in the  same location as the
sintering.
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     In the  separate analysis of Sudbury workers in sinter plants, 248 deaths
were observed, with  a  nonsignificant overall SMR of 110.  A large excess of
neoplasia deaths was seen;  74 deaths observed as compared to 41.78 expected
(SMR =  177,  p <  0.001).   Among other Sudbury workers excluding sinter plant
workers,  the overall SMR was  104  (0/E = 4,376/4,218.70).  A total  of 795
deaths were attributed to neoplasia (SMR = 99).
     At Port  Col borne, workers  in  leaching, calcining,  and sintering experi-
enced  an  excess  of deaths from neoplasia  (0/E  = 121/65.52,  SMR = 185, p <
0.001).   For  all  causes  of  death,  the SMR was 109 (0/E  = 366/335.29).   These
analyses  did  not take  into  account any process  change  in the late 1940s and
1950s, when the sintering process may have been radically altered and began to
be transferred to  Copper Cliff (Sutherland, 1969).   Any excess of mortality
attributable to the early, dusty exposures could have been diluted by including
men exposed  after  1958  only.   Other Port Col borne workers  did  not show an
excess  of mortality  due  to any  cause,  except for a nonsignificant finding for
nervous system deaths (0/E = 5/3.51, SMR = 142).
     Four sites  of cancer were  explored in  more  detail  in further analysis as
a  priori  or  previously  implicated sites:    nasal sinus,  larynx,  lung, and
kidney.   Among non-sinter workers  at Sudbury or  Port Colborne, no significant
excess  of deaths due to cancer of  the  a  priori sites was seen.  Table 8-5
shows  the results for  the  a  priori  sites  among sintering plant workers.
Statistically significant excesses of lung cancer and nasal cancer deaths were
seen at Copper Cliff and at  Port  Colborne,  where  the SMRs for nasal cancer
were exceedingly  high  (1,583  at Copper  Cliff and 8,000  at  Port Colborne), and
were  also elevated for  lung  cancer  (see  Table  8-5).   The smaller Coniston
plant  (where low-temperature  sintering was  carried out) showed a significant
excess  of lung cancer deaths  (SMR =286, p < 0.05).
     One  death due to laryngeal cancer was ascertained in a Port Colborne
sinter  worker,  for a nonsignificant SMR of  112  (0/E = 1/0.89).   Port Colborne
sinter  workers  also  experienced the only kidney cancer deaths (0/E = 3/1.59,
SMR = 189, not statistically  significant).
     Further  analysis  of sinter  workers  showed that all  the  nasal  cancer
deaths  occurred  more than 15  years after  first  exposure.   Among  Port Colborne
sinter  workers  with  at  least 15 years since first exposure, the nasal cancer
SMR was 16,883 (p <  0.001) for those  with  at  least  5 years  of exposure, but
was lower for those  with less than  5 years  of exposure  (SMR = 3,297, p <0.001).
                                    8-28

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                     TABLE 8-5.   A PRIORI  CAUSES OF CANCER DEATHS AMONG ONTARIO SINTER PLANT WORKERS


Sinter
Plant
m
£ Copper CUff
Conlston
Port Col borne
ap <0.05.
bp <0.001.
Cancer site
Lung
Obs.

41
5
50


Exp.

9.68
1.75
17.90


SMR

424b
286a
279b


Nasal
Obs.

2
0
16


Exp.

0.13
0.01
0.20


Larynx
SMR Obs. Exp. SMR

1583b 0 0.50
0 0.09
8000b 1 0.89 112


Kidney
Obs.

0
0
3


Exp.

0.92
0.16
1.59


SMR

—
—
189


Source:   Adapted from Table 4 of Roberts  et al.  (1982,  unpublished).

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The dose-response relationship of  duration  of exposure to nasal  cancer death
risk at Port Colborne, as well  as the very large SMRs,  provide strong evidence
that the statistical  association  may be causal in nature.  The finding that
the excess  risk was  restricted to workers who had been followed  for at least
15 years since first  exposure may be related to the latent period required by
nasal   cancer,  as  well as  to the exposure received by workers whose first
exposure occurred in the earlier sintering exposure between the late 1920s and
1958,   according to Roberts et al. (1983, unpublished).   It should be recalled
that the sintering process  at  Port Colborne was  changed  and  may have been
discontinued by 1958, although  calcining continued through 1973.
     Most of the  cases  of lung cancer occurred at least 15 years after first
exposure (92 of the  97  lung cancer deaths), with a  suggestion of a greater
excess risk at the  Sudbury sintering plants.   The excess  risk was  somewhat
higher among those with 5 or more years of exposure.
     Risks among non-sinter workers were not elevated significantly.  However,
one interesting case  raises  an important issue in all  of the  analyses of the
Ontario workers.   The one  nasal cancer death among non-sinter workers at  Port
Colborne was that of a  man who had  worked  for 20 years in the electrolytic
department at Port Colborne.   Of particular interest is the fact that he had
worked previously for 20  years at INCO's New Jersey plant, and had  been  in-
volved in many roasting/calcining operations; however, he was classified  as a
non-sinter worker in this analysis.   This observation illustrates the problems
of misclassification  which can arise when complete occupational histories are
not taken.  Not only  can workers with potentially  risky exposures be  misclass-
ified  into  low-risk  categories,  or vice versa, obscuring the  differences be-
tween  job categories, but also  the duration of exposure can be underestimated,
obscuring dose-response relationships  and  latency period results.   This pro-
blem is  more  likely  to  occur in  locations  like the Sudbury area of  Ontario,
where  a  man may have  worked for two  nickel  refining companies  (e.g.,  INCO and
Falconbridge), while  exposure  data  may only exist for one company.   The pro-
blem can also  occur  within a single company,  where  a  worker may have been
exposed  at  two geographically  distant  locations,  yet only one  location may be
counted.  While  this misclassification  problem may occur  in  any  study of
disease  risks  in  the workplace, within-company  movement among  INCO  plants, as
well as  movement  to  other nickel-producing  companies in the Sudbury area, may
                                    8-30

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have increased the  extent  of the problem in these studies.  Generally, such
misclassification problems tend  to  obscure  risks and underestimate SMRs re-
lated to specific exposures.
     Analysis of additional  cancer  sites  showed an excess  of  deaths  due to
cancers of the buccal  cavity or pharynx,  and of bone, especially among Port
Colborne sinter workers  (SMR for buccal cavity/pharnynx = 299, p <  0.05;  SMR
for bone = 402,  p < 0.01).   The authors suggest that this result may be due to
misclassification of nasal cancer  on death  certificates.   Such misclassifi-
cation would  lead  to an underestimate  of the SMR for  nasal  sinus  cancer.
     An excess of  kidney cancer in  the Sudbury  plants  was also suggested,
although it was  not seen among workers with  20 or more years of exposure.   The
authors interpret this result as an indication that the risk for kidney cancer
"if real,  is small  and non-specific."
     The finding that  the  excess of deaths due to nasal and lung cancers  at
Port Colborne appeared mainly  among the  sinter workers (i.e., men  in the
leaching,  calcining, and sintering  departments)  is in contrast with the con-
clusion from Sutherland's work  that  the increased  risk exists  among all occu-
pational groups at  the  refinery; however, differences in  the  definition  of
sinter workers (men ever exposed to  sintering versus men exposed only  to sin-
tering) may account for the discrepancy.
8.1.2.2.3  Roberts et al. (1983, unpublished; 1984).  These papers, presented
at the 1983 IARC Nickel Symposium,  summarize the 1982 report by Roberts et al.
and also provide some  new  analyses.   Of particular interest is the  reclassi-
fication of  several cancers  to  the nasal  cancer category,  based on additional
information.   Three  bone cancer and two  nasopharyngeal  cancer deaths were
determined to have  been misclassified on  the death certificates, and actually
were due to nasal cancer.   All five deaths occurred among Port Colborne workers.
Such reclassification generally  is  not appropriate in mortality studies that
must rely on death certificates, since the same reclassification is  not applied
to the  group  from  which expected numbers are  derived.   It would seem to be
more legitimate with  rare  cancers  such as these,  however,  in  order to allow
the best possible  estimate  of mortality  risk.  Furthermore,  in  a  situation
where a tumor that  is rare occurs in epidemic proportions,  the probability is
increased that any  tumor occurring at the same anatomical  site is also one of
the "rare" tumors.
                                    8-31

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     Nasal cancer mortality  rates  per 1,000 person-years are shown in Table
8-6 by duration of exposure at the Sudbury sinter plants and the Port  Colborne
sintering operation.   The nasal cancer risk was appreciable at both locations,
but was  much  higher  at Port Colborne; among men with at least 15 years since
first exposure and with  5 or more years  of exposure,  the rate was 0.31 per
1,000 person-years for the Sudbury sinter plants, compared to 3.44 per 1,000
person-years for Port Col borne's sintering operation.  A weighted least-squares
estimate  (linear model)  of the slope of  risk  with  duration of exposure  is
0.030 for  Sudbury  (95  percent confidence interval of 0 to 0.07) and 0.23 for
Port Colborne (95 percent confidence interval of 0.12 to 0.34).
     One  of the  main observations of this  study  was that elevated risks of
respiratory cancer mortality were not seen among the  nearly 48,000 Sudbury
workers  not exposed  to sintering.   The authors'  calculations of  statistical
power show that the study had 90 percent power to detect an SMR as low as 121.
8.1.2.2.4  Copper Cliff Medical Screening (Sudbury,  Ontario).  The findings of
an  increased  respiratory cancer risk among sinter  workers at Copper  Cliff
(Sutherland,  1969)  was  followed  by the  initiation  of a medical screening
program  for evidence of  lung cancer  among  exposed  men (McEwan, 1976, 1978;
Nelems  et al.,  1979).   Because these three reports discussed  observations
resulting  from the same medical screening program, all three will be discussed
together in this section.
     The screening program  was carried out in  1973 and 1974 and included
workers  who had  been exposed  to the sintering  process  at Copper Cliff prior to
the  1963 process change.   McEwan  (1976) presented cross-sectional  tabulations
of  sputum cytology by  smoking category, with clinical  work-up results  for men
with positive  findings.   The  clinical findings were  updated  in a 1978 abstract.
Nelems  et al.  (1979) reported longitudinal  follow-up observations on  broncho-
genie cancer  through the  end of 1978.
     None of  the above reports showed  any  analysis relating level  of nickel
exposure to subsequent findings of  positive sputum cytology and/or cancer.
Instead they  focused on  the  use  of sputum cytology, per se, in a group pre-
sumed to be at increased risk for  cancer.
                                     8-32

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                  TABLE 8-6.   NASAL CANCER MORTALITY RATE AMONG ONTARIO SINTER PLANT WORKERS
                          WITH AT LEAST 15 YEARS OF EXPOSURE, BY DURATION OF EXPOSURE

CO

CO





Sinter plant
Sudbury
Port Col borne

<5 years

Number of deaths 1000
1
3
Duration

Rate per
person-years
0.067
0.26
of exposure


Number of
1
18

5+ years
Rate per
deaths 1000 person-years
0.31
3.44
Source:  Adapted from Table 4 of Roberts et al.  (1983, unpublished).

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     Of the men who  worked  in the sintering plant  at  some time between its
opening in  1948  and the major process  change  in 1963 (more than  483  men,
according to other  reports),  fewer than 300 participated  in the 1973 sputum
cytology screening program.   Recruitment for screening included the following:
workers who were  still  employed at Copper Cliff;  former sinter men, whether  on
pension or  employed  elsewhere;  and men located by a special committee of the
local  branch  of  the United  Steelworkers of America.  None  of  the reports
addressed the question  of  the relationship between the men in the Sutherland
report and the men in this cytology screening program.
     McEwan (1976) reported on 282 present or former workers.  Cytology results
indicated further clinical investigations  on 11  of  the 282 men.  Of the 11, 6
apparently were diagnosed as having squamous cell carcinoma of the lung, while
the  other 5 men  did not have  radiographically detectable  lesions, but were
under  medical surveillance.   Work exposure histories were not presented, al-
though the  author  states  that this information was gathered.  No analysis of
the  possible  relation of  nickel exposure to  lung cancer  or to positive  sputum
cytology was presented.   In 1978,  in an abstract summarizing clinical  findings
(McEwan, 1978), the sample was reported to include 583 men who had participated
in  the program  for one or more years.  The relationship of this large number
of  men to  the smaller  numbers presented  in  the  1976 and 1979 papers was  not
explained.
     Nelems  et al.  (1979) reported  on 268 men who  had  been tested in the
1973-1974  sputum  cytology screening program.  Of  these, 12 showed positive
cytology by the  end of 1978  (11  men were current  smokers,  while  one  was a
former smoker).  Ten of the 12 developed lung cancer (squamous cell type),  one
developed maxillary sinus cancer  (squamous cell),  and one developed microin-
vasive squamous  cell  cancer of the  larynx.   The authors  did not  provide a
description of the  cohort, nor did they  present  any  data or analysis on nickel
exposure  levels,  time,  or age-specific rates of  disease.  Thus,  this  study  is
not of value  in the evaluation of the  carcinogenicity of nickel.
8.1.2.3  Summary of Studies on the Ontario INCO  Mining and Refining Processes.
      In  summary,  studies of  INCO's  Ontario  work force  have explored  cancer
 risks  associated with  most  phases of nickel mining  and processing.   These
phases include  mining,  pyrometallurgical refining of the ore (at Coniston and
 Copper Cliff),  matte refining (Copper  Cliff  and Port  Col borne),  and  electro-
                                      '34

-------
lytic refining (Port Colborne).  Two major groups of studies have been carried
out: the  early  studies  (reviewed in section 8.1.2.1), based on  Sutherland's
(1959)  cohort;  and more  recent studies, primarily  by  McMaster University
(reviewed in section 8.1.2.2), which used a new cohort definition.
     The  results of  these studies were  inconsistent with  results  found for
Falconbridge, Ltd.'s Ontario  workers in  mining and low-temperature  sintering,
as  well  as with results  found for Falconbridge, Ltd.'s Norway  workers in
electrolytic refining of  nickel  which  is presumably from the same deposit in
the area of Sudbury, Ontario.   (Refer to summary table 8-10 for SMRs.)  On the
other hand, INCO workers in matte refining experienced increased risks of lung
and nasal  cancers,  consistent with findings at Clydach,  Wales; Falconbridge,
Norway; and  Huntington,  West  Virginia.   The comparability  of  study results
would be  greatly increased if uniform definitions of cohorts  and  exposures
could be applied to the various data sets.

8.1.3  Falconbridge, Ltd., Work Force (Falconbridge,  Ontario)
     A mortality study  of workers employed by the Falconbridge  Nickel Mines
Ltd. , at  Falconbridge in  the  Sudbury area of Ontario, Canada, was carried out
by Shannon and co-workers of McMaster University and Falconbridge Nickel Mines
Ltd.  Two  reports  of  this study have been  reviewed  here.   The first is the
unpublished version which  was presented at the  IARC conference  on  Nickel in
Lyon, France  in  1983 (Shannon et al.,  1983,  unpublished).   The second was
published  in the proceedings  of that conference  (Shannon et al., 1984).  Both
are reviewed because each  presents some  material which is not included in the
other.   Most importantly,  the unpublished  version presents many statistical
tables which are not included in the published  1984 version,  although the
conclusions of those analyses of cancer risk remain essentially unchanged in
the 1984 publication.   The 1984 paper includes information  on process and work
environment which  is  not  available  in the 1983 manuscript.   However,  the
environmental data are  used for descriptive rather  than analytical  purposes.
     The Falconbridge facility employed workers in nickel mining, milling,  and
smelting.   According to the authors, until 1978  the smelting process included
a sintering step which  was identical  to that at INCO's  Coniston plant,  i.e.,
low-temperature sintering.  Roberts  et al.  (1983, unpublished)  also stated
that low-temperature sintering of nickel ore was used at both the Falconbridge
and the Coniston plants.
                                    8-35

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     The cohort was  identified  (Shannon et al., 1983, unpublished) as 11,594
men who  had  been  employed by the company for at least six months and who had
worked at  Falconbridge  between  January 1, 1950 and December 31, 1976.  More
than one-third of the cohort had less than 2 years of exposure at Falconbridge.
These men  were  followed for mortality and cause  of  death from 1950 through
1976, using  the Canadian  National Mortality Data  Base with additional tracing
of men of  unknown  vital status.  Follow-up was completed on  10,342 men,  or
89.2 percent  of the  total cohort of  11,594.  The  explanation of the  follow-up
is somewhat  confusing.   In  the  1983 (unpublished) version, it  appears  that
vital status  was  determined  first  through company records for  the entire
cohort.   The  national   database was  then  searched for all men  known to be
deceased, all men of unknown vital  status, and a sample of men who were "known
to be alive."  Those of unknown vital  status were sought  through telephoning,
drivers'  licenses, and  other  means.   In the 1983 version, the authors  state
that it  is  likely  that any deaths in  Canada  among  the 1,252  men of unknown
vital status  would have been  discovered through the "record linkage  process."
This implies  that  the  men of unknown  vital status  may have been treated as
alive in the  analysis.   However,  in the 1984 report, the authors  imply that
some who were "labeled alive by follow-up" were treated as dead in the analysis.
This is  an  important methodological  point which should be clarified, since a
potential  misclassification  of  10 percent  of the cohort could  affect  the
conclusions of the study.
     SMRs for the cohort  were calculated based on age- and calendar  time-spe-
cific rates  for Ontario males.   SMRs were also calculated for subgroups that
included five exposure  categories:   mines, mill,  smelter, service, and  admin-
istration.   Workers were  assigned to each exposure category in which they  had
worked,  adding person-years to  that  category beginning with the date of first
exposure.  If the  workers had died,  they also  contributed  a  death to  each
category of  exposure in which they had worked. This method introduced several
problems.  Some deaths  appeared in  more than one  category,  without regard to
latency.   Person-years  were contributed to more than one  category, increasing
the number of expected deaths and thus decreasing the SMR.   Analyses of time
since first  exposure may  have been  based on time in  that exposure category
only, regardless of  whether prior  exposure had occurred in another category.
The information on the number of persons in each exposure  category in this
study does not  provide an adequate basis for a full  understanding of how the
risk estimates were made.   The number of deaths observed in all  of the exposure
                                    8-36

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groups combined totals 996, a marked  increase over the reported total of 804.
     The results of the study did show an increased overall  SMR of 108 (p < 0.05)
for all  causes  of  death  in all exposure  categories  combined,  while the SMR
for cancer  deaths  was not significantly increased  (SMR =  101).   Specific
causes of death showed a nonsignificant excess for  lung cancer  (SMR = 123,
p = 0.08), and a significant excess for laryngeal  cancer (SMR = 261, p = 0.046),
while no  deaths from nasal  cancer were observed (0.43 expected).  The SMR for
kidney cancer was  58 (2 observed versus 3.47 expected).
     The analysis  in the 1983 (unpublished) paper showing SMRs for exposure
categories suggests an excess  of lung and laryngeal  cancer deaths,  primarily
among men  who had worked  in  the  mines,  the mill, and/or the  smelter,  and
kidney cancer deaths among men who had worked in the mill (Table  8-7), but not
among those who had worked in service or administration.   As seen in Table 8-7,
the lung cancer excess  appeared  in all exposure  categories  (mines,  mill,
smelter, and  service) except administration.  The excess among workers cannot
necessarily be attributed  to  nickel,  since  these workers were exposed  to a
number of potentially carcinogenic  substances.   The laryngeal cancer excess
was confined to mine,  mill, and smelter workers, reaching statistical  signifi-
cance among miners  (SMR  =  400,  p < 0.05).  Additional analyses of  length of
exposure by time since first exposure are difficult to  interpret in view of
the overlap of workers  among exposure categories,  as discussed earlier.
     Prostate cancer deaths appear to be increased among men who  worked in the
mills and in  the  smelter (Shannon et al.,  1983,  unpublished),  as shown in
Table 8-7.  All  four  prostate  cancer deaths which  occurred  among  smelter
workers  occurred in men  with at least 20 years since first exposure and who
had at  least  5  years  of  the exposure  itself;  the SMR among workers in this
exposure sub-group was 302,  p < 0.05 (1983, unpublished).   As pointed out by
Shannon  et al.  in  the 1984  publication, this excess among smelter workers was
consistent with the observation by Enterline and Marsh (1982) of an increase
in prostate cancer  among nickel refinery workers in West Virginia.  Roberts
and Julian  (1982)  also  noted an  increase in cancer of  the  prostate  among
nickel miners in Canada.
     Cancer mortality was  also  increased  among workers  at the sinter plant,
which was closed after 1978.   As pointed out by  Shannon et al.  (1984),  the
increase in lung cancer mortality among these workers (SMR = 214) was consistent
with the similar increase among INCO's Coniston sinter plant workers.
                                    8-37

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                TABLE 8-7.   MORTALITY 1950 - 1976 BY EXPOSURE CATEGORY FOR LUNG, LARYNGEAL, AND KIDNEY CANCER,
                                                 AT FALCONBRIDGE LTD., ONTARIO
CO

oo
00
Cause of Death
Lung cancer



Laryngeal cancer



Kidney cancer



Prostate Cancer




Obs.
Exp.
SMR

Obs.
Exp.
SMR

Obs.
Exp.
SMR
Obs.
Exp.
SMR
Mines

28
19 65
142D

4
100
400°

1
1.82
55
2
2.58
78
Mills

5
3.81
131

1
0.20
507

1
0.37
274
2
0.54
370
Exposure
Smelter

13
9.92
131

1
0.59
196

0
0.92
0
4
1.83
219
category3
Service

20
12b34
162D

0
0.63
0

0
1.13
0
1
2.07
48
Administration

0
1.40
0

0
0.07
0

0
0.13
0
0
0.14

    Some workers and deaths appear in more than one category,  as explained in the text.
   bp <0.05.

   Source:   Adapted from Shannon et al.  (1983,  unpublished):   Lung, laryngeal, and kidney
            cancer statistics from Table 5; prostate cancer (observed and expected numbers)
            from Table 13.

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     In summary, the study provides some evidence for excess risks for several
cancers among miners  and  mill  and smelter workers.   These findings should be
pursued further, with analyses using more refined methods of exposure classifi-
cation, within  the Falconbridge  plant.  Attention should also  be  given to
occupational exposures  in other nickel processing companies  in  the geographic
area.   It   is entirely  feasible  that  complete occupational  histories  of
Falconbridge workers  might  show  additional  exposures  at Copper Cliff, for
example, which is located less than 25 miles from Falconbridge.   Such exposures
might have occurred before or after employment by Falconbridge Ltd. ,  and might
explain some of the excess mortality in some exposure groups.
     The finding  of an excess lung  cancer  risk among Falconbridge  smelter
workers (SMR =  131),  although not statistically  significant,  is  consistent
with the excess risk at INCO's Coniston  plant,  reported by Roberts et al.
(1983,   unpublished).   This  consistency  adds weight  to  the epidemiologic
evidence of a lung cancer risk among low-temperature sinter workers.

8.1.4  Falconbridge Refinery Work Force (Kristiansand, Norway)
     The Falconbridge  nickel  refinery in Norway  opened  in  1910,  using the
electrolysis process  to  refine  nickel  ore shipped from Ontario, Canada.  The
first epidemiologic  investigation  of risk was reported  in 1973 (Pedersen  et
al., 1973), and was  followed by a  series  of  studies  up to the present on both
cancer risks and biologic monitoring.
     The refining process begins with partially refined ore containing approx-
imately 48  percent  nickel,  27 percent copper, 22 percent sulfur,  and trace
metals (Hrfgetveit and Barton, 1976).  The process is divided into four  steps:
crushing,  roasting,  smelting, and electrolysis.   Over time  and particularly
since 1950, it  has been noted that the production process at Falconbridge  has
undergone  a number  of changes,  resulting in greatly reduced worker exposures
to  dust and fumes.   Unfortunately, these changes are  not specified in the
literature.   Efforts  have been  made  to characterize the  range  and  types  of
nickel  exposures by category of work.  Workers in roasting and smelting opera-
tions are primarily  exposed  to  "dry dust,"  containing nickel subsulfide and
                                                         3
oxide,  with an  average concentration of about  0.5 mg Ni/m .  The electrolytic
workers are exposed to aerosols of nickel sulfate and chloride, with an aver-
                                                      3
age ambient nickel  concentration  of  about 0.2 mg Ni/m .   Other process work-
ers  are exposed to miscellaneous nickel  composites  at  an average level of
0.1 mg Ni/m .    However,  the  species  are not defined  for this  latter group.
                                    8-39

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Data in these  studies  on the species of nickel  and magnitude of exposure are
based on atomic absorption analysis of  relatively  recent air samples (Torjus-
sen and Andersen, 1979).  The relationship between these recent data and past
exposures is not known.
     Between 1973 and 1983,  eleven investigations were reported on the Falcon-
bridge workers.  Three dealt strictly with cancer  risks in the cohort (Peder-
sen et al., 1973; Kreyberg, 1978; Magnus et al., 1982).  Two studies reported
on the relationship  between  histopathology of the nasal mucosa, nickel  expo-
sure, and  nickel content of  the mucosal tissue  (Torjussen et al., 1979a,b).
Another five reports were issued on the use of plasma, urine, and nasal  mucosa
levels of nickel as biological  markers of exposure.  Finally, one study reported
on the use of a serum factor as a possible screening test for nasal cancer risks
(Kotlar et al., 1982).   Taken  together, this set of studies provides what is
perhaps the most comprehensive information available on cancer risks from nickel
exposure, the  relationship between  nickel  exposure and tissue deposition and
retention, and specific associations for various nickel species.
8.1.4.1  Pedersen et al.  (1973).  This  was a  study of workers employed  for  at
least 3 years at some time between 1910 and 1961 at the Falconbridge Refinery,
and who were alive  in 1953.   A  total  of 3,232  individuals entered the  plant
prior to 1971.  One  thousand nine hundred  sixteen  met the cohort  criteria.   A
majority (80 percent),  started work  in  the plant after 1944, which meant  that
the few cases that were missed between 1910 and  1953 were from the earlier and
smaller cohort.  Exposure was  defined by department  or category  of work of
longest employment, and  in some analyses by length of  employment.   However,  if
someone had been a process worker for several years but had spent more  time  in
a  non-process job, he was classified as a process worker.  The exposure groups
and  size  of each were as follows:  roasting  and smelting (462); electrolysis
(609);  other  processes  (299); other  and  unspecified work (546).   The  last
category included laborers, plumbers, fitters, technicians, and administrative
personnel.  Cancer  cases and deaths were identified  from the National  Cancer
Registry and a national mortality file.   It  is assumed that deaths  prior to
1953  were  identified and that no one  was  lost  to  follow-up.   However,  it is
likely  that a  number of  subjects who died before  1953 were not identified  as
such  and  were  considered alive  during  the  follow-up period.   A  total  of 48
lung  cancer,  14 nasal  cancer,  and 5 laryngeal cancer cases  were identified in
the  follow-up  period.   All  cases were  reviewed and confirmed using hospital
records.   Expected cancer deaths  were based on the  age-specific national
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mortality rates by 5-year age groups for each calendar year during the period
1953 to  1970.   Expected  numbers  of cancer cases were  based  on age-specific
incidence rates for 1953 to 1954, 1955  to 1959,  1960 to 1964,  etc.
     All four job categories were associated with an excess risk of cancer for
all respiratory organs  combined.   However,  the  SMR for other and unspecified
workers was only  190  (95 percent confidence interval  of 69 to 414),  and,  for
the most part,  was  confined to nasal cancer.  Workers  in  the roasting and
smelting department showed  the  highest  risk of nasal cancer, with an SMR of
5,000 (0/E =  5/0.1).   Two groups showed an excess  risk of laryngeal cancer:
roasting and  smelting  (R/S)  workers, with an SMR of 1,000  (0/E = 4/0.4),  and
other process  workers,  with an SMR  of  500  (0/E  =  1/0.2).   Workers  in  the
electrolysis department  showed an  excess risk of nasal cancer (SMR = 3,000,
0/E = 6/0.2) and had the highest risk of lung cancer (SMR = 812,  0/E = 26/3.6).
The SMR for lung cancer among R/S workers was 480 (12/2.5).   P-values were not
reported.  However, of  the  SMRs  noted,  only the SMR for laryngeal cancer in
other process workers  was not statistically  significant (p  >  0.05).
     It  is not  possible  to estimate median latency  for any of the tumor sites
because  early onset cases  (those diagnosed  before  1953) were not ascertained
for the  earlier cohort  and  the follow-up period  for the later cohorts is  too
short (at most 26 years).  However, a comparison  can be made  of the distribution
of cases by  calendar  time.   For the cohort starting employment between 1945
and 1954,  the  only cohort  for which there is complete  case  ascertainment
throughout the follow-up period,  one case of laryngeal  cancer occurred in  each
of the three follow-up periods (1953 to  1958,  1959  to 1964,  and 1965 to  1971).
In contrast, 17 of 23  lung cancer cases  and  the  only nasal  cancer case occurred
between 1965 and 1971.   Five of 14 nasal cancer  and 27  of 48  lung cancer cases
occurred between 1965  and 1971.
     The prevalence of smoking probably  increased with each subsequent cohort
defined by start date.   As a result, the observed and expected values for  lung
cancer probably increase with calendar  time.   This  may  in part account for the
distribution of lung cancer  cases  by calendar time, i.e.,  a  disproportionate
number in the later calendar time periods.   A lower SMR could be observed  even
if the  overall  risk of lung cancer from nickel  exposure had not declined.
This must  be  considered when evaluating the magnitude  of  risk by calendar
time.
     When analyses are restricted to the roasting and smelting and electroly-
sis departments,  and to  the cohort starting between 1910 and 1940, all of the
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nasal cancer cases are  confined  to those with more than 15 years of employ-
ment.  However, given that there  was no follow-up before 1953,  cases with less
than 15 years'  employment  could  have  been missed.  The SMR for nasal cancer
and  lung cancer  is associated  with length of employment (15+ years) for both
the 1910 to 1929 cohort and the 1930 to 1940 cohort.
     The pattern  of  risk by cohort and  calendar  time  is incomplete, since
cases in the earlier cohort who  were diagnosed before  1953 are not included.
This is a  problem when  attempting  to summarize the changes in pattern of risk
by cohort and calendar time.  It  is especially difficult if the latency periods
for the different tumor sites are different.  The picture is further complicated
by the increasing age at first employment and decreasing duration of employment
for  each cohort,  as  defined by start  date.   Given  these limitations, it is
difficult to evaluate latency and risk by duration of work.  Nonetheless, some
findings from this study are noteworthy.   The highest risk of nasal and laryngeal
cancer occurred  among  R/S workers  who were primarily exposed to particulates
containing  nickel  subsulfide and  oxide.   The highest  risk of  lung cancer
occurred among  electrolytic workers who were exposed to  aerosols  of nickel
sulfate and  chloride.   It is noteworthy that differences in risk by category
of work were found for  different tumors  even  though  the exposure variable was
imprecisely  defined,  i.e.,  by area of longest duration.  The  use of more
precise definitions  of exposure  by both  category and  duration of work  may
improve the discrimination  of tumor-specific risks by exposure setting.
     Four  of the five cases of  laryngeal  cancer  were  first employed on or
after 1940,  whereas  only one of 14 nasal  cancer cases occurred among those
starting after 1940.   It would be  of interest to  know if changes in the roast-
ing  and  smelting department are related  to the  changing risks in nasal and
laryngeal  cancer,  and whether  there has  been a change  in the size  and concen-
tration of particulate  matter.
8.1.4.2  Hdgetveit and  Barton  (1976).  This  is a  report on biologic monitoring
conducted  at the Falconbridge refinery  for blood and  urine  nickel  levels  in
126  R/S  workers, 179 tankhouse electrolysis workers, and  187 university stu-
dents.  Nickel  levels were  measured using  flame!ess absorption spectrophoto-
metry.  The average  plasma nickel  level  was higher in  electrolysis workers  as
compared  to R/S workers (7.4 pg/1  versus 6.0 ug/1).   There was no  correlation
between  start  date (which  is  a  proxy  for duration of  exposure) and plasma
 level.   In active workers,  plasma levels  probably reflect current or recent
exposure.
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     In a comparison  group of university students, the average plasma  level
was 4.2 ug/1,  significantly  lower than process workers.  Plasma nickel  levels
correlated with  urine  nickel  levels both within individuals over time and by
groups.  However, plasma and urine nickel can vary widely in an individual and
can drop to normal levels two weeks after cessation of exposure.
     The authors  stated  that  "the highly soluble  nickel salts  in the  inspired
air produced  greater  biological  levels but were more  quickly excreted."   This
statement is  in  reference  to the nickel  chloride  and sulfate  salts  in the
electrolysis  area but  was  made without  knowledge  of  ambient levels.  Subse-
quent reports showed that even though the total  ambient nickel  level was lower
in the  electrolysis  area as  compared to  the  R/S  area, the plasma levels of
electrolysis  workers  were  higher.   The  data presented in  this  report  are
consistent with  the conclusions  of  Torjussen  et al. (1979a) summarized  below.
8.1.4.3  Kreyberg (1978).  This is a case series study of 44 lung cancer cases
identified from  the  Falconbridge Refinery.   The report is  anecdotal  and  the
analysis is  somewhat  arbitrary.   Thirteen cases were excluded because of in-
adequate material  for histologic typing.  The  cases  were  divided into two
groups; series I  cases,  who  started work between  1927  and 1939; and series II
cases, who started work  on or after 1946.  The cases  were  diagnosed  between
1948 and 1974.
     The primary objective of this study was to  determine the role of cigarette
smoking in the risk of lung cancer among nickel  workers.   There was no control
group, and the conclusions regarding the role of cigarette smoking as a risk
factor in lung cancer independent of nickel  were  based on  indirect evidence
and anecdotal  information.   As  a result, very little  conclusive information
can be derived from this study.
     Smoking  history was obtained in 41  out of 44  cases, and this  information
was derived  from  hospital  records or patients' statements as noted by labora-
tory staff.    Some of  the information included notes  on  smoking  methods and
amounts of tobacco smoked.   In other instances  the statements  were less com-
plete, such as "smoked since the age of 6 years" and "heavy smokers."   Smoking
history does  not  appear  to have  been collected in  a systematic fashion  either
from hospital records, the  workers themselves, or the next-of-kin.
     Kreyberg concluded  that  "the  evidence  presented  indicates that  tobacco
smoking is an important  additional  factor in lung cancer in nickel workers.
As a consequence, neither  factor can be ignored when the development  time is
evaluated."    This has  been noted in the  risks of  the  Clydach plant workers,
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where the  relative  risk  or SMR declined with calendar time of first employ-
ment.  Doll (1970) has suggested that part of the decline in the SMR is due to
the  secular change  or secular  increase in the amount smoked.  In essence, the
risk of lung cancer attributable to nickel  declines with time only because the
risk of  lung  cancer attributable to smoking and the prevalence of smokers in
the  population  increase  with  time.   As the  attributable risk for nickel de-
clines, so does the relative risk.
     In summary,  the  primary  conclusion  to  be  derived from this paper  is an
obvious one for which no direct evidence is provided:   When evaluating the
lung cancer risks from nickel  exposure, one  should  take  smoking into account.
It  is  difficult to  determine whether or not  a decline in lung cancer risk was
due  to  more controlled conditions  in the workplace  and the  reduction in expo-
sure,  or  to  a decreasing attributable risk  for lung cancer from nickel expo-
sure.
8.1.4.4  Hdgetveit et al. (1978).  This is a follow-up to the 1976 publication
on  biologic monitoring,  with  an improved method of  measuring urine  and  plasma
nickel  levels  and the addition of ambient monitoring data.   Ambient levels
were measured  by using personal  and  static samplers.  Blood  and urine  samples
were taken before and after work on the first  test day and after work on the
second  and third test days.   Two measures of nickel  levels  were made for  each
sample.   The  plasma and  urine  levels were reported  as an average  of the eight
measures  (4 samples times 2 measures each).
     A  dramatic decline  in plasma  nickel was shown  for workers  from before  to
after  the introduction of protective masks.   However, levels are  presented  on
electrolysis  workers for the  "before" measures and on  R/S workers for the
"after"  measures.   The conclusion  may  not be in error but  cannot  seriously  be
inferred  from the data,  especially when a previous report showed that  plasma
nickel  levels  were  lower in R/S workers.
     The  correlation between  plasma and urine  nickel levels was 0.76 to 0.77
for R/S and electrolysis workers.  It was lower for non-process workers (0.63).
In  contrast,  there  was a poor  correlation between ambient  levels and blood  and
urine  nickel  levels.   The ambient measures  used were from personal samplers.
The correlations between ambient and plasma and urine  nickel  levels  for  R/S
workers were  the lowest; workers showed a slightly  negative  correlation (-0.11)
between ambient and plasma levels.   The correlations were  slightly higher for
electrolysis  workers (0.31 for  urine and ambient  levels,  and 0.21  for  plasma
and ambient levels) and  highest for  other process workers  (0.67 for plasma  and
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ambient levels, and 0.47 for urine and ambient levels).
     As a group,  the  electrolysis workers had the highest average plasma and
urine  nickel  levels (11.9 ug/1  and  129.2 ug/1), followed  by R/S workers
(7.2 ug/1  and  65  ug/1),  and  other process workers (6.4 ug/1  and 44.6 ug/1).
In contrast, the  electrolysis  workers were exposed to by far the lowest mean
                                      3
air concentration of nickel (0.23 ug/m ), followed by other process department
workers (0.42 ug/m ) and by R/S workers (0.86 ug/m3).
     This evidence  supports the  conclusion of Hrigetveit and Barton (1976) who
suggested that soluble nickel  salts,  i.e., nickel sulfate and chloride,  result
in elevated body fluid levels.   One other factor worth noting is the relative-
ly high nickel  exposure and elevated plasma  and urine  levels among "other
process workers."  It would be of some value to more specifically characterize
the exposures for this group.   Finally, factors which may account for the poor
correlation between ambient and body fluid levels of nickel include ingestion,
positioning of the worker, and clothing blocking inspiration.
8.1.4.5  Torjussen  et al.  (1978).  This  is a study  of the  concentration of
nickel, copper, cobalt,  zinc,  and iron levels in the nasal mucosa of 30 nickel-
exposed and  six  unexposed individuals to determine if a sulfide silver stain
was sensitive to the tissue level of these metals.   The  stain was not found to
be sensitive to  any single metal, nor to  total  metal in  the  mucosal tissue.
The results of the test are not relevant to this review.   However,  the mucosal
level of each metal is worth noting.
     Workers at the refinery were selected at random.  Two subjects with nasal
carcinoma and a history of nickel exposure were also selected.  Twenty-five of
the 30 workers were from  either  the electrolysis or  the R/S departments.  The
average ages of R/S and electrolysis workers were 53.5 and 52.9, respectively.
Controls were considerably younger (mean = 39.7).  Five  were involved in other
work at the  refinery.  The six controls presumably had never  been employed at
the plant.   All biopsies were taken from the middle nasal  turbinate.
     As a group,  the exposed subjects did not have a statistically significant
higher mean concentration of mucosal  nickel than did the controls,  even though
the means were 354 and 21, respectively.  The  standard  deviation for  both
groups was extremely high.  In contrast, the mean nickel  level for the  11 R/S
workers was significantly higher than that of other workers.   In addition,  the
mucosal levels of  copper  and  zinc were also higher  among R/S workers.  How-
ever, no statistical test was conducted.
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     In summary,  the  results on mucosal  nickel  levels  are consistent with
other investigations.   It  is  of interest to note the higher content of other
metals among R/S  workers.   It is not well established how these other metals
are related to workplace exposures.
8.1.4.6  Torjussen and Andersen (1979).   The  primary objective  of this study
was to obtain quantitative data on active and retired nickel plant workers and
unexposed controls regarding  nickel  levels in the nasal mucosa, plasma,  and
urine, and the relationship of this information to duration of exposure.   Four
groups were  selected  for  study:   a random  sample of workers employed  for at
least 8 years  at  the  nickel refinery in the crushing, roasting, smelting, or
electrolysis areas as of October 1976;  a  20 percent  random  sample of non-pro-
cess workers; 15 male pensioners; and 57 age-matched unexposed subjects selected
from a  local  hospital.   Out of a total  of 370 current and former  refinery
workers invited to participate  in the  study,  318 participated.  The average
age  and  time from "first"  nickel exposure  were  similar among roasting and
smelting workers,  electrolysis workers, and non-process workers.
     The average  plasma nickel  levels  were  much  higher  among the electrolysis
workers (8.1 ug/1 ± 6.0) as compared to the  R/S workers  (5.2 ± 2.7)  or the
non-process workers (4.3 ± 2.2).  The  same  pattern was  found for urine nickel
levels.   In  contrast, the  R/S  workers had a significantly higher average
nickel content  in the nasal mucosa  (467.2 ug/100 g), and,  surprisingly,  the
electrolysis workers had the lowest mucosal nickel levels.   The plasma, urine,
and  mucosal  nickel levels  of  retired workers  were between  those  of  the active
workers and the unexposed controls.   In general, tissue nickel  levels were not
correlated with either plasma or urine  nickel  levels among active workers.  In
contrast,  significant correlations were  found in the  15  retired workers.
     The authors  noted  the "highly significant correlations between duration
of  nickel  exposure and  plasma, urine,  and mucosal   levels."   Correlation
coefficients appear to  have been  derived  within  each category of work  and for
total duration of exposure  to nickel for  all  categories combined.  Duration of
exposure  in  the  R/S  workers was  significantly correlated  with  nasal mucosal
levels  only.   In contrast,  duration of work in  the electrolysis  area was
highly  correlated with  plasma and urine levels,  but  was negatively  correlated
with  nasal  mucosal  levels.   The correlation coefficients  for overall  duration
of  nickel  exposure  were significant (p < 0.01); however, all were  lower  than
the  coefficients  derived by the specific  categories  of work.
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     A half-life for retention of nickel in the nasal mucosa was derived from
the data on retired workers.  Using length of time since retirement and muco-
sal nickel  level,  a half-life of 3.5 years  was estimated.   It should be noted,
however,  that this estimate  was  highly dependent on measures  from a single
subject 10 years after retirement, and should therefore be considered  unreli-
able.   It would be of interest to know the  mucosal  nickel  levels in this group
at some time in the future to better estimate the tissue half-life.
     Exposure status was  based  on the subject's current job  as of November
1976,  and not on the job of longest duration.   This definition of exposure may
be most relevant for plasma and  urine nickel  levels, which are  more likely  to
reflect current and recent exposure status.   In contrast, the nickel level  of
the nasal mucosa may  reflect both past and current exposure, and an exposure
definition based on jobs of longest duration may be more relevant.   If there is
a  low  rate  of  movement between  departments,  the results will be essentially
the same when  using  current versus longest job.  A more definitive analysis
could  have  been done by defining the  length of time spent in each  category  of
work and adjusting the category-specific coefficients for the length of time
spent  in other work categories.
     In summary, this  investigation  provides  information that  is  consistent
with the  mortality  study  summarized previously.  The  highest  tissue nickel
levels occurred among  the R/S workers who  were predominantly exposed to dust
containing  nickel subsulfide  and oxide.   As the authors suggested, this pat-
tern is consistent with the expected  deposition pattern in the  upper respira-
tory system.   In contrast, electrolysis  workers who were primarily exposed  to
aerosols  of nickel  chloride  and sulfate had the highest urine and plasma
nickel levels.  Whether this  was related to a higher deposition of the aero-
sols  in  the lungs and more  ready absorption  of these water-soluble nickel
species was  not  determined.   The tissue nickel  level  of retired workers was
between that of active and unexposed  workers.  One can  infer a  time-dependent
release of  nickel  from the tissue.   The half-life is uncertain, however, and
warrants further investigation.
8.1.4.7  Torjussen et  al.  (1979a).  This was  a study of histopathology of the
nasal   mucosa among nickel  refinery workers, non-nickel industrial workers, and
subjects without  industrial  exposure.   Ninety-eight male nickel workers were
selected, of which  91  were active workers  and 7 were retired or former work-
ers. Three  of  the  7 were diagnosed during the study as having nasal carcino-
mas.   Exposed workers were divided into three groups:   crushing, roasting, and
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smelting (n = 55),  electrolysis department (n = 28), and other process workers
(n = 15).  Individuals were divided into groups defined by work area of long-
est employment or  highest  exposure.   Sixty-one subjects without a history of
nickel  exposure  comprised  the control group.   Sixteen  were  employed in an
electrochemical plant  which  was described  as  "dusty."   The  remainder were
hospital patients  or  military recruits.   The  average age  was 50.1 for the
nickel-exposed group and 37.5 for the unexposed group.
     Nasal  biopsies were from the  middle turbinate and from  the cavity "with
the best air passage or side  where  the pathologic changes were mainly located."
All biopsies were graded blind on an 8-point scale ranging from normal respira-
tory epithelium to  carcinoma.  Two  readings  were made on each  biopsy, presum-
ably by  different  readers.   There  was exact agreement  in  148  of  159  samples
(93 percent).  Three  histologic  groups  were defined:  normal (0), limited to
moderate changes (1 to 5),  and dysplasia to carcinoma (6 to 8).
     Twenty-five subjects  had a grade  of zero, 22 of which  were from the
non-industrial group.  Twenty-two subjects  had a grade  of  6  to 8,  all of whom
were nickel  workers with 10 or more years of employment.   Individuals with 10
to 19 years  in the  nickel refinery had the same average grade and distribution
by grade as  workers employed 20 years or more.  Workers in the R/S and elec-
trolysis departments had similar average histologic scores, both of which were
higher than  other  process  workers.   Six of  15 R/S  workers had scores  in  the
most severe  category  (6  to 8), all  of whom  had severe dysplasia or carcinoma
(scores of 7 to 8).  In contrast, the seven  electrolysis workers with the most
severe grade had scores of 6.  No relationship was observed between histologic
score and smoking status.
     The results are consistent with the higher risk of nasal cancer among the
R/S  workers  observed in other studies.   However,  no information on  age  at
first employment and  length  of employment by  category of work was given, al-
though  both  variables are  related to histologic  score.   Simple and partial
correlations between histologic score and a  number of variables were described.
Data from  all  159   subjects were used,  and  given  the wide  differences in  the
age  distribution of exposed  workers and  controls,  it  may  not be  possible to
adequately  adjust  for age  in  the analysis.   Nonetheless,  partial  correlations
for  R/S  and electrolytic process work with  age and years  from first exposure
were statistically  significant.
8.1.4.8   Torjussen et al.  (1979b).   This was  a study  of  the relationships
between  histopathology of  the nasal mucosa and exposure to nickel, age,  smok-
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ing status, and  nickel  level  in the nasal  mucosa,  plasma,  and urine.  The
objective and methods were essentially the same as in the pilot study described
above (Torjussen et  al.,  1979a).  The population and methods are described by
Torjussen and Andersen  (1979).   Plasma  and urine nickel levels were included
in addition to the variables described in the pilot study.
     A smaller percentage of active compared to retired workers had histologic
scores greater than 5, i.e., epithelial  dysplasia or carcinoma.  Twelve percent
of the R/S workers,  11 percent of the electrolysis workers, and 10 percent of
the non-process workers  exhibited  epithelial  dysplasia, i.e., a score of 6.
All but  one  of  the  non-process workers  with  dysplasia were former process
workers.   Two percent of the R/S workers (n = 25) had carcinoma i_n situ,  i.e. ,
a score of 7.   No other active workers had a score greater than 6.   Fifty-three
percent of the retired workers had a score of between 0 and 5,  and the remaining
47 percent had a score of 6.  Among the  controls, only one subject (2 percent)
had a score of  greater than 5.   The average histologic score was highest for
retired workers  (4.93),  followed  by R/S workers (3.25), electrolysis workers
(3.01),  and non-process  workers (2.49).   The average score among the  controls
was 1.88.
     The average histologic score increased with age among active nickel-exposed
workers,  but not among the unexposed controls.   Since age is probably correlated
with length of exposure,  this pattern would suggest that changes in the nasal
mucosa are primarily correlated with duration of exposure.
     Simple and  partial   correlation  coefficients  were estimated between a
number of dependent  variables  and the histologic scores.   Statistically sig-
nificant partial correlation coefficients were  found between histologic score
and R/S work,  electrolysis work, and age.  In contrast to the pilot study, the
partial  correlation  in this study was not significant  according to years  from
first nickel  exposure, but was significant for amount smoked.
     Several  factors  probably account for the differences between the pilot
study and the more extensive  investigation described above.   The exposed and
control  groups differed-in  definition and size.  The larger investigation was
limited to workers with  at least 8 years of  employment in the plant.  As a
result,  there was probably less variation in length of employment and a greater
average length of  employment.   This may be responsible for the absence of a
significant partial  correlation between  histologic score and time since first
employment.   The control  group  was  not  matched  for  age  in  the pilot study
(Torjussen et al.,  1979a), as  it was in  the larger investigation.
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8.1.4.9  Hrigetveit et at. (1980).   The  purpose  of this study was to investi-
gate the diurnal variation in urine and plasma nickel  levels and its relation-
ship to  ambient  levels.   Three workers were  selected  from  both the R/S and
electrolysis departments.   No protective  masks  were  worn  during  the test
period.  Blood,  urine,  and  personal  air monitoring samples were taken  every
hour from the start to the end of the working day.
     Hourly urine  nickel  levels  were found to be  highly  variable  within an
individual.  As  a  result,  single  measures are thought to be  unreliable as  a
marker of  recent exposure.   One factor  which  may  contribute to  the  high vari-
ation, as  the  authors noted, is the greater  risk of  contamination of urine
samples  in  contrast  to  blood samples.   Plasma nickel  levels  in electrolysis
workers tended to increase throughout the day and were, on the average, higher
than those  of  the  R/S workers.  In contrast,  the  ambient  nickel  levels  in the
R/S department  were  more than twice  the level in  the electrolysis department.
     In  summary, the results of this study are consistent with  other  investi-
gations  of the  relationship  between body  burden,  work setting, species of
nickel exposure, and ambient levels.    In addition, a  single  urine  sample is
probably inadequate to measure the body burden from recent nickel exposure.   A
single plasma  sample will probably yield  a more reliable  relative estimate  of
recent exposure  to nickel.
8.1.4.10   Magnus et  al.  (1982).  This  was an update of the study reported  by
Pedersen et al.  (1973).   The  follow-up  period was extended to 1979  for  a total
of 26 years of follow-up, an  increase of eight years.   The study group  included
all men  starting employment  before 1966 who were alive on January 1, 1953,  and
who had  been  employed for at  least  three years.   The problems  with  such a
cohort definition  have been  noted in the above review of the  Pedersen et al. (1973)
paper.   A  total  of 2,247 subjects met the cohort criteria, and  during follow-up,
82 lung  cancer,  21 nasal cancer, and 5  laryngeal cancer cases were  identified.
In  addition,  smoking histories were acquired for almost all of the  cohort
members. However,  information on  smoking status only  and  not on amount smoked
was used,  and individuals were classified simply as present  and past smokers
(ever  smoked)  or nonsmokers.  Analyses were  presented  by  job category,  calen-
dar time of first employment  and years since first exposure, and smoking and
nickel exposure  status.
      SMRs  in  four job categories were  determined for  nasal cancer, laryngeal
cancer,  and lung cancer.  The four job categories were roasting and smelting,
electrolysis,  other  specified processes,  and  administration/service and unspec-
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ified.   An excess  risk  of nasal  cancer was shown in all  four job categories.
The highest SMR  (4,000,  0/E = 8/0.2), was in the roasting and smelting cate-
gory,  followed by 2,600 (0/E = 8/0.3) in the electrolysis category,  2,000 (0/E
= 2/0.1) for  other specified processes, and 1,500 (0/E = 3/0.2) for admini-
strative jobs.  Only  two  categories  showed an excess risk for laryngeal  can-
cer.   The R/S workers had an SMR of  670  (0/E  = 4/0.6),  and other specified
process workers had an SMR of 330 (0/E = 1/0.3).   Only one case was  identified
in the  latter category.   No cases of laryngeal cancer were identified in the
electrolysis group or the administrative  group.   The pattern for lung cancer
was somewhat different.   The electrolysis group showed the highest  SMR,  550,
which was followed by an SMR of 390 (0/E = 12/3.1) for other specified process
workers, and an  SMR  of  360  (0/E = 19/5.3)  for the R/S group.   The  adminis-
trative group showed  an excess risk,  but  it was  relatively  low with an SMR of
170 (0/E =  11/6.3).   The higher risks  of  nasal  cancer and laryngeal  cancer
among R/S workers are consistent with the results from studies that  have shown
this group to have had the highest concentration of nickel in the nasal mucosa.
In contrast, the  electrolysis  group,  which was  shown  to  have had the  higher
plasma  and urine  levels  of nickel and had typically been exposed to aerosols
of nickel sulfate and chloride, showed a higher risk of lung cancer.
     Observed-to-expected ratios were  displayed  by year of first employment
and number of years since first employment.  (These  dates may not correspond,
however, to year  of  first exposure and time since first exposure.)   No nasal
cancer cases occurred within 3 to 14 years of first employment,  even among the
cohorts which started work  later, e.g., 1940 to  1949,  1950  to 1959, etc.  For
a fixed  number of  years since  first employment (i.e.,  3-14, 15-24, 25-39, and
35+),  there was a  consistent decrease  in  the SMR as  the year of  first  employ-
ment increased.  This suggests that  exposure to  the carcinogen  which  caused
nasal  cancer  could have  been  decreasing  with  calendar time either because
ambient  levels  decreased or  the  duration of exposure was  shorter  in more
recent cohorts.
     The pattern  of  risk for  lung cancer is  somewhat different from that
described for nasal cancer.  Excess risks can be found within 3 to 14 years of
first employment.   Later cohorts, i.e., those starting in 1940 to 1949 or 1950
to 1959, showed a  peak SMR  15  to 24 years after  first  employment, whereas the
earlier cohort, i.e., those first employed between 1930 to 1939, showed a peak
25 to 34 years after  first  employment.  The risks within  subgroups defined by
year since first employment do not consistently decline with calendar time,  as
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was shown  for  nasal  cancer.   The pattern of risk for lung cancer is somewhat
difficult to explain.   The  later cohorts, which might be expected to incur a
lower exposure, experienced  shorter  latency periods.   The authors  suggested
that the patterns  noted may have been due  in part to the changes in smoking
habits with calendar  time,  or,  as suggested by  Kreyberg (1978),  to the in-
creasing age of first employment with calendar time.
     The authors assessed the combined effects of smoking and nickel exposure
on the risk of lung cancer, and  concluded  that  the effects are likely  to  be
additive since the  risk ratio of smokers to nonsmokers is 5.9 for non-nickel
workers and 2.0  for nickel  workers.   If interaction were operating, the risk
ratio among nickel  workers  who  smoke would be much  higher  than that among
nickel workers who  do not smoke.  The inference with  regard  to an additive
effect might be  more  direct if expected  rates among  smoking  and nonsmoking
nickel workers were  derived by  applying the age-specific rates of the survey
population to  the  age-specific  distribution of person-years among each  of  the
smoking and nonsmoking nickel workers.  If the differences between the observed
and expected  rates were  equivalent  for the smoking  and nonsmoking nickel
workers, one could infer a simple additive model.
     The results of this study are consistent with the 1973 report.   Interpre-
tation of  SMRs by  start date is  simplified, however, because  time since first
employment and not calendar year is used.  The relationships  between job
category and tumors  of highest risk are consistent with the previous report.
8.1.4.11  Kotlar et a!. (1982).   This was an investigation of the utility of a
medical screening test, a serum antigen, for nasal and lung cancer.   The study
provided no information on the risk of lung or nasal cancer, either by  species
of  nickel  exposure or from nickel  exposure in  general.   Four  groups were
selected for study.   These  were:  18 randomly selected current employees who
had worked at  the Falconbridge refinery for 6 to 10 years; 33 randomly  selected
active workers who had  been employed for  more  than  10 years;  17 randomly
selected office  workers with no  refinery work experience;  and  6 cases with
nasal  carcinoma  of the  squamous cell type, 2 of whom  had  an occupational
history of  nickel  exposure.   Nasal  biopsies were obtained from all subjects,
and histological grades were assigned.   Questionnaire interviews were  admin-
istered to  obtain  occupational  histories,  including duration of work  in the
nickel industry and information  on habits and medical histories.
     The mean  ages of each  group were 51 for the controls, 38 for the  short-
term workers,  54 for  the long-term workers, and  70 for the nasal cancer cases.
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The subjects were  tested  for three antigens:   lung cancer, nasal  cancer, and
breast cancer.   The breast  cancer antigen was included  as  a non-specific
marker.   The percentages of  positive responses to the lung,  nasal, and breast
cancer antigens were  higher  for the nickel-exposed workers than for the non-
exposed workers.   The  long-term workers showed more positive responses  than
the short-term workers.  The six subjects with nasal cancer  had the highest
percentage of  positive responses  for  the lung and  nasal  cancer  antigens.
These differences  may  have  been due in part to differences in age, since the
percentage of positive responses correlated with age.
     The authors conclude that the "present data strengthens the usefulness of
the H-LAI test for identification  of individuals with a high  risk  of cancer."
The results of  the study,  however, do  not  support  such  a conclusion.    The
sensitivity of the nasal  cancer antigen was good (83 percent)  for the cases
with  nasal  cancer.  However, the  specificity  of  this  test was essentially
unverified,  and given  the number of positive responses to  all three antigens,
it is likely that  the  specificity  was extremely poor unless  the risk of  nasal
cancer among current workers  is on the  order of 20 to 30 percent,  much higher
than would be  expected under present conditions.   In addition, age  was not
effectively controlled in this study.
8.1.4.12  Summary of Studies on the Falconbridge Refinery (Norway).  The studies
on cancer risk, in combination with the numerous studies  on biologic monitoring,
provide valuable information  on the association between the  risk of nasal  and
lung cancer and specific nickel species.
     The highest risk  of  nasal  cancer was found to  occur  in  R/S workers who
had been exposed primarily to particulate matter containing  nickel subsulfide
and oxide.  This  association is corroborated  by the fact that R/S workers
currently have the highest  nasal  mucosal nickel levels and  the highest  fre-
quency and  severity of nasal mucosal dysplasia.  The  highest risk of lung
cancer occurred  in electrolytic workers who had  been  exposed primarily to
aerosols of  nickel sulfate  and chloride.   Although the  ambient  levels  of
nickel were higher in  the electrolytic  tankhouse, the nasal mucosal levels of
nickel were the lowest of all the process workers.   In contrast, the urine and
plasma levels, which  for  the most part reflected  current or recent exposure,
were highest.   The exposures of other process  workers were not well  defined,
and it would be of some use to better characterize their  exposure  and associa-
ted risks.
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     The occurrence of laryngeal cancer and the disappearance of nasal cancer
appear to have been associated.  Four of the five laryngeal cancer cases were
first employed during or  after 1940,  whereas  only one of the 14 nasal cancer
cases occurred among those starting after 1940.  The  refinery appears to have
been inactive between 1940  and 1945.   It would be  of interest to know what
changes in production and control measures were introduced, and the relation-
ship of such  measures  to  changes in dust particle exposure and distribution
and  nickel species  exposure.   As an alternative  explanation,  the increased
risk of laryngeal cancer could  reflect changes in smoking patterns.   However,
data were not presented to address this question.
     Two methodological  problems present some  difficulty in the interpretation
of  risks on  the  basis  of these studies.   Exposure groups were defined on the
basis of work area  of  longest duration or highest exposure, whereas duration
of  exposure was,  for  the  most part, defined  as  total length of employment.
Using these exposure criteria can result in heterogeneously defined exposure
groups, and  it  is possible that the risks associated with certain work areas
may  have been due in part  to  exposures incurred while being  employed  in  other
work areas.    Defining exposure more precisely can only improve the understanding
of  tumor-specific risks associated with different exposure settings.  A second
problem is related to the definition of the cohort and the loss of early-onset
cases.  Approximately one-third of the total cohort was first employed between
1916 to 1949.  Follow-up did  not begin until 1953.  As a result, earlier-onset
cases  from the pre-1950 group were  missed.  It is  likely  that these methodol-
ogical  problems  affect  the magnitude of  risk  estimates  but not the relative
order of risk by  exposure category.

8.1.5   Hanna  Miners and Smelting Workers, Oregon (U.S.A.)
     Cooper  and  Wong  (1981,  unpublished)  reported on a nonconcurrent  prospec-
tive study of an  incidence cohort of 1,307 men employed for at  least  12  months
at  the  Hanna  Nickel Smelting  Company between June 1954 and  December 1977.   The
ore mined  and processed in Oregon  is  sulfur-free.   According  to  the  authors,
workers are  not exposed to arsenic,  nickel  sulfide, or nickel carbonyl.  In
this report,  documentation  of exposure  and  description  of the cohort  are
excellent, and the  analysis  is  complete and straightforward.
      The  follow-up period was from 1954 to 1977,  for a total of 24 years.   Of
the cohort,  21 (1.6 percent) were lost to follow-up.  One hundred twenty-nine
deaths  were   identified in the  follow-up  period,  of  which  12  were due to lung
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cancer  and 2 to laryngeal cancer.   No  nasal  cancer cases were  identified.
     Personnel  records  were  used to identify the  jobs  held  by each worker.
Each job  title  was  classified into  one  of  four  exposure  categories,  and  indi-
viduals were  categorized  by  exposure groups as  defined  by the  job  title and
length  of  time  the  job was  held.   The  industrial  hygiene data  used  had  been
collected  by  the  U.S.  Public Health Service  in 1967 and by NIOSH  in  1976.
According  to Cooper and Wong, the ambient nickel levels measured were relative-
ly  low  for both periods.   Twenty-two samples were collected in 1967 in the
smelting building.  All were below the threshold limit value (TLV) of mg/m  as
a time-weighted average.   Four were above 0.1  mg/m ; 15 were below  the  0.01
detectable  limit.   The  survey in 1976 was based on 81 samples in which the
                                       3
nickel  ranged from  0.004  to  0.420 mg/m .  Six  percent  of the  samples were
              3                                     3
above 0.1  mg/m  ,  and 22 percent were above 0.01 mg/m .   A number of controls
were introduced between 1954 and 1967,  before the  first  ambient measures were
made.  These controls included dust filters installed on the melting furnaces,
crusher house,  and  storage  bins in 1958,  and  electrostatic precipitators,
which were installed on the  calciners,  the wet  scrubbers, the dryers,  and the
ferrosilicon furnace.   A  total  of 342 workers  were employed at the highest
exposure  level  for  at  least  12  months.  Five hundred fifty-seven were never
exposed in the  highest  exposure group.   Expected  values were  derived using
rates for  U.S. white males.  Analyses were presented by calendar time of first
exposure,   level  of exposure,  and location of work.
     The overall SMR was 78,  significantly less than 100 (p < 0.05).   No nasal
cancer  cases were identified,  but only 0.07 was expected.   The SMR  for  lung
cancer was slightly in  excess of that expected (SMR = 105),  but was not sta-
tistically significant.   The SMR for laryngeal cancer was 380 among all workers
and was 393 among those who had ever worked in the smelter,  refining furnaces,
skull plant, or ferrosilicon area.  Neither of  these  SMRs was  statistically
significant.  A statistically  significant  SMR was found for laryngeal cancer
among employees observed  15  or more years after their hire  date (SMR =  909,
p < 0.05).  Analysis by latent period did not result in any differences from
the overall SMRs  for  lung or laryngeal cancer;  however,  the group with the
longest follow-up period had a maximum follow-up of 24 years  and included both
exposed and unexposed workers.   In  addition,  there were only  1,192 person-
years of follow-up more than 20 years after exposure.   The SMR for lung cancer,
more than  20 years  after  first exposure, was 215,  which was  not statistically
significant.  No statistically  significant  excess  risks were found  for  lung
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cancer or other  causes  for the highest exposure group.   In fact, the highest
SMR was  found  in the lowest exposure group.   In addition, no excess risk was
shown by location of work, whether in the mines or the smelting areas.
     The results  suggest  that  there was no excess  risk  for lung, nasal, or
laryngeal cancer  from  nickel  exposure at the Hanna facility.   However,  given
the relatively small  statistical  power of the study, and the short follow-up
period used, the conclusions are somewhat limited.  The authors indicated that
the study had  an 80 percent power of  detecting  an  SMR  for nasal cancer of
8,900.   Another  consideration  with regard to this  study  is related to the
ambient  levels of nickel  and the  length  of employment in  the highest exposure
groups.  The combination  of low ambient nickel  levels and short-term employ-
ment  in  high-exposure groups resulted  in relatively  low exposures, even among
those defined as the high-exposure group.

8.1.6  Nickel  Refinery and  Alloy  Manufacturing Workers, West Virginia (U.S.A)
     This was  a  study of  the disease  risks in a  cohort of workers at a nickel
refinery and alloy manufacturing plant in Huntington, West Virginia, by Enter-
line  and Marsh (1982).  This plant  received matte from an INCO smelter in the
area  of  Sudbury,  Ontario.   Three  groups of workers  were  defined for study:
those  hired before  1947,  who had worked a year  or more in  the refinery, and
who were working there  at some time  during 1948 (n  = 266); workers with the
same characteristics as defined above, but who had worked in the refinery area
for less than  a  year (n =  1,589);  and those hired after  1946  (less than one
year  before  the  calciners  were shut  down).   The first two groups  had  the
highest nickel  exposures.
     The refinery consisted of two  departments:   1)  calcining, and 2) melting
and casting.   The calcining department operated  from 1922 to 1947.  Matte for
the refinery was obtained from a Sudbury smelter, and was a "high copper-nickel
matte."  The concentration  of  total particulates was found to be "very high"
where the matte was crushed, ground, and handled, and lower around the calcin-
ers (20  to  350 mg Ni/m  and 5 to  15 mg Ni/m  , respectively).   Vital status of
cohort members and cases was determined through company records, and follow-up
was carried out  through  the Social  Security Administration,  the Veterans
Administration,  the  U.S.  Postal Service, and direct  telephone  inquiries.  The
period of follow-up  was from January  1,  1948 to  December  31, 1977, a total of
29  years.   Sixty-five lung cancer, 2  nasal  cancer,  and 2  laryngeal cancer
deaths were  identified.   Expected values were derived using 5-year age- and
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calendar time-specific mortality rates by cause for white males nationally and
locally.  Exposure groups were defined in several  ways:   by the cohort defini-
tions noted above,  by duration of employment, and by cumulative nickel expo-
sure.
     The refinery workers had elevated SMRs for nearly all causes (in contrast
to nonrefinery workers),  ranging  from a low  of 86.2  for heart disease to a
high of 181.8  for "other malignant neoplasms."  The SMR for nasal cancer was
the only one to exceed 200  (SMR = 2,443.5), with 2 observed and  0.08 expected
cases.   However,  there was  no large excess of lung  cancer  among refinery
workers (SMR = 118.5);  the SMR was slightly lower among non-refinery workers
(107.6), and was  highest among those hired after  1946.   Nasal  cancers were
exclusive to  the  refinery  workers.   Restricting  the  analysis  to workers
followed 20  or more  years  after first  exposure  did not  change the SMRs
appreciably.   There was  no  apparent  relationship between  duration of work and
SMR for lung  cancer;  however, the analysis included  both refinery  and non-
refinery workers.    The  highest SMR found was  for  workers employed  20 to 29
years (SMR = 119.3), and the lowest was for those who had worked for less than
20 years (SMR = 64.1).
     All of the nickel workers were  assigned  cumulative  nickel exposure  esti-
mates based on department and duration of work shown  on  the subjects'  person-
nel records.  When  all  respiratory cancer cases  were combined and cumulative
nickel  exposure was restricted to the 20 years after first exposure, there was
a  dose-response  relationship across 4 exposure categories,  with an SMR of
161.1 in the highest cumulative dose group.
     This study showed an excess risk of nasal sinus cancer among nickel refin-
ery workers.   Surprisingly,  there  was no significant excess  of  lung cancer.
However, a measurable dose-response  relationship was  shown between cumulative
nickel   exposure  and  lung  cancer,  although the SMRs  were  generally  low in
contrast to those of  other studies.   Enterline and Marsh  suggested  that the
actual  exposure level  at the Huntington plant may have been considerably lower
than that  reported at plants  where  larger  excess  risks had  been reported.

8.1.7  Sherritt Gordon Mines Workers (Alberta, Canada)
     Hydrometallurgical  nickel-refining  operations were  begun at Fort  Saskat-
chewan, Alberta,  in 1954.   In the refinery, nickel was  recovered from  concen-
trates  in  a process  which  produced complex  metal  amines,  copper sulfide,
nickel   sulfate,  and pure metallic nickel  powder.   Further refining of  the
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remainder produced nickel  sulfide and cobalt sulfide.   In another operation at
the same plant, nickel  powder  was treated and compacted  into  briquettes or
fabricated nickel  strips.   Air  sampling began in  1977 (Egedahl  and Rice,  1983,
unpublished; 1984),  and showed high to moderate  levels  of airborne nickel
dust in specific locations in the plant.
     Egedahl and  Rice  (1983, unpublished;  1984)  carried out a nonconcurrent,
prospective study of cancer  incidence  and mortality among  men  who had been
employed for at least  12  consecutive months at Sherritt Gordon Mines between
January 1,  1954 and December 1978.  Active employees, retired pensioners,  and
terminated workers were included  in the study.  Two groups  of workers exposed
to nickel were identified:  (1) 720 men who were  employed in the nickel  refinery
processes, and (2) 273 maintenance employees, including steamfitters, welders,
painters, and  others.   The vital  status of the past employees was  ascertained
as of the end of 1978 through "traditional information sources" and the Alber-
ta Health Care  Insurance  Commission, with confirmation of  the vital  status  on
a  total  of  94  percent  of  the cohort.  Cancer  cases  were identified by  the
Alberta Cancer  Registry,  and deaths among those  cases were verified by the
Alberta Vital Statistics Division.
     Expected  numbers  of  cancer  cases  were  calculated using age-  and calendar
time-specific incidence rates for males in Alberta, Canada.  Rates for 1964-1968
were applied to  the  person-years accumulated from 1954  to 1964 because the
actual rates were not available.   It should be noted that the expected numbers
of cancer cases would be overestimated if cancer death rates actually increased
in the  later time period as they have done elsewhere; this would  inflate the
denominator of the SMR  and produce an  underestimate of the  SMR.
     The  results  showed no cases of nasal  cavity,  paranasal sinus, laryngeal,
or lung cancer among the  720 nickel process workers.   Two cases of lung  cancer
occurred among 273 maintenance workers, both of whom were smokers  who had  been
exposed  to  nickel concentrate, soluble nickel compounds, and metallic nickel
in  the  leaching area.   The  SMR  for  lung cancer among maintenance  workers was
175, which  was not statistically significant (p  < 0.05,  0/E = 2/1.14).   Renal
cell cancer showed an  SMR of 303  (0/E  = 1/0.33) among nickel workers, 370  (0/E
=  1/0.27)  among maintenance  workers, and  333 (0/E =  2/0.60) among all  workers
combined,  none of which were  statistically  significant  (p < 0.05):   Both of
the  two  men with  kidney cancer had  worked  in the  leaching  area, where they had
been exposed to  nickel concentrate,  soluble nickel  compounds, and  metallic
nickel,  and both  were  smokers.
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     The authors  concluded  that no association was seen between nickel expo-
sure and lung  or nasal cancer.  However, the ability of this study to detect
an association  is small.   The cohort was  not  large  (993 total), and  most  of
the  men  in the cohort were young.   Ninety-one percent of the person-years
among the  nickel  workers were accumulated  under  age  50, and  79 percent of  the
person-years among  the maintenance workers were accumulated  in that  younger
age group.

8.1.8  Nickel Refinery Workers (U.S.S.R)
     Two studies  of cancer mortality among  nickel  refinery workers  in the
U.S.S.R.  were  reported by Saknyn  and Shabynina  (1970,  1973).  In the 1970
report, a  plant in the Urals which  refines  oxide ore was  studied.  The pro-
cesses used  included drying-and-pressing,  smelting, roasting-reduction, and
briquetting, but  not  electrolysis.   Exposures included sulfide  and oxide
nickel in  the  pyrometallurgy  production shops, and cobalt and arsenic in the
cobalt shop.
     The cohort under study apparently comprised persons  "in the  personnel
roster books  of the combine,  beginning  with its foundation."  The authors
characterized the  plant  as  "one of the oldest nickel combines in the Urals,"
but did not  give  the year in which it was opened.   Follow-up appears to have
been carried out  "by family,"  based  on  information  in the  company's archives.
Cancer mortality  from  1955  to 1967 among workers was compared to that in the
urban population  of the  area  as a whole according to age  and sex groupings.
Cancer mortality  among the workers  was  also compared with  that in  1)  the
local oblast (an  oblast  is  a political  subdivision of a Soviet republic);  2)
the Russian Soviet Federated Socialist Republic (RSFSR), the republic in which
the combine is  located; and 3) the U.S.S.R. as a whole.
     The results  indicated  an excess of cancer  mortality  among the  nickel
workers.   The excess was consistent among men and women and by age  group.   The
workers'  lung cancer death rate "exceeded  that of the urban  population by  180
percent,"  and appeared to  be  highest in the roasting-reduction shop  and the
cobalt shop.  An  excess  of  stomach cancer deaths among  all  of the workers
combined was statistically significant among those aged 50  and older.
     The 1973  report  presented results  of a similar study  of  four  nickel
plants.   Pyrometallurgical and electrolytic processes were used.  Apparently,
two of the  plants processed  oxide ores and two processed  sulfide ores.  The
English translation uses the term "oxided nickel  ores"  throughout.   The authors
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concluded that  cancer  mortality from 1955 to 1967  was  higher among nickel
plant workers than  in  the  urban population in the  same  geographic area for
each nickel  plant.   In particular,  lung and stomach cancer deaths were  seen in
excess,  as  were deaths due  to  sarcomas (especially of the hip,  lung,  and
intestine).
     For both  the  1970 and  1973 reports,  it is difficult to  evaluate  the
findings due to  the  lack  of information on cohort definition,  follow-up,  and
analytical  methods.   The authors did not state  whether a person-years  method
was used, but the  numbers  shown suggest that it  was  not; thus,  the results
cannot be interpreted reliably.

8.1.9  Oak Ridge Nuclear Facilities (Tennessee,  U.S.A.)
     Several studies  of the possible  carcinogenicity of  nickel  have  been
conducted utilizing data on  employees  of the Oak  Ridge  nuclear  facilities.
     One set of  studies (Section 8.1.9.1:  Godbold and Tompkins, 1979; Cragle
et al. ,  1983, unpublished; 1984) focused on workers exposed or not exposed to
metallic nickel  powder, which  also may have been accompanied by exposure to
nickel oxides when  the fine  metal  powder was exposed to air.   These studies
included 814 men who worked in  the  "barrier"  manufacture  department of  the Oak
Ridge Gaseous Diffusion Plant (ORGDP),  and nearly 8,000 men who were employed
at the ORGDP but not in barrier manufacture.
     Another set of  studies  (Section 8.1.9.2:   Polednak,  1981;  Gibson,  1982)
focused  on welders exposed or not  exposed to nickel oxide through the welding
of nickel-alloy  pipes.  These  studies  included  536 welders who worked  at  the
ORGDP, where nickel-alloy pipes were welded,  and 523 welders who worked at two
other  Oak  Ridge plants and  whose  exposure  to  nickel oxide was  much less.
     It  is  unclear whether there is  any overlap of study subjects in the bar-
rier manufacture and  the  welding  studies.   The possible  impact  of such an
overlap, if  any, will  be  discussed  in the summary of the  Polednak (1981)
paper.
8.1.9.1  Oak Ridge Gaseous Diffusion Plant, Metallic Nickel Powder Exposure.
Metallic nickel, in the form of a finely divided,  very pure powder,  is  used in
the manufacture  of  a  porous  "barrier"  employed  in the isotopic enrichment of
uranium  by  gaseous  diffusion.   Production  of barrier from metallic nickel  is
carried  out at the Oak Ridge Gaseous Diffusion  Plant (ORGDP)  of Union Carbide's
Nuclear  Division in Oak Ridge,  Tennessee.  A brief description of the history
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of barrier production at  this  plant and the population  under  study will  be
followed by  a summary of  the  methods  and results reported by  Godbold  and
Tompkins (1979) and by Cragle et al.  (1983,  unpublished;  1984).
     Workers who manufactured the barrier were  studied in regard to two  factors:
(1) the NIOSH  (1977a) position that metallic nickel is a suspect carcinogen
because fine dusts  of nickel  may oxidize and be inhaled as nickel oxides by
workers; and  (2)  the  equivocal evidence on the carcinogenicity  of airborne
metallic nickel per se.
     The manufacture of  barrier at ORGDP began  in  January 1948.   By the  end of
1972,  980  workers had worked  in the barrier plant  for  at  least one day.
Because 852/980  (87 percent) of the workers had had  some experience in the
barrier plant by the end of 1953, and because setting the cut-off date for the
study cohort at 1953 allowed at least 19 years  of  follow-up  for each worker in
the study,  only those employees who had worked  at  some time  between January 1,
1948 and December 31, 1953 were included in the study.  The study cohort of
exposed "barrier" workers  was  limited  to the 814  males who  had worked in the
barrier plant  for at  least one day in  the specified time period.  The cohort
did not include females  because so few  (38) were available for study.
     The duration of work  in the barrier plant  ranged  from 3 days to  25 years
(mean = 5.3  years;  median = 3.8 years).  Six men  worked less  than one month;
65 worked  1  to 6  months; and a total of 161  (20 percent) worked  for  1 year  or
less.  The short duration of exposure of such a large proportion of the  cohort
could  have  been used  in the  analysis to illuminate the possible  relationships
between exposure and mortality; but, as will be discussed, neither report took
the duration of exposure into account.
     An "unexposed"  cohort was  also studied.   This  cohort comprised white
males who  had worked  at least  one  day  at ORGDP between January 1, 1948 and
December 31,  1953 and who  had  no record of  having worked  in the  barrier plant
or of  having had other exposure to  nickel at ORGDP.  The  exact  number of  such
workers was  not reported consistently in the two papers.   Godbold and Tompkins
(1979)  studied a 25 percent systematic sample of these workers; they studied
1,600 workers,  which  implies that the group originally  comprised  6,400 men.
On the other  hand,  Cragle et al.   (1983, unpublished;  1984)  studied 7,552
workers, a number in excess of the 6,400 estimated from the Godbold and Tompkins
report.
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     In both studies, vital  status was ascertained through the Social  Security
Administration, and underlying causes of death were determined from death cer-
tificates.   Godbold  and Tompkins  followed workers through December 31,  1972;
Cragle et al.  continued through December 31,  1977.  Godbold and Tompkins coded
causes of death according to the ICDA revision in effect at the time of death;
Cragle et al.  used one system throughout, the  Eighth  Revision of the ICDA.
8.1.9.1.1  Godbold and Tompkins (1979).   In  this  study,  814 barrier workers
and 1,600 "control"  workers with  at  least one day of employment at ORGDP were
followed for  mortality through December 31, 1972.  Death certificates  were
obtained for  all  but one  of the 85 deaths among barrier workers,  and for all
but 11 of the 273 deaths among unexposed workers; in the analysis, the remain-
ing deaths were  distributed among the known causes of death in proportion to
the distribution of those causes among the 262 with known causes.
     Analysis of each cohort (barrier and unexposed workers) for each underly-
ing cause of  death was performed by comparing the observed numbers of deaths
with the numbers  expected based on age  group-,  calendar  time-, and cause-spe-
cific rates for U.S. white males.   An SMR and its 95 percent confidence inter-
val was presented for all-cause mortality.  For cause-specific mortality, only
the observed and expected numbers of deaths were  shown for most causes.
     The results  showed that each cohort experienced  lower total mortality
than expected,  based on overall  statistics  for white  males  in the U.S.  The
SMR for  the  barrier workers was  75  (95 percent confidence  interval of  60  to
94), and for  the unexposed cohort was  84 (74  to  94).  These  are  not  unusual
findings in occupational  studies, in which such  results  are often attributed
to  the  "healthy-worker effect."  However, since  this  effect should operate
less strongly  in cohorts in which only a small proportion of workers are still
employed at the end of the study, the healthy-worker effect may not  fully
explain  the  lower-than-expected  mortality in the ORGDP cohorts.   (Of the 814
barrier  workers,  only 69 were still  employed at the plant in  1974,  and  of  the
1,600  unexposed workers, only 203 were still  employed.)   Godbold  and  Tompkins
suggested that three factors  may  be  operating:  (1) the healthy-worker effect,
(2) underreporting of deaths by  the  Social  Security  Administration,  and (3)
the active occupational health program  at ORGDP.  Other possible  factors,  such
as  a  lower  proportion of  cigarette smokers  among ORGDP employees  than in U.S.
white males overall,  were not explored.   No  smoking data  were  collected  before
1955,  but  smoking information was presented for more  than half of the barrier
workers  and for nearly  half of the unexposed workers.
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     The barrier workers had only 3 respiratory cancer deaths, while 6.68 were
expected (SMR =45,  95 percent confidence interval of 9 to 131).   Unexposed
workers had 21.85  respiratory  cancer deaths (note that the fractional number
is a  result of  the allocation of  deaths  of unknown cause) compared to 19.42
expected (SMR = 113, 95 percent confidence interval of 71 to 171).   All  of the
respiratory system  cancer  deaths  were due to  lung cancer.   No nasal  cancer
deaths were seen.   The deficit among barrier workers does not appear to have
been due entirely  to  the relatively decreased proportion of  smokers  in that
cohort.  It is not advisable to compare the SMRs from the two cohorts directly
because the age  distributions  and thus the person-year distributions differ;
according  to  Cragle et  al.  (1983, unpublished; 1984),  the  barrier cohort
was somewhat younger than the unexposed cohort.
     The barrier  workers showed  some  excess  of genitourinary organ  cancer
deaths (SMR =  161,  0/E = 3/1.86), while unexposed workers did not (SMR = 63,
0/E =  4.16/6.64).   Data were not presented for specific genitourinary sites.
The barrier workers  had a statistically significant deficit of deaths due to
diseases of the  circulatory system (SMR =65, 95 percent confidence interval
24 to  90).  The  SMR for this cause among unexposed workers was 89 (no confi-
dence  interval given).   Godbold and Tompkins  suggested that the deficiency in
this  cause of death may be due  to the "extensive program  in occupational
medicine"  at the  ORGDP.   Both cohorts also experienced smaller than expected
numbers of deaths  due  to diseases of  the  digestive  system:  SMR =  44 among
barrier workers  (0/E = 3/6.90);  SMR = 6 among unexposed workers (0/E = 1.04/
18.07).  The authors offered no explanation for this finding.
     Overall,  this  report  showed  no evidence of an increase in risk of death
due to respiratory  cancer among  workers exposed to metallic nickel dust in a
barrier plant.   The  length  of  follow-up was at  least  19 years  for  each member
of the exposed and unexposed cohorts.  The degree of exposure of  the nickel
workers in the barrier plant appears  to have  been  "substantial."   The authors
stated that "it  can be assumed that all of the  (barrier) workers were exposed
                                                                    3
to levels  greater  than the recommended NIOSH  standard of 0.015 mg/m  during
most of the work day."   Thus it would appear that,  for this length of follow-up
and this  level  of  airborne nickel dust,  metallic nickel exposure in this
cohort was not associated  with  respiratory  malignancy  deaths.  The  study,
however, did not take into account either the broad variability in duration of
exposure or the  variation in airborne nickel  level  in  areas  of the barrier
plant, and thereby may have obscured a possible association.
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8.1.9.1.2  Cragle et al.  (1983.  unpublished; 1984).   In these reports, the data
set presented by  Godbold  and Tompkins (1979) was extended  and new analyses
were performed.   Since the 1983  and 1984 versions were very similar, they will
be discussed together  here.   The same cohort of 814 exposed barrier  workers
was studied, while the 25 percent sample of the unexposed workers was expanded
to include  all of the  7,552  white male workers.  The mortality follow-up  time
was extended an additional 5 years, to December 31,  1977.  All  of the underlying
causes of  death  were coded to the Eighth Revision of the ICDA.  Follow-up of
the cohorts was slightly less complete up to 1977, as compared to the follow-up
to 1972  by Godbold  and Tompkins.  The vital status of 90 percent  of  the  814
barrier  workers  and  of 93 percent of the  unexposed workers was  ascertained.
Of 137 deaths among  barrier  workers  and  1,920 deaths among  the other  workers,
death certificates were obtained for 97 percent.
     The results  of  two  methods of  analysis were presented:   SMR analysis,
with 95  percent confidence intervals, based on age-  and calendar year-specific
rates among U.S.   white males; and directly standardized death rates for several
selected causes  of  death, based on the entire combined ORGDP data set as the
standard population.  While  the  latter analysis provides the ability  to directly
compare  the rates in the  two cohorts,  the  use of the  combined  cohorts instead
of the  unexposed cohort  as  the  standard population may  tend to  minimize  any
differences between  the two  cohorts.
     The results for  selected  causes of  death as  indirectly standardized
mortality  ratios  are shown  in Table 8-8.   Among nickel-exposed  workers,  the
suggestion of  lower SMRs for all-cause  mortality,  respiratory diseases,  and
diseases of the  circulatory system  among  nickel workers, observed by Godbold
and  Tompkins (1979),  continued  to  be observed with the extended  follow-up
time.  Deaths from cancer of the respiratory system continued to be fewer than
expected among  nickel  workers (SMR = 59, 95 percent confidence interval  21  to
128, with  6 observed deaths).   The  directly adjusted death rate for  respira-
tory cancer was   lower among  nickel  workers as  compared to other,  unexposed
workers  (0.39 versus 0.81 per 1,000  person-years).
     The SMR for death from cancer  of the buccal  cavity and pharynx was 292
among  nickel  workers,  with  a wide  confidence  interval  including  100 (59 to
845),  according  to  Table  2  in both  the 1983 and 1984  versions  of the  report.   A
statistically  significant deficit  of this  cancer  was  observed  among the
unexposed  workers:   SMR  =  23,  95 percent  confidence  interval  of 5  to  67.
Additional evidence of a difference  between the groups  is  seen  when  directly
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   TABLE 8-8.   STANDARDIZED MORTALITY RATIOS (SMRs)a FOR SELECTED CAUSES OF
               DEATH AMONG NICKEL WORKERS AND UNEXPOSED WORKERS
Cause of death
All causes
Disease of the
circulatory system
Disease of the
digestive system
Respiratory disease
Malignant neoplasms
Cancers:
Buccal cavity and
pharynx
Digestive organs
and peritoneum
Respiratory system
Prostate
Kidney
All lymphopoietic
No.
137
56
6
6
29
3
8
6
1
0
4
Nickel workers
(n = 814)
SMR
(confidence
interval)
92
(77-109)
78
(59-102)
68
(25-149)
80
(29-174)
100
(67-143)
292
(59-854)
104
(45-205)
59
(21-128)
92
(1-512)
(0-465)
123
(33-316)
Unexposed workers
(n = 7552)
SMR
(confidence
No. interval)
1920
984
68
101
352
3
79
151
21
12
41
98
(94-102)
98
(92-104)
65
(51-83)
93
(76-114)
92
(83-102)
23
(5-67)
73
(58-91)
116
(98-136)
104
(65-159)
121
(62-211)
105
(75-142)
 Expected deaths based on overall U.S.  white males.

 95% confidence interval assuming that the observed deaths follow the Poisson
 distribution.

Source:   Adapted from Tables 1 and 2 of Cragle et al.  (1983, unpublished).
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standardized death rates are  compared:   the adjusted mortality rate for this
cause among nickel workers was 0.32 per 1,000 person-years (95 percent confi-
dence interval  of 0.0  to  0.69),  while the  similarly adjusted rate among
unexposed workers  was 0.02 per  1,000 person-years  (95  percent  confidence
interval of 0.0  to 0.03).   Thus,  the rate  among  exposed workers was higher
than the upper  limit  of the 95 percent confidence  interval  for  the rate in
unexposed workers.  It  should be noted that these are head and neck tumors,  a
finding  consistent with the  site  of other tumors  associated  with nickel.
8.1.9.2  Oak Ridge Plants,  Primarily Nickel  Oxide Exposure to Welders.   At one
plant of the  Oak Ridge  nuclear facilities  (the Oak Ridge Gaseous Diffusion
Plant,  known  as  K-25),  nickel-alloy pipes  "are a major  constituent of  the
plant."  Welders  assigned  to  K-25  are thought to have been exposed to higher
levels of airborne nickel and nickel oxide than welders at either of two other
Oak Ridge plants  (X-10  and Y-12).   Industrial hygiene data substantiated this
difference  in exposure  levels.  The major air and urinary contaminants at the
K-25 plant  were  nickel  and fluoride, while  at the other  plants they were iron
and chromium.   It should be noted that K-25 welders  may also  have worked at
the other plants.
     Polednak (1981) focused on this difference in nickel exposure levels in a
mortality study  of welders at Oak  Ridge.  Polednak1s  study design  and results
are described below,  as well  as a  published  comment on  the study by Gibson
(1982).
     All of the  white male welders employed at the Oak  Ridge nuclear facili-
ties between  1943 and January 1, 1974  (n =  1,059) were followed  for  mortality
through January 1, 1974.  Ninety-three percent of the cohort were followed for
at  least 13 years.  Vital  status was ascertained through the Social Security
Administration and current employment  status; vital  status was unknown  for  83
of  1,059 men, who were  then assumed  to be  alive  at the  end  of the follow-up
period.   Death  certificates were  obtained  for  all  but  7  of the 173 known
deaths.   SMRs based  on  U.S.  white male mortality, with  95 percent confidence
intervals,  were calculated.
     The  1,059  welders  were  classified as to  the  plant at which  they had been
employed.   Five  hundred thirty-six welders had worked at K-25,  the plant  at
which higher  levels of  nickel exposure had  occurred,  and 523 had worked  at the
X-10  or Y-12 plant.   The author did not comment on  the possibility that a  man
may have worked  at K-25 and also X-10 or Y-12,  or how such an  individual might
be  classified in  the  analysis.
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     The K-25 welders and the other welders were similar in age at entry (mean
age, 31.5 versus  33.8  years);  mean year of entry (1949.0 versus 1951.3); and
person-years of follow-up (12,553 versus 11,121).  Data are not given regard-
ing duration of employment.   The scanty data on smoking habits suggest  that
the proportion of  K-25 welders who were heavy  smokers  was lower than among
other welders  and similar to  overall  U.S.  rates;  therefore,  any increased
respiratory cancer mortality among K-25 welders would be unlikely to be due to
an excess of cigarette smokers.
     Results of the  analysis among the entire group of 1,059 welders showed a
nonsignificant increase  in  lung cancer deaths:  SMR =  150,  with 17 deaths
observed and 11.37 expected; 95  percent confidence interval of 87 to 240.  No
deaths  due  to  nasal  sinus cancer were  seen.   A nonsignificant increase in
deaths due  to  diseases of the  respiratory  system was reported  (SMR = 133) and
was attributable mainly to emphysema.
     In the separate analyses of K-25 and other welders, the only statistical-
ly significant SMR was that seen among K-25 welders for deaths due to diseases
of the circulatory system:   SMR =70,  95 percent confidence interval 49 to 98.
Nonsignificant increases  were observed  for lung cancer deaths  among K-25
welders (SMR = 124)  and other welders (SMR =  175),  and for diseases of the
respiratory system among other welders (SMR = 167) but not K-25 welders (SMR =
101).
     To allow  for  a  biologically plausible latency period in the analysis of
respiratory cancer deaths, an  analysis was  performed excluding men with  fewer
than 15 years  from date of hire to date of death or end of follow-up.   Among
922 welders with  at  least 15 years of  follow-up, respiratory cancer showed an
SMR of  176  (0/E  = 16/9.10).   Among the 478 welders at the K-25 plant with at
least 15 years of follow-up, the respiratory cancer SMR was 126 (0/E = 6/4.76).
The 95 percent confidence intervals were not shown.
     Additional subgroup analysis considering length of employment as a welder
showed a nonsignificant  excess of lung cancer deaths among K-25 welders with
at  least 50 weeks of exposure (SMR =  175), while the SMR among all welders
with at least 50 weeks of exposure was 121.  However, methodological consider-
ations, as  well as the observation pointed  out  by Gibson (1982) that respira-
tory cancer among  the  K-25 welders was the  single cause of death presented in
which the SMR  increases  with length of employment, would  suggest that a new
analysis of this subgroup should be carried out.
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     The interpretation  of  the  findings of this  study  is  subject to  several
problems.  Most  importantly, welders were  exposed to a  variety of potentially
harmful  agents,  some  of  which are  known to be carcinogenic.  The K-25 welders
included many  men  who had very short periods of  exposure  in the K-25 plant,
and thus any  excess  risk due to nickel exposure  may have  been obscured.   In
addition, the  possible  overlap  in  study subjects between  the  Cragle et al.
(1983,  unpublished;  1984) study,  which included  1,600  workers  in  "barrier"
manufacture at the Oak  Ridge Gaseous Diffusion Plant (ORGDP) and the  Polednak
(1981)  study's 523 welders  at  the K-25 plant, which  seems to be the ORGDP
itself,  remains  to be clarified.   If the K-25 welders worked in the location
where  "barrier"  was  being manufactured,  they would have been exposed to pure
metallic nickel powder as well  as the nickel  oxide which resulted from welding
nickel-alloy pipes.  Any increase in lung cancer deaths could be attributed in
part to  the  combined exposures  to both the  nickel  oxide and the pure metal
powder, and not just to the welding exposure itself.
     In  summary, this  study does  not provide evidence  of  an association be-
tween  nickel  oxide exposure among  welders at the K-25 plant and lung cancer.
However, the  SMR of  176  for respiratory cancer among welders with at  least 15
years  of follow-up was  of borderline statistical significance,  as  calculated
by Wong et al. (1983, unpublished).

8.1.10  Nickel-Using Industries
     A  number  of recent reports have been issued on the risks among workers
employed in  industries which use nickel.   The industries studied include die-
casting and electroplating, metal  polishing and plating, nickel  alloy manufac-
turing,  and  nickel-cadmium battery  manufacturing.   The predominant  nickel
species  in these studies  are metallic nickel dust or powder and nickel  oxide.
In several of  the  studies,  there was concurrent  exposure  to other metals, a
factor  that poses  problems  in  establishing associations between cancer risks
and nickel exposure.   This  aspect  of the present review of the literature is
not comprehensive, but  is included to illustrate the possible risks of expo-
sures  to nickel  in industries  other than  the  mining and  refining process.
8.1.10.1   Die-casting and Electroplating  Workers (Scandinavia).   A   nested
case-control  study of deaths among workers in a die-casting and electroplating
plant  that opened  in the 1950s was  carried out  by  Silverstein et al.,  1981.
Deaths  occurring between  January  1,  1974 and December 31,  1978 were studied.
In the 1950s  and 1960s, the major operations  of the plant were zinc alloy
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diecasting; buffing, polishing and metal cleaning of zinc and steel  parts; and
electroplating with  copper,  nickel,  and chrome.   Specific exposures  at the
plant were not precisely characterized.   A preliminary proportionate mortality
ratio (PMR) study  of 238 deaths occurring among  workers employed at least 10
years showed an excess PMR for lung cancer among  both males and females.  This
was the only  cause of death which showed a statistically significant excess
PMR.  The authors subsequently initiated a nested case-control  study of the 28
white male  and 10  white female lung cancer deaths.   Two age- and sex-matched
controls were selected for each case from among those who died of nonmalignant
cardiovascular disease.   Cases and controls were  compared for length of employ-
ment in individual  departments.   Work histories  of cases  and  controls  were
abstracted from company personnel records.
     Odds ratios were  estimated for work in 14  different  departments.   For
males in three departments (identified as Departments. 5, 8,  and 38),  the odds
ratio increased with length  of time worked in those  departments.  The  trend
was most significant for Department 5, in which the major activity was die-cast-
ing and  plating.   According to  the  authors,  the case-control  study  lacked
internal consistency.  They stated that Department 6 for example, was  probably
the most  similar to Department 5 in  the nature  of chemical  exposures in  the
1950s and  the  1960s,  but  that  there was no increase in  trend of  relative  risk
among white males in that department.
     In summary,  this study suggests that the risk of lung cancer mortality is
associated with work in the plating and die-casting plant.   However,  because
workers were exposed to a number of possible carcinogens in addition to nickel,
and because definitive information on exposure is missing, it is impossible to
state whether  the  risk of lung  cancer  resulted  from  nickel  exposure.  This
study,  therefore,  provides no  definitive  information on the  risk  of lung
cancer either from nickel exposure or from specific nickel species.
8.1.10.2   Metal Polishing and  Plating Workers  (U.S.A.).   Workers engaged  in
the polishing, electroplating,  and  coating of metals are exposed not only to
metals  (e.g.,  nickel,  chromium, copper, iron, lead, zinc) but also to acids,
alkalies, and  solvents.   An exploratory study  of cancer mortality among these
workers was reported by Blair (1980).
     In this  proportionate mortality  study, 1,709 deaths among members  of the
Metal Polishers,  Buffers, Platers, and Allied Workers International  Union were
studied.  The  deaths were ascertained through  obituary  notices in the union's
journal and thus were limited to workers who  were  in good  standing  in the
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union at the  time  of  death.   These deaths occurred  between  1951 and 1969.
Death certificates were  obtained  for  1,445 (85 percent),  and causes of death
were coded  according  to  the  Eighth Revision  of  the ICDA.   Analyses were
restricted to the 1,292 white males for whom death certificates were obtained.
PMRs were calculated  based  on 5-year age  and  calendar  time-specific deaths
among U.S.  white males.
     Of the  1,292  deaths,  53 percent occurred among workers  who were younger
than 66 years of age.  This disproportionately young distribution  of age  at
death is probably an artifact of the method of ascertainment and the fact that
most decedents  were active  members of the union  at  the time  of  death.  When
interpreting  the results of  the  analyses, it should be  kept in mind that
deaths among  retired  and older  workers thus were  underrepresented relative to
all workers in  the industry.  However, the PMR does take into account the ages
of the decedents whose deaths were counted.
     A  significantly  increased PMR was  observed  for esophageal cancer  (10
observed versus  5.4 expected, PMR = 185, p < 0.05) and primary liver cancer (5
observed versus 1.8  expected, PMR = 278,  p < 0.05).  Nonsignificant excesses
were seen of  deaths from cancer of the buccal cavity and pharynx, rectum,  pan-
creas,  and  larynx,  as well as  from non-Hodgkin's lymphoma and Hodgkin's dis-
ease.  No excess of lung cancer deaths was seen (62  observed  versus  58.7 expect-
ed).  No nasal  cancer deaths were ascertained, while 0.6 were expected.
     There  was a statistically significant excess of deaths  from all cancers
among those  who had died  at ages  66 and  older; 111 cancer deaths were observed
compared to  92.6 expected,  PMR  =  120, p  <  0.05; among deaths  at  65  or younger,
133  cancer  deaths were observed  compared  to  131.2 expected, PMR = 101, not
statistically significant (p > 0.05).   This finding is  not surprising in view
of the  latent period between exposure and death from cancer.   The observation
that the excess of esophageal and primary liver cancer  (as well as  cancers of
the  colon,  rectum, pancreas, prostate, and bladder) was stronger among deaths
occurring  at age 66  and  older,  combined with the fact  that deaths  among men
who  had left  the  industry  probably were underascertained because this study
was  limited to active union members,  suggests  that the  study result may  not be
 generalized  to  all  workers  in  the industry.   Further and more definitive
 studies using a cohort design should be  carried out.
      On the  other hand, the slight excess of deaths  due to cancer of  the
 buccal  cavity and pharynx,  non-Hodgkin's lymphoma,  and  Hodgkin's disease among
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deaths occurring at  age  65 or younger suggests that these causes should also
be given further attention among workers in this industry.
8.1.10.3  Nickel Alloy Manufacturing Workers (Hereford, England).  Exposure to
metallic nickel and  nickel  oxide,  but not  nickel  subsulfide,  occurs  in the
manufacture of  nickel  alloys  from  raw  materials.   Other exposures include
chrome, iron,  copper, cobalt, and molybdenum.   A cohort mortality study of men
employed at a nickel  alloy manufacturing plant in  Hereford,  England,  was
reported by Cox et al.  (1981).
     Industrial hygiene measurements  of  specific airborne metals, including
nickel, in the  various operating areas  of the plant were made systematically
since 1975, and the data were summarized in Table 2 of the study.  The average
                                                                            3
concentration  of airborne  nickel between 1975  and  1980 ranged from 0.84 mg/m
in the melting, fettling,  and  pickling  areas,  to  0.04  mg/m  in the  process
stock handling, and distribution and warehouse areas.  Some data were presented
on the state  in which  the airborne nickel  was found in specific areas of the
plant, ranging  from 14 percent  metallic  nickel in  the  welding  section to
50 percent in  the  fettling area, and from 14 percent water-soluble nickel in
the melting department to 49 percent in  the extrusion section.
     A cohort was  identified of 1,925 men who  had worked  in the operating
areas of the plant for at least 5 years, excluding breaks,  from the opening of
the plant  in  May 1953  through  the end of March  1978.  The men were classified
into six occupational categories corresponding to the five areas with airborne
nickel measurements  reported  in Table 2 of the  study, plus a sixth category
for men who had been transferred to  the staff from other occupations.   One
subgroup analysis  considered men who were "likely to have had more than average
exposure to atmospheric  nickel" (Cox et al.,  1981) i.e., those who fell into
either of the  two  occupational  categories with the highest total  dust exposure
     3
(mg/m ).   There is  no  discussion of the possibility that excluding from this
analysis the men who had transferred from other occupations to the staff might
have excluded men who  were  experiencing health  effects of workplace exposure,
and thus might  have  decreased  the number of pertinent deaths in the  subgroup
analyzed.
     The cohort was followed  for  mortality through April 1, 1978,  with  a
potential  range of  follow-up time  from  zero to 20 years after satisfying the
cohort criterion of a minimum of 5 years of employment.   No data were given on
the distribution of  follow-up  time  or the proportion  of the  cohort  with at
least 20 years  at risk of  cancer death in the  follow-up  period.  Of the 1,925
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men, 22 were  not  traced and 22 had emigrated; these were withdrawn from the
person-years calculation at the time of last contact or emigration.
     One hundred  seventeen deaths were ascertained, and the underlying causes
of death were coded according to the Eighth Revision of the ICDA.   To calculate
SMRs, expected numbers  of  deaths  were obtained using age- and calendar time-
specific rates for men in England and Wales; and a correction for geographical
location was made "by multiplying by the standardized mortality ratios for the
urban areas of the  county  in which the factory was located"  using mortality
ratios for men 15 to 64 years of age in 1969 to 1973.   It should be noted that
this correction for geographical area constitutes a methodologic strength, but
that sometimes if the working population of  the plant  of  interest constitutes
a large proportion  of  the  geographic area's population, the effect of such a
step could  be to  make the expected numbers  of deaths  more  like the observed
numbers of  deaths for  the  SMRs ultimately obtained, bringing the "corrected"
SMRs closer to 100.
     Results  showed  an  SMR  for  overall mortality  of 74 when calculated by  the
usual method, and 81  when  corrected for geographical area.   No  excess  of
cancer, lung  cancer, or other  respiratory disease deaths  was  seen.  No deaths
due  to  nasal  sinus  cancer were ascertained, while 15 deaths were due to lung
cancer  and  one  to laryngeal cancer (SMR not given).   Despite the very  low
numbers of  deaths,  sub-group analyses were  performed.  These  showed  no excess
of  deaths  from  specific causes, but the power  of the analysis to detect an
excess  was  small.   The corrected SMR for  lung  cancer among men with  above
average exposure  to airborne nickel was 124.
     In summary,  while  this study provided  no  evidence  of excess mortality
risk among  men exposed  to metallic  nickel  and nickel  oxide,  the  study was  not
designed  to provide  a powerful test of the hypothesis.   The  sample  size was
not  large,  and the follow-up time was relatively  short.
8.1.10.4   High-Nickel  Alloy Plant Workers  (U.S.A).   Redmond  et al.  (1983,
unpublished;  1984)  completed a mortality follow-up  study of 28,261 workers
from 12 high-nickel  alloy plants.  The study group included workers employed
for  at  least  one  year in a nickel alloy plant, who had worked for at  least one
month  between 1956  and 1960.   Workers employed  strictly  as  administrative
office  personnel, such  as  secretaries, were  excluded.   The calendar time
criteria  for  defining most of  the  cohort,  i.e.,  1956 to 1960,  was  different
for four  of  the  plants, for which  the calendar  periods  were  1962  to 1966,
1967,  1956 to 1966, and 1961.   Ninety  percent of the cohort  was  male,  and
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92.5 percent was white.  The  follow-up  period was from  1956  to 1977, for a
total of 21 years.   Deaths  were ascertained through the Social Security Adminis-
tration and company  records.   Three percent were  lost to follow-up.  During
the follow-up period, 292 lung cancer,  9 laryngeal  cancer,  2 nasal  cancer, and
25 kidney cancer cases were identified from death certificates.
     Exposure was defined  by  category  of work and length of employment.   All
job titles were  classified into one of 11 work areas.   Some data on exposure
to metals  and  particulates by work area were  noted,  and are summarized  in
Table 8-9.   The  predominant nickel  species to which the workers were exposed
appear to  have been  nickel dust and oxide, although the  authors' descriptions
did not clearly  spell  out  the associations between species and work setting.
The levels of  exposure to  nickel were relatively low, ranging from an average
                 3                                                 3
low of 0.064 mg/m   in the  cold working  area  to a high  of  1.5  mg/m   in the
powder metallurgy area.
      TABLE 8-9.   POSSIBLE NICKEL EXPOSURES AND LEVELS OF EXPOSURE BY
              CATEGORY OF WORK IN THE HIGH-NICKEL ALLOY INDUSTRY
Category of work
Cold working
Hot working
Melting
Grinding
Allocated services
Foundry
Powder metallurgy
Admi ni strati ve
Possible Ni species
Ni dust
Ni dust
Ni oxide
Ni dust
Ni oxide
Ni dust
Ni oxide
Many non-Ni exposures
Ni dust
Ni powder

Exposure level
Range
0.001-2.3
0.001-4.2
0.001-4.4
0.001-2.3
0.001-0.350
0.004-0.900
0.001-60.0

(mg Ni/m3)
Average
0.064
0.111
0.083
0.298
0.071
0.098
1.5

Source:  Adapted from Redmond et al.  (1983, unpublished).
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     When analyses were done by work area, the authors did not classify indi-
viduals into mutually exclusive categories.   If a worker had  ever been employed
in a work area, presumably for at least one  day,  that individual  was  considered
in the analysis for that work area.   An individual could therefore have contributec
his person-years to  several different work categories.  As a result, there is
some lack of  independence  in  the SMRs by work area.   Twenty percent of the
work force had been employed for 20 or more  years.  SMRs were calculated using
race- sex-,  age-, and time-specific U.S.  rates for all diseases.   Lung, laryngeal,
kidney, and nasal  cancers  were the specific  focus  of this  study.  Analyses
were presented by race, sex, plant, number of years exposed  (length of employment),
and work area.
     The results of this study were predominantly negative.   The few statisti-
cally significant SMRs were relatively low.   The SMR for all  males and females
did not  show  a statistically  significant  excess  risk  for the four tumor sites
of  interest.   SMRs  for  lung  cancer  by plant  for white  males,  the largest
group, ranged  from 37.7 to 190.8.  However, none were statistically signifi-
cant.  The  other three tumors were too infrequent to analyze by plant.  SMRs
for lung, laryngeal, and kidney cancers were estimated by length of employment
(less  than  20 years versus 20 or  more years).   The only significant excess
risk was shown for lung cancer (SMR = 118, p < 0.05) among white males working
less than 20  years,  but not among those  with 20 or more years of employment
(SMR = 100).   No dose-response relationship  was  shown using  length of  employ-
ment as a measure  of dose.  However, the excess  risk could reflect differences
in  the jobs  held  by short- and  long-term  workers,  e.g.,  unskilled versus
skilled labor.   Analyses were  also done by work  area  for the same  three tumors.
The  following statistically significant  excess risks  were found:   lung cancer
among  white males  in Allocated Services  (SMR =  120, p < 0.01),  and  kidney
cancer among  white males in the  cold  working area (SMR = 263.4,  p < 0.05).
     SMRs were estimated for  subgroups defined  by work area, number of years
employed  (less  than  5 years versus 5 or more years),  and number of years since
first  employment (less than 15 years versus 15 or more years).   The  only  sta-
tistically  significant SMRs were found for  lung cancer  in Allocated Services
for  those working 5 or  more  years,  both among those with  less  than  15 years
(SMR  = 142.8, p < 0.05)  and  those with  15 or more  years  (SMR  = 124.3,  p <
0.01)  after first employment; for lung cancer in the melting area, for those
with  less than  5  years'  exposure  and  15  or  more years after first employment
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(SMR =  172,  p  <  0.05);  for  kidney  cancer  in  the melting  area,  for  those work-
ing less  than  5  years and with  less  than  15  years  since  first  employment  (SMR
= 555.6, p < 0.05); and for kidney cancer among foundry workers with 5 or more
years'  exposure and 15 or more years since first exposure (SMR = 769.2, p < 0.05).
     The  statistically  significant SMRs  for lung  cancer among the Allocated
Service workers  occurred  for  those employed longer, and are based on a large
number of  observed cases  (36  and 161, respectively).  On the other hand,  the
statistically  significant  SMR  for  lung  cancer in the melting area  is for
short-term workers, and is  inconclusive.   In addition,  the  SMRs  for kidney
cancer are based on a very small number of observed cases (3 and 2,  respect-
ively), and  are  only  significant for  those with shorter, but not longer,  term
employment.  The SMRs for kidney cancer may be due to chance, especially given
the large number of SMRs estimated.
     The  excess  lung  cancer risk in Allocated Services (includes "pattern and
die, maintenance,  guards  and  janitors,  and other") appears to have been con-
centrated among  white male  maintenance  workers.   However,  the data presented
do not enable  a  conclusion  to be made about the specific exposures which may
be associated with the excess  risk.
     The  results  of this  study  were largely negative, with the exception of
the few statistically significant  SMRs  noted above.  The predominant  nickel
species appears  to have been  nickel dust or powder, and nickel oxide.   While
there was some discussion of nickel exposure by work area,  there was  no discus-
sion of the  species-specific exposure by  job category.  As a result, exposure
groups defined by  work  area may have been quite heterogeneous.  Nonetheless,
the great  number of SMRs that were derived must be considered  when evaluating
the relatively few statistically significant SMRs  in this study.  In  addition,
the absence  of a coherent relationship  among significant SMRs suggests  the
possibility  of either chance associations or that  exposures other  than nickel
may have  been  involved.   The  latter may be of special significance given  the
variety of exposures  in the plant  including, in the Allocated Services area,
potential  exposure to welding  fumes, solvents,  lubricants,  cleaning materials,
resins, and other chemicals.   Finally, the assignment of individuals  to exposure
categories on the  basis of  "ever working" in particular areas is  likely  to
have significantly reduced  the  findings  as to risks associated with  specific
types of  work, because  of the potentially large number of  short-term workers
in these categories.
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8.1.10.5  Nickel-Chromium Alloy Workers (U.S.A).   Landis  and Cornell (1981,
unpublished) and Cornell and Landis (1984) conducted a proportionate mortality
ratio (PMR) study of 992 male deaths (out of 1,018 total  deaths) among nickel-
chromium alloy workers from 26 plants.   Of these plants,  six had opened before
1945, and  20 had  opened  after 1945.   The  target  population  included both
current and  retired  workers.   The period of death  ascertainment was  between
1968 and 1979.   Identification of deaths and information on exposure status
were provided by  the foundries;  none of the primary data collection was done
by the  authors.   The method  of data collection  does  not provide any  assurance
of completeness of  data collection,  reliability of exposure classifications,
quality of information, or comparability among the 26 plants.
     Individuals were  considered  to  have been  exposed if they  had worked  in
any  operation  which  had  potential  nickel-chromium exposure.   "All  foundry
workers in  a given foundry were presumed to be exposed if they worked during
the  period  after the  initial  year of  nickel-chromium production  for that
foundry."   No  information was  provided regarding  the organization  of the
foundries.    It is possible that the foundry is divided into a number of depart-
ments,  each with different exposures.  It appears that a worker was considered
unexposed if he had  been employed during a  time when nickel-chromium production
was  not in  operation  at  that foundry; thus, the  unexposed  group  may have
worked  at different  calendar times than the exposed group.
     Personal monitoring  data on  nickel and chromium  levels  from  six plants
were obtained.   Since these  were  recent measures,  it is  likely  that  they were
lower  than  would  have been obtained for past  exposures.   For  nickel, the
arithmetic  means  for different areas  in the plant ranged  from 14 pg/m  to  233
     •3
pg/m .  Because of the relatively low ambient levels of both nickel  and chromium,
and  the likelihood of short-term  employment in  the foundry,  it  is  likely that
a  large proportion of  the exposed group had relatively low exposures.
     Cause-of-death  distributions  for all  U.S.  male deaths in 1974  by 5-year
age  subgroups and  race were  used to compute expected values for the  standardized
PMRs.   The year 1974 was  selected as a  standard because it was the median year
of death.   Although the authors stated  that  the  distribution of deaths may
have  changed over  the 12-year period from 1968  to 1979,  they provided no
justification  for using the single year,  1974, in order to standardize the
PMRs.   It  would have been simpler and more straightforward  for  the authors to
have used calendar year-  and age-specific ratios  to derive the  expected values.
Standardized PMRs (SPMRs) were provided  separately on those dying before  age
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65, and at age 65 and older.   For those dying before age 65, the SPMR for lung
cancer was 0.8,  which  is not statistically significant.  The SPMR for kidney
and ureter cancer was in slight excess (SPMR = 110), but was not statistically
significant.   The only  statistically  significant SPMR was for diseases of the
respiratory system,  at 168 (p < 0.05).  Workers dying at age 65 or older had a
statistically significant SPMR for lung cancer of 148 (p < 0.05).   This subgroup
also showed an  SPMR  greater  than 1 for  diseases  of the respiratory system;
however, it was  not  statistically significant (SPMR = 123).  The authors did
not standardize  the mortality  ratios  by  length of employment for age or  race.
Therefore, it is  not  possible to make any  inference  about  the relationship
between length of employment  and the PMR for respiratory cancer.
     In the 1981 paper the authors directly compare the proportionate mortalities
of 851 exposed deaths with 139 unexposed deaths.  The proportionate mortalities
were not standardized to some external population.   Age may be a confounder in
this analysis since it appears from the definition of exposure that the exposed
and unexposed workers were likely to have been employed at different times and
may have had different age distributions.
     The authors  (1981)  showed that among exposed workers there was a direct
relationship  between  the proportion  of  deaths due to  lung  cancer and the
length of  employment.   However,  the proportionate mortalities for the groups
defined by length of  employment were not standardized for age.   Nonetheless,
the authors discounted the relationship by noting that the lung cancer propor-
tionate mortality in  unexposed workers was almost  equivalent  to  that found
among the  exposed workers  with the greatest length of employment.   Again, as
noted above,  this is probably  not a valid comparison for  two reasons.  First,
given the definition of exposure, it is likely that the unexposed workers were
employed at a different time  than the exposed group.  Second, these ratios are
not adjusted  for age,  and as a result, the comparison could be confounded by
age.  What is striking is the apparent dose-response relationship among exposed
workers.  To  test for  a trend by length of employment  while controlling  for
age, the  authors  distributed the 60 exposed cases among 12  categories  defined
by  length  of  employment (four groups) and age  (three  age-at-death groups).
The test for trend with length of employment was not statistically significant.
However, since  60 cases were distributed over 12 categories, the statistical
power of the data was severely limited.
     The authors  noted  that  "it can be concluded that the respiratory cancer
rates do  not  show a significant increase across length of exposure subgroups
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after adjustment for age, race, and length of employment.  Thus, the apparent
trend in respiratory cancer  rates...may  be associated with either increasing
age or  length  of  foundry employment,  regardless of the  exposure  to nickel-
chromium."   This conclusion does not seem justified given the problems  discussed
above, and cannot  be evaluated without more details  on  the  distribution of
deaths by age and year  of employment.   The authors  noted that "the exposed and
unexposed subgroups exhibit  similar  increases  in respiratory cancer with in-
creasing length of  employment."   In fact, the  patterns seem to be different.
The exposed workers showed  an increasing ratio with increasing length  of em-
ployment, and  the  unexposed  workers showed a somewhat decreasing ratio with
increasing length of employment.
     In their  conclusion,  the authors stated that  "workers and retirees from
the foundry industry ... do not experience a  significantly different  propor-
tion  of deaths from cancer,  and  specifically  from cancer of  the  lung and
cancer  of the  kidney,  than would be  expected  from the age-specific propor-
tional  mortality  patterns observed in the United  States as  a whole."   The
analysis in this paper  is  inadequate  to  support  this  statement.   In  fact, the
evidence suggests  that  the contrary may  be true, at least  in the case  of  lung
cancer, for which a statistically significant PMR was  shown, and for which the
PMR (not standardized)  showed an association with increasing length of  employ-
ment. In summary,  this  study should not be considered as evidence of no risk
from nickel-chromium exposure in the alloy foundry industry.   Given the concurrent
exposure to both  nickel  and chromium, however,  it is  impossible to determine
if nickel alone could account for the noted patterns of death.
     The 1984  published paper is an abbreviated  version of the 1981 unpublished
document and  does  not  contain the same  details regarding either the  data
collection methods  or analysis.   In the  1984 paper the  authors note  that  "the
increase in  respiratory cancer percentages  is not  statistically  significant
across  length  of exposure subgroups after adjustment for age,  race, and length
of employment."   However, no data are provided  to  support  this statement.   In
addition,  it   is possible that in adjusting for length of employment, the
association  between length  of  exposure and respiratory cancer percentages
could  be eliminated, especially  if  length  of  employment  and exposure are
highly  correlated.
8.1.10.6  Stainless Steel  Production  and  Manufacturing Workers (U.S.A.).
Cornell  (1979, unpublished;  1984) conducted a  PMR  study of 4,882  deaths among
workers in  12 stainless steel plants.  Deaths  were identified  from records  on
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retirees eligible for  insurance  benefits  and from records on active workers.
All of the deaths except one occurred between 1973 and 1977; one death occurred
in 1962.  Presumably,  deaths of  "active workers" were deaths that occurred on
the job. A  total  of 4,487 deaths were of  white males,  the only group large
enough for  serious  considerations  of PMRs.  Data were  obtained,  coded,  and
transcribed by company physicians  and other personnel,  except in the case of
one company,  for which  deaths  were coded by the  state health department.
Expected values were derived  by applying  the U.S. white male  1974  five-year
age- and cause-specific proportions to the total number of deaths in the study
group.
     This was  a  study with predominantly  negative  results, and the  author
suggested that the  study supports  the "conclusion that work in  steel plants
manufacturing and processing  stainless  steel  has not resulted in a  shift in
the proportion of deaths  due to  cancer toward cancer of the lung or  cancer of
the kidney, whether  or not there was a potential  for exposure to metallic
nickel."  While this statement  may be correct, caution must be  exercised in
the interpretation of these findings and in inferring the absence of an excess
risk of cancer.   Although the number of deaths was large,  several methodologic
problems exist in relation  to the period of case ascertainment,  the  frame for
identifying cases, the latency from first exposure to death, the definition of
exposure, and the opening dates  of  the plants.  These problems severely  limit
any conclusions  that can be drawn  from this  study.   One striking  finding,
however, given the large number of deaths  identified, was the complete absence
of nasal cancer deaths (no expected value was derived).
     Among  3,323  deaths  classified  as "exposed," the PMR for  lung cancer was
97 compared to 80 for  the non-exposed.   None of the PMRs for any cancer site
were  above  unity  for those exposed.  The  PMR for other neoplasms was statis-
tically  less  than 100  (0.91).    Similarly,  for  the  1,164  white male  deaths
without potential exposure  to  nickel, none of the PMRs for cancer sites were
greater than 100, with the exception of laryngeal cancer (PMR = 114).  The PMR
for lung cancer,  as noted above, was 80.   The PMR for kidney and ureter cancer
was 35, far less than the PMR for the same site among the exposed group (PMR =
98).  Although almost all of the PMRs for tumor sites were  less than 100 (note
the PMR above for laryngeal cancer) for both the exposed and unexposed workers,
the PMRs  for  two  cancer  sites of importance, cancer  of  the  lung  and  cancer of
the kidney  and ureter,  in addition  to the  category labeled  "other neoplasms,"
were  higher among the  exposed  workers than among the  nonexposed workers.
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     There are  several  major  problems with this study,  in  addition to the
limitations which are characteristic of the typical  PMR analysis.   No informa-
tion was used relating latency from first exposure  and calendar time of employ-
ment to cancer.  Exposure was defined  in terms of metallic nickel.  Two cate-
gories of exposure were defined.   Nickel-exposed workers were considered to be
those  involved  in  "any  operation  in which nickel-bearing steel  or nickel
alloys are processed  or handled"  for any  length of time.  All other workers
were considered  unexposed.  Given this definition, the exposed group probably
comprised a  large  number of short-term workers and longer-term workers with
variable  degrees  of exposure.  As  a result,  any excess risk  among a  more
homogeneously defined group with probable high exposure could have been signi-
ficantly obscured.
8.1.10.7   Nickel-Cadmium Battery Workers (England).   Sorahan and Waterhouse
(1983) performed a cohort mortality study of  3,025  nickel-cadmium workers.
While  the  study focused on  exposure  to cadmium and not  nickel, battery makers
were  listed  in  the NIOSH  criteria  document (1977)  as having potential
occupational  exposure  to nickel,  and the authors stated that, except for one
high-exposure job,  "all  jobs  entailing high cadmium exposures were  also asso-
ciated with  high nickel exposure."  The nickel exposure in  this  setting was
primarily nickel hydroxide.
     In this study,  3,025  workers (2,559  men  and  466 women) who worked at
least  one  month between 1923 and 1975 were followed for vital status through
January 31, 1981.  The  authors stated that "mortality was investigated for the
period 1  January 1946 to 31  January 1981."   Thus  it would  appear  that all
3,025 members of the cohort were known to  be alive on December 31,  1945, which
would  imply  that the members of the cohort  who began work between 1923 and
1945 were "survivors" to the  end of  1945.  This is an important point, because
exposure  in the  earlier years had been much greater than in  recent  times.   The
authors stated  that "in the early  factories  there  was little exhaust ventila-
tion," and  that measured levels of airborne  cadmium were reduced  dramatically
"after installation of  extensive exhaust ventilation  in 1950," with even lower
levels  having  been achieved  in 1967.  The definition of the study cohort  as
those  workers who  survived  through the end of 1945 would have tended to exclude
many  of  the  workers with the greatest exposures,  and would especially have
tended to exclude  those who were most  susceptible to  the  effects of such
exposures.   This bias  might have limited the power of the analysis  to  indicate
a  real relationship between high exposure  levels and  mortality.
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     Death certificates  were  obtained,  and underlying causes  of  death were
coded using  the  Eighth  revision of the  ICDA.  SMRs were calculated based on
age-, sex-,  and  calendar year-specific mortality rates for England and Wales.
     Overall, the SMRs  showed  a statistically significant excess of respira-
tory cancer  deaths  among men  and women  combined:  89  deaths observed, 70.2
expected, SMR =  127, p  < 0.05.  The excess was not seen among  women when they
were analyzed  separately (SMR = 91).   Among  men  employed  between 1923 and
1946, the SMR  for  respiratory cancer was 123 (0/E = 52/42.4), while for men
employed between 1947 and  1975, the SMR was 137 (0/E = 35/25.6)  In the dis-
cussion section, the authors acknowledge that the "survivor population effect"
could have  produced an  underestimated  SMR in the early  employment group.
     In an analysis  using  regression  models in life  tables,  workers who died
were matched to  all  workers who survived at least until  the year of death of
the  index case,  controlling for sex,  year of hire,  age at hire, and duration
of employment or employment status.   The effects of time  in high-exposure jobs
and  of  time  in  high- or moderate-exposure jobs were  analyzed.  The results
showed  a significant effect of  duration  of employment  in a high- or moderate-
exposure job on  respiratory system  cancer deaths and prostate cancer deaths.
     It was  not  possible to attribute the excess in respiratory system deaths
to  nickel  or to cadmium,  since the two exposures occurred  at high levels
simultaneously.   However,  because prior studies  suggested  an association
between cadmium  exposure and  lung and prostate cancer deaths, and  since no
nasal cancer deaths (which would have  implicated nickel)  were seen,  this study
provides evidence  neither   for  or against a  carcinogenic  effect  of nickel
hydroxide.
8.1.10.8  Stainless  Steel Welders (Sweden).   The  study by  Sjogren  (1980),
which focused on exposures of stainless steel  welders to  chromium,  is relevant
here because such workers are also exposed to nickel primarily in the  form of
nickel  oxides.
     The author  assembled   a  cohort  (234 men from eight  different  Swedish
companies) who had  welded  stainless  steel for at least 5 years between 1950
and  1965.  Mortality was traced through  December 1977, and death certificates
were obtained.   Expected numbers of  deaths were calculated using  Swedish
national age-  and  year-specific rates,  applied to person-years accumulated
after the initial 5 years of welding experience.
     While no excess of deaths  of cancers of all sites was  seen (4 observed
versus   4.01  expected),   a nonsignificant excess  was  observed  for pulmonary
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tumors (3  observed  versus 0.68  expected).   The author concluded  that  the
excess might have been  due  to inhalation of hexavalent chromium,  but did not
discuss the possible role of nickel.
     In view of the small sample size, as well as the chromium exposure, this
study is not seen  as  providing evidence on  the  question  of nickel carcino-
genesis.

8.1.11  Community-Based Case-Control  Studies
     Several community  based case-control  studies  have been  conducted to
assess the  association  between  nickel  exposure and cancer.   The results from
the studies are  of  secondary importance compared to the occupational cohort
studies that have been  discussed previously.  The community-based  studies  are
by definition  cross-sectional,  and in relation to occupational risk factors
are typically  insensitive.   However,  they can be used to estimate a calendar
time-specific measure of attributable risk.
8.1.11.1   Hernberg et al. (1983).  This  was  a case-control  study of  nasal  and
sinal nasal cancer  in Denmark,  Finland, and Sweden.  All cases with primary
malignant  tumors of the nasal cavity  and paranasal sinuses  diagnosed in those
countries  between July  1, 1977 and December 31, 1980 that had been reported to
the National Cancer Registers were selected  for  study.  To  ensure  the quality
of the  data,  only  individuals who were  alive  and could be interviewed were
included for study.   Out of a  total  of 287  cases  identified,  167  (110  males
and 57  females)  were  located and interviewed.   Controls with  malignant  tumors
of the  colon  and rectum diagnosed over  the  same time  period  were  matched  to
cases on the basis of country,  sex, and  age.  Questionnaires were  administered
to cases  and  controls,  and  inquiries were  made  about occupational  history,
smoking history, personal habits,  and hobbies.   Exposure indices were developed
independently  of case and control status for  wood dust;  exposure  to various
metals, including chromium and  nickel; and exposure to formaldehyde.
      A  statistically  significant association was shown  between the risk  of
nasal  cancer   and  occupational  exposure to  soft  wood  dust  alone,  and  more
significantly  to  hardwood and softwood dust in combination.  Twelve cases  and
five  controls  reported  histories of occupational  exposure to  nickel.  The  odds
ratio for  nickel  was 2.4, with 95 percent  confidence intervals from 0.9  to
6.6.   The  odds ratio for chromium exposure  was 2.7,  which  was statistically
significant at the p = 0.05 level.  In addition, those reporting exposures to
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chromium and/or  nickel  had odds ratios  of  3.3,  with 95 percent confidence
intervals from 1.1 to 9.4.
     The relative odds for exposure to nickel in this case-control study were
low in comparison with  some  cohort studies of nickel  exposure.   This is in
part due to  the  inherent limitations of a community-based case-control study
for identifying  occupational  risk  factors,  and, perhaps, also  due  to the
declining levels of  exposure  in work settings associated with nickel.  This
study provides  no useful  information  on risks  associated with  a  specific
nickel species.   The authors  noted, "Chromium and nickel exposure often consisted
of the welding of  stainless  steel, which contains up to 30 percent  chromium
and some nickel.   These exposures mostly occur together, and can therefore not
be separated statistically."
8.1.11.2  Lessard et al. (1978).   This  was  a community-based case-control
study in New Caledonia,  initiated  because of the strikingly high lung cancer
rates on this  island as  compared to other South Pacific Islands.  Nickel had
been mined and smelted  on  the  island since 1866.  A total of 92 lung  cancer
cases were ascertained between 1970 and 1974, and were confirmed by reviews of
medical   records  and  pathology data.  Sixty-two  cases were  confirmed patho-
logically, and 30 by means of "clinical  and radiologic information."   Of these
cases, 81 were males and 11 were  females.  Controls were selected,  for male
cases only,  from the same  hospital as the  cases.   Subjects  with neoplastic
disease were  excluded.   The  controls,  which were not  age-matched,  had been
admitted to  the  hospital  during the summer of 1975.   The method of selection
was not  discussed.   Most of  the controls were interviewed about occupational
history,  smoking habits,  residential  history,   and  demographic  variables.
Since most of the  cases  were deceased,  information was obtained from medical
charts,  death certificates,  administrative  files,  worker compensation files,
and the  records  of the nickel company.   A person was considered  "not exposed"
if a  history of  nickel  exposure was not  reported  by any of these sources.
Information  on smoking  habits was  available  for 68  of  the 81 male cases.   A
total of 109 control subjects were included for the analysis.
     The cases  and controls were  markedly  different as to age.  Fifty-one
percent of the controls were less than 45 years of age, whereas  only 6 percent
of the  cases were  less than 45 years of age.  In contrast, 54 percent of the
cases were 55 years  of age or older, and only 17 percent of the  controls were
above 55 years of age.   Forty-three percent  of  the  cases were classified  as
having a  history of  nickel exposure, whereas 20 percent of the  controls were
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classified as such.  Given the description of the data collection methods, it
is not clear  if  different sources of information were used to classify cases
and controls  as  nickel-exposed.   The authors stated  that "lung cancer and
nickel occupation were  significantly  associated  independently of the effects
of age and  cigarette  smoking."   The relative risk was  3.0 (p < 0.05).  No
significant interaction was  noted between cigarette  smoking and occupational
exposure to nickel.
     It is  noteworthy  that  66 of 68 cases and 69 of 109  controls reported
histories of smoking.   However,  13 of the 81  cases were excluded because there
was no data  on  smoking history in  the  medical record.   If smoking  history
among male  lung  cancer patients  is more likely to be recorded in the medical
record for  smokers, then  the proportion of non-smokers among cases  would be
underestimated.   The very high relative  odds for  ever smoking and lung  cancer
(R0=22) suggests that  proportionately  more non-smoking cases were excluded.
[For ever  smoked versus never smoked, one  expects a RO  in  the range  of  4.5 to
14.0 (U.  S. Department of Health, Education,  and  Welfare,  1979)].  Although the
study reported a positive association between nickel  exposure and lung cancer,
several factors must be considered.  The method  of selecting  controls was not
defined.   Controls were selected from those admitted to the hospital  after the
calendar time period during which cases were  identified.  The cases and controls,
as noted,  were  quite  different in  their distribution  by  age, and it is not
clear that any statistical adjustment procedure would have adequately controlled
for the  differences on this variable.   Finally,   the  method of ascertaining
exposure  information on  cases and  controls appears to  have been different.
     Langer et al.  (1980) noted that the  ore mined and smelted in New  Cale-
donia was  derived  from serpentinized  host rocks.  These rocks contained large
amounts of  chrysotile  asbestos.   As a  result, asbestos  exposure in the  mining
and smelting  operations  must be considered when  evaluating the relationship
between nickel exposure and  lung cancer.
8.1.11.3   Burch et al.  (1981).   This  was a community-based case-control  study
of cancer  of the larynx  in  southern  Ontario.  Two hundred fifty-eight cases
histologically confirmed  as  cancers of  the larynx and diagnosed between March
1977  and  July 1979 were  identified at  two hospitals.   Of the 258  cases,  204
were  interviewed  (184  males and  20 females).  Sex- and age-matched  neighbor-
hood  controls were selected.  Cases and  controls were interviewed about smoking
history,  alcohol  consumption,  and occupational history.   Specific  probes  were
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developed  for  nickel  and asbestos  exposure,  and separate measures  of asbestos
and nickel exposure were derived from the occupational histories.
     Significant associations were found for cigarette smoking, cigar smoking,
cigarillo  and  pipe  smoking, and alcohol consumption.   Fourteen  cases and 9
controls were  identified with  histories  of occupational  exposure to  asbestos.
The relative  odds of  exposure  to nickel, adjusted  for cigarette  smoking,  were
2.3 (p = 0.052).  Thirteen cases and 11 controls were classified with histories
of occupational  exposure to nickel.   The relative  odds  adjusted for smoking
were 0.9,  which is  not  statistically significant.   The  results of this study
suggest that  nickel exposure was not a  risk  factor  for  laryngeal cancer cases
diagnosed  between March  1977 and July 1979.

8.1.12  Summary of Epidemiologic Studies
     Published  and  unpublished  epidemiologic studies of workers in more than
16 different  industrial  settings have been reviewed to evaluate the  epidemio-
logic evidence  for  the carcinogenic  risk of nickel  exposure  in humans.   The
industries are  listed  in Table 8-10,  with the date of the most recent publica-
tion reviewed  for each.   The most extensive sets  of investigations  were of
workers at the  sulfide matte refineries in Wales and Norway, and the sulfide
ore mining and  refining  operations in Ontario,  Canada.   A  number  of reports
have been  issued recently on workers  in the alloy metals industry,  electropla-
ting operations, and  other  end use activities  with nickel.   These investiga-
tions also are covered in this review.
     Cancers of the nasal  cavity  and  lung were the  first  reported  tumors
associated with  nickel exposure.   In  later investigations, other  sites were
involved,   and  include  cancers of the larynx, kidney,  and prostate.   The risks
of these cancers and other  nonmalignant conditions  are discussed for cases in
which the  relevant data were included  in the  reports.
     The evidence accumulated  to  date  strongly suggests that nickel  is  a
carcinogen in humans.  Specifically,  smelting  and  refining of sulfide nickel
ores have  been found to be associated  with  tumors of the lung and nasal  cavity.
However, it is  not  possible at this  juncture to identify with certainty  the
nickel  species  which act as carcinogens in humans.   The  available  information
is inadequate to clearly define the process  changes that have taken  place at
the mining, smelting,  and  refining operations  in Canada, Wales, Norway,  and
the U.S.,  and the associated changes  in  exposure to nickel species  and relatec
substances.  In addition, in most of the available  studies, the epidemiologic
                                   8-85

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   TABLE 8-10.   INDUSTRIES  FOR WHICH  EPIDEMIOLOGIC  STUDIES  OF  CANCER  RISKS
                 FROM  NICKEL (Ni)  EXPOSURE  HAVE  BEEN REVIEWED


                                                         Year of  most  recent
       Industry                                            report reviewed

  I.     Ni  ore  mining
           Sulfide  ore
             Falconbridge, Ontario                               1984
             Sudbury,  Ontario                                    1982

           Oxide ore
             Hanna, Oregon                                        1981
             New Caledonia                                        1978

 II.     Ni  ore  refining
           Sulfide  ore -  Pyrometallurgical  processes
             Coniston, Ontario                                    1984
             Copper Cliff, Ontario                               1984
             Falconbridge, Ontario                               1984

           Sulfide  ore -  Hydrometallurgical processes
             Fort Saskatchewan, Alberta                          1984

           Oxide ore
             Hanna, Oregon                                        1981
             Noumea,  New  Caledonia                               1978
             RSFSR, Soviet Union                                  1973

III.      Ni  matte refining
           Clydach, Wales                                        1984
           Copper Cliff,  Ontario                                  1984
           Port Col borne, Ontario                                1984
           Falconbridge,  Norway                                  1982
           Huntington, West  Virginia                             1982

 IV.      Electrolytic refining
           Falconbridge,  Norway                                  1982
           Port Colborne, Ontario                                1959

  V.      Ni metal use
           Die-casting and electroplating                        1981
           Polishing, buffing,  and plating                       1980
           High Ni  alloy manufacturing                           1984
           Ni alloy manufacturing                                1981
           Ni/chromium alloy manufacturing                       1984
           Stainless   steel  and low Ni
             alloy manufacturing                                 19.84
           Ni "barrier" manufacturing                            1984
           Ni-cadmium battery manufacturing                      1983
           Ni alloy welding                                      1981
                                   8-86

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data have not been analyzed to determine if changes in process corresponded to
changes in risk.   Within the limitations of the information available, however,
an effort has been made herein to discuss health risks in relation to selected
nickel species.
     Cohort studies have provided the most reliable estimates of  these risks,
and the  interpretation  of  risks from such studies generally should supersede
the results of PMR or case-control studies if  there is a conflict  in  results.
On occasion,  studies of two different plants with  similar methods  of  process-
ing have yielded  results which are in  apparent  contradiction.   However,  in
such cases a number of factors must be considered:   differences in the defini-
tion of the cohort, including calendar time of exposure and age composition of
the cohort; differences in definition of exposure  categories, e.g.,  inclusion
of all  workers  ever  exposed versus exclusion  of workers with limited work
duration; the size of the cohort and length of follow-up, i.e., factors asso-
ciated with statistical power  and cancer latency from  first exposure, both of
which have been  found  to  be quite variable between  studies;  and method of
analysis and  adequacy  of  adjustment  for potential  confounding variables  such
as calendar time,  length  of employment, and age.  Given these limitations  on
the  interpretation of  results  between  studies,  some  conclusions have been
drawn from the literature.
     The disease  risks by industry are  summarized  in Table 8-11.   Some of the
SMRs  shown in Table  8-11  are based on  subgroup  analyses and were  chosen for
their information  value in  this summary section, although these SMRs may not
correspond directly to  risks  cited in  the text.   In some cases,  the  SMRs in
Table 8-11 provide a more definitive measure of  risk for subgroups of workers
defined  by exposure  to  a  process,  by calendar time of exposure, or by length
of time followed.
     The risks from  nickel  exposure  are first summarized for the  mining and
refining of  nickel ore.  Two  types  of  nickel ore are mined and  refined:
sulfide nickel ore, which  is the predominant form,  and oxide nickel ore (INCO,
1976). The risks  from  each  of  these types of  ores are discussed.  Finally,
risks from nickel exposure in other settings are summarized.
8.1.12.1  Mining  of Nickel Ore.  The  sulfide  ore  mining operation does  not
appear to have been associated  strongly with respiratory cancers  in  the study
of INCO  miners in the Sudbury  area of Ontario  (Roberts and Julian, 1982), but
mining of ore from the same Sudbury  area by Falconbridge workers does show a
significantly increased risk  of lung  cancer (SMR = 142) and laryngeal cancer
                                   8-87

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                                       TABLE 8-11.   SUMMARY OF  CANCER  RISKS  BY NICKEL INDUSTRY  AND  WORKER  GROUPS
oo
oo
oo
                       Industry
                                        Lung     Nasal
Larynx
    Cancer risks
Buccal and                            Other cancer/
pharyngeal    Kidney      Prostate        comments
               I. N1 ore Mining

                  Sulflde ore

                    INCO, Sudbury, Ontario            105        166
                    (Roberts and Julian,  1982)
                    Falconbrldge,  Ontario             142       None
                    (Shannon et al.,  1983)
    Oxide ore

      Hanna, Oregon                      128
      (Cooper  and Wong, 1981)

II.  N1 ore refining

    Sulflde ore - Pyrometallurglcal processes

                                        131
                    Falconbrldge,  Ontario (low
                    temp,  sintering)
                    (Shannon et al.,  1983)

                    Conlston smelter  (low
                    temp,  sintering)
                    (Roberts et al.,  1982 and 1983)
                                        286a
                  Sulflde ore -  Hydrometallurglcal processes

                   Fort Saskatchewan,  Alberta         None
                   (Egedahl and Rice,  1984)
                 Oxide ore

                   Smelting
                   Hanna, Oregon
                   (Cooper and Wong,  1981)
                                        72
                                                             102
                                                             400"
                                                                          45
                                                                                     137
                                                                                      55
                                   167U
                                                                                                 78
                                                                None
                                                                           None
                                                                                       None
                                                 None
                                                 None
                                                None
                                                None
 196
                                                             None
                                                            None
                                                            393
                                                                          89
            None
           1 case
                                                                        None
                                                                                    None
                                                                                    None
                                                                                   303
                                                                                               219
                                                                                               559
                                                                                               None
                                                 15+ years  since
                                                 first exposure
                                                 Pancreas (142 )

                                                 Larynx (1145a) among
                                                 men with less than 5
                                                 years of exposure
                                                 and with at  least 20
                                                 years since  first
                                                 exposure
                                                                                                                           Sulfur-free ore
                                                                                                             Smelter workers
                                                 Lung cancer SHR for workers
                                                 with >5 years of exposure
                                                 and >T5 years since first
                                                 exposure was 581
                                                Nickel workers
                                                (not maintenance)
                                                Colon &  rectum  (363)
                                                Lower Up  (357)
                                                                                                            Sulfur-free ore
                                                                                                            Ever employed In
                                                                                                            smelting, refining
                                                                                                            furnaces, skull
                                                                                                            plant, or ferro-
                                                                                                            slllcon area
                                                                                                             (continued on the following page)

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                                                                  TABLE  8-11.    (continued)
00

00
ID

Industry
III. N1 matte refining
Clydach, Wales
(Peto et al., 1984)
Copper Cliff, Ontario
(Roberts and Julian, 1982)

Lung Nasal

510b 26,667b
424b 1583b
Cancer risks
Buccal and
Larynx pharyngeal Kidney Prostate

__
None None None 251 (All
Sudbury)
Other cancer/
comments

Among workers
starting before 1925
Hay not Include all
men exposed to ore
                  Port Col borne, Ontario
                    (Roberts  et al., 1983)
    FalconbHdge,  Norway
      (Magnus,  et  al., 1982)

    Huntlngton, W.Va.
      (Enterline and Marsh, 1982)

IV.  Electrolytic refining

    INCO,  Port  Colborne
      (Sutherland, 1959)

    Falconbrldge,  Norway (longest
      job  held)
      (Magnus et al.,  1982)

 V.  Nickel Metal use

    Die-casting and electroplating
      (Sllversteln et  al., 1981) (PMR)
                                        298U
360"
                                                      118
                                                      105
                                                      550"
                                                      195L
          9412b       None        299a
4000b       670b
          2443U
          None
            None
          None


         2670b        None
            330
77
                                    213
96
                                                                                                               74
                                   processing

                                   Has received feed
                                   fron both Canada
                                   and New Caledonia
                                                            Workers with "pure"
                                                            exposure history
PMRs for white  males
                                                                                                               (continued on  the following page)

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                                                                  TABLE 8-11.   (continued)
00
Industry
Polishing, buffing, plating
union
(Blair, 1980) (PHR)
High N1 alloy Manufacturing
(Redaond, 1983)
N1 alloy manufacturing
(Cox et al . , 1981)
N1 /chromium alloy Manufacturing
(Landls and Cornell, 1981) (PMR)
Stainless steel and low N1
alloy steel manufacturing
(Cornell, 1979) (PMR)
N1 "barrier" manufacturing
(Cragle et al., 1983)
N1-cadm1um battery (N1 hydroxide)
(Sorahan et al., 1983)
N1 alloy welding
(Polednak, 1981)
Lung Nasal
106 None
100 None
124 None
148° None
97 None
59 None
127* None
124 None
Cancer risks
Buccal and Other cancer/
Larynx pharyngeal Kidney Prostate comments
143 ? Ill 111 Esophageal (185a) a
Primary liver (278a)
71.2 — -- 104 20+ years employment
(white Males)
—
None ~ — 75 PMRs In white males
who died at age 65+
79 — — 98
None 292 None 92 Liver (387)
121 Cadmium exposure.
__ __ __ __
ap < 0.05.
"- * n ni
               — = The site-specific tumor was not studied, not reported, or not specified for the defined  group of workers.

               PMR = Proportionate mortality ratio study.

               NOTE:
While this table does summarize positive evidence of Increased risks, the  lack of such evidence may be attributed merely
to factors such as study design, cohort definition,  length of follow-up, bias, or lack of statistical power, etc.
Generally, the one most appropriate report for each  worksite was  chosen for use 1n this summary table.  Refer to the text
of this report for the critique.

-------
(SMR = 400) (Shannon et al.,  1983, unpublished).   Prostate cancer was signifi-
cantly increased among  miners  in the INCO study  (SMR  = 167) but not in the
Falconbridge study  (SMR  = 78).   However, the designs of both studies created
an overlap of exposure classification among mining and  other processes, which
may have  spuriously  increased  or decreased the miners' actual cancer risks.
The possibility also exists that the cancers among miners may not have resulted
from nickel exposures at all  but from exposures to other potential carcinogens
encountered in the  mines,  although Roberts and Julian  (1982) did state that
the Ontario ore  contained no asbestos-like material  and that radon daughters
were low  in the  Sudbury mines.   However,  a worker was  defined as a miner in
the Falconbridge study  if he "ever worked" in the mines.   As a result,  there
is the possibility  that  an individual  classified as a  miner could have been
employed for some time in the smelting or refining operation.
     Cohort studies reviewed of risks associated with oxide nickel ore include
a study of workers  at the Hanna mining  and refining plant in Oregon (Cooper
and Wong,  1981). No excess risk of lung or nasal  cancer appears  to have been
associated with  oxide nickel ore mining.   The  follow-up period for the cohort
was relatively short compared to studies of other miners,  especially since the
latency periods  for  nasal and lung cancers are long.  While there was a maxi-
mum of 24 years  of follow-up from first exposure, only 1,192 person-years of
observation were accumulated  in workers more than 20 years after first expo-
sure.
8.1.12.2  Nickel  Ore Refining.   Sulfide  nickel ore is processed at INCO's Cop-
per Cliff  and  Coniston  facilities, and  at Falconbridge, Ltd.'s Falconbridge,
Ontario plant.   Analyses  of  cancer risks associated with the early stages of
processing of  sulfide nickel ore  showed no excess risks  among  workers  at
Copper Cliff  in  smelting and converting of sulfide  nickel  ore (Sutherland,
1971).   However, these data were not analyzed  in  such a way that  cancer risks
among those employed  before  and after process changes  can be separated.  At
the Coniston  and Falconbridge  smelters, only small increases in  lung cancer
risks were seen (statistically significant at Coniston but not at Falconbridge).
Coniston  sintering workers experienced  a nonsignificant increase in prostate
cancer deaths  (SMR  = 559),  while Falconbridge workers  had a nonsignificant
excess of  laryngeal  cancer  (SMR = 196).  Since the ores for both plants were
obtained  from  the  Sudbury,  Ontario nickel deposit, and the  low-temperature
sintering process is said to have been the same at both places, any differences
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in exposure that could account for the slight differences in risks are likely
to be subtle.
     No excess risk  of  lung or nasal cancer appears to have been associated
with refining of sulfur-free, oxide nickel ore.   Laryngeal  cancer was found to
be in excess  among  all  workers at the Hanna, Oregon plant, but the SMR was
not  statistically  significant.   A statistically significant SMR  was found,
however, for  laryngeal cancer  among  employees who were still  working 15 or
more years after beginning  employment (SMR = 909, p < 0.05).  The follow-up
period for the cohort was relatively  short compared to studies  of other refin-
ery workers,  especially  since the latency periods  for respiratory cancers are
long.  While there  was a maximum of 24 years of  follow-up  from  first exposure,
only 1,192 person-years of follow-up  were accumulated more  than 20 years after
first exposure.   Moreover, the exposure levels at Hanna may have been consider-
ably lower than the  levels  encountered at  sulfide nickel  ore  sites such as
Sudbury, Ontario,  which may result in a lower relative risk and longer latency
than experienced at the other refineries.
8.1.12.3  Nickel  Matte Refining.   In  the  early years  of the refineries, INCO's
Sudbury area  facilities  were producing crude converter matte, some  of which
was sent to other  facilities for further refining while some was refined at
Copper Cliff.   This matte was further refined using either  the  carbonyl process
(Clydach and  Copper  Cliff)  or electrolysis (Port Colborne).  The composition
of this converter matte was changed in approximately  1948,  which resulted in a
lower copper  and sulfur  content  than was present in  the matte  prior to 1948.
By 1963, and possibly earlier, Copper Cliff was  supplying  the other sites with
a matte that had already been oxidized to nickel  oxide.
     In the case of  the  Clydach refinery,  several changes  were  made in the
material used as feed to the plant.   From 1902  to 1932, the refinery had re-
ceived converter matte directly from  Copper Cliff, Ontario, and separation  by
the Orford process was  done on-site   in Wales.   From 1932  to 1948,  Clydach
received low-copper nickel matte and  discontinued its Orford process.  Through-
out its operation,  the carbonyl process was used in the final  step of refinement.
     Before 1930 at  Clydach, Wales,  the  predominant nickel species  from the
refining of nickel  matte were nickel  subsulfide,  nickel  sulfide,  nickel oxide,
and nickel carbonyl.   Other exposures included  copper sulfate, arsenic, and
trace elements of selenium and cobalt.  There was an  extraordinarily high risk
of lung and  nasal  cancer among Clydach workers who  started their employment
before 1925.   The SMR for nasal cancer was highest for workers  starting between
                                   8-92

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1910 and 1914  (SMR  = 64,900).   The risk  began  to decline after 1914 (SMR =
9,900 for those  first  employed between 1920 and 1924), and no cases of nasal
cancer occurred  among  workers  first employed after 1924.  Gauze  masks were
introduced in the plant between 1922 and 1923, and were found to be correlated
with a virtual absence of nasal cancer after 1924.   Studies by INCO (1976)
showed that the  gauze  mask effectively reduced the total dust exposure (60 to
81 percent efficacy with  one pad and 85 to 95 percent  efficacy with two pads)
and altered the  size  distribution  of dust particles.   The fact that the risk
of nasal  cancer began to decline after the introduction of masks may,  in part,
have been an artifact of the cohort definition,  i.e.,  workers starting earlier
who met the cohort criteria by definition had to have  worked longer.
     The other notable change  in  the process at Clydach was in the calcining
step.   However,  the data  do  not permit determinations as to when the changes
took place, or their  effects  on exposures.   The risk  of lung cancer,  in con-
trast to nasal  cancer,  was high among workers starting employment before 1920,
and peaked among workers  starting  between 1920  and 1924 (Peto et al., 1984).
Doll et al.  (1977)  showed that the lung  cancer risk was still in excess and
appeared to be increasing with continued follow-up for workers starting between
1925 and 1929.   Peto  et al.  (1984) noted that the highest risks of lung and
nasal  cancer were associated  with  the copper sulfate  process and the Orford
furnace.   However, very high  risks for both of these  tumors appear to have
been associated  with  other aspects of the refining process  as well, since
those who did  not work in either  the  furnace or  copper sulfate area had an
excess risk of lung (SMR = 340) and nasal  (SMR = 14,700) cancers.
     Cancer risks in matte refining at Copper Cliff were found to be very high
for nasal  cancer (SMR = 1583,  p <  0.01) and significantly high for lung cancer
(SMR = 424,  p  <  0.01)  among men with  any exposure to sintering (Roberts et
al., 1982).  The process  implicated treats a low-copper feed with downdraft
traveling grate  sintering  machines at high temperatures (1,650°C); exposures
may have  included nickel  sulfide,  subsulfide,  and oxide, as well  as coke
particles (INCO,  1976).
     At Port Col borne  from the  1920s to 1973, nickel copper matte from Copper
Cliff was calcined  in  enclosed calciners to oxidize nickel subsulfide.   From
1926 to  1958,  sintering  at high  temperatures was used  after  calcining  to
oxidize the ignited sulfur charge,  using traveling grate sinter machines on an
open hearth at 1,650°C, with  the  addition of coke.  According to Roberts et
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al.  (1982), the calcining/sintering  process  was dusty, and caused exposures
similar to those in the calcining sheds at Clydach.
     At Port Colborne,  Sutherland  (1959)  showed high risks of both lung and
nasal  cancers (SMR = 379 and 2,874, respectively) among men whose entire work
histories were spent as furnace workers (cupola, calciners, sinter, and anode
furnace).   These workers included  men  who had been exposed before and after
the changes in  the  feed from high to  low copper concentration and to nickel
oxide.   The author did not  present sufficient data to enable the separation of
exposures.  Based  on  mortality  follow-up of a  somewhat  differently  defined
cohort, Roberts et  al.  (1982)  continued to find  high  risks among men "ever
exposed"  to leaching,  calcining,  and sintering.   Among workers with  at least
15 years  since  first  exposure,  the SMR for lung cancer was 298; the SMR was
445 (p <  0.01)  in the  subgroup with at  least 5 years of exposure.  The excess
risk of nasal  cancer was shown by a very high SMR of 9,412, which is  consistent
with the  findings  at  other matte refineries.  However, it,is  not clear that
all of the excess risk can  be attributed to sintering,  since a large  proportion
of all  of the lung  and nasal cancer cases had worked for short periods in  the
sintering  department  and for long periods  in  other departments, including
electrolysis (INCO, 1976).
     At the Falconbridge refinery  in Norway, the  highest risk  of nasal cancer
was found in  roasting  and  smelting (R/S) workers, who were exposed primarily
to particulate matter containing nickel subsulfide and oxide.   This association
was strengthened by the fact that R/S  workers  had  the highest nasal mucosal
nickel  levels,  and  had the most frequent and severe mucosal dysplasia among
the current workers.   The  highest risk of lung cancer was  found in electro-
lytic workers who had been exposed primarily to aerosols of nickel sulfate and
chloride.   Although the ambient levels of nickel  were higher in the  elec-
trolytic  tankhouse, the nasal mucosal  levels of nickel for  these workers were
the lowest of  all  process  workers.  In contrast, the urine and plasma levels
were highest in these workers.
     There  appears  to  have  been an association  between the  occurrence of
laryngeal  cancer  and  the disappearance of nasal  cancer  at the Falconbridge
refinery  in Norway.   Four  of five laryngeal cancer cases were first employed
on or  after 1940,  whereas  only  one  of 14 nasal cancer cases occurred among
those  starting after 1940.   The  refinery appears to have been inactive between
1940 and  1945, with changes in production and control measures being introduced
after  1945.   It would be of  interest to know the  relationship  of such  control
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measures  with  changes in dust levels and particle size distribution, and the
specific  nickel species  involved.  As an alternative explanation, the increased
risk  of  laryngeal  cancer could reflect  changes  in smoking patterns.   However,
data were not presented  to address this question  directly.    '
     The  oxidation  process  in the final  refining  of  the  impure  nickel  sulfide
has varied between calcining  and  sintering at the different sites in different
time  periods.   The  fuels in  these steps, and the temperatures needed for the
processes, have also  varied.  Some plants have used an electrolytic separation
method, while  others  have used a carbonyl process.  All of these changes, as
well as control measures, could have resulted in  differences in exposures over
time at these facilities.
     In  summary,  sulfide ore smelting  and refining have  been  found  to be
associated with excess risks  of lung, nasal, and  laryngeal cancers, and possi-
bly buccal and  pharyngeal,  prostate, and  kidney cancers.   A clear delineation
of these  risks  is  problematic, however, because  of  the  complex operational
changes at the  INCO Sudbury  (Ontario),  Port Col borne, Coniston, and  Clydach
(Wales) facilities, all  of  which are related to  each  other and to those in
Huntington, W.  Va. , through  the  use  and exchange  of  common products.  Because
of the  inadequacy  or  inconsistency of the  available  information,  it  is not
possible  to state with certainty  how changes in the  operation at one  facility
affected  the  materials  processed  at another facility, or to  relate  these
changes to changes in exposure and in risk.   In addition, exposure was typically
defined on the  basis  of  longest job held.  As a result,  the risks associated
with a  specific processing  step may, in part,  be accounted for by employment
in other areas of a plant.
     In conclusion, several  general patterns are noteworthy.   The risk of lung
and nasal cancer among miners has  been found to be low in  comparison with the
risks among smelter and  refinery workers, although there does  appear to have
been some excess  risk for lung,  nasal,  and laryngeal cancers at the Sudbury
and Falconbridge mines.  Sulfide  ore  processing at Falconbridge (Ontario) and
Coniston  was  not  associated  with  an excess risk of nasal cancer,  but was
associated with an excess risk of  lung cancer.  However, the lung cancer risk
was found to  be low in relation to that among nickel matte refinery workers.
The risk  of nasal  cancer was shown  to be  exclusive  to sulfide nickel matte
refinery  workers,  and appears to  have been  restricted  to smelter workers.
However, the electrolytic tankhouse workers at Falconbridge, Norway, showed a
large excess  risk of nasal cancer (Magnus et a!.,  1982).
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8.1.12.4  Other Nickel-Related Industries.   Nickel  exposures may  occur in
several other  industries and at  other worksites.   The form of  the  nickel
varies, and can include  metal  alloys, powders,  and salts.   The  exposures may
occur  in manufacture  of  the nickel-containing product, such as  in stainless
steel or nickel-cadmium batteries, or may occur in end-uses of nickel,  such  as
in electroplating or  welding.  Worker populations in several  of these  indus-
tries were examined,  but in most  cases the  risks were not found to be  high.
On the  other hand,  the studies generally were not rigorous or did not attempt
to separate the risks associated  with nickel from the risks associated with
other metals or materials in the  environment.  It is important that advantage
be taken of appropriate  opportunities  to obtain more information on exposures
to nickel  in species and situations not related to refineries.
8.2  EXPERIMENTAL STUDIES
     Experimental carcinogenesis  has been  the  subject of numerous reviews
(Sunderman, 1984a,b,c, 1983, 1981, 1979, 1977, 1976, 1973; Rigaut 1983; National
Institute of  Occupational  Safety  and Health, 1977a; International Agency for
Research on Cancer,  1976; National Academy of Sciences, 1975).   The qualitative
and quantitative  character  of the carcinogenic effects of nickel, as seen in
experimental studies, has been shown to vary with the chemical  form and physical
state of  nickel,  the route of administration,  the  animal  species  and  strain
employed, and the amounts of nickel compound administered.
     The  following  sections will  discuss  animal  studies by inhalation  and
ingestion,  as  these  are most relevant  to  the  assessment of potential human
risk from  environmental  exposures  to  nickel.  The carcinogenesis  testing data
for specific  nickel  compounds,  as well as  relevant chemical  and biological
indicators, will then be summarized to promote an understanding of our current
knowledge of the carcinogenic activities of these compounds.

8.2.1  Animal Studies by Inhalation and Ingestion
8.2.1.1   Inhalation  Studies.   Ottolenghi  et al.  (1974)  exposed Fischer 344
rats to  an airborne  nickel subsulfide  concentration of 0.97 mg nickel/m  (70
percent  particles smaller  than 1  urn) 6 hours/day,  5 days/week,  for  78 to 84
weeks.   The animals  were observed for an  additional 30 weeks thereafter.  The
treated  groups  consisted of 226 rats of both sexes.  The control group consisted
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of 241 rats  exposed  to filtered air.  One-half of  the  control  and treated
groups were  injected intravenously with hexachlorotetrafluorobutane, an agent
used to induce pulmonary infarction.   According to the authors,  this treatment
had no effect on the induction of tumors.   During  the last 26 weeks of exposure,
mortality increased among  nickel-exposed  rats.   Fewer than 5 percent of the
nickel-exposed rats were alive  at the end of  108  weeks,  as compared to 31
percent of the  controls  (p < 0.01).   The lungs were the most affected.  The
nickel-exposed rats also had a higher incidence of inflammation  of the respira-
tory tract.   In addition, 12 percent of the treated rats had adrenal medullary
nodular hyperplasia and  pheochromocytoma,  as  compared to 1 percent among the
controls (p  <  0.01).   Table 8-12 presents the results of the histopathologic
evaluation of the lung tissues from this study.  This study is the only inves-
tigation available which is of  sufficient quality or has sufficient strength
of response  to  permit  its  use in the quantitative assessment of cancer risk.
     Historically, the first attempts to confirm the carcinogenic potential of
airborne nickel  are the  studies of Hueper (1958) and Hueper and  Payne (1962).
Hueper (1958)  reported a  study  of the carcinogenic  potential  of airborne
concentrations of  elemental  nickel.  The experimental animals were  exposed to
99 percent pure  nickel,  4  pm or less in size,  at a  concentration  averaging 15
mg/m  for 6  hours/day, 4 or 5 days/week, for 24 months or  until  death.  It is
not clear if the chamber concentrations were measured or calculated.   Guinea
pigs  (32  males,  10 females), Wistar rats  (50  males,  50 females),  Bethesda
black rats (60  females),  and C57 black mice (20 females) were exposed to the
nickel dust.    By the end of the first year, 45 percent of  the guinea pigs, 64
percent of the Wistar rats, 52 percent of the Bethesda rats, and 85 percent of
the mice  had died.   All  of the treated animals died by the end of the second
year.   The description  of  the study does not  indicate  the consistency with
which organs other than the lungs  were examined histopathologically.  The
author indicated  that  the  mice had hyperemic to hemorrhagic conditions  in  the
pulmonary tract  but  showed no neoplastic reactions which  were  judged to be
from nickel  exposure.   The only tumors reported among the mice were two lympho-
sarcomas.  Thirty-seven guinea pigs were evaluated histopathologically.   Seven
of eight  guinea  pigs  dying  in the first  six  months of the study had lower
grades (1 and  2)  of adenomatoid proliferations, while 20 of 29 pigs surviving
7 to 21 months had higher grades (3 and 4).   In six animals, the author reported
that the intra-alveolar and  intrabronchiolar epithelial  proliferations approached
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                TABLE 8-12.  HYPERPLASTIC AND NEOPLASTIC CHANGES IN LUNGS OF  RATS  EXPOSED  TO  NICKEL SULFIDE3
CO

<£>
00
Pathologic changes
Typical hyperplasla
Atypical hyperplasla
Squamous metaplasia
Tumors:
Adenoma
Adenocarcinoma
Squamous cell carcinoma
Fibrosarcoma
Controls
Males
(108°)
26 (24)
17 (16)
6 (6)

0 (0)
1 (1)
0 (0)
0 (0)
Females
(107°)
20 (19)
11 (10)
4 (4)

1 (1)
0 (0)
0 (0)
0 (0)
Nickel
Males
(110°)
68 (62)
58 (53)
20 (18)

8 (7)
6 (5)
2 (2)
1 (1)
sulfide
Females
(98°)
65 (66)
48 (49)
18 (18)

7 (7)
4 (4)
1 (1)
0 (0)
      aValues represent the number of affected animals in each group.  Percent of affected animals  is  given  in
       parentheses.  Subtreatment groups were combined, as no significant' differences were found  among them.

       Number of animals.

      Source:  Ottolenghi et al. (1974).

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"the character of microcarcinomas."  In addition, one guinea pig had an intra-
alveolar  carcinoma,  while a second was found  to have  a retroperitoneal  node
judged  to originate  from a pulmonary carcinoma.   Fifteen of 50 rats  evaluated
histopathologically  had adenomatoid formations.  The  author concluded that
lung lesions  in  the  rats and guinea pigs  were  "equivalents  of  the  respiratory
neoplastic  reactions  seen in copper-nickel matte smelter workers."  Although
suggestive  lesions were found in rats and guinea pigs,  the data presented do
not clearly indicate carcinogenicity attributable to elemental nickel.  Because
of the  limited  survival times in this  study  (less  than 2 years), the data
contained in the study  report cannot be considered adequate for the assessment
of carcinogenicity.
     Hueper and  Payne  (1962), experimenting with rats  and hamsters,  attempted
to confirm the carcinogenic potential  of nickel previously reported.   Airborne
powdered  nickel, particle  size 1 to 3 urn, was administered with sulfur dioxide
and powdered limestone.  (The limestone was added to prevent the nickel particles
from forming conglomerates, to dilute the nickel, and to decrease the toxicity
observed  in the previous study.   Sulfur dioxide was added to test its potential
as a co-carcinogen.)  Chamber concentrations of nickel  were not specified; the
animals were exposed for 6 hours/day to a mineral mixture (3 or 4 parts nickel
to 1 part limestone for the hamsters and 1 part nickel  to 1 part limestone for
the rats) released into the  chamber at 50 to 65 g/day,  along with  sulfur
dioxide at a concentration of 20 to 35 ppm.  One hundred male hamsters and 120
rats (60 males,  60 females) were exposed.   All  died within 24 months.  Control
animals were not mentioned.  Cancers of the lung were not observed in the rats
or the  hamsters.  The  lungs  from hamsters  showed minimal effects attributable
to exposure.  The hamsters probably had lower exposure  to nickel particulates,
but in view of a likely high pulmonary burden of dust and irritant vapor,  this
study may only suggest  that  hamsters are  not responsive  to  inhaled irritants.
While the authors  indicated  that many of the rats had  inflammatory fibres ing
changes with  bronchiectasis, squamous  cell  metaplasia,  and  peribronchial
adenomatosis,  they did not consider these changes to be malignant or  premalig-
nant as in the previous study.
     Wehner and co-workers  (1984)  have recently summarized their work on the
toxicity and potential  carcinogenicity  of airborne  concentrations of nickel
oxide in  hamsters  (Wehner  et al.,  1975, 1981).   In  the 1975 study,  51 male
Syrian golden hamsters  (random bred ENG:ELA) were exposed to airborne concen-
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trations of  nickel  oxide  dust (count median diameter  0.3  urn)  at a concen-
                     3
tration of  53.2 mg/m  for 7  hours/day,  5 days/week for up  to  2 years.   A
similar group was exposed (nose only) to  cigarette  smoke and nickel oxide  for
10 minutes,  three times  a day.   A control  group  was maintained for each of
these treatment regimens.
     The histopathologic  evaluation  revealed that  among the  hamsters dying
late in the study, there was an increasing cellular response of both an inflam-
matory and proliferative  nature.   There  was no marked difference between the
nickel-oxide-plus-smoke and  the  nickel-oxide-only treatment effects, except
for brownish cytoplasmic  inclusions  and  an increase in laryngeal lesions  in
the former  group.   The authors concluded that  while lung  lesions  (massive
pneumoconiosis) developed from chronic exposure to nickel  oxide, "neither a
significant  carcinogenic  effect  of the  nickel  oxide nor a co-carcinogenic
effect of cigarette  smoke"  was  found.   However,  it is noteworthy that three
malignant musculoskeletal tumors (two osteosarcomas and a rhabdomyosarcoma in
the thoracic skeletal muscle) were  found  among the nickel  oxide-exposed hamsters.
No such tumors were  present among  the control animals.  A rhabdomyosarcoma is
the same type of tumor produced by  injection of nickel  oxide.
     Wehner et al.  (1981) also investigated the effects of chronic  inhalation
of nickel-enriched fly ash (NEFA) in  the  Syrian golden hamster (outbred LAK:LVG).
Four groups of 102 male hamsters  were exposed 6 hours/day,  5 days/week,  for up
to 20 months.  The  first group was exposed to 70  ug/1 of NEFA which contained
approximately 6 percent nickel.  The airborne concentrations were reported as
"respirable aerosol  concentrations" based on measurement with a cascade impac-
tor.   No further details were given.   The second  group was exposed  to 17 ug/1
of NEFA (6 percent nickel).   The  third group was exposed to 70 ug/1  of fly ash
(FA) which contained 0.3 percent  nickel,  while the fourth group was  exposed to
filtered air and served as a control  group.  Five animals from each  group were
killed after 4, 8,  12, and 16 months of  exposure.  In addition, five animals
were withdrawn from exposure at the same  time intervals and maintained without
exposure until the  end of the study, when all  surviving animals were killed.
The mean survival times  were 474,  495, 513, and  511 days for the NEFA-high,
NEFA-low,  FA, and control  groups,  respectively.  The  lung weights  and lung/
body weight ratios were increased in  the  NEFA groups (p < 0.01) as compared to
the controls.  This trend was evident even after four months.   The mean nickel
lung concentrations  after 20  months  of exposure  were 731, 91,  42,  and 6 ug,
respectively.  The  authors suggested that the apparent increased  retention of
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nickel in  the high-exposure group  may have been due to  reduced pulmonary
clearance.   The severity of the interstitial reaction and bronchiolization was
greatest in the  NEFA-high  and  FA-exposed groups as compared to  the NEFA-low
group, suggesting  that these  effects  are  related more to  the  actual  dust
concentrations than to  the  nickel  levels.   While malignant pulmonary tumors
(one mesothelioma and  one  adenocarcinoma)  were found in two hamsters of the
NEFA-high group,  no statistically significant carcinogenic response was evident.
     The particle size in the Wehner et al.  (1975) study was small compared to
that in the Ottolenghi  et  al.  (1974)  study.  Because of this, clearance was
probably faster.   The  adequacy of  the studies by Wehner et al.  (1975, 1981)
for determining  carcinogenic potential  is  questionable, however, because of
the possible lack of sensitivity of the experimental  animals to inhaled carcin-
ogenic materials.  Hueper and  Payne  (1962)  demonstrated a lack of response of
hamsters to airborne nickel  as compared to rats.   Similarly, Furst and Schlauder
(1971) have reported  that  rats are much more sensitive to tumor induction by
nickel injection  than hamsters.
     Kim et al.  (1976),  in  an unpublished inhalation study at the University
of Toronto, exposed male Wistar rats to various  combinations  of nickel  and
iron dusts.   There were  77,  76, and 67  rats  in  treatment groups I, II,  and
III, respectively,  and one  control  group of 67 animals.   Approximately one-half
of  the  rats  in each group were  young  and  one-half were old.  Group  I  was
                                                         3          3
exposed to nickel powder at a concentration of 87.3 ug/ft  (3.1 mg/m ).   Group
II was exposed to a mixture  of equal weights of nickel powder, "Dust C" (24.1
percent nickel sulfate, 68.7 percent nickel sulfide, and 7.2 percent nickel
oxide), hematite,  and pyrrhotite.   The total nickel  concentration  was  59.5
     33                                                    3
ug/ft  (2.1  mg/m ),  and the  iron  concentration averaged 53.2  ug/ft  (1.9
    3
mg/m ).  The  actual airborne concentration  of nickel was not reported.  Group
III was exposed to an iron  mixture  (iron, hematite, and pyrrhotite) at an iron
                           3          3
concentration of 85.0  ug/ft   (3.0  mg/m ).   Within each group,  subgroups were
exposed from  7 to  16  months,  and identical exposure schedules were used for
all three  dust combinations.   Ninety-eight percent of the  particles were
smaller than  2 urn.  The rats in  groups I and II (with nickel exposure) had a
greater granulomatous  response as  compared to the controls  or to the rats
exposed to iron.    In  group  I,  three of 60 rats evaluated histopathologically
had lung tumors  (two  carcinomas and one lymphosarcoma).  This group had the
greatest nickel  exposure.   Among the  61 rats  evaluated histopathologically
from group II, there was only  one lung tumor, a squamous cell carcinoma.  The
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group III rats,  exposed  to  an iron mixture, developed two carcinomas and one
papillary adenocarcinoma among  the  58 evaluated histopathologically.  Among
the  55  control  rats evaluated  hi stopathol ogi cally  there  was  only one lung
carcinoma.   The authors concluded that under the conditions of the experiment,
there was no  evidence  of lung cancer as the result of a  direct carcinogenic
action  of  the inhaled dust.  The  data  presented in the  Kim  et  al.  (1976)
report  did not allow for further analysis related to latency  period  or to  the
relative effects of nickel  on rats of different age groups.
     Horie et  al.  (1985) presented limited information  on the  results  of
exposing male Wistar  rats  to airborne nickel concentrations.  The rats were
exposed 6 hours per day,  5 days per week, for one month to nickel oxide concen-
trations of 8.0  and 0.6 mg/m .  The experimental rats of  interest with regard
to carcinogenic assessment were observed 20 months.   There was one adenocarci-
noma  in the  low-exposure group  of  the  6 animals examined.   There  were  no
cancers among the 4 rats exposed to the  higher  dose or among  the five control
animals.  Because the  number of experimental animals was  small, this study is
only qualitatively suggestive.
     Sunderman et al.  (1959) and Sunderman and Donnelly (1965) reported car-
cinogenic responses in rats variably exposed to nickel  carbonyl  [Ni(CO),] by
inhalation.   Sunderman et al.  (1959)  exposed three  groups  of  male Wistar  rats
to nickel carbonyl:  64  rats were exposed to 0.03 mg/1 three  times weekly  for
one  year; 32  rats  were exposed to 0.06 mg/1 three times weekly for  one year;
and  80  animals were exposed  once to 0.25 mg/1.   In each case, exposure was for
30-minute periods.  Forty-one control animals  were exposed to a vapor of  50
percent  ethanol/ether,  the  solvent for the nickel carbonyl.  Of  the nine
animals exposed  to  nickel  carbonyl  and  surviving  2 years or  more,  four were
reported to have tumors:   one animal  from repeated nickel carbonyl exposure of
0.03 mg/1, one from inhaling  0.06 mg/1 repeatedly, and two from a single heavy
exposure.  No  assessment of tumorigenicity  was  done on the animals  that  died.
It is possible that tumor incidence may  have been enhanced among these animals,
but  it  is  difficult to be more  specific.  The  similar death  rate  for controls
and  treated animals suggests  that no  enhanced mortality due to exposure occurred.
The  survival  rate  in  this  study, even for  controls, was  lower than  expected.
Two  of  the animals showed  masses  of clear-cell carcinoma having an adeno-
carcinomatous pattern  (one  from the  large-single-dose group  and one from  the
group  chronically  exposed to nickel  carbonyl  at 0.06 mg/1), while  one  rat
showed  a  squamous  cell carcinoma (chronic  exposure to  nickel  carbonyl  at  0.03
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mg/1).  The fourth animal showed two small papillary bronchial adenomas (single-
large-exposure group).   No  pulmonary tumors were seen in the three surviving
controls.
     In the report of Sunderman and Donnelly (1965), six groups of male Wistar
rats were used.  Three of these groups were control groups.   Two of the control
groups, 19 animals in each, were exposed to the solvent for the nickel carbonyl
(ethanol/ether,  1:1)  for 30  minutes in a single  exposure  and were either
treated  or  untreated with  "dithiocarb"  nickel  chelating agent.  The  third
control group  of 32  animals inhaled solvent for  30 minutes,  three times a
week,  for their  lifetimes.  The exposure  groups consisted of   (a) 285  animals
exposed once to  0.6  mg/1 of carbonyl  for 30  minutes and followed for their
lifetimes, (b) 60  rats  exposed as in  (a)  above,  but receiving an injection
of "dithiocarb"  nickel  chelate 15 minutes after exposure,  and (c) 64 animals
exposed for 30 minutes  3 times weekly  to  0.03 mg/1  carbonyl for the remainder
of their lifetimes.
     In the chronic  and acute nickel carbonyl  exposure groups, three animals
of the 80 surviving  the 2-year exposure  and/or  observation  period showed
pulmonary carcinomas  with metastases,  one with papillary adenocarcinoma,  one
with  anaplastic  carcinoma,  and one with  adenocarcinoma.  No  pulmonary neo-
plasms were noted  in any of the 44  animals remaining in the  control groups.
     The  two studies cited above, taken  in the  aggregate,  reveal that six
animals of 89 (surviving to 2 years of age or more) exposed to nickel  carbonyl
developed malignant  lung tumors  with either acute  high  inhalation  exposure
(three animals)  or chronic  time-graded exposure (two animals,  exposed  for one
year;  one animal,  exposed for 26 months).  It should also  be emphasized that
in the second  study  all lung malignancies had metastasized to other organs.
While statistical analysis was not carried out,  given the small sample size of
survivors, it  should  be noted that spontaneous pulmonary malignant neoplasms
in the Wistar  rat  are very rare,  so that even a small  incidence of pulmonary
malignant tumors should be of some significance.
8.2.1.2  Oral  Studies.   Three  studies  of  the carcinogenic potential of nickel
salts  in  drinking  water were  found in  the  literature (Schroeder et al., 1964,
1974;  Schroeder  and  Mitchener, 1975).   All three  studies produced  negative
results,  and all three  used the same  relatively  low dose  level of 5 ppm  of
nickel in the drinking water.
     In the first  study, Schroeder et al. (1964)  gave  74  Swiss mice 5 ppm
nickel acetate in  drinking water for  the  duration of  their lives.   Tumors
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(types not specified) were reported in 10 of the 74 test animals and 33 of 104
controls.   However,  the diet in this study was considered to be chromium-defi-
cient, and the study was  repeated by  Schroeder  and Mitchener (1975).   In that
study, 108 male and female Swiss mice were given 5 ppm nickel  acetate in their
drinking water for the duration of their lives.   Tumors were found in 14 of 81
test animals  and  in  19 of 88 controls.   In the third study, Schroeder et al.
(1974) exposed Long-Evans rats (52 of each sex) to drinking water containing 5
ppm of  nickel (unspecified  salt)  for their  lifetimes.   The  average daily
nickel consumption was  estimated  to be 2.6 pg/rat for  the  controls  and 37.6
(jg/rat for the test  animals.   Similar tumor incidences were reported for the
test and control  groups.  A slight increase (13.3 percent) of focal myocardial
fibrosis was  reported  for the test animals as  compared with controls.  In
these studies only one exposure level was investigated, and there is no evidence
that a maximum tolerated dose was used.   In  addition,  data on  site-specific
tumor incidence are not included.   Therefore,  these studies may be regarded as
inconclusive  with  respect to  the  carcinogenic potential of  5  ppm soluble
nickel in the drinking water of rats and mice.
     Chronic  studies of nickel  in the diet of experimental  animals have also
been reported.  The  studies  were conducted using much  higher concentrations
than those used in the rodent drinking water studies previously described, but
failed to  indicate any  potential  for  the  induction of cancer by  nickel.
Ambrose et al. (1976) administered nickel, as sulfate hexahydrate fines (NiSO^
6hLO; 22.3 percent nickel), in the diet of Wistar-derived rats and beagle dogs
for two years. The dietary nickel concentrations were 100, 1000, and 2500 ppm.
There were 25 rats and three  dogs  of  each  sex assigned  to each  dose  group.  A
similar number of  untreated animals were maintained  and served as  controls.
The changes  among  the  rats were minimal at the higher dietary concentrations
and consisted of  depressed growth rate.  The females of the 1000-ppm and the
2000-ppm  treatment  groups showed  increased heart/body  weight and decreased
liver/body weight  ratios.   The rats  in  the 100-ppm  group had no treatment-
related  changes.   In  the  dogs,  only the highest level-treatment  group was
affected.  The 2500-ppm diet depressed growth,  lowered hematocrit and hemo-
globin values, and  increased kidney/body weight and  liver/body weight ratios.
Two of  the 6 dogs  showed marked polyuria.   There were no other signs of toxi-
city  reported.   Histopathologic evaluation  indicated  no  treatment-induced
lesions  among the  rats.  Among the dogs,  histopathologic evaluation indicated
that  all  dogs in  the high-dose group had lung lesions,  and  two of the six  had
                                   8-104

-------
granulocytic hyperplasia of the bone marrow.   The other treatments were without
effect.   The dog  study  may be inadequate, as  the  duration of the study was
relatively short.  The  rat study would appear to  be  adequate to detect the
cancer induction  potential of the treatment and supports the  lack of carcino-
genic response observed in the studies of Schroeder and co-workers.
8.2.2  Animal Studies of Specific Nickel Compounds
8.2.2.1  Nickel Subsulfide (Ni'3$2).   Though nickel  subsulfide (Ni3$2) is the
most studied nickel  compound, only one  study employed  inhalation as the route
of exposure.  As  reviewed  in the previous section, nickel  subsulfide predomi-
nantly produced adenomas  and  adenocarcinomas  of the lung in Fischer 344 rats
(Ottolenghi et al.,  1974).  Yarita and  Nettesheim  (1978),  using Ni3$2 pellets
implanted  into  heterotopic tracheas grafted  in  Fischer 344 rats, produced
mainly sarcomas with a low yield of carcinomas. Kasprzak et al.  (1973) reported
no pulmonary tumors in Wistar rats given 5 mg Ni^Sp intratracheally.   However,
when nickel  subsulfide  (5 mg)  was administered with  benzpyrene  (2  mg), the
yield of  bronchial metaplasia  increased  from 31  to  62 percent.   Numerous
injection  studies  have  shown  nickel  subsulfide to be  a potent carcinogen by
injection.    All  routes  of  administration  employed, with  the exception of
buccal brushing  of Syrian  golden  hamsters,  submaxillary  implantation  into
Fischer rats (Sunderman  et al.,  1978) and intrahepatic injection of Sprague-
Dawley rats  (Jasmin  and Solymoss,  1978) and Fischer  rats  (Sunderman et al.,
1978), have led to positive tumor response.   Table 8-13 summarizes some of the
many studies on nickel subsulfide.  These data are more comprehensively reviewed
by Sunderman (1984b,c,  1983,  1981,  1976) and IARC (1976).   When the data are
taken in aggregate, it can be concluded that nickel subsulfide is carcinogenic
in animals.
     Studies comparing  species and strain, route of administration, and organ
sensitivity, as  well as  dose-response  characteristics of  nickel  subsulfide
carcinogenesis, have  also been performed (Gilman,  1962; Gilman and Yamashiro,
1985; Daniels, 1966;  Friedmann and Bird, 1969; Hildebrand  and Biserte,  1979a;
Sunderman  et al.,  1978,  1979b).   These data have  been reviewed by Sunderman
(1983) and Gilman and Yamashiro (1985) and are presented in Tables 8-14 through
8-17.  While there are definite differences in tumor response between species/
strain and route  of  administration,  different experimental conditions  among
laboratories make  cross  comparison difficult.  Oilman's analysis  (Table 8-14)
seems to indicate that rats are more susceptible than mice, rabbits, or hamsters.
                                   8-105

-------
                           TABLE 8-13.   EXPERIMENTAL STUDIES OF NICKEL  SUBSULFIOE CARCINOGENESIS
Nickel Compound    Animal
                                          Route,  Dose
                                                     Response
                                                                Reference
                       Rat, mouse   Intramuscular, 20 mg/thigh
    N13S2
CO
i
o
c-i
 benzpyrene

N13S2/
 benzpyrene
         l
     (70% particles
     < lum)
    N13S2
    N13S2
    N13S2
    N13S2
Rats
 Fischer

Cats
Rats


Rats
Rats
 Fischer
Rats
Rats
                   Rats
                    Sprague-
                    Dawley

                   Rats
                    Fischer

                   Rats
                    Fischer
Intrasplenlc Implant,
 10 mg

Sinus Implant
 (dose not given)
                                    Intramuscular, 10 mg/5 mg
                                    Intratracheal ,
                                     5 mg N13$2/2 mg benzpyrene
Inhalation,  0.97 mg N1/m
 6 hrs/day,  5 days/wk for 78
 to 84 weeks
Intrarenal,
 5 mg/sa11ne or glycerol

Intratestlcular,
 0.6-10 mg

Intrahepatlc, 10 mg
             Intrahepatlc,  5  mg
             Submaxlllary Injection,
              2.5 mg
                                                                  Rhabdomyosarcomas

                                                                  Sarcomas  1n  20%
                                                                   of  rats

                                                                  Ep1dermo1d carcinomas
                                                                   and adenocarclnomas
                                                                   of  sinuses

                                                                  Sarcomas
                                               Squamous  cell
                                                carcinomas
                                                                 Adenomas, adeno-
                                                                  carclnomas, squamous
                                                                  cell carcinomas 1n
                                                                  * 14% of treated rats
                                                                        Gllman,  1962

                                                                        Gllman,  1966
Gllman, 1970
 as reviewed
 by Rlgaut, 1983

Maenza et al., 1971
                                                           Kasprzak et  al . ,  1973
                                                                                               OttolengM  et al.,  1974
                                                                 Renal adenocarclnomas    Jasmin and Rlopelle, 1976
                                              Flbrosarcomas and
                                                rhabdomyosarcomas

                                              No tumors
                                  No tumors
Damjanov et al., 1978


Jasmin and Solymoss, 1978



Sunderman et al., 1978
                                  No tumors                Sunderman et al., 1978

                                 	       (continued on following  page)

-------
                                                   TABLE 8-13.  (continued)
00
I
Nickel Compound
N13S2
W13S2
Animal
Hamster
Syrian
golden
Hamster
Syrian
golden
Route, Dose
Buccal mucous membrane
brushing, 1 or 3 mg
3 time/week for 18 weeks
Intramuscular, 5 or 10 mg,
single
Response
No tumors
Sarcomas
Reference
Sunderman et al . ,
Sunderman et al . ,

1978
1978
N-$2 Implanted
 Tn tracheas
 grafted
 under dorsal
 skin of 1so-
 genlc recipi-
 ents

Hamster fetal
 cells trans-
 formed by
 N13S2
 (0:161.0)
 ug/ml medium)
     N13S2
     N1-S2 Injected
      Into vitreous
      cavity of right
      eye
Rat          1 or 3 mg N1.S2/gelat1n
              pellet Implanted 1n
              tracheas 4 weeks
              post-grafting
                        Nude mice    Subcutaneous Injection
                        Mice
                         NMRI
Rats
 Fischer

Rats
 (juvenile)
             Intramuscular,  subcutaneous,
              10 mg
             Intrarenal  Injections,  10 mg


             0.5 mg/rat
                                                                      10 percent carcino-
                                                                       mas, 1 mg; 1.5 per-
                                                                       cent, 3 mg; 67 per-
                                                                       cent f1bro-/myosar-
                                                                       comas, 3 rag
                                               Sarcomas
                                                                  Local  sarcomas  1n
                                                                   11  of 16  (s.c.) and
                                                                   6 of  16 (1.m.)

                                                                  Renal  cancers 1n
                                                                   18  of 24

                                                                  Malignant  ocular
                                                                   tumors by 8 mo.
                                                                   1n  14/15  treated
                                                                   rats
                                                                       Yarlta and
                                                                       Netteshelm, 1978
                                                                        Costa et al., 1979
Oskarsson et al., 1979



Sunderman et al., 1979a


Sunderman et al., 1980
                                                                            (continued on following page)

-------
                                               TABLE 8-13.  (continued)
Nickel Compound    Animal
                   Route,   Dose
                                                                             Response
                              Reference
                   Rats         Intramuscular Injections
                    (pregnant)   on day 6
                                               Local  sarcomas  In
                                               all dams, no excess
                                               tumors  1n progeny
                                                                                                Sunderman  et al., 1981
a-N13S2
I   "-N13S2
00
N13S2
N13S2
Rabbits      Intramuscular  Implantation,
 Albino       80 mg
                   Rats         Intraocular,  0.5 mg
                    Fischer
Rats
 Fischer
 and Hooded
Rats
 Wlstar

Rats
                                     Intramuscular




                                     Intramuscular,  40 umol


                                     Intrapleural  Injection
Rhabdomyosarcomas,
 flbrosarcomas,
 lelomyosarcomas

Retlnoblastomas,
 gllomas, and
 melanomas

Rhabdomyosarcomas,
 lelomyosarcomas,
 flbrosarcomas, and
 lymphosarcomas

Sarcomas
Malignant tumors 1n
 the chest cavity,
 mostly rhabdomyo-
 sarcomas
                                                                                                Hlldebrand  and Tetaert,
                                                                                                 1981
                                                                       Albert et al., 1982
YamasMro et al., 1983
                                                                                          Kasprzak et al., 1983
Skaug et al., 1985

-------
      TABLE 8-14.   SPECIES DIFFERENCES TO Ni,S,>:   INTRAMUSCULAR INJECTION
Species and
Dose (mg)
Syrian (5)
Hamster3 (10)
Mice? (2.5)
Mice0 (5)
Rabbit0 (80)
Rat° (5)
Rat (10)
Rate (10)
No. Animals
(% Tumors)
15
20*
453
16
38
23
63
(33)
(71)
(55)
(60)
(100)
(92)
(96)
(94)
Tumor Type (%)
Rhabdomyosarcomas Other
20
50
few
10
most
54

66
80
50
most
90
few
44

34
pBA/2 and C5-,BL/6;  C,H and Swiss outbred
 Bilateral injections;  exact nos.  not stated
aSunderman (1983);/Gilman (1962); cHildebrand and
 Biserte (1979a); °Sunderman (1979); eYamashiro
 et al.  (1980).

Source:  Gilman and Yamashiro (1985).
  TABLE 8-15.   STRAIN DIFFERENCES IN RATS TO Ni:   INTRAMUSCULAR INJECTION
Strain and
Dose (mg)
Sprague - ,
Dawley (20)1
Hooded (10)
Fischer (10)
Wistar (10)
% Tumors
Sited
37

96
78
82
%
Rhabdomyosarcomas
82

91
87
86
% Other
Sarcomas
18

9
13
14
rFriedmann and Bird (1969)

Source: Gilman and Yamashiro (1985).
                                   8-109

-------
   TABLE 8-16.   STRAIN DIFFERENCES:
CARCINOGENICITY OF Ni'3S2 AFTER A SINGLE INTRARENAL INJECTION  IN FOUR RAT  STRAINS
Rat Strain
Long-Evans


Fischer


NIH Black


Wi star- Lewis


Sexa
M
F
M+F
M
F
M+F
M
F
M+F
M
F
M+F
Dose
(mg/rat)
5
5
5
5
5
5
5
5
5
5
5
5
Rats
With
Renal
Tumors
0/6
0/6
0/12
5/18
4/13.
9/31D
3/6
3/6 „
6/12C
2/5
5/6
7/llC
Median
Tumor
Latent
Period (mo)



11
17
13
12
10
11
10
17
14
Tumors
With
Distant
Metastases



1/5
1/4
2/9
2/3
3/3
5/6
2/2
3/5
5/7
Survivors
at End of
Study
4/6
4/6
8/12
9/18
3/13
12/32
1/6
3/6
4/12
0/5
1/6 c
1/11
Median
Survival
Period (mo)
>24
>24
>24
23
22
23
11
12
llb
12
13h
13b
. M= male; F = female.
 p < 0.05 versus corresponding value for Long-Evans Hooded rats.
 p < 0.01 versus corresponding value for Long-Evans Hooded rats.

Source:   Sunderman (1983).

-------
TABLE 8-17.  ROUTE OF ADMINISTRATION DIFFERENCES AND DOSE-RESPONSE:  CARCINOGENICITY OF
                                                                                                 IN MALE FISCHER RATS

Route of
Single Injection
Intramuscular





Intrarenal

3
i
i
t

Intrahepatic


Intratesticular

Intraocular


Dose
(mg/rat)
0
0.6
1.2
2.5
5.0
10.0
20.0
0
0.6
1.2
2.5
5.0
10.0
0
5.0
10.0
0
10.0
0
0.5
Submaxillary gland 2.5
fp < 0.001 versus
CP < 0.05 versus
corresponding
corresponding
	 	 	 	 __ _• * _
Rats With
Local
Tumors
0/142a
7/29*
23/30a
105/1123
35/38a
22/23a
9/9a
0/35
0/11
0/12
0/12r
5/18^
18/24a
0/6
0/13
1/6
0/18a
16/19a
0/lla
14/15a
0/11
controls.
controls.
. A. ^
Median Tumor
Latent
Period (mo)

11
10
10
7
6
7




11
9


13

10

8



Tumors With
Distant
Metastases

4/7
5/23
37/105
17/35
27/22
6/9




1/5
13/18


1/1

4/16

1/14



Survivors
at End
of Study
69/142
7/29.
5/30Da
2/112a
1/38°
0/23a
0/9a
26/35
10/11
7/11
8/12.
9/18°
2/24a
1/6
3/13
0/6
10/18r
0/19C
d
d
3/11


Median
Survival
Period (mo)
23
14
15r
12
9*
7a
8a
>24
>24
>24
>24
23a
14a
17
18
13
18
11C


17


     0.01 versus corresponding controls.
"The intraocular carcinogenesis study was terminated at 10 months.

Source:  Sunderman (1983).

-------
Sunderman (1983) indicates that  absolute  species susceptibility is difficult
to rank because  differences  arise  when experimental conditions or routes of
administration differ.   Sunderman (1983),  in the same report,  showed a definite
dose-response relationship for tumor  induction  by Ni,Sp following intrarenal
and intramuscular injections  (Table 8-17).   Gilman and Yamashiro (1985) suggested
a relative strain susceptibility  ranking of Hooded > Wistar >  Fischer > Sprague-
Dawley rats when Ni-S? was administered intramuscularly (Table 8-15).  Sunderman
(1983), on the other hand, reported a relative strain susceptibility of Wistar
> NIH Black > Fischer > Hooded, when Ni-Sp was administered via the intrarenal
route  (Table  8-16).   Comparison of the routes  of  administration on organ
susceptibility of Fischer rats to Ni',5,, carcinogenesis gave a  relative ranking
of eye  > muscle > testis ~  kidney > liver  (Sunderman,  1983;  Table 8-17).
8.2.2.2  Nickel Metal.   Powdered or pelleted metallic nickel  has been tested
for carcinogenic potential using  different animal models and several routes of
administration. Although  the  inhalation studies  have  not shown  that  nickel  in
the  metallic  form will  produce  respiratory  tract  tumors,  Hueper's (1958)
studies  reported  the observation  of adenomatoid lung  lesions  in rats and
bronchial  adenomatoid  lesions in  guinea  pigs.   Furthermore,  Hueper  (1958)
reported that  an  alveolar anaplastic carcinoma  was  found  in  one guinea pig
lung, and a "metastatic  lesion" (lymph node) was found in a second animal.   As
previously mentioned,  however, this study has been  criticized  as no  control
animals  were  used.   Several   injection  studies  have shown the  induction of
malignant  sarcomas  at  the site of  administration whereas others have  shown  no
induction.  The  data are summarized in Table 8-18.   Intrafemoral  injections
induced tumors in rats and rabbits  (Hueper,  1952, 1955).  Intravenous  injections
produced tumors  in  rats but  not in rabbits  and  mice, (Hueper,  1955).  Intra-
muscular  injection  was  the  route most  studied,  and tumors were  observed in
rats  and  possibly  hamsters  but not  in  mice (Hueper,  1955;  Heath and Daniel,
1964; Furst and Schlauder, 1971;  Furst et al., 1973; Haro et al.,  1968; Jasmin
et al.,  1979;  Sunderman and  Maenza, 1976;  Sunderman,  1984a).   Sunderman and
Maenza  (1976)  observed a dose-response relationship  between  tumor formation
and  levels of  nickel injected intramuscularly.
      Based on  the  strong tumor response from intramuscular injection studies,
the  observation  (albeit somewhat questionable)  of  adenomatoid  lesions of the
respiratory tract from  inhalation  studies,  metallic  nickel  should be  considered
as a potential animal carcinogen.
                                    8-112

-------
                              TABLE 8-18.   EXPERIMENTAL STUDIES OF NICKEL METAL CARCINOGENESIS
00
I
Nickel Compound
Nickel metal
(powder)
Nickel metal
(powder) 99%
pure (<.4um)


Nickel metal
(powder)
Nickel metal
(powder)
Nickel metal
(dust)
Nickel metal
(powder)
Animal
Mice
Rats
VMstar and
NIH Black
Mice
C57BL
Guinea pigs
Hamsters
Dogs
Rats,
albino
(female)
Rats
Osborne-
Mendal
(female)
Route, Dose
Inhalation, dose not given
Inhalation, 15 mg/m
6 hrs/day, 4-5 days/week
for 2 years or over
M
it
Inhalation, level not specified
3
Inhalation, 5-6 mg/m
10 minutes/day for 6 months
Intratracheal Injections,
10 mg N1/rat
10 mg N1 + 5 mg
methyl chol anthrene
Intrapleural, 5 monthly
Injections of 0.5 ml
of 12.5% (by volume)
suspension
Tumor Response
Some tumors
(no controls used)
No tumors
15/50 rats with
adenoma told lung
lesions
2 lymphosarcomas 1n
20 mice
Bronchial adenomatold
lesions
No tumors
No cancer
(flbrosls only)
0/7
3/5 squamous cell
carcinomas
4/12 rats with
Injection site
sarcomas
Reference
Campell, 1943 as reviewed
by Rlgaut, 1983
Hueper, 1958
ii ii
ii n
Hueper and Payne, 1962
Sellvanova 4 Ponomarkov,
1963 as reviewed by
Rlgaut, 1983
Mukubo, 1978 as reviewed
by Sundennan, 1981
Hueper, 1952
                                                              (continued on following  page)

-------
                                                       TABLE  8-18.   (continued)
         Nickel  Compound    Animal
                                      Route,  Dose
Tumor Response
Reference
oc
I
                            Rats         Intrafemoral, 21 mg
                             Osborne-      (0.05 ml of a 12.5% (by volume)
                             Mendal        N1  suspension 1n  lanolin)
                               "          Intranasal

         Nickel  metal        Rats          Intrafemoral  Implant, 50 mg
          (powder)            Wistar       (0.1 ml of a 5% suspension  1n
                                          20% gelatin  1n saline)
                   Rabbits      Intrafemoral Implant,  54 Dig/kg
                    Dutch        (0.25 ml of a 12.5% by volume
                                 N1 1n lanolin)

                   Mice         Intravenous, weekly for 2 weeks
                    C57BL        0.05 ml of a 0.005% N1 1n
                                 2.5% gelatin

                   Rabbits      Intravenous, 6 times of a
                                 1% N1 suspension 1n 2.5%
                                 gelatin at a rate of 0.5
                                 ml/kg

                   Rats         Intravenous, 6 times of
                    Wistar       0.5% N1 suspension 1n saline
                                 at 0.5 ml/kg

Nickel metal       Nice         Intraperltoneal,  0.02 ml  of
 (powder)           C57BL        a 0.05% N1 suspension 1n
                                 2.5% gelatin

                   Mice         Intramuscular, 0.02 ml
                    C57BL        of a 0.05% N1 Suspension
                                 1n 2.5% gelatin

Nickel metal       Rats         Subdermal Implant, 4 pellets
 (pellet)           Wistar       of 2 mm
                                                                  4/17 rats with tumors
                                                                   1 squamous cell
                                                                   carcinoma, 3
                                                                   osteosarcomas

                                                                  No tumors
                         Hueper, 1952
                         Hueper, 1952
28% of treated rats      Hueper, 1955
 with tumors of Injected
 thighs, compared to 0%
 1n control rats

1/6 rabbits with              "
 flbrosarcomas
                                                                          No tumors
                                                                          No tumors
                                                                          7/25 rats with tumors
                                                                          No tumors
                                                                          No tumors
                                                                          5/10 rats, sarcomas
                                                                            around  pellet
                         Mitchell et al., 1960
                                                                     (continued on following page)

-------
                                                TABLE 8-18.   (continued)
Nickel Compound
Nickel metal
(powder)
Nickel metal
(powder)
Nickel metal
(powder)
Nickel metal
(powder)
Animal
Rats
NIH
Black
Rats
Hooded
(female)
Rats
Fischer
Rats
Fischer
Route , Dose
Intrapulmonary, 4 mg/rat
Intramuscular, 28.3 rag
1n 0.4 ml fowl serum
Intramuscular, 50 mg
Intramuscular, 5 monthly
Injections of 5 mg N1 1n
Tumor Response
1/14 rats with sarcoma
of Injection site In
In 18 months
10/10 rats with local
rhabdomyosarcomas
66% rats with sarcomas
38/50 rats with
flbrosarcomas
Reference
Hueper and Payne,
Heath and Daniel,
Haro et al . , 1968

1962
1964

Furst and Schlauder, 1971
Nickel metal
 (powder)
Nickel metal
 (powder)
Nickel metal
 (powder)
Nickel metal
 (powder)

Nickel metal
 (powder)
                   Hamsters
Rats
 Fischer
Rats
 Fischer
Rats
 Sprague-
 Dawley

Rats
 Fischer

Rats
 Fischer
                                 0.2 ml  tHoctanoln
Intrapleural,  5 monthly
 Injections of 5 mg N1  1n
 0.2 ml  saline

Intramuscular, nickel  1n 0.5 ml
 penicillin G  Procaln

 3.6 mg/rat
 14.4 mg/rat
Intrarenal,  5 mg and 10 mg
Intrarenal,  7 mg
Intramuscular, 14 mg
2/50 hamsters with            "
 flbrosarcomas

2/10 rats with pleura]   Furst et al., 1973
 mesothellomas
                                                                  0/10 rats with local
                                                                   tumors
                                                                  2/10   "   "   "   "
                                                                        Sunderman and Maenza,  1976
No cancer of the kidney  Jasmin et al., 1979
0/18 rats with renal     Sunderman et al., 1984
 tumor

65% rats with sarcomas   Sunderman, 1984a

-------
     As noted above,  some species,  strain, and route of administration differ-
ences were observed. Both the intramuscular and intravenous routes (Furst and
Schlauder, 1971;  Hueper, 1955)  showed that rats  are more susceptible than
hamsters, rabbits,  or  mice.  Sunderman  and Maenza  (1976) have  observed a
dose-response relationship  using the  intramuscular route of administration.
The route of  administration and tumor production seem to follow a ranking of
intramuscular > intrapleural :> intrafemoral >  intrarenal > intravenous.
8.2.2.3  Nickel Oxide.   The carcinogenicity of nickel (II) oxide in experimental
animals has not been well studied.  The  inhalation  studies have  been  reviewed
in section 8.2.1.1 of this chapter.   While the results of Wehner et al.  (1975)
showed no significant  carcinogenic  effects from nickel oxide exposures alone
or in  conjunction  with cigarette smoke,  it is difficult to determine if this
was a consequence of the animal  model  used (Syrian golden hamsters).   Horie et
al. (1985) reported  the observation of one lung adenocarcinoma out of 6 rats
sacrificed 20  months after  a one-month exposure to 0.6 mg/m  of NiO aerosol.
The significance  of  this later  study is uncertain because of the limitations
of the experiment design.   Intratracheal  injection studies (Parrel 1 and Davis,
1974;  Saknyn  and  Blohkin, 1978)  gave  negative to  equivocal results.   However,
nickel oxide  was  tested to be carcinogenic in  five intramuscular injection
studies  (Oilman,  1962,  1965,  1966;  Payne,  1964; Sunderman, 1984a), with  tumor
incidence ranging  from 5 to 93 percent,  dependent upon the dose and  species
and strain of animal used.   It  should be noted  that controls were not used  in
some  of  these studies.   Nickel  oxide was  also  carcinogenic  by  intrapleural
injections, with  an  activity that approached  that of nickel subsulfide  (Skaug
et al.,  1985).  It has  not been  tested to be carcinogenic by intrarenal  injec-
tions  (Sunderman  et al., 1984).  These  data  are  summarized in  Table 8-19.
Taken  together,  the  data supports the evaluation  of nickel  oxide as having
limited  evidence  as  an animal carcinogen.  Nickel (III)  oxide (Ni'203) has not
been  tested  to be carcinogenic  in two intramuscular injection  studies (Payne,
1964;  Sosinski,  1975).   But the Sosinski  (1975) study  gave a marginal (2/40)
tumor  response by  intracerebral  injections.
8.2.2.4   Nickel  Refinery Dusts.   Nickel   refinery  flue  dust  (^ 20 percent
NiSO., 57 percent  Ni-Sp,  6.3 percent  NiO)  was tested  for carcinogenic potential
by Oilman and Ruckerbauer  (1962).   They found  the  refinery flue  dust to be  a
strong inducer of injection site sarcomas in  rats and mice.   According to a
review by Rigaut (1983), Fisher et al.  (1971)  tested the carcinogenicity of
                                   8-116

-------
                              TABLE 8-19.  EXPERIMENTAL STUDIES OF  NICKEL OXIDE CARCINOGENESIS
    Nickel  Compound   Animal
                   Route,   Dose
                                  Tumor Response
                              Reference
00
    Nickel  oxide dust
     (N10),  0.3 pm
     Baker  Analyzed
     reagent
    Nickel  oxide
     (N10)  aerosol
     Soekawa Chem Ind
     Japan
    Nickel  Oxide
     (N10)
     Herok  PA
Hamsters
 Syrian
 golden
(male)
 5 animals/
 group
Rats
 Wlstar,
 (male)
Rats
 Wlstar
 (male)
    N10
     (green-grey)
     Matheson,  Coleman
     & Bell

    N10
     (green)
Rats,
 Fischer
 344 (male)
1.  Inhalation, 53.2 rag/m
 life span exposure at 7 hr/day,
 5 days/wk + sham-smoke
2.  + cigarette smoke 10 minutes
 2 x before and 1 after the
 7 hr dally exposure
3.  Sham-smoke + sham dust
4.  Smoke + sham dust

Inhalation, 0.6 mg/m  and
 8 mg/m  6 hrs/day, 5 days/wk
 for 1 month
Intrapleural Injection,
 1 x 10 mg 1n 0.4 ml saline
Intramuscular Injection
 14 mg N1/rat 1n 0.3-0.5 ml
 1:1 glycerol-water or procain
 penicillin G suspension
Rats,        Intrarenal  Injection
Fischer       7 mg N1/rat 1n 0.1 or 0.2 ml
 344 (male)   of vehicle 0.14M NaCI (or
              glycerol)  and water 1:1
                         Wehner et al., 1975
                         Horle et al., 1985
2 osteosarcomas
2 osteosarcomas
 and 1 rhabdomyosarcoma
1 pulmonary adeno-
 cardnoma 1n 6 rats
 of the 0.6 mg/m
 exposure group after
 20 months.

31 of 32 rats with
 sarcomas (mostly
 rhabdomyosarcomas)
 after 30 months

5 of 32 rats with
 tumors in controls
 (no rhabdomyosarcomas)
14 of 15 rats with sar-  Sunderman, 1984a
 comas (* 50% rhabdomyo-
 sarcomas)
                         Skaug et al.,  1985
                                  No tumors observed
                                   1n 12 rats
                         Sunderman et al., 1984
                                                               (continued on following page)

-------
                                                      TABLE 8-19.  (continued)
00

I—1
I—1
CO
Nickel Compound
N10 particles
(0.5 to 1 urn)
N10
Animal
Hamsters
Syrian
Mice
Swiss
Route, Dose
Intratracheal , 30 wkly
Injections of 0.2 ml of a
2g N10 1n 100 ml 0.5% gelatin
1n saline (120 mg total)
Intramuscular Inplant,
5 ing
Tumor Response
1 respiratory tumor 1n
1n 50 hamsters
compared with 4 1n 50
carbon dust group
5 rhabdomyosarcomas and
16 flbrosarcomas 1n 50
Reference
Parrel 1 & Davis,
1974
Gil man, 1965
N10



N10


N10



N10


N10


N10
      N1,0,
       (black oxide)

      N1203
       (black oxide)
                          Rats, VHstar  Intramuscular, 20-30 mg
                          Mice, Swiss        "     5 mg
                          Rats, Fischer     "     20-30 mg
Rats
 NIH Black

Rats
 Wlstar
                         Mice
                          .Swiss

                         Mice
                          C3H

                         Rats
                          albino
                   Rats
                    NIH Black

                   Rats
                    Wlstar
                    (male and
                    female)
Intramuscular Implants,  7 mg


Intramuscular Injection,  20 mg
 mice (no controls used)

65% rats with sarcomas
66%    u      "
 5%    "      "

4 sarcomas In 35
 rats after 18 months

26 local tumors 1n 32
 rats (80%) (no
 controls used)
G11man, 1966



Payne, 1964


Oilman, 1962
             Intramuscular Injection,  5 mg     35% mice with tumors     Oilman, 1962


             Intramuscular Injection,  5 mg     23% mice with tumors     Gllman, 1962
             Intratracheal,  20  to  40  nig/rat



             Intramuscular Implant, 7 mg


             Intramuscular Implant, 10 mg

             Intracerebral,  3 mg
                                  1/20  rats with  squamous  Saknyn and Blohkln,  1978
                                   cell  carcinomas           as reviewed by Sunderman,
                                                            1981

                                  0/35  after  18 months      Payne, 1964
                                  No  tumors  1n  20 male
                                  and 20 female rats
                                  1  sarcoma, 1 menlngloma
                         Sos1nsk1, 1975

-------
refinery dust (59 percent Ni-Sp, 20 percent NiSO., 6.3 percent NiO) in rats by
inhalation.   The refinery dust was one of 6 types of dust exposures administered
to 348 rats,  and  11 pulmonary tumors were observed for the combined refinery
dust, synthetic dust,  Ni3$2  and FeS groups. Kim  et al.  (1976) indicated the
observation of one lung cancer in 60 rats exposed by inhalation.
     Sunderman (1981)  reviewed  the carcinogenesis  studies of nickel from 1975
to 1980  and  reported on a study  by  Saknyn and Blohkin  (1978), who  used  a
feinstein dust (an intermediate product of nickel refining which  contains  NiS,
NiO,  and metallic nickel) at a level  of 70 mg dust/m , 5 hours/day, 5 days/week
for 6 months.  Squamous cell  carcinomas were found in 2 of 5 rats  which survived
the treatment.  Saknyn and Blohkin (1978) also treated albino rats by intraperito-
neal  injections with  feinstein  dust at a dosage of 90 to 150 mg/rat.   Six of
39 rats developed injection site sarcomas.
     The Rigaut (1983) report also reviewed an inhalation study by Belobragina
and Saknyn (1964)  on  rats exposed to  nickel  dust from roasting  (31 percent
Ni'3S2,  33.4 percent NiO + SiO^ and oxides of iron and aluminum).   At 80 to 100
mg/m  5  hr/day  for 12 months, no tumors were found.   A summary of these data
is included in Table 8-20.  The data seem to indicate that some nickel refinery
dusts are potentially  carcinogenic,  but further  studies are  needed  to more
fully understand their carcinogenic activities.

8.2.2.5  Soluble and  Sparingly  Soluble  Nickel Compounds.   The  soluble nickel
compounds—nickel sulfate (NiSO.), nickel chloride (NiCK), and nickel acetate
(Ni(CH300)2)  -- have  received a limited amount of study, and the  findings  are
summarized in Table 8-21.
     Nickel acetate was  studied for carcinogenic potential by Payne  (1964),
Haro et  al.  (1968),  Schroeder et al. (1964, 1974), and Stoner et  al.  (1976).
Haro et  al.  (1968) observed  that 22 percent  of  the rats developed sarcomas
when injected intramuscularly with nickel acetate. The  observation  of lung
adenomas and adenocarcinomas (significant for the 360-mg/kg group) in Strain A
mice receiving intraperitoneal injections are particularly interesting because
their presence  demonstrates  that  soluble nickel  compounds  are capable of
inducing tumors  in animals.   Other  injection studies  have  shown negative
results, and the drinking water studies of Schroeder et al.  (1964) and Schroeder
and Mitchener (1975) are inadequate to draw any firm conclusions.
     Another  soluble  nickel  compound,  NiSO^,  has been tested, mainly via  the
intramuscular route  (Gllman,  1962, 1966;  Payne,  1964;  Kasprzak et  al.,  1983),
                                   8-119

-------
            TABLE  8-20.  EXPERIMENTAL  CARCINOGENESIS STUDIES OF NICKEL REFINERY  AND OTHER  DUSTS
oo
i
i—"
PO
o
Nickel Compound
Nickel refinery
flue dust
(20% N1SOA.
57% N1,S,"
6.3% NT(T
(Source: Fort
Calborne, Canada)


Refinery dust
(59% N1-S,,
20% NISO.f
6.3% N10J
Nickel refinery
dust (24.1%
N1SO., 68.7%
7.2JTN10)
Metallic nickel
dust, hematite,
and pyrrhotlte
Animal
Rats


Hooded
Wlstar

Mice

Rats

Rats
Wlstar




Route , Dose
Intramuscular, 20 or 30 mg
one or both thighs




Intramuscular, 10 mg
each thigh
Inhalation, 5-15 mg/m3

Inhalation, 2.1 ± 0.2 mg N1/m3
2.1 + 0.2 mg N1/m,
1.9 + 0.2 mg Fe/mJ



Tumor Response Reference



52/66 rats with Gil man and Ruckerbauer, 1962
sarcomas
8/20 rats with
sarcomas
23/40 mice with Gllman and Ruckerbauer,
sarcomas 1962
11 pulmonary tumors In Fisher et al., 1971
refinery dust, synthetic as reviewed by Rlgaut, 1983
dust N1,S., FeS groups
1/60 rats with lung K1m et al. , 1976
cancer




          Nickel  dust  from    Rats
           roasting
           (31% N1.S»,
           33.4%  NTO**
           S10- and oxides
           of iron  and
           aluminum)

          Dust from          Rats
           electric furnaces
           (95% N10)

          Felnsteln dust
             Inhalation,  80-100 mg/mj
              5 hrs/day,  12 months
No cancers
Belobraglna and Saknyn, 1964
 as reviewed by Rlgaut, 1983
             Inhalation, 80-100 mg/ni
              5 hrs/day, 12 months
No cancers
Belobraglna and Saknyn,  1964
 as reviewed by Rlgaut,  1983
Rats         Inhalation, 70 mg dust/m          2 of 5 surviving rats    Saknyn & Blohkln, 1978
 (albino,     5 hr/day, 5 days/wk for 6 months  with squamous cell       as reviewed by Sunderman,
 nonpedlgree)                                   carcinomas                1981
            IntrapeMtoneal  Injection         6/39 rats  with           Saknyn and Blohkln, 1978
             90-150 mg dust/rat                Injection site  sarcomas   as  reviewed by Sunderman,
                                                                        1981

-------
               TABLE 8-21.   EXPERIMENTAL CARCINOGENESIS  STUDIES OF  SOLUBLE  AND  SPARINGLY  SOLUBLE  NICKEL COMPOUNDS
00
I
Nickel Compound
Nickel acetate
[N1(CH3COO)2]
N1(CH-.COO),-4H,0
O £. c.
N1(CH3COO)2
anhyarous
N1(CH3COO)2
N1(CH3COO)2
Nickel sulfate
N1S04
n
"
"
Nickel sulfate
N1S04 ' 6H20

Animal
Rats
Fischer
Rats
NIH Black
Rats
NIH Black
Mice
Swiss
Mice
Strain A
Rats
Wlstar
Rats
Fischer
Rats
NIH Black
Rats
Wlstar
Rats
Wlstar
Dogs
beagle
Route, Dose
1. m. Injections, 35 mg/kg
monthly for 4-6 months
(trloctanoln as vehicle)
1. m. Implant, 7 mg
n n n
Ingestlon (drinking water),
5ppm
Intraperltoneal , 24 Injections
3/week at 72,180,360 mg/kg
1. m. Injection, 5 mg
1. m. Injection
Muscle Implant, 7 mg
1. m. Injection, 66 umole/rat
15 x 4.4 umole doses
Ingestlon 1n solid food
0,100,1000 and 2500 nickel
as nickel sulfate
Tumor Response
22% rats with sarcomas
1/35 rats with sarcomas
0/35
No treatment-
related tumors
Lung adenomas and
adenocarclnomas
(significant for
360 mg/kg group)
No tumors
No tumors
1/35 rats with
Injection site sarcomas
0/20
No tumors
0/6 dogs with tumors
from all dosage groups
Reference
Haro et al. , 1968
as reviewed by Rlgaut,
Payne, 1964
n M
Schroeder et al . , 1964
Schroeder and Mltchener
Stoner et al., 1976
Gllman, 1962
Gllman, 1966
as reviewed by Rlgaut,
Payne, 1964
Kasprazak et al . , 1983
Ambrose et al. , 1976
n n

1983


, 1975


1983




                                                                (continued on following page)

-------
                                                    TABLE 8-21.   (continued)
    Nickel Compound    Animal
                   Route,  Dose
                                  Tumor Response
                              Reference
ro
ro
    N1C1.
    N1CO-
    N1(OH)2, air
     dried gel
Rats
 NIH Black

Rats
 NIH Black
    Nickel hydroxide   Rats
     (form not          Wlstar
°°    specified)
Rats
 Fischer

Rats
 Wlstar
    N1(OH)2 crystalline   "
Muscle Implant, 7 mg
Muscle Implant, 7 mg
             1.  m.  Injections,  bilateral
              5 mg/th1gh
1.  m.,  120 umole
0/35
Payne, 1964
 as reviewed by IARC, 1976
4/35                     Payne, 1964
 Injection site sarcomas
                                  48% local sarcomas
                                   (19 of 40 sites)
5/19 rats with
 sarcomas (2 meta-
 stasis to lung)

3/20 rats with
 sarcomas (1 meta-
 stasis to lung)
                         Gllman, 1965, 1966
                          as reviewed by Rlgaut, 1983
                          or Oilman and YamasMro, 1985
Kasprzak and Po1r1er, 1985
    N1(OH)2 colloidal
                                               0/13

-------
and no treatment-related  tumors  have been observed.   Payne (1964) did report
one sarcoma of 35 rats receiving NiSO. by muscle implant.   In the only ingestion
study by  Ambrose et al.  (1976),  no  tumors were observed  in  rats or dogs.
     Payne (1964) is the  only  investigator to have studied the carcinogenesis
of nickel  chloride  using muscle  implants.   None of the 35  NIH  black rats
receiving 7 mg of nickel chloride developed sarcomas.
     For the sparingly soluble nickel compounds, both nickel  carbonate (NiC03)
(Payne,  1964) and nickel  hydroxide (Ni(OH)?) in the crystalline, dried, and
colloidal forms have been studied (Gilman, 1965, 1966;  Kasprzak et al., 1983).
Payne (1964) observed 4 of 35 rats with sarcomas after muscle implants of 7 mg
nickel carbonate/rat.
     Gilman  (1965,  1966) observed the development of  local  sarcomas in 48
percent of rats receiving nickel  hydroxide (form not specified) intramuscularly.
Kasprzak et  al.  (1983)  further studied the  effect of  the  physical  state of
Ni(OH)? on carcinogenic  activities  and found that intramuscular injection of
120 umole of the dried gel  gave  a  higher yield of sarcomas  as compared to
crystalline nickel  hydroxide.   The colloidal  form produced no sarcomas.
     The data seem to  indicate that  both  soluble and sparingly soluble nickel
compounds have the potential to  induce tumors in animals,  but these  compounds
have not been adequately tested to support a judgement of their carcinogenicity.

8.2.2.6  Specialty Nickel Compounds.   Nickelocene  is  used as a  laboratory
reagent.   It  has been  studied  only in  regard to  intramuscular injection (Haro
et al.,  1968; Furst and  Schlauder, 1971).  Fibrosarcomas,  in  particular, were
observed in rats and hamsters in these studies (see Table 8-22).
     Nickel  carbonyl was  used  as  an  intermediate in the refining  of  nickel by
the Mond process  (IARC,  1976), but  it is  also  a specialty reagent  for the
fabrication  of  nickel  alloys and in  the  manufacture  of catalysts.    Nickel
carbonyl  has been tested by inhalation (Sunderman et al.,  1957,  1959; Sunderman
and Donnelly, 1965) to be carcinogenic, producing lung neoplasms.  Because of
the high toxicity of nickel carbonyl,  the  testing regimen was around the ID™
and mortality was high.   The intravenous  injection study by  Lau et al. (1972)
produced malignant tumors at various sites. Taken together, these studies show
sufficient evidence  that nickel carbonyl  is carcinogenic to animals.

8.2.2.7  Potentiations and Inhibitions of Nickel Carcinogenesis.   In addition
to the studies of the carcinogenicity of nickel  compounds,  studies to investi-
                                   8-123

-------
                       TABLE  8-22.   EXPERIMENTAL CARCINOGENESIS STUDIES OF SPECIALTY NICKEL COMPOUNDS
       Nickel Compound    Animal
                   Route,   Dose
                                               Tumor Response
                              Reference
00
i
       N1(CO),
       N1(CO),
       Nickel carbonyl
        N1(CO)4
        Nlckelocene
        Nickelocene
        Nlckelocene
Rats         Inhalation,  1 x 30 minutes
 Wlstar       of 0.6 mg/£
                     or

             3 x 30 in1nutes/wk for life
              0.03 mg/£
             Inhalation,  3 x 30 m1n/wk for
              12 months
              0.03 mg/£,  64 rats
              0.06 mg/£,  32 rats
              1 x 0.25 mg/£, 80 rats
              controls, 41 rats
             1. v.t 6x50 ul/kg
              (9 mg N1/kg)
             Intramuscular
             1. m.  Injections, 12x12 mg
              nlckelocene 1n 0.2 ml
              trloctanoln or
              12x25 mg nlckelocene In 0.2
              ml trloctanoln
Hamsters     1. m.  Injections,  1x25 mg
              nlckelocene 1n 0.2 ml
              trloctanoln or
              8x5 mg nlcklocene 1n 0.2 ml

              trloctanoln
Rats
 Wlstar
 (male)
Rats
 Sprague-
 Dawley
Rats

Hamsters

Rats
 Fischer
1/35 rats with pulmon-
 ary adenocarclnomas,
 with metastases that
 survived 2 yrs or more
 1/8 rats with pulmonary
 adenocarclnomas with
 metastases that sur-
 vived 2 yrs or more;
 0/44 1n control

4 exposed/ 9 surviving
 lung neoplasm; 2 from
 single exposure group

0/3 surviving 1n
 controls
19/121 rats with
 malignant tumors at
 various sites 2/47
 rats with pulmonary
 lymphomas (p<0.05)

Sarcomas
18/50 rats with
 flbrosarcomas

21/50 rats with
 flbrosarcomas
 0/50 In controls

4/29 hamsters with
 flbrosarcomas

No tumors
                                                                        Sunderman & Donnelly,  1965
Sunderman et al., 1957, 1959
Lau et al.,  1972
Haro et al.,  1968
Furst & Schlauder, 1971
                                                                        Furst 4 Schlauder,  1971

-------
gate the potential  for  synergism and antagonism were also performed.  Maenza
et al.  (1971)  observed  that Ni,S?, co-administered with benzpyrene, signifi-
cantly  reduced  (30  percent)  the latency period for  sarcoma  induction by the
intramuscular route.  Kasprzak et al.  (1973) studied the effects of co-adminis-
tering  NigS^ and  benzpyrene  to rats by  intratracheal  injections. They found
that none of the  rats receiving Ni^S^ alone developed bronchial metaplasia,
while 62 percent  of rats receiving Ni.^ and  benzpyrene  and 31 percent of
those receiving benzpyrene alone developed bronchial metaplasia.
     Sunderman et al.  (1975,  1976) observed a dramatic reduction of sarcomas
(from 73  percent  to  7  percent) in Fischer rats when  manganese powder  was
co-administered with Ni-^Sp by intramuscular injections.  Furthermore, Sunderman
et al.  (1979a)  observed  the  inhibitory effects of manganese  on  Ni^S,, carcino-
genesis by  intrarenal  injections.   The  results of  the intrarenal  injection
study were  less dramatic,  however (from 75 to 32  percent).   Kasprzak  and
Poirier (1985)  found that basic magnesium  carbonate was  inhibitory to the
production of injection site sarcomas by Ni,S? in rats.  Calcium carbonate was
ineffective in  the  same  experiment.   Nickel oxide and metallic nickel  were
also investigated for synergistic effects with polycyclic aromatic hydrocarbons.
The results of these studies are summarized in Table 8-23.
     The results of the  studies on Ni_S? indicate the  synergistic and antago-
nistic  effects  of  NioSp when combined with other  agents.   The results for
nickel  oxide and  metallic nickel are, however, inadequate  to  draw any firm
conclusions.

8.2.3   Physical, Chemical, Biological, and Toxicological  Correlates of
        Carcinogenic Activities
     In addition to epidemiologic and animal studies,  investigations have been
conducted in an attempt  to correlate the physical,  chemical, and biological
properties  of  nickel compounds  with  carcinogenic  activities.   In order to
compare the relative  carcinogenic  activities  of different  nickel compounds,
the following section summarizes studies on the chemical  and biological  indices
related to carcinogenicity.
8.2.3.1  Solubilization  of Nickel  Compounds.   In  a  study  with nickel (II)
hydroxides and  nickel  (II)  sulfate,  Kasprzak et al.  (1983)  found an inverse
relationship between  carcinogenic  activity  and dissolution kinetics in human
serum,  artificial  lung  fluid,  and  ammonium acetate  buffer.  Groups  of  male
Wistar  rats received  intramuscular injections  of nickel  compounds.   The pre-
                                   8-125

-------
                    TABLE  8-23.  POTENTIATIONS  AND INHIBITIONS OF  NICKEL COMPOUNDS WITH OTHER  AGENTS
     Nickel Compound    Animal
                                     Route,  Dose
                                              Tumor Response
                                                               Reference
     N13S2 +            Rats
      bfinzpyrene (BP)
                                Intramuscular, 10 mg
                                 N13$2 ± 5 mg BP
                                              100% rats with tumors    Maenza et al., 1971
                                               all groups, N13$2 + BP
                                               group has a 30% latency
                                               reduction compared to
                                               NiS» alone
oo
r\>
cr>
     N13S2 +            Rats
      benzpyrene (BP)
N1,S, +
 manganese
Rats
 Fischer
Intratracheal,  5 mg N1
 2 mg BP
 N13S2 alone

 BP alone
 N13S2 + BP

Intramuscular,  1.2 mg
 1 mg Mn powder
 N1-S2 alone
                                        32
                                      Mn afone
                                      Controls
                                              Mn
                                                                       0/13  (0%)  rats with
                                                                        bronchial metaplasia
                                                                        4/13 (31%)
                                                                        8/13 (62%)
                                                                 22/30 (73%) rats with
                                                                  sarcomas
                                                                  1/14 (7%)
                                                                  0/14
                                                                  0/39
                                                                                          Kasprzak et al., 1973
                                                                                                Sunderman et al.,  1975, 1976
      manganese
     N13S2 +
      magnesium
                        Rats
                         Fischer
                   Rats
                    Fischer
                                Intrarenal, 10 mg
                                 6.9  mg  Mn
                                 N13$2 alone

                                 N1S + Mn
Intramuscular,  2.5  mg  N1«S«  ±
 6.3 mg (4 MgCO-,-Mg(OH),,-nfU);
                                      40.6% MgO;  Mg
                                            alone
                                                                       75%  rats with
                                                                        carcinomas  of  kidney
                                                                        32% rats with
                                                                        carcinomas  of  kidney
                                                                       Sunderman et al. , 1979a
                                               Injection site sarcomas  Kasprzak and Poirier, 1985
                                                                  70-90% rats with tumors
                                      N1~S2 + magnesium basic carbonate   25%
                                                                 (continued on  following  page)

-------
                                                  TABLE 8-23.   (continued)
Nickel Compound Animal
N10 +
Rats
Route, Dose
Intratracheal , dos
age not given
Tumor Response
5/30 rats with tumors
Reference
Toda, 1962
   methylcholanthrene  (albino)

   N10 +              Hamsters
    dlethylnltrosourea Syrian
    (DENU)             golden
oo
t—•
ro
   N10 + smoke
   Nickel metal H
     fly ash  (FA)
    N1SO. +
     ethylnltrosourea
     (ENU)
             Intratracheal,  4  mg N10 wkly
              for 30 weeks,  0.25mg DENU
              subcutaneously weekly for
              12 weeks
              N10 alone
              DENU alone
              N10 + DENU
              Controls
Hamsters
 Syrian
 golden
 (51 animals/ N10 +
 group)       N10
Inhalation,  53.2 mg/trf
 ± cigarette smoke
                                          sham smoke
                                        + cigarette smoke
   Nickel metal
    (powder) +
   methylcholanthrene
   (MC)
Rats
 (albino)
Hamsters
 Syrian
 golden
 Sham dust + sham smoke
 Sham dust + cigarette smoke

Intratracheal,  10 mg N1 ± 5mg MC

 N1 alone
 MC alone
 N1 + MC

Inhalation, 6 hrs/day,
 5 days/wk for 4-14 wks
 nickel enriched fly ash (NEFA)
 NEFA 17 mg/m,
 NEFA 70 mg/m^
 FA   70 mg/m
 Controls
                                                                     0     rats with nasal tumors
                                                                     3/200   	      "
                                                                     4/50    "    "    "      "
                                                                     Q       II    II    II      II
                                                                Farrell and Davis, 1974
                              Wehner et al., 1975
No effect
2 osteosarcomas
2 osteosarcomas +
1 rhabdomyosarcoma
no tumors
no tumors
                                               0   rats with epldemold tumor Mukubo, 1978
                                               2/7  "    "      "        "     as reviewed by
                                               3/5  "    "      "        "     Sunderman, 1981
                                               4 cancers (none pulmonary)
                                               3 cancers (2 pulmonary)
                                               3 cancers (none pulmonary)
                                               4 cancers (none pulmonary)

                                               Increased tumor
                                                obtained by ENU
                                                                                                   Wehner et  al.,  1981
                                                                Ivankovlc and Zeller, 1972
                                                                 Zeller and  Ivankovlc, 1972
                                                                 as reviewed by Rlgaut,
                                                                 1983

-------
dominant tumors observed were  injection  site pleomorphic rhabdomyosarcomas.
Frank hematuria was observed in all  of the rats dosed with colloidal  nickel(II)
hydroxide and  seven  of  these animals dyed during the first two months of the
study.   One  rat  receiving  air-dried nickel(II) hydroxide died with hematuria
during the  first  week  of the study.  Histological examination of the kidneys
of the  rat  revealed  acute  renal  inflammation with numerous foci  of glomerular
and  tubular necrosis.   The dissolution  rates  of the compounds  tested were
different in the  three  media used,  but the order of  the  dissolution  rates was
inversely related to carcinogenic activity.
     Cellular uptake and solubilization of particulate nickel compounds appears
to play an  important mechanistic role in nickel-induced carcinogenesis.  Costa
and  Mollenhauer  (1980b) have  shown that  crystalline  nickel  subsulfide is
actively phagocytized  by  cultured  Chinese hamster  ovary  (CHO)  and Syrian
hamster embryo  (SHE) cells.  In  contrast,  no active  phagocytosis was  observed
in cells exposed to  amorphous nickel monosulfide.  Costa et al.  (1981b) observed
phagocytized nickel  particles  in the cytoplasm  of CHO  and SHE cells.   These
particles were solubilized  to  a form capable of entering the nucleus and
interacting with nuclear macromolecules  (Costa et al., 1981b).
     The effect  of particle size on  the toxicity and  phagocytosis of metal
compounds further  substantiates  the hypothesis that  the  biological  effects  of
insoluble metal  compounds  are preceded  by,  and are  probably  dependent  on,
phagocytosis.   Costa et al. (1981a) have  shown  that particles of crystalline
NiS  having  mean diameters  of 2  to  4 urn  were phagocytized six  times more than
NiS  particles  having mean  diameters of  5  to 6 urn.   In  contrast, the size  of
the  particle had  no effect on  the  phagocytosis of  amorphous NiS.   Recent
studies by  Costa  and Mollenhauer (1980a,b) demonstrate that crystalline CoS  is
similarly a potent  inducer of morphological transformation in  CHO cells, while
amorphous CoS  lacks  such activity.   Since  crystalline CoS is  actively  phagocy-
tized  and  amorphous CoS is  not,  these  results tend  to  support  the  effects
noted  with  nickel  and may  be characteristic  of other metals as well.
     The  crystal  structure of the  nickel  compounds  appears  to be one of the
factors  affecting the  biological activity of  these  compounds.  Costa et al.
(1981a)  studied seven  particulate nickel compounds  in  regard to their ability
to induce  morphological transformations in  SHE  cells  and to  phagocytize  in
CHO  cells.   Crystalline Ni^, NiS, and Ni3Se2 were  significantly more active
in inducing cell  transformations  and were more actively  phagocytized than
amorphous  NiS, metallic Ni, Ni203,  and NiO.   Intracellular uptake and distri-
                                    8-128

-------
bution of crystalline  NiS  particles  appear to occur by normal endocytic and
saltatory processes  during the  formation  and breakdown of macropinosomes.
Using time-lapse video microscopy, Evans et al.  (1982)  recorded the endocytosis
and intracellular distribution  of crystalline NiS in CHO cells.   Crystalline
NiS particles were phagocytized  by CHO  cells  in regions of membrane ruffling.
While these particles  remained  bound to the cell  surface for periods  ranging
from minutes to hours, cellular uptake generally required only 7 to 10 minutes.
Endocytosed crystalline NiS particles  exhibited saltatory motion.   Lysosomes
were observed to repeatedly interact with the NiS particles in a manner similar
to the digestion  of  macropinosomes.   NiS particles were never observed to be
exocytosed from the CHO cells.   Over time,  most of the  particles aggregated to
the region  of  the nucleus, with  vacuoles  forming  around the particles.  The
observed lysosomal interaction with phagocytized cytoplasmic NiS may accelerate
dissolution of particulate nickel, allowing the entry of ionic Ni(II)  into the
nucleus.   Studies by  Abbracchio  et al.  (1982) suggest that the dissolution of
phagocytized crystalline NiS  particles  is  accelerated  by several cytoplasmic
events.    Lysosomal  interaction  appears  to  be the most predominant factor,
since the acidic  pH of  lysosomes  could  enhance the dissolution of  crystalline
NiS particles.
     Kuehn  and  Sunderman   (1982)  determined the  dissolution  half-times of
seventeen nickel compounds in water, rat serum,  and renal cytosol.   Concentra-
tions of  dissolved  nickel  were analyzed by  electrothermal atomic  absorption
spectrophotometry, and  dissolution  half-times were computed using  a Weibull
distribution.   Ni, NiS, amorphous NiS, Ni^Sp, NiSe, Ni^Se^, Nile, NiAs, Ni-,-,ASg,
NirAsp,  and Ni.FeS, dissolved more  rapidly  in serum  or  cytosol than in  water.
No detectable dissolution was observed for NiO,  NiSb, NiFe alloy, or NiTiO., in
any of the  media.   The dissolution  half-times of  Ni.,Sp  in serum and cytosol
are in close agreement with the excretion half-time of 24 days in urine follow-
                                 c o
ing  intramuscular injection of    Ni^Sp in  rats  (Sunderman  et al., 1976).
These data  suggest  that J_n vitro dissolution half-times of  nickel  compounds
may be used to predict J_n vivo  excretion  half-times,  since the dissolution
process is the rate-limiting step of distribution and excretion.
8.2.3.2   Phagocytosis of Nickel  Compounds.    Costa  et al. (1982)  reported that
crystalline NiS particles were actively phagocytized and induced morphological
transformation in Syrian hamster  embryo (SHE) cells  in a concentration-dependent
manner.   In contrast, amorphous NiS was not actively phagocytized by SHE cells
and was  relatively  inactive  in  inducing morphological  transformation at both
                                   8-129

-------
cytotoxic and noncytotoxic concentration levels.  Chemical reduction of posi-
tively charged amorphous  NiS  with LiAlH. resulted in active phagocytosis and
increased morphological transformation  of  exposed SHE cells.   In experiments
with Chinese hamster  ovary  (CHO)  cells, Costa et al. (1982) found that only
crystalline, not  amorphous,  NiS caused strand breaks in  DMA.   Phagocytized
inert particles  such as  latex  beads did not induce  transformation  or DNA
damage,  suggesting that genotoxic dissolution products  such as Ni(II) rather
than the  phagocytized particles  are  responsible  for the observed cellular
transformation and damage to DNA.   In these experiments, NiCl2 was one-third to
one-half as potent in inducing cellular transformation as compared to crystalline
NiS on a weight basis.  These results  suggest a correlation between  selective
phagocytosis of nickel compounds and their ability to induce cellular transfor-
mation.
     Entry  of nickel  sulfide  particles into cells appears  to  be related to
surface charge and to the degree of negative charge on the surface microenviron-
ment.  Heck and Costa (1982)  found  that the  incidence of  morphological trans-
formation of SHE  cells following exposure to crystalline NiS  particles  was
significantly greater than  that following  a  similar  exposure to  amorphous  NiS
particles.  They attributed the differences in potency to the selective phago-
cytosis of  crystalline NiS  particles into the  SHE cells, since  no uptake  of
amorphous NiS was  observed.   Chemical  reduction of  amorphous  NiS and  LiAlH^
resulted  in an  increase in phagocytic  uptake by CHO cells and an increase in
morphological transformation in SHE cells.  The phagocytosis and  morphological
transforming activity of  crystalline NiS was  also  increased  by reduction with
LiAlH..  These results are consistent with the hypothesis that the transforming
activity  of particulate metal compounds is proportional  to  their uptake  by
phagocytosis.   Studies by Abbracchio  et al.  (1981,  1982) have  demonstrated
that  crystalline  NiS  particles have a negative surface  potential  (-28  mV)
while amorphous  NiS  particles have  a  positive  surface  charge (+9 mV).  The
negative  surface  charge of crystalline  NiS appears  to be directly related to
cellular  uptake  by phagocytosis.   The  extent of  phagocytosis  of crystalline
NiS  particles  is  not affected  by the  components of  the tissue culture medium
used  (Abbracchio  et  al.,  1981).   Altering  the particle  surface of both crystal-
line  and amorphous NiS by  reduction  with  lithium aluminum hydride  enhanced
phagocytosis  by CHO  cells  and,  in the case  of amorphous NiS,  resulted in
induction of morphological  transformation  of  SHE cells.   Heck  and Costa  (1983)
have  found  that crystalline NiS,  Ni^, and  NiO, which  are carcinogenic by the
                                    8-130

-------
intramuscular  injection  route,  exhibit strongly negative  surface  charges  in
distilled water  and enter CHO cells  readily  by phagocytosis.   Under similar
experimental conditions,  amorphous  NiS,  which  appears to be noncarcinogenic,
is positively  charged and not extensively phagocytized.   The greater dissolu-
tion  rate of amorphous NiS,  in comparison to crystalline NiS,  may contribute
to its  reduced cellular uptake, due  to alteration of the particle surface or
generation of  dissolution products which  inhibit cellular uptake.
     Maxwell and Nieboer (1984) reported that  the ranking of eight nickel
substances  (size <10 urn, with known  X-ray patterns)  according to hemolytic
ability  correlated  with  the external  roughness  of  the particulates as charac-
terized by scanning electron  microscopy.   Ranking (at p <0.025) of the materials
by human  serum albumin adsorption (given as  ug/mg  in parentheses) yielded a
similar reaction sequence:  colloidal  Ni(OH)2  (568 ± 13) » NiO (8.0 ± 0.5) >
Ni powder, non-spherical and  rough (4.3 ± 0.4)  > aNiS, pNiS (3.4 ± 0.2); dried
Ni(OH)2 (2.9 ± 0.1); aNi^ (2.2 ± 0.4) > Ni  powder, smooth spheres  (0.4 ± 0.1).
The authors  concluded that surface passivity of relatively insoluble nickel
compounds might be an important determinant in  nickel carcinogenesis.
     Kuehn  et  al.  (1982) measured  the relative phagocytosis  of seventeen
nickel compounds iji vitro in  monolayer cultures of rat peritoneal macrophages.
The macrophages  were  exposed to nickel particles (median diameter 1.5 urn) at
concentrations of  2 ug/ml  of medium  for  one  hour  at 37°C.  The phagocytic
index,  the  percentage of macrophages  with one  or  more engulfed particles,
ranged  from  69 percent for NiO to 3  percent  for amorphous NiS.  In  order  of
decreasing  phagocytic indices, the 17 nickel compounds  were  ranked: NiO  >
Ni4FeS4 > NiTi03 >  NiSe >  Ni3S2 >  Ni >  Ni5As2 > NiS2 > NiFe alloy > NiSb >
NlllAs8 > Nl3Se2 > NiS > NlTe > N1As > NlAsS >  amorPnous NiS.   Rank correlation
(p <0.03) was  observed  between the relative phagocytic indices of the nickel
compounds and  their dissolution half-times in  rat  serum  (Table 8-24).   The
biological  data  are  summarized  in  Table 8-25.   Data  from carcinogenicity
bioassays of 18 of the  compounds  tested  ui  vitro do not  exhibit  any rank
correlation between the phagocytic indices of nickel compounds  and the inciden-
ces of  injection site sarcomas  after intramuscular administration  to  rats
(Sunderman,  1984a).   These data are summarized  in Table 8-26.
     Costa et  al. (1981b)  performed  X-ray fluorescence spectrometry measure-
ments of metal  levels in subcellular fractions  isolated from CHO cells treated
with crystalline Ni-S-, crystalline NiS,  and amorphous NiS.  Amorphous NiS did
not significantly enter  the cells  as either phagocytized nickel  particles or
                                   8-131

-------
                  TABLE 8-24.  RANK-CORRELATIONS BETWEEN CHEMICAL AND BIOLOGICAL PARAMETERS OF NICKEL COMPOUNDS
oo
i
CO
ro
Parameters Compared by Rank
Sarcoma Incidence versus:
nickel mass-fraction
serum T50 d
cytosol T50
phagocy tic. Index
hematocrit
Hematocrlt versus:
nickel mass-fraction
serum TBO d
cytosol T50
phagocy tic Index
Phagocy tic Index versus:
nickel mass-fraction
serum T50 d
cytosol T50 b
Nickel massif ractl on versus:
serum TBO d
cytosol JSQ
Serum T50 d
Cytosol T60
No. of
Compounds
Compared

18
16
16
17
17
17
16
16
17

17
16
16

16
16

16
Kendall
Correlation
Coefficient

0.35
0.07
0.11
0.17
0.72
0.51
0.06
0.08
0.32

0.15
0.35
0.28

-0.17
-0.09

0.79
Z-Scorea

2.0
0.39
0.62
0.93
4.0
2.5
0.35
0.44
1.8

0.87
1.9
1.5

0.92
0.58

4.3
P

0.02
-
:
<0.0001
<0.01
-
-
0.04

—
0.03
—

-
~

<0.0001
       Correlation coefficient divided by Us standard error.
       Sarcoma Incidence 1n rats at two years after 1.m.  Injection (14 mg N1/rat).
      cProport1onal weight of nickel per unit weight of substance.
      Dissolution half-time during 1n vitro Incubation at 37°C (2 mg N1/ml).
      ePhagocytos1s by rat peritoneal macrophages 1n vitro (10 ug/ml).
       Mean blood hematocrit of rats at two months after 1.r.  Injection (7 mg N1/rat).
      Souce:  Sunderman (1984a).

-------
                                          TABLE 8-25.   BIOLOGICAL CHARACTERISTICS  OF NICKEL COMPOUNDS
Compound











CO
1
1 — 1
CO
CO


Nickel
Nickel
Nickel
Nickel
Nickel
Nickel
Nickel
Nickel
Nickel
Nickel
Nickel
Nickel
Nickel
Nickel
Nickel
Nickel
Nickel
Nickel
dust
oxide
dlsulflde
monosulf Ide
monosulflde
subsulflde
monoselenlde
subselenlde
tellurlde
sulf arsenide
monoarsenlde
subarsenlde
subarsenlde
an t1 won Ide
ferrosulflde
alloy
tltanate
chromate
aThe dissolution half-time
during 1n vitro Incubation
Dissolution half- Dissolution half-
Formula time In rat serum time 1n renal cytosol
N1
N10
N1S2
pN1S
Amorphous
aN13S2
NISe
N13Se2
NITe
NIAsS
NIAs
N1,,As.
N15As2
NISb
N14FeS4
N1FCl „
NITlOg
N1Cr04
HI
FP*
2.6
N1S 24
34
1.1
50
7.9
1.0
46
246
73
>11
4.5
>11
years
years

years
days
days
years
days
years
years
days
days
days
years
years
years
>11 years
NDr
represents the estimated time
(37°C, 2 mg

for dissolution of
8.4
FP*
1.4
19
21
161
88
171
1.1
14
20
110
>11
329
>11
years
years

years
days
days
days
days
days
years
days
days
days
years
days
years
>11 years
NDT
50% of

nickel -containing
Phagocytlc Index 1n Hematocrlt of rats afti
rat macrophages 1.r. Injection
19.51 5.9
69.01 18.4
16.51 6.2
7.41 6.9
3.41 2.4
28.41 6.3
32.01 6.1
8.01 4.4
6.31 5.2
4.31 2.2
4.81 5.9
8.81 2.1
17.31 5.4
13.01 3.2
43.81 10.0
16.31 6.2
36.51 7.5
NDT
particles In rat
671
721
661
711
481
741
711
671
491
611
491
501
501
491
701
491
49f
NDT
1
9
7
1
3
8
7
2
7
2
1
2
2
4
1
2

ld
U















serum or renal cytosol
Nl/ml) (Kuehn & Sunderman, 1982).
 The phagocytlc Index  represents the percentage (mean  1SD) of rat peritoneal macrophages that phagocytlzed  one or more particles during Incubation
 for 1 h at 37°C In  medium that contained nickel  compounds (10 ug/ml) (Kuehn et al., 1982).
cBlood hematocrlt (X,  mean 1 SD) 1n groups of 11-57  rats at two months after Intrarenal  Injection  of  nickel compounds (7 mg N1/rat).  The
 corresponding mean  hematocrlt 1n 79 control  rats at two months after Intrarenal Injection of vehicle was 491 3X (Sunderman & Hopfer, 1983).
 p<0.01 versus vehicle controls.
"Formation of flocculent precipitates (FP) during Incubation of nickel dlsulflde 1n rat serum and  renal  cytosol precluded measurements of Its
 dissolution half-times.
fNot determined.
Source:   Sunderman (1984a).

-------
                     TABLE  8-26.   SUMMARY OF  SURVIVAL DATA AND SARCOMA INCIDENCES  IN  CARCINOGENESIS TESTS
                                       BY INTRAMUSCULAR INJECTIONS  OF 18 NICKEL COMPOUNDS
Category
Controls
Class A
00
,L Class B
CO

Class C



Class D
Class E


Test Substance
Glycerol vehicle
Penicillin vehicle
All controls
Nickel subsulflde (aN13S2)
Nickel monosulflde (BN1S)
Nickel ferrosulflde (N14FeS4)
Nickel oxide (N10)
Nickel subselenlde (N13Se2)
Nickel sulf arsenide (N1AsS)
Nickel dlsulflde (N1S2)
Nickel subarsenlde (N15As2)
Nickel dust
Nickel antlmonlde (NISb)
Nickel telluHde (NITe)
Nickel monoselenlde (N1Se)
Nickel subarsenlde (N1nASg)
Amorphous nickel monosuTflae (N1S)
Nickel chromate (N1CrO.)
Nickel monoarsenlde (NTAs)
Nickel tltanate (N1T10,)
Ferronlckel alloy (NIFe^ 6)
Survivors at two
years/
total no. of rats
25/40
24/44
49/84
0/9Cr
0/14^
0/15^
0/15^
0/23^
0/16^
0/14^
0/20F
4/20b
9/29°
12/26
7/16a
5/16*
5/25b
10/16
13/20
11/20
11/16
(63%)
(55%)
(58%)
(0%)
(0%)
(0%)
(0%)
(0%)
(0%)
(0%)
(0%
(20%)
(31%)
(46%)
(44%)
(31%)
(20%)
(63%)
(65%)
(55%)
(75%)
Rats with local
sarcomas/
total no. of rats
0/40
0/44
0/84
9/9cr
14/14^
15/15c
21/23^
14/16^
12/14^
17/20^
13/20^
17/29C
14/26^
8/16^
8/16h
3/25b
1/16
0/20
0/20
0/20
(0%)
(0%)
(0%)
(100%)
(100%)
(100%)
(93%)
(91%)
(88%)
(86%)
(85%)
(65%)
(59%)
(54%)
(50%)
(50%)
(12%)
(6%)
(0%)
(0%)
(0%)
Median tu-
mor latency
(weeks)
30
40
16
49
28
40
36
22
34
20
17
56
33
41
72
-

Median survival
period (weeks)
>100
>100
>100.
36
58b
57b
47S
44b
42b
66b
80b
72b
88b
71b
>100
>100
>100
>100
Rats with
metastases/
rats with sarcomas
5/9
10/14
10/15
4/14
18/21
10/14
6/12
9/17
6/13
10/17
8/14
3/8
6/8
3/3
1/1
-

(56%)
(71%)
(67%)
(29%)
(86%)
(71%)
(50%)
(53%)
(40%)
(59%)
(57%)
(38%)
(75%)
(100%)
(100%)


"p<0.05 versus corresponding vehicle controls.
 p<0.01 versus corresponding vehicle controls.
 p<0.001 versus corresponding vehicle controls.

Source:  Sundermart (1984a).

-------
in a  solubilized form.   In  contrast,  the other two  nickel  compounds were
actively taken up.   Experiments with CHO cells suggest that at least 20 percent
of the  nickel measured in nuclei isolated from cells  treated with Ni'3S2  is no
longer part of a sedimentable particle with the same particle size and solubil-
ity properties as the  parent compound.   A substantial portion of the  nickel
associated with  the  nuclear  fraction coprecipitates with the trichloroacetic
acid insoluble fraction,  which suggests that nickel strongly binds to cellular
macromolecules.   Costa et al.  (1981b) found that particulate nickel  compounds
isolated from CHO cells  after phagocytosis were more cytotoxic  and induced
more morphological transformations  in SHE cells than  did the same particulate
compounds which had not been phagocytized.
8.2.3.3  Erythrocytosis Induced by Nickel Compounds.   Sunderman  et  al. (1984)
studied the association of erythrocytosis to  renal  cancers  in rats  exposed to
seventeen nickel compounds.   Erythrocytosis (defined as peak hematocrit values
that averaged >55 percent)  occurred in 9 of  17 nickel-treated groups  (NiS,,,
p-NiS, a-Ni'3S2,  Ni'4FeS4,  NiSe, Ni'3Se2,  NiAsS, NiO, Ni dust).  Renal  cancers
developed in 9  of  17 nickel-treated groups (NiS2,  p-NiS,  crNi^,  Ni^FeS^,
NiSe, Ni' Se9, NiAsS, NiAs,  NiFe alloy) within 2 years after the injections.
        «J  I.
The results of their studies are presented in Table 8-27.   Using these results
the authors concluded  that  rank correlation  (p <0.001) was observed between
the incidences of erythrocytosis  and renal  cancers in the  17 nickel-treated
groups.   Rank correlation (p <0.001) was observed between the present incidences
of renal  cancers and  the sarcoma  incidences  previously reported following
intramuscular administration  of  the 17 nickel compounds to Fischer 344  rats
(14 mg  Ni/rat).   The  incidences  of renal cancer  were  not correlated with
(1) the mass-fractions  of nickel  in the 17 compounds, (2) the  dissolution
half-times of the compounds  in rat serum or renal  cytosol, or (3) the phago-
cytic indices of the compounds in rat peritoneal  macrophages.
     Pronounced  erythrocytosis  and  reticulocytosis and expanded blood volume
occur in  rats  one to five months  after intrarenal administration  of  Ni.,S2
(Hopfer et al., 1978; Jasmin and Riopelle, 1976;  Morse et al., 1977).  Erythro-
cytosis induced by intrarenal  injection of Ni'3S2 is apparently due to enhanced
production of renal  erythropoietin  (Hopfer et al.,  1978; Solymoss and Jasmin,
1978).  Jasmin and Solymoss  (1975) reported that a single intrarenal injection
of 10 mg  of Ni-Sp in rats induced pronounced  erythrocytosis.  They  observed a
1.5-fold increase in blood erythrocyte count and a 2.4-fold increase in eryth-
                                   8-135

-------
                    TABLE 8-27.   CANCERS  IN THE INJECTED  KIDNEY  OF RATS FOLLOWING I.R.  INJECTION  OF NICKEL  COMPOUNDS
cc
i
OO
CTi
Group
A
B
C
D
E
F
G



H
I
J
K
L
M

N
0
P
Q
R
S
T
Treatment
Controls (saline)
Controls (glycerol)
Controls (Fe dust)
N1 dust
N10
N1S-
BN15 (cryst.)



N1S (amorph.)
aN1,S-
N1S8 i
N1,Se,
N1?e 2
N1AsS

NIAs
N1nAso
•14 A*-
Nllb 2
NI.FeS.
N1Fe,, (alloy)
N1Tl6°
No. of rats with
renal cancer/total
no. of rats
0/46
0/33
0/18
0/18
0/12r
2/105
8/14d



0/15d
4/15d
1/12
2/23
0/19,.
3/15c

1/20
0/15
0/17
0/20
1/12
1/14
0/19
Peak hematocrlt
(%) 1n tumor-
bearing rats





77-78
70-83




76-82
80
65-79

61-66

56


78
51
Tumor latent
period (weeks)





69-76
36-73




35-61
46
48-100

44-73

95


36
25
Rats with
metastlc .
renal cancer





1
4




4
1
2

3

0


1
0
Hlstologlcal types of renal cancers





flbrosarcoma (2)
flbrosarcoma (3), mesanglal cell
sarcoma, lelomyosarcoma, rhabdo-
myosarcoma, renal cell carcinoma,
carclnosarcoma

mesanglal cell sarcoma (4)
flbrosarcoma
flbrosarcoma (2)

carclnosarcoma, lelomyosarcoma,
undlfferentlated sarcoma
renal cell carcinoma


undlfferentlated sarcoma
nephroblastoma
     Peak hematocrlt values >55* were observed during 1-4 months post-Injection In 22 of  23 rats that subsequently developed cancer In the
    .Injected kidney; peak hematocrlt values averaged 73 + 8%  1n rats with renal cancer.
     The most frequent sites of metastases were lung, perTtoneum, liver and spleen.
     .p<0.05 versus corresponding vehicle controls (Group A or  B), computed by Fisher's exact test.
     p<0.001 versus corresponding vehicle controls (Group A or B), computed by Fischer's  exact test.

    Source:   Sunderman et al. (1984).

-------
rocyte mass five  months  following administration.   Ni-jSp-induced erythrocy-
tosis was not accompanied by alteration of erythrocyte 2,3-diphosphoglycerate
levels.   Jasmin and  Solymoss  (1975)  speculated that erythrocytosis may have
been mediated  by  increased erythropoietin levels.  Oskarsson  et al.  (1981)
evaluated the effects of nickel chloride and nickel subsulfide on the develop-
ment of erythropoiesis in female  Fischer 344 rats.  NiClp was  administered  by
a single intrarenal injection.   Ni^Sp was administered by continuous intraperi-
toneal infusion from  an  implanted osmotic minipump.   Infusion of NiClp (0.85
mg Ni per day  for 24 days) had no effect on blood hematocrit or reticulocyte
counts.   In contrast, a single intrarenal injection of Ni^S^ caused pronounced
erythrocytosis and reticulocytosis.
     Jasmin and Riopelle (1976) studied the relationship between carcinogenicity
and erythrocytosis in  female  Sprague-Dawley rats following administration of
nickel and  several other metal compounds.  When Ni,S? was administered intra-
venously, no polycythemia or renal neoplasms were observed.   Intrarenal admini-
stration of Ni-Sp, in either glycerin or saline,  rapidly caused erythrocytosis.
Hemoglobin  and  erythrocyte  values were significantly increased  in  the rats
receiving Ni-Sp intrarenally.   Renal  carcinomas were observed in approximately
40 percent of the treated animals.  In general, erythrocytosis subsided approxi-
mately eight months  after  intrarenal  injection of Ni.,Sp, even in those rats
with renal  carcinomas.   Other  nickel  salts and a  variety  of other divalent
metals failed to produce similar responses when administered by the intrarenal
route.
     Morse et al.  (1977) found that the duration and magnitude of erythrocytosis
induced by Ni.,Sp was dose-related.  Female Fischer rats received single intra-
renal injections  of Ni.,Sp  at  dosages ranging from 0.6  to 10 mg per  rat.
Administration  of Ni-Sp induced  marked  erythrocytosis at  all  dose levels
tested.    The  duration and  magnitude of  erythrocytosis  was dose-related.
Maximum erythrocytosis was  observed approximately  two months after  intrarenal
administration.   This  study also  demonstrated  that intramuscular injection  of
NigSp did not  cause  erythrocytosis  at a dose  of  10  mg/rat.   The failure of
erythrocytosis  to develop  after  intramuscular injection  is  consistent with
                                                                  CO
kinetic studies which  show that after intramuscular  injection of   Ni-S«  in
      63
rats,   Ni(II)  is slowly mobilized from  the site of injection  and excreted  in
the urine (Sunderman et al., 1976).
     Gitlitz et al. (1975)  found that proteinuria was induced in female Fischer
rats after  a  single  intraperitoneal  injection of  NiClp  in  dosages of 2 to
                                   8-137

-------
5 mg/kg.   Generalized craminoaciduria was found after a single intraperitoneal
injection of 4 to 5 mg/kg of NiCl?.  Amino acids in the plasma were normal or
slightly diminished from 1 to 48 hours after administration of Ni(II).   Electron
microscopy of kidneys of five rats sacrificed 48 hours after receiving 68 pmol/kg
of Ni(II) revealed  fusion  of foot processes of glomerular epithelial cells.
Focal tubular necrosis was present in the kidney of one of the rats examined.
The proteinuria was probably due to glomerular injury.  Aminoaciduria may have
been due  to  inhibition of ami no acid transport systems located in the luminal
and/or peritubular  membranes of  the  renal  tubules  and increased excretion of
nickel-histidine chelate, one of several ultrafilterable complexes involved in
the renal excretion of Ni(II).

8.2.3.4   Interaction of Nickel Compounds with DMA and Other  Macromolecules.
     There is little  information  on  the mechanism of nickel interaction with
cellular  nucleic  acids.   Recent  studies have shown  that  nickel  can cause
DNA-protein  crosslinks and  DMA  strand breaks.   The work of Si rover and  Loeb
(1976) has  shown that metals can  cause a  decrease in the  fidelity  of  DMA
transcription.   Robison  et al.  (1982)  have  shown that NiClp  and crystalline
NiS produce  DMA  strand breaks in  CHO cells, while amorphous NiS has no effect
on DMA.   Exposure  to activated charcoal, which was actively phagocytized,  had
no effect on the DMA of CHO cells.  The effect of NiCU and  crystalline NiS
was both  time-  and concentration-dependent.   Robison and  Costa (1982) found
that both NiCl2  and crystalline NiS induced strand  breaks  in the DNA of CHO
cells  at concentrations  which did not  significantly  impair normal  cellular
division.  Crystalline Ni-jS,,, NiCl?,  and NiS have been shown to induce concen-
tration-dependent DNA repair in CHO cells (Robison et al., 1983).   In contrast,
amorphous NiS did not induce DNA repair  under similar experimental conditions.
     Nishimura and  Umeda (1979) studied  the effects of nickel chloride,  nickel
acetate,  potassium  cyanonickelate, and nickel  sulfide in a line of C3H  mouse
mammary  carcinoma  cells.   All  four compounds  were  readily taken up by  the
cells and reacted with protein, RNA,  and possibly DNA.  Measurements of  leucine,
uridine,  and thymidine  uptake during exposure showed that the  synthesis  of
protein  and  DNA was more extensive than  that of RNA.  NiCl2,  Ni(CH3COO)2,  NiS,
and  K2Ni(CN).  induced  chromosomal  aberrations  consisting  of gaps, breaks,  and
exchanges.   Ciccarelli  et  al.  (1981) observed dose-dependent lesions  in DNA
 isolated  from  kidney nuclei  obtained from  rats 20  hours after intraperitoneal
 injection of NiC03.  DNA strand breaks  and DNA-protein crosslinks were observed.
                                   8-138

-------
Ciccarelli and  Wetterhahn  (1982) observed single strand  breaks  in lung and
kidney nuclei and  both DNA-protein and DNA  interstrand crosslinks in  kidney
nuclei isolated from rat tissues following intraperitoneal injection of NiCO~.
     A correlation was observed between tissue and intracellular nickel concen-
trations  measured  by electrothermal atomic  absorption  spectroscopy and the
level of  DNA  damage  and  repair.  NiCCL  had no  effect  on DNA  isolated from  the
nuclei of  liver or thymus.  The ability  of  nickel to interact with cellular
macromolecules and its demonstrated organotropic effects on DNA i_n  vivo may be
related to  its  carcinogenic effects.   Nickel(II) may be directly  responsible
for  the  DNA-protein crosslinks  because  in  aqueous  solution, nickel(II) is
multifunctional, forming octahedral  complexes  (Cotton and Wilkinson,  1980).
Nickel sulfide  caused spindle  fiber  abnormalities in  cultured  rat embryo
muscle cells  (Swierenga  and Basrur, 1968) and  cylindrical  laminated bodies in
the  contractile proteins of rabbit rhabdomyosarcomas  (Hildebrand and Biserte,
1979b).
     Many studies  have shown that  nickel(II) is  capable of binding to  protein
as well as  DNA.  The formation  of  soluble complexes between  nickel(II), serum
albumin,   and  serum  ultrafiltrates  has  been observed in  rats administered
nickel chloride (Decsy and Sunderman, 1974; Van Soestbergen and Sunderman,
1972; Asato et  al.,  1975).   Purified serum albumins  from  rabbits,  rats, and
man  have  been found to bind nickel(II)  (Callan  and  Sunderman,  1973).   Rao
(1962) reported a strong  interaction between  nickel(II)  and the  imidazole
groups of bovine serum albumin histidine residues, and a weak interaction with
carboxylate groups.  Tsangaris  et  al.  (1969) have found a strong  interaction
between nickel(II)  and the  ami no-terminal residues  and imidazole  group of
histidiae residues,  and  a  weak interaction between nickel(II) and the sulf-
hydryl groups of  cysteine  residues.   Lee et al.  (1982)  reported that solubi-
lized nickel(II)  is  bound  to DNA  with  an  apparent  equilibrium constant of
730 M   and with a saturation binding value of one nickel  per 2.4 nucleotides.
Spectroscopic and  equilibrium  binding studies of the interaction  of  nickel
with DNA  are  consistent  with the binding of nickel(II) to phosphate groups.
DNA  melting temperature  studies performed by Eichhorn and Shin  (1968) have
shown that nickel(II) binds to both phosphate and base groups of DNA.   However,
nickel(II)  has  a  much stronger affinity for DNA phosphate  groups.  X-ray
crystal!ographic studies of  the complexes between nickel(II) and  unhindered
nucleotides,  inosine-5'-phosphate,  guanosine-5'-phosphate, and  adenosine-51-
                                   8-139

-------
phosphate showed that nickel(II) is bound directly to the N-7 position on the
base and  indirectly to two phosphate oxygen atoms through hydrogen-bonding of
nickel-liganded water  molecules  (Clark and Orbell,  1974;  DeMeester et al. ,
1974; Collins et al.,  1975).
8.2.3.5  Induction of Morphological  Transformation of Mammalian Cells in Culture.
Casto et al.  (1979a) demonstrated that NiS04 enhanced SA7 viral  transformation
of Syrian hamster embryo cells.   Treatment with crystalline Ni'3S2 and NiS04 by
DiPaolo and  Casto  (1979)  resulted  in the  morphological  transformation  of
Syrian hamster embryo  (SHE)  cells  in a dose-related fashion, while amorphous
nickel sulfide caused no transformations.   Costa et  al.  (1979, 1981a,b, 1982)
and Costa and Mollenhauer (1980a,b)  have studied the morphological transforma-
tions of mammalian cells in culture  by several nickel compounds.   Their studies
have demonstrated that nickel compounds vary widely in their ability to induce
morphological transformations of SHE  cells.   Costa and Mollenhauer (1980a,b)
hypothesized that  j_n  vitro transformation  ability  of  insoluble  particulate
nickel compounds are  determined  by  their potential  to  be  endocytosed.   The
data supporting the above  reasoning have been  summarized  by Costa and Heck
(1982) and Heck and Costa (1982), and are presented in Table 8-28.

 TABLE 8-28.   RELATIONSHIP BETWEEN PHAGOCYTOSIS AND INDUCTION OF MORPHOLOGICAL
              TRANSFORMATION BY SPECIFIC METAL COMPOUNDS

Metal compound                Phagocytosis                  Incidence of
(<5 urn                        activity                 tranformation  (percent
particle size)                                         relative to crystalline
                                                                 NiS)
Crystalline NiS
Crystalline Ni'S2
Crystalline Ni^Se^
Amorphous NiS
Metallic Ni
Ni* 0-
NiS 3
NiCl2
Latex beads
24%c
22%c
27%c
3%
4%
5%
2%
Nd
Nd
100%c
118%c
115%
8%
18%
17%
9%
41%
8%
Determined in cultured Chinese hamster ovary cells [10 ug ml   exposure
 (1.27 ug cm  ), 24 h].  Number of cells with metal particles/total number
,of cells examined.
 Number of transformed colonies/total number of surviving colonies.
Standardized tothe incidence of transformation produced by crystalline
NiS. (10 ug ml    exposure, 4 days).«
 P<0.01 v. amorphous metal sulfide X  test. ND, not determined.
Source: Costa and Heck (1982).
                                   8-140

-------
     Hansen and Stern  (1983)  compared the transformation  activities  of  five

nickel compounds  (Ni welding  fume,  Ni^p, NipO.,, NiO, and NHCH-COO)^) using

baby hamster kidney (BHK-21) cells.   They found that at 50 percent cell survival,

the compounds  produced equal  numbers of  transformed  colonies.   The authors

postulated that the  cell  toxicity,  and thus transforming  activity  of nickel

compounds, depended on intracellular bioavailability of Ni[II].  They concluded

that it takes  10  times as much NiO  as  Ni~S2 to induce the  same degree  of

transformation of BHK-21 cells.

     Synergistic effects of nickel compounds with benzopyrene (BP) were observed

by Costa  and Mollenhauer  (1980b)  and  Rivedal and Sanner (1981).   The  combined

treatment of nickel  sulfate  and benzopyrene in Rivedal and  Sanner1s (1981)

study showed a  transformation  frequency of 10.7 percent,  as compared to 0.5

percent and 0.6 percent for NiSO,  and benzopyrene alone.   The cell transforma-

tions studied  have  been  summarized  by Sunderman (1984c),  and the results are

presented in Table 8-29.


                  TABLE 8-29.   MAMMALIAN CELL TRANSFORMATION BY NICKEL
          Authors
     Cells
               Results
DiPaolo and Casto (1979)

Costa et al. (1978, 1979)
Costa and Mollenhauer
 (1980 a,b)
Costa et al. (1982)
Saxholm et al.  (1981)
Hansen and Stern (1983)
SHE cells

SHE cells



SHE cells



SHE cells
C3H/10T
1/2 cells

BHK-21
cells
Rivedal and Sanner (1981)     SHE cells
NiSO., Ni-S? pos.; amorph. NiS neg.

Ni,Sp pos.; amorph.  NiS neg.;
 transformed cells induce sarcomas
 in nude mice

Transforming activity of cryst. Ni
 compounds related to phagocytosis
 rate

Cryst. NiS potency 2.5-times that of
 NiCl2

Ni'3$2 pos.; long microvilli in
 transformed cells

Ni dust, Ni3S2, Ni203, NiO and Ni
 acetate produce equal transformation
 percentages at equitoxic dosages

Synergism between Ni[II] and benzo(a)-
 pyrene
Source:  Sunderman (1984c).
                                   8-141

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8.2.3.6  Relative Carcinogenic Activity.   Sunderman and Hopfer (1983) reported
a significant  rank  correlation between the induction  of  erythropoiesis  and
carcinogenicity following the  administration  of particulate nickel  compounds
to  rats  at equivalent  doses.   The rank correlation suggests  that  certain
nickel compounds produce both erythrocytosis and carcinogenesis in rats (Sunderman
and Hopfer, 1983).   These  data do not provide a sufficient basis to conclude
that  the  two  phenomena are  related  biologically.   However,  pharmacokinetic
data  and  studies  showing that  Ni^S,,-induced erythrocytosis and carcinogenesis
are both  inhibited  by manganese dust (Hopfer and  Sunderman, 1978;  Sunderman
et al., 1976,  1979a) provide indirect evidence that these effects are related.
Dissolution half-times  and  indices of phagocytosis, summarized in Table 8-25,
have  been proposed  as  indirect measures of  carcinogenic  potency of  nickel
compounds due to correlations observed between these variables and the incidence
of injection site sarcomas.   The results of Sunderman and Hopfer (1983) apparently
contradict the  hypothesis that the carcinogenic potency of particulate nickel
compounds are related to dissolution rates or cellular uptake due to phagocytosis
(Costa  and  Mollenhauer, 1980  a,  b)   No  significant rank correlations were
observed  between  dissolution half-times  or phagocytosis and the incidence of
injection  site  sarcomas after administration of equipotent  doses  of nickel
compounds by the  intramuscular route.  Until  the mechanism of  nickel  carcino-
genesis and associated  processes  are better understood, there is no a priori
basis for using indices of phagocytosis, dissolution half-times, or erythrocy-
tosis as predictors of  the carcinogenic potency of particulate nickel compounds.
      Sunderman  (1984a)  reported the  incidence of  injection  site sarcomas  in
male  Fischer rats administered nickel compounds by the intramuscular route.
Eighteen  nickel  compounds  were tested at  equivalent doses  of 14 mg Ni/rat.
Results from this study are  presented in Table 8-26.  The results of Sunderman
(1984a) provide an adequate  basis for ranking the  relative carcinogenic activi-
ties  of the compounds  tested.  Based  on  these  data,  the apparent  relative
carcinogenic activities of  nickel compounds in decreasing order are  Ni'3S2 =
pNiS  cryst  =  Ni4FeS4 > NiO  >  Ni*3Se2 >NiAsS > Ni$2 > Ni*5As2  >  Ni dust >  NiSb
>NiTe > NiSe =  Ni.j-.ASg  > NiS amorphous > NiCrO^.   NiAs, NiTi03 and  NiFe-^g were
not carcinogenic  under  the  conditions of this study.   Based  on the  results of
this  study, the earlier observation of Gil man (1962) that Ni3S2 is  more active
than  NiO  in the induction of injection site sarcomas when injected  intramuscularly,
                                   8-142

-------
and the observation  of  Payne (1964) that Ni_Sp is most active among 8 nickel
compounds  studied, with the  following order of carcinogenic activities: Ni-Sp
> NiCO, > NiO  > Ni(CH,COO)   it can be stated that nickel subsulfide is most
      O               O    C-
active when  administered intramuscularly.
     In another series of  studies,  Sunderman  et al. (1984) found that 9 of 17
nickel compounds  tested carcinogenic when  injected  intrarenally at  equivalent
doses of 7  mg/rat.  The results of  the  intrarenal  injection study ranked the
carcinogenic activities of nickel compounds by this route: pNiS crystalline  >
Ni3$2 > NiS2 = NiAsS > Ni3Se2 = NiSe = NiFe$4 > NiFe16 > NiAs.  It is apparent
that the relative carcinogenic activities of different nickel  compounds may be
route-specific. Based upon the  intrarenal  studies, however,  Ni,S?  was still
more active  than other nickel compounds, with crystalline pNiS the most active.
     To a  more limited extent, Oilman's (1962) and Payne's (1964) observations
on the relative carcinogenic  activities of different  nickel compounds support
Sunderman1s   (1984a)  data.   Unquestionably, all  three authors found nickel
subsulfide to be the most potent of all  nickel compounds studied by intramuscular
injections.

8.2.4  Summary of Experimental Studies
     Experimental  nickel carcinogenesis  test  results  and short-term i_n vitro
test results that have  evolved out of various laboratories are summarized in
Table 8-30.   Numerous investigators have reported tumors, particularly rhabdo-
myosarcomas   and/or  fibrosarcomas,  following  injection or  implantation  of
nickel or its  compounds.   These investigations are summarized in Tables 8-13
through 8-23.
     The significance of tumors resulting from injection of chemicals has been
the subject  of considerable  discussion.  Most recently, Theiss (1982) pointed
out that nearly half of the chemicals which induced local tumors only were not
tumorigenic   by other routes.   This is  certainly not  the  case  with nickel
subsulfide and  nickel  carbonyl,  as  they have  produced tumors by inhalation.
     Three studies of  the  carcinogenic  potential of nickel salts in drinking
water were  found  in  the literature (Schroeder et  al.,  1964,  1974;  Schroeder
and Mitchener,  1975).   All three studies produced negative results; however,
all three used the  same relatively low dose  level  of  5 ppm of nickel in the
drinking water.
                                   8-143

-------
                      8-30.  SUMMARY OF ANIMAL AND  IN  VITRO TEST RESULTS  OF SPECIFIC NICKEL  COMPOUNDS
oc
            Nickel compound (Number
                 of studies)
            Ni3S2 (>40)
            Nickel  metal  powder (<20)
            NiO (>10)
            Ni203 (2)
   Tumor Response, Route (Number of studies)
     I_n vitro assays
       Response, test system
+  inhalation (1),  heterotopic trachea (1)
   intramuscular injections and implants  (>22)
   intrarenal injections (4)
   intratesticular  injections (1)
   intraocular injections (2)
   subcutaneous injections (1)
   intrapleural (1)
-  buccal brushing  (1)
   intrahepatic injections (2)
   submaxillary injections (1)

+  intramuscular injections (6)
   intrapleural      "      (2)
   intrafemoral      "      (2)
   intravenous       "  in rats (1)

+  inhalation (1),  intrapulmonary  (1)

-  inhalation (4)
   intratracheal (1)
   intraperitoneal  (1)
   intranasal (1)
   intrarenal (2)
   intravenous in mice and rabbits (1)

+  intramuscular injections and implants  (5)
   intrapleural injections (1)

+  inhalation (1),  intratracheal (1)

-  inhalation (1)
   intratracheal injections (2)
   intrarenal (1)

+  intracerebral injections
+  cell transformation assay
   SHE and BHK-21 cell lines
+  sister chromatid exchange
   tests
Inhibits DNA synthesis
Nickel concentrates in cell nucleus
Induces ONA strand breaks
Induces DNA repair synthesis
+  cell transformation assay
   SHE cells
   (activity -15% of Ni-S.)
-  sister chromatid exchange
   tests
+  cell transformation assays
   BHK-21 cell line
   (activity is ~1/10 of Ni3$2)
-  cell tranformation assays
   SHE cell line
+  cell transformation assays

   SHE and BHK-21 cell  lines
                                              -  intramuscular, injections
                                                  (activity in SHE is ~ 1/10 of
                                                  Ni3S2 and in BHK-21 ~ Ni3S2)
                                                                     (continued on following page)

-------
              8-30.   SUMMARY OF ANIMAL AND  IN  VITRO TEST  RESULTS OF SPECIFIC  NICKEL COMPOUNDS (continued)
      Nickel compound (Number
           of studies)
   Tumor Response,  Route (Number  of  studies)
     In vitro assays
       Response, test system
      Ni203 (2)
      NiS04 (5)
±  intracerebral  injections
-  intramuscular injections
-  intramuscular injections (4)
   injection (1)
CO
en
      NiC£2 (1)
-  muscle implants
                              (continued on foil owing page)
+  cell transformation assays
   SHE and BHK-21 cell lines
   (activity in SHE is -1/10 of
    Ni.S, and in BHK-21 ~ Ni-S,)
      3 f.               ~"   3  f.

+  cell transformation assay
   (activity ~% of Ni,S2)
+  sister chromatid excnange tests
+  in vitro chromosomal aberration
+  gene mutation of yeast and
    mammalian cells in culture
Induce B to Z conformational
 transition of DNA
Decrease fidelity of DNA synthesis
Enhancement of viral transforma-
 tion

+  cell transformation assay
   (activity -4/10 of Ni3S2)
+  sister chromatid exchange tests
+  _in vitro chromosomal aberration
+  gene mutation of yeast and
    mammalian cells in culture
+  gene mutation in S. typhimurium
    1A1535 and corneEactenum
Induce B to Z conformational
 transition of DNA
Inhibit protein, RNA and DNA
 synthesis
Induce DNA strandbreaks
Induce DNA repair synthesis
Inhibit interferon synthesis
Decrease fidelity of DNA
 synthesis
Ni bound to liver and kidney DNA

-------
              8-30.   SUMMARY OF ANIMAL  AND IN VITRO  TEST RESULTS OF SPECIFIC NICKEL COMPOUNDS (continued)
           Nickel compound (Number
                of studies)
   Tumor Response, Route (Number of studies)
     In v^tro assays
       Response, test system
00
I
CTl
           N1C03 (1)


           N1(CH3COO)2 (5)
           N1(OH)? (2)
           N1(OH)2 (1) colloidal

           Nickel refinery dusts (5)
           Nlckelocene (2)

           N1(CO) N1(CO)4 (3)
           N13S. +
            mltfiylcholanthrene (1)

           N1,S2 +
            benzpyrene (2)
             ,2 +
            manganese (2)
           N13S2 +
            baste magnesium carbonate (1)
+  muscle Implant
+  Intramuscular Injections (2)
   1ntraper1toneal  Injections (2)
-  1ngest1on via drinking water (2)
+  Intramuscular Injections
-  Intramuscular Injections

+  Intramuscular Injections (1)
   1ntraper1tonea1  (1)
i  Inhalation (2)
-  Inhalation (1)

+  Intramuscular Injections

+  Inhalation (2)
   Intravenous (1)
No effect, Intramuscular Injections
 shortened latency,  Intramuscular  Injections
Doubled observed tumor,  Intratracheal
 Injections rate

Inhibit tumor formation,  Intramuscular
 Injections
Inhibit tumor formation,  Intrarenal
 Injections

Inhibit tumor formation,  Intramuscular
 Injections
Induce DNA-prote1n crosslink
Induce DNA strandbreaks

+  cell transformation assay
   (activity -1/10 of N1.S-)
   Inhibit protein, RNA anti DNA
   synthesis

Not tested
Not tested
Not tested

N1 bound to liver and kidney
 DNA
Inhibit RNA polymerase
                                              ?(continued on following pacie)

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                   8-30.   SUMMARY OF  ANIMAL AND  IN VITRO TEST RESULTS  OF SPECIFIC NICKEL  COMPOUNDS  (continued)
          Nickel compound (Number
               of studies)
                                     Tumor Response, Route (Number of  studies)
     In vitro assays
       Response,  test  system
CX)
NiO +
 methylcholanthrene (1)

NiO +
 smoke (1)

Ni +
 flyash (1)

Ni +
 methylcholanthrene (1)

NiS04 +
 ethylnitrosourea (ENU)

NiO +
 diethylnitrosourea (DENU)
          NiSO. +
           ben?
     pyrene
                                            Cocarcinogenic, intratracheal injections
                                            No effect, inhalation
                                            No effect, inhalation
                                            Cocarcinogenic, intratracheal Injections
                                            Increase tumor obtained by ENU
                                            Cocarcinogenic, Intratracheal injections
                                  Not studied
Increase cell  transformation by
 18 times
Co-mutagenic

-------
     In the only ingestion study, Ambrose et al. (1976) administered nickel as
sulfate hexahydrate  fines  (NiS04 6H20; 22.3 percent  nickel)  in the diet of
Wistar-derived rats and beagle dogs for two years.   The dietary nickel concen-
trations were  100,  1000,  and 2500 ppm.  There were 25 rats and three dogs of
each sex assigned  to each dose group.  A similar number of untreated animals
were maintained  and served  as  controls.   No treatment-related tumors were
observed from this study.
     Sunderman et  al.  (1978) painted the buccal mucous  membranes of Syrian
golden hamsters with Ni-S2 and observed no tumors.
     Nickel carcinogenesis by inhalation has not been adequately studied.  The
Ottolenghi  et al. (1974) study using Ni3$2 and Fischer 344 rats is of adequate
design to  determine  the carcinogenicity of  Ni3$2 by  inhalation.   The  observed
neoplasms were predominantly adenomas (8/110 male;  7/98 female) and adenocarci-
nomas (6/110 male; 4/98 female).   Additional tumors  were  squamous  cell carci-
nomas (2/110 male;  1/98  female) and a fibrosarcoma  (one male).  Inhalation
studies using  nickel  carbonyl  (Sunderman et al., 1957,  1959;  Sunderman  and
Donnelly,  1965)  have produced  pulmonary  tumors,  although the  studies have
limitations due  to  high  mortality from the high toxicity of nickel carbonyl.
     Carcinogenesis testing of other nickel compounds by inhalation are either
very limited or are non-existent.  In general, the results from animal inhalation
studies for these compounds tend to be negative or equivocal.
     Nickel subsulfide  (NigS,,) is the most studied  nickel compound.  In  a
study of the carcinogenicities of various metal compounds, Gil man (1962)  noted
that nickel subsulfide (Ni'3S2)  was a  potent inducer  of  rhabdomyosarcomas when
given intramuscularly.  Later studies of the carcinogenicity of nickel subsul-
fide demonstrated  adenocarcinomas in  rats  given the substance intrarenally
(Jasmin  and  Riopelle, 1976);  rhabdomyosarcomas, fibrosarcomas, and fibrous
histocytomas in  rat  testicular tissue after intratesticular dosing (Damjanov
et al.,  1978);  and epidermoid and adenocarcinomas in the lung  in Fischer 344
rats inhaling  nickel subsulfide  (Ottolenghi  et al., 1974).  Hamster  fetal
cells transformed  by Ni-Sp will induce sarcomas when injected  subcutaneously
into nude mice.  In the study of Yarita and Nettesheim (1978),  tracheas grafted
onto isogem'c  rats  showed mainly sarcomas but also a low yield of carcinomas
with Ni'3S2  implantation  as early as  6 months.  Sunderman et  al.  (1980)  have
extended the site  tumorigenicity of Ni'3S2 to the eye, where injection of 0.5
mg into  the  vitreous cavity in rats led to a high incidence of ocular tumors
by 8 months.
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     Differences in  tumor response between  species,  strain, and  route  of
administration,  as well  as  dose-response  relationships,  have been observed.
These observations have  been well summarized by Sunderman (1983).  The induc-
tion of morphological transformation of mammalian cells in culture and sister
chromatid exchanges,  the inhibition of DMA synthesis  and  induction of DNA
strand breaks, and the observation of  nickel  concentrating  in the cell  nucleus
are all  supportive of the carcinogenicity  of  nickel  subsulfide.
     Nickel  carbonyl administered to  rats  via inhalation produced pulmonary
adenocarcinomas  (Sunderman et al., 1957, 1959; Sunderman and Donnelly, 1965),
and  intravenous  injections  into rats  produced malignant  tumors at various
sites (Lau et al., 1972). Biochemical   studies have shown that the nickel from
nickel carbonyl  is bound to DNA and inhibits  RNA  polymerase activities.
     Nickel  containing dusts from  refineries  have been studied  for potential
carcinogenicity.  Nickel  refinery flue dust  containing 68 percent Ni^S^, 20
percent NiSO. and 6.3 percent NiO produced either negative  results (Belobragina
and Saknyn,  1964;  Kim et al., 1976)  or equivocal  results  (Fisher et al.,  1971)
from inhalation studies.  However,  intramuscular injections produced strong
tumor responses  in rats and mice (Gilman and  Ruckerbauer,  1962).   The presence
of squamous  cell carcinomas in  2 of 5  surviving rats exposed to  feinstein dust
(Saknyn and  Blohkin, 1978),  an  intermediate product of nickel refining containing
NiS, NiO and  metallic  Ni, lends credence  to  the  concern  that nickel  refinery
dusts are potential  human carcinogens.  These dusts  have  not been studied
using i_n vitro short-term test  systems or  tests for macromolecular interactions.
     Nickel  metal, in the form  of dust or  pellets, has led  to the induction of
malignant sarcomas at  the site of dosing  in  rats,  guinea  pigs, and rabbits
(Heath and Webb, 1967; Heath and Daniel, 1964; Mitchell et al.,  1960; Hueper,
1955), while  inhalation  of  nickel  dust has  been reported to lead  to  lung
anaplastic carcinomas and adenocarcinomas  (Hueper,  1958).   In the inhalation
study of nickel dust carcinogenesis,  Hueper  (1958) reported that an alveolar
anaplastic carcinoma was found  in  one guinea pig lung, and a  "metastatic
lesion" (lymph  node) was found in a second animal.  However, this study has
been criticized as  being inconclusive  because the lymph  node tumor could not
be associated with a primary lung tumor, nor were control animals used in the
guinea pig experiment.
     Nickel  oxide (NiO) has been tested to be carcinogenic  in five intramuscu-
lar  injection  studies  (Gilman,  1962,  1965,  1966;  Payne,  1964;  Sunderman,
1984a) and one  intrapleural  injection  study  (Skaug et al., 1985).   As in the
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case above,  no controls were  used  in some of the  intramuscular  injection
studies; however, in the intrapleural injection study, controls were used and
the response by this route was  strong, approaching that produced by Ni-Sp.  One
inhalation study (Wehner et  a!.,  1975)  conducted on  Syrian  golden hamsters
showed neither a carcinogenic effect of nickel  oxide alone nor a co-carcinogenic
effect with cigarette  smoke.   Another inhalation study (Horie et  al., 1985)
used too few animals to allow any definitive conclusions to be drawn.   Responses
from various  intramuscular injection studies  have  varied depending on the
dosage, animal  species, and  strain  used.   In general, where  responses  have
been seen, NiO  has  been shown to have  a  lower carcinogenic potential  than
Ni-Sp.   Cell  transformation assays have given equivocal results:  negative with
SHE cells  and  positive with  BHK-21 cells, with  an  activity about one-tenth
that of Ni-Sp.
     Nickel (III) oxide (Ni907) has not been tested sufficiently to allow any
                           C~ O
conclusions to  be drawn.   Intracerebral  injection (Sosinski, 1975) of NipCL
produced a marginal  tumor  response  in rats, but intramuscular injections did
not.   Furthermore,  no  tumors were produced  in another  intramuscular injection
study  (Payne,  1964).   However, Ni203 has  proven to be more  active  in  the
induction  of morphological transformations  of mammalian cells in culture than
NiO.   The  transforming activity  in  BHK-21 cells  approximates that of Ni-S^,
but in SHE cells it is only about one-tenth the activity of Ni.^.
     Soluble nickel  compounds tested  for carcinogenicity include nickel  sulfate
(NiS04),  nickel  chloride   (NiCl2),  and  nickel  acetate (Ni(CH3COO)2).   The
results of four intramuscular  injection studies  (Gilman,  1962, 1966; Payne,
1964;  Kasprzak  et al. , 1983) and one ingestion  study  (Ambrose  et  al., 1976)
with nickel  sulfate have  been negative.  Only one intramuscular implantation
study  (Payne,  1964),  was  conducted with nickel chloride and the test results
were negative.  However, both the sulfate and the chloride induced morphological
transformations of mammalian cells in culture, induced sister chromatid exchange,
induced chromosomal  aberrations  ijn  vitro,  induced gene mutations  in yeast  and
mammalian  cells in  culture, decreased fidelity of DNA  synthesis, and responded
positively to  other indicators of potential  carcinogenicity.  The  observation
(Stoner et al., 1976)  of pulmonary tumors in strain A  mice from the administration
of  nickel  acetate  by  intraperitoneal  injections  and the ability  of nickel
acetate to transform mammalian cells  in culture to inhibit RNA and DNA synthesis,
supports a concern  that soluble nickel compounds  may have carcinogenic potentials.
However,  tests  on  these soluble  nickel compounds are too limited  to support
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any definitive judgement.
     The above discussion has focused on the ability of nickel compounds alone
to induce carcinogenic responses.   An equally important aspect of carcinogenicity
is the interaction of nickel with other agents, since environmental situations
entail simultaneous exposure to a number of such substances.
     Experimental data exist  to  indicate that nickel has a cocarcinogenic or
synergistic effect on the carcinogenicities of polycyclic aromatic hydrocarbons.
Toda (1962) found  that  17 percent of  rats  receiving intratracheal doses of
both nickel oxide  and 20-methylcholanthrene developed squamous cell carcino-
mas. Maenza et  al.  (1971) showed a synergistic, rather than additive effect,
in the  latency  period reduction  (30 percent)  of  sarcomas  when simultaneous
exposure to benzopyrene and nickel  subsulfide was carried out.   Kasprzak et
al.  (1973) observed pathological reactions  in  lungs  of rats given  both  nickel
subsulfide and  benzopyrene that were  greater  than  for either agent alone.
However, Wehner et al. (1975) did not find a significant carcinogenic response
of NiO  administered alone or with cigarette smoke.  Syrian golden  hamsters,
whose sensitivity to inhaled particulate is questionable, were used.
     Virus-nickel  synergism  is  suggested by the observation  of  Treagan and
Furst (1970)  that  i_n  vitro suppression of  mouse L-cell  interferon  synthesis
occurs in response to the challenge of Newcastle Disease virus in the presence
of nickel.
     Nickel ion combined with benzo(a)pyrene enhanced the morphological  trans-
formation frequency in  hamster  embryo cells over that seen with either agent
used alone (10.7  percent  versus  0.5 percent and 0.6 percent  for nickel and
benzo(a)pyrene, respectively) at levels of  5 pg/ml nickel salt and  0.78 pg/ml
benzo(a)pyrene.   Furthermore,  in  a mutagenesis system using  hamster embryo
cells, as  described by  Barrett et al. (1978),  a co-mutagenic effect between
nickel sulfate and benzo(a)pyrene was also observed (Rivedal  and Sanner, 1980,
1981).    These observations are supported by cocarcinogenic effects between
nickel compounds  and  certain  organic carcinogens (Toda,  1962; Maenza et al.,
1971;  Kasprzak et al., 1973).
     Comparative carcinogenicity of various nickel compounds  has been studied
and demonstrated  in  various laboratories (Sunderman et  al.,  1984, 1979 b;
Sunderman and Maenza, 1976;  Jasmin  and Riopelle, 1976;  Payne, 1964; Gil man,
1962;  Sunderman, 1984a).
     Sunderman and Maenza  (1976) studied the incidence of sarcomas  in Fischer
rats followed two years after single intramuscular injections  of four insoluble
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nickel-containing powders:  metallic nickel, nickel sulfide, ornickel subsul-
fide, and  nickel-iron sulfide matte.   Amorphous nickel sulfide  showed  no
tumorigenic potential, while nickel  subsulfide  was the most active of the test
compounds.   The  relative carcinogenicity of nickel-iron  sulfide matte was
intermediate between  nickel subsulfide and metallic nickel powder, suggesting
to these authors that there may also be a previously unrecognized carcinogenic
potential in other nickel-sulfur mineral  systems, as well  as the corresponding
arsenides,  selenides, and tellurides.
     In a  later  study,  Sunderman (1984a) reported the relative carcinogenic
activities  of 15  nickel  compounds by administering equal dosages of compounds
(14  mg  Ni/rat)  intramuscularly  to  rats.  While Ni3S2 was one  of  the most
potent  carcinogenic  nickel  compounds,  crystalline nickel  sulfide  (NiS)  was
equally carcinogenic.  Amorphous nickel sulfide was not carcinogenic under the
conditions  of this experiment.
     Looking at the  literature in aggregate,  there appears  to  be a general
inverse  relationship  between   solubility  and carcinogenic  potential  of the
nickel  compounds  which  have been studied—insoluble nickel  metal,  nickel
oxide,  and nickel subsulfide  being variably carcinogenic, with most nickel
salts generally being non-carcinogenic.  It has been suggested that the prolonged
contact of insoluble compounds is requisite to  carcinogenic manifestation, the
clearance of soluble nickel being shorter than  the induction interval for such
manifestation.   However,  careful examination of  the  data  reveals that the
mechanisms  leading  to carcinogenic manifestation  may be  more complex than
basic postulates  regarding the solubility or insolubility of nickel compounds.
     Sunderman  and  Hopfer  (1983)  reported  a .significant  rank correlation
between  the  induction of  erythropoiesis and  carcinogenicity following the
administration of particulate  nickel  compounds to rats at equivalent doses.
Dissolution half-times and  indices  of  phagocytosis, summarized  in  Table 8-25,
have  been  proposed as indirect  measures of carcinogenic  potency  of  nickel
compounds, due  to correlations observed  between these variables and  the  inci-
dence of injection  site  sarcomas.   The results  of  Sunderman  and Hopfer (1983)
contradict  the  hypothesis  that  the carcinogenic  potency  of a particulate
nickel  compound  is  related to dissolution rate or cellular uptake  due  to
phagocytosis.   No significant  rank correlations were observed between disso-
lution  half-times or phagocytosis and the incidence of injection site sarcomas
after administration  of  equipotent doses of nickel compounds by the intramuscular
route.   Until the mechanism of nickel  carcinogenesis  and associated  processes
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are more clearly  understood,  there is no a priori  basis for using indices of
phagocytosis, dissolution half-times,  or erythrocytosis as predictors of the
carcinogenic potency of particulate nickel compounds.
     A number of  studies employing nickel compounds in  various jji vivo and  ui
vitro test  systems  have been  reported.   These studies help to provide further
insight on some of the mechanisms by which carcinogenic metals in general, and
nickel in particular,  may  express such  effects  in intact organisms.  Recent
reviews by  Sunderman  (1979,  1981, 1983, 1984b,c) have summarized much of the
pertinent literature.
     Several authors  have  noted the  enrichment of the nucleus by nickel  when
different nickel compounds are employed  in various experimental  systems.   Webb
and co-workers  (1972)  found that  70 to 90 percent of  nickel  in nickel-induced
rhabdomyosarcomas was  sequestered in  the nucleus, of which  half was in the
nucleolus and half  in  nuclear sap and  chromatin.  In  addition, nickel binding
to RNA/DNA  has  been shown by  both Beach and Sunderman  (1970), using Ni(CO)4
and rat  hepatocytes,  and  Heath and Webb  (1967), in nuclei from Ni3S,,-induced
rat rhabdomyosarcomas.  In vivo inhibition of RNA synthesis by nickel compounds
has also been demonstrated (Witschi, 1972; Beach and Sunderman,  1970).
     The reports of Si rover and Loeb (1977) and Miyaki et al. (1977) demonstrate
the ability of nickel ion (nickel sulfate) to increase the error rate (decreas-
ing  the  fidelity)  of  DNA polymerase  in E.  coli and avian  myeloblastosis
virus.
     Studies (Table 8-29) using test systems of varying complexity have demon-
strated  both  the  direct cellular  neoplastic  transformation  potency  of soluble
nickel compounds  (nickel  sulfate, nickel choride),  insoluble nickel  compounds
(Ni'3S2,  Ni203,  NiO),  and  nickel  dust,  as well  as the further enhancement of
transformation  due  to viral   inoculation  (DiPaolo and Casto,  1979;  Traul et
al.,  1979;  Casto  et al,  1979a, b; Costa et al., 1978).  In one  study, (Casto
et al., 1979b) the  nickel(II)  enhancement of transformation  in virally infected
cells was  seen  to  involve increased  amounts of viral (SA7) DNA in  cellular
DNA,  suggesting  that  enhancement of viral transformation results from damage
to cell DNA, which  then increases the  loci for  attachment of viral DNA.
      In  hamster  cells in  culture, nickel compounds have been shown  to induce
DNA  strand  breaks (Robison and Costa,  1982; Robison  et al., 1982)  and  DNA
repair synthesis  (Robison et  al., 1983).  Recently, nickel has also  been  shown
to form  a protein-nickel-DNA  complex  in mammalian systems (Lee  et al., 1982;
Ciccarelli  et  al.,  1981).   These observations  suggest  that nickel  compounds
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with carcinogenic activities  can  induce damage to DNA  and  form DNA-protein
crosslinks.
     While  the  mechanism of  nickel  carcinogenesis  is  not well understood,
comparative carcinogenesis, biochemical, and macromolecular interaction studies
and short term tests seem to indicate that the nickel ion may be the carcinogenic
species.   Thus,  the difference in  carcinogenic activities among different
nickel   compounds could  be  the result of the ability of the different  nickel
compounds to enter the cell and be converted to the nickel ion, and the chemical
form and physical state  of  the nickel compounds are  important  determinants of
their bioavailability.
8.3  QUANTITATIVE RISK ESTIMATION FOR NICKEL
8.3.1  Introduction
     This quantitative section deals with the incremental  unit risk for nickel
in  air  and the potency  of  nickel  relative to other  carcinogens  which the
Carcinogen Assessment Group (CAG) of the U.S. Environmental Protection Agency
has evaluated.  The  incremental  unit risk estimate for an  air pollutant is
defined as the  additional  lifetime  cancer risk occurring in  a hypothetical
population in which all  individuals  are exposed continuously from birth through-
out their lifetimes to a concentration of 1 ug/m  of the agent in the air they
breathe.  This  calculation  is  done  to estimate, in quantitative  terms,  the
impact of  the  agent  as  a carcinogen.  Unit  risk  estimates  are used for two
purposes:  1)  to compare the carcinogenic potency of  several agents with each
other, and 2)  to give a  crude  indication of the population  risk that might  be
associated with exposures to  air or water contaminated with these agents,  if
the actual exposures  are known.   The data used for the quantitative estimate
is one or both of two types:  1) lifetime animal  studies,  and 2) human studies
where excess  cancer  risk has  been  associated with exposure  to  the agent.

8.3.2  Quantitative Risk Estimates Based on Animal Data
8.3.2.1    Procedures  for Determination of  Unit Risk from Animal  Data.    In
animal studies  it  is  assumed,  unless evidence exists  to the contrary,  that  if
a carcinogenic response occurs at the dose levels used in the study, responses
will also occur at all lower doses with an incidence determined by the extrapo-
lation model.  This is known as a nonthreshold model.
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     There  is  no  solid scientific basis for  any  mathematical  extrapolation
model which relates  carcinogen  exposure to cancer risks at the extremely low
concentrations which must be dealt with when evaluating environmental  hazards.
For practical  reasons,  such low levels of  risk cannot  be measured directly.
     Based on  observations  from epidemic logic and animal cancer studies, and
because most dose-response relationships have not been shown to be supralinear
in the  low  dose  range, the linear nonthreshold model has been adopted as the
primary basis  for animal-to-human risk  extrapolation  to low levels of  the
dose-response relationship.  The risk estimates made with this model should be
regarded as conservative,  representing  the  most plausible upper  limit for the
risk, i.e., the true risk is not likely to be higher than the estimate,  but it
could be lower.
     The mathematical  formulation  chosen to describe the linear nonthreshold
dose-response  relationship  at  low doses is the linearized multistage model.
This model  employs  enough arbitrary constants to be  able  to fit almost any
monotonically  increasing  dose-response  data.   It  is  called a  linearized  model
because it incorporates a procedure for estimating the largest possible linear
slope (in  the  95  percent confidence limit  sense) at low extrapolated doses
that is consistent with the data at all dose levels of the experiment.
8.3.2.1.1   Description of the  low-dose animal -to-human extrapolation model.
Let  P(d)  represent  the lifetime risk (probability) of cancer at dose d.   The
multistage model has the form

                P(d) = 1 - exp  [-(q0 + qid + q2d2 + ... + qkdk)]
where
                            q. £ 0, 1 = 0, 1, 2, .... k
Equivalently,
                  Pt(d) = 1 - exp [-(qid + q2d2 + ... + qkdk)]
where
                              p (d) = PCd) - P(0)
                              KtlflJ    i - p(d)

is  the  extra risk over background rate  at  dose  d,  or  the  effect  of  treatment.
     The  point  estimate of the  coefficients  q.,  i  = 0,  1,  2,  ... , k,  and  con-
sequently  the extra risk function Pt(d)  at any  given  dose  d,  is  calculated  by

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maximizing the  likelihood  function  of the data.   (In the section calculating
the risk estimates, P^(d) will  be abbreviated as  P).
     In fitting the dose-response model, the number of terms in the polynomial
is chosen equal to (h-1), where  h is  the  number of dose groups in the experi-
ment including  the control  group.   For nickel subsulfide, the only compound
for which the  data are suitable for animal-to-human dose-response extrapola-
tion, the polynomial reduces to  k=l or  a  one-hit model, since the only avail-
able inhalation study used one  dose level  plus a  control.
     The point  estimate, q.^ and the  95 percent upper confidence limit of the
extra risk Pt(d) are  calculated by using the computer program GLOBAL83,  developed
by Howe (1983,  unpublished).  At low doses, upper 95 percent confidence  limits
on the extra risk and lower 95  percent confidence limits on the dose producing
a given risk are  determined from a 95 percent upper confidence limit,  q?,  on
parameter q-,.   Thus,  the value  q? is taken as an  upper bound of the potency of
the chemical in  inducing cancer at low doses.  It represents the 95 percent
upper-limit incremental  unit risk consistent with a  linear nonthreshold dose-
response model.
8.3.2.1.2  Calculation of human equivalent dosages from animal  data.   Following
the suggestion of Mantel and Schneiderman (1975),  it is assumed that mg/surface
area/day is an  equivalent dose between  species.  Since, to a close approxima-
tion, the surface  area  is proportional  to the two-thirds power of the weight,
as would be the case  for a perfect sphere, the exposure in mg/day per two-thirds
power of the weight  is  also considered  to be equivalent exposure.  In an ani-
mal experiment, this  equivalent dose is computed  in the following manner.   Let

     L  = duration of experiment
     1  = duration of exposure
     m  = average dose per day  in mg during administration of the agent
          (i.e., during 1 ), and
     W = average weight of the  experimental animal

Then, the lifetime average exposure is

                                        1  x m
                                     , _  e
                                    d - —
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Inhalation exposure.   When exposure is via inhalation,  the calculation of dose
can be considered  for  two cases where 1) the carcinogenic agent is either a
completely water-soluble  gas or an aerosol, and is absorbed proportionally to
the amount of air breathed in, and 2) where the carcinogen is a poorly water-
soluble gas that reaches  an equilibrium between the air breathed and the body
compartments.   After equilibrium  is  reached,  the  rate  of absorption of these
agents is expected to be  proportional to the metabolic rate, which  in turn is
proportional  to the rate of oxygen consumption,  which in turn is a function of
surface area.
     Agents that are  in the  form of particulate matter,  such  as Ni-Sp,  can
resonably be expected  to  be  absorbed proportionally to  the  breathing rate.
In this case the exposure in  mg/day may be expressed as

                                   m = I x v x r

                                      3          3
where I = inhalation rate per day  in m  , v = mg/m  of the agent in  air, and r
= the absorption fraction.
     The inhalation rates, I,  for various species  can  be calculated from the
observations (Federation of American Societies for  Experimental  Biology,  1974)
that mice weighing 25 g breathe 34.5 liters/day and rats weighing 113 g breathe
105 liters/day.   For mice and rats of other weights, W (in kilograms), the sur-
face are
follows:
                                                                    3
face area proportionality can  be  used to find breathing  rates  in m /day as
                    For mice, I = 0.0345 (W/0.025)273 m3/day

                    For rats, I = 0.105 (W/0.113)2/3 m3/day
                              3
For humans, the  value  of 20 m /day*  is adopted as  a  standard breathing  rate
(International Commission on Radiological  Protection, 1977).
                                     2/3
     The equivalent exposure  in  mg/W    for these agents can be derived from
the air intake data in a way analogous to the food intake data.   The empirical
*From:  Recommendation of the International Commis%ion#n Radiological Protec-
 tion, page? 9. 3 The  average  breathing rate is 10  cm   per 8-hour workday
 and 2 x 10  cm  in 24 hours.
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factors for the  air  intake  per kg per day, i = I/W, based upon the previous
stated relationships, are tabulated as follows:

                    Species             W           i = I/W
                      Man            70              0.29
                      Rats            0.35           0.64
                      Mice            0.03           1.3

Therefore, for particulates  or completely absorbed gases, the equivalent expo-
            2/3
sure in mg/W    is
                                              _ iwl/3
                                              - 1W   vr
In the absence of experimental information or a sound theoretical argument to
the contrary, the fraction  absorbed,  r, is assumed  to  be the same for all
species.
8.3.2.1.3  Calculation of the unit risk.   The  95 percent upper-limit risk
                       pTo
associated with d mg/kg   /day  is obtained from GLOBAL83 and, for most cases
of interest  to risk assessment,  can be adequately approximated by P(d) = 1 -
exp (-q?d).  A "unit risk"  in units X  refers to the  risk  corresponding to an
                                                                          2/3
exposure of X = 1.   This value is estimated by finding the number of mg/kg   /day
that corresponds to one unit of X and substituting this value into the relationship
                                                             3
expressed above.   Thus, for example, if X is in units of ug/m  in the air, for
nickel particulates,  d =  0.29 x 701/3  x 10"3 mg/kg2y/3/day when pg/m3  is  the
unit used to compute parameters in animal experiments.
     If exposures are given  in terms of ppm in air,  at  a  temperature of 25°C,
the following equation can be used to convert exposure units to mg/m :
                        = 1 2 x mo^ecu^ar weight of gas in mg
                           '     molecular volume of air in m"
An equivalent  method  of calculating unit risk would  be to  use mg/kg  for  the
animal
amount
animal  exposures and then  to  increase the j   polynomial  coefficient  by an
                         (Wh/Wa)j73   j = 1, 2,
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and use the mg/kg equivalents of ppm or [jg/m  for the unit risk values in man.
8.3.2.1.4  Interpretation of quantitative estimates.   For several reasons, the
unit risk  estimate  is  only an approximate indication of the absolute risk in
populations exposed to known concentrations of a carcinogen.  First, there are
important host factors, such as species differences in uptake,  metabolism, and
organ distribution  of  carcinogens,  as well as  species differences  in target
site susceptibility, immunological  responses,  hormone function, and disease
states.  Second, the concept of equivalent doses for humans compared to animals
on  a  mg/surface area  basis  is virtually without experimental   verification
regarding carcinogenic response.  Finally, human populations are variable with
respect to genetic constitution and diet, living environment, activity patterns,
and other cultural factors.
     The unit risk estimate can give a rough indication of the  relative potency
of  a given agent  compared  with other  carcinogens.  The comparative  potency of
different  agents  is  more  reliable when the comparison is based on studies in
the same test  species, strain, and sex,  and  by the  same route of exposure.
     The quantitative  aspect of the carcinogen  risk  assessment is included
here because it may be of use in the regulatory decision-making process, e.g.,
setting regulatory  priorities,  or evaluating  the adequacy of technology-based
controls.   However,  it should be recognized  that  the estimation of cancer
risks to humans  at  low levels of exposure is uncertain.   At best, the linear
extrapolation model  used  here provides a rough but plausible estimate of the
upper limit of  risk;  i.e., it is not likely that the true risk would be much
more than  the  estimated risk, but it  could very well be considerably lower.
The risk estimates  presented  in  subsequent sections should  not  be  regarded as
accurate representations of  the  true  cancer risks even when the  exposures are
accurately defined.  The  estimates  presented may,  however, be  factored  into
regulatory decisions to the extent that the concept of upper limits of risk is
found to be useful.
8.3.2.1.5  Alternative methodological  approaches.  The  methods presented in
the Guidelines for Carcinogen Risk Assessment (U.S.  EPA,  1984)  and followed by
the CAG for quantitative assessment are consistently  conservative, i.e., avoid
underestimating risks.   The most important part of the methodology contributing
to  this conservatism  is the linear nonthreshold extrapolation  model.  There
are a variety of other extrapolation models which could be used, most of which
                                   8-159

-------
would give  lower  risk  estimates.   In other documents, other models have been
used for comparative purposes  only.   However, the animal inhalation data for
nickel have  only  one  dose group plus a  control;  these limited data do  not
allow estimation  of the parameters necessary for fitting these other models.
     The position  taken by the  CAG is that  the  risk estimates obtained by  use
of the  linear  nonthreshold  model  are upper limits and the true risk could be
lower.
     With  respect to  the choice  of  animal  bioassay  data as  the  basis for
extrapolation, the present  approach  is  to  use  the most  sensitive  responder.
Alternatively, the average  responses of all  the  adequately tested bioassays
could be used.  Again, with only the one positive nickel subsulfide study, the
data are too limited for alternative approaches.
8.3.2.2    Calculation  of Cancer Unit Risk Estimates Based on  Animal  Studies.
While the  animal  data  base  indicates that many  nickel compounds induce cancer
at the injection  site,  only nickel acetate  and  nickel carbonyl have been shown
to  cause  tumors  distal  to  the injection site.    The  one dietary  and three
low-level  drinking water studies  in which  soluble nickel  salts were  given
orally have  shown  no evidence of cancer.
     Animal  studies have shown sufficient  evidence for  carcinogenicity  only
for  nickel  subsulfide and nickel carbonyl.  A risk estimate cannot be calculated
from the  nickel  carbonyl inhalation experiment of Sunderman et al.  (1959,
1957) because  survival  was  too poor. Only  9 of 96 (9 percent)  of  the  exposed
animals survived  for 2  years.   The toxicity can be attributed to the administra-
tion of nickel carbonyl in an  alcohol-ether  mixture, evidenced by the  fact
that only  3 of 41 (7  percent)  of the vehicle control rats  survived 2  years.
In  a subsequent experiment (Sunderman and Donnelly, 1965), only one of 64  rats
chronically exposed to  nickel carbonyl developed  a lung  tumor.  In rats  acutely
exposed,  two lung tumors were  observed.  Because the acute and chronically
exposed  groups cannot be combined, the  number of lung tumors  observed was too
small  for an  incremental unit  risk  to  be estimated from these data.   A high
incidence  of malignant  lymphomas was also  observed   in this experiment.   The
authors  concluded that a relationship to nickel exposure appeared doubtful in
view of a  high spontaneous incidence of lymphoma in rats  reported in  the
 literature and found  among  control animals.
                                    8-160

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            In the Ottolenghi  et al.  (1974)  study,  110  male and 98 female Fischer 344
                                     o
       rats were exposed to 970 pg/m  nickel  sulfide  inhalations  for  78 weeks (5
       days/week,  6 hours/day).  Compared with 108 male and 107 female controls, the
       treated groups of both  sexes  showed statistically  significant  increases  in
       both adenomas and adenocarcinomas  of the  lung.   These  results  are  shown in
       Table 8-31.
            The results  show significant increases  in adenomas and in combined adeno-
       mas/adenocarcinomas  for both males and  females and also an  increased incidence
       of squamous cell  carcinoma  of the lung in treated males and females.  Since
       the authors concluded  that  these "benign  and malignant neoplasms.. .are  but
       stages of development of a single proliferative  lesion," a  unit risk assessment
       can be calculated which includes combined  adenomas and adenocarcinomas.
            Based on combining  adenomas  and adenocarcinomas and adding in squamous
       cell carcinomas,  the treated males had  a 14.5 percent incidence (16/110)  versus 1
                     TABLE 8-31.   HYPERPLASTIC AND NEOPLASTIC CHANGES
                        IN LUNGS  OF RATS EXPOSED TO NICKEL SULFIDE
Controls
Pathologic changes
Typical hyperplasia
Atypical hyperplasia
Squamous metaplasia
Tumors:
Adenoma
Adenocarcinoma
Squamous cell
carcinoma
Fibrosarcoma
Males
(108a)
26b
17
6

0
1

0
0
(24)
(16)
(6)

(0)
(1)

(0)
(0)
Females
(107a)
20
11
4

1
0

0
0
(19)
(10)
(4)

(1)
(0)

(0)
(0)
Nickel
Males
sulfide
Females P values
(110a) (98") Males
68
58
20

8
6

2
1
(62)
(53)
(18)

(7)
(5)

(2)
(1)
65
48
18

7
4

1
0
(66)
(49)
(18)

(7) 0.005
(4) 0.06

(1)
(0)
Females




0.02
0.05



 Number of animals.
 Values represent the number of affected animals in each group.   Percentage of affected
 animals is given in parentheses.  .Subtreatment groups were combined,  since no signifi-
 cant differences were found among them.
Source:  Ottolenghi  et al.  (1974).
                                          8-161

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percent (1/108) for the controls.   The equivalent lifetime continuous exposure
is:
          970 ug/m  x ^f hours x | days x ^j weeks = 122.8 ug/m
     Since nickel sulfide  is  a parti cul ate,  the equivalent  human  dosage  is
estimated according to section 8.3.2.1.3, where

                                  d = iW1/3vr

                                      2/3
where d =  equivalent  exposure in mg/W   , i for rats = 0.64, i for humans =
               3
0.29, v =  mg/m  of nickel  sulfide in air,  and r,  the absorption fraction, is
assumed equal in both species.  Setting d equal in both species gives

          v       = (i    /i      ^fW    /W      1   v
           humans   v rats   humans'^ rats  humans'    rats

Filling in the numbers gives

           vh = (0.64/0.29)(0.35/70)1/3 • 122.8 ug/m3 = 46.3 ug/m3

     Use of  the  multistage model with the above  data results in a maximum
likelihood estimate (MLE) of the linear term of q,  = 3.2 x 10~3 (ug/m3)'1 and
                                                                     ~3      3
an upper- limit risk estimate of the linear component of q? = 4.8 x 10   (ug/m )
     Thus, based  on  animal studies, the upper-limit risk to humans breathing
1 ug nickel sulfide/m  over a lifetime is 4.8 x 10  .

8.3.3  Quantitative Risk Estimates Based on Epidemiologic Data
     Epidemiologic studies have shown strong evidence that smelting and refin-
ing of nickel sulfide ores by pyrometallurgical refining processes cause nasal
and  respiratory  tract cancers  in  exposed  workers.   However, the  extensive
review in  this document  of epidemiologic data  on  nickel  has  not produced  suf-
ficient evidence  for  the estimation of  incremental  unit  risk values  for  any
nickel compounds except nickel subsulfide and nickel refinery dust.  This lung
and  nasal  cancer effect seen only for these latter nickel compounds might be
partially  or mostly  explained by the  formerly  high  dust  and  nickel  subsulfide
                                   8-162

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levels at refineries  (up  to 40 million times ambient levels of total nickel
and approximately 1,000 times the nickel levels recorded in some occupational
studies of workers not exposed to nickel subsulfide).  However, some of these
non-nickel subsulfide nickel exposures were 10,000 to 1,000,000 times those of
ambient nickel  levels  but still  showed no significant cancers  (Egedahl  and
Rice,  1984;  Cox et al.,  1981; Cragle et  al., 1984; Redmond et  al. ,  1983,
1984).  Conclusions from these studies, however,  were limited by other consid-
erations  detailed  in Section 8.1.  Furthermore,  the Roberts  et al. (1982,
1984)  studies comparing the sintering (including calcining and leaching) and
non-sintering workers at  Port Colborne and Sudbury,  Ontario, isolated all  the
increased lung cancer among the sinter workers.
     The  one  outstanding  contradiction  to  the hypothesis that the pyrometal-
lurgical  process  and nickel  subsulfide  exposures  are responsible  for  the
observed  cancer, is  the  high cancer  response in  the electrolytic tankhouse
workers observed in Kristiansand, Norway (Pedersen et al.,  1973, 1979;  Magnus,
1982).  Here, workers  exposed to nickel  sulfate  and nickel  chloride showed
large  increases  in both  lung and nasal  cancer.   These  increases  were  not
observed, however, in  the electrolysis operations at Port Colborne, Ontario
(Roberts et al. , 1984; INCO, 1976).   Sutherland (1959) reported an increase in
lung  cancer  among  electrolytic workers at Port Colborne, but the subsequent
analyses  of  updated  results confirmed that the increase was  limited to the
sintering, leaching,  and calcining areas of the refinery.
     The  following is  an  analysis of the epidemiologic  data available for a
quantitative assessment of risk from exposures to nickel.  In section 8.3.3.1.2,
the  dose-response  data available for a choice of  model are  evaluated.  In
section 8.3.3.2, that  analysis  is used to estimate the quantitative risk for
several available data sets.  Data  sets from  nickel  refineries in Huntington,
West Virginia; Copper Cliff, Ontario; Clydach, Wales; and Kristiansand,  Norway
are examined  because  they possess information available either for choice of
model or  for separation of risk by the type of nickel exposure.   The dose-response
information from Port  Colborne  (Roberts  et al.,  1984) is not presented here
because its  analysis  produces results very similar  to that of Copper Cliff.
8.3.3.1   Choice of Epidemiologic Models:   Investigation of Dose-Response and
Time-Response Relationships for Lung Cancer
8.3.3.1.1  Description of basic models.   The choice of a model  for risk extrap-
olation from human studies always involves many assumptions,  primarily because
                                   8-163

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the data  are very limited for quantitative  analysis.   Two assumptions are
nearly always necessary:

     (1)  Response is  some function  of  some cumulative dose  or exposure.
     (2)  The measure  of response,  either the excess  risk or the relative
          risk,  is a linear function of that cumulative exposure.

     For  nickel  subsulfide and  nickel  refinery  dust, the  assumption  of  a
cumulative exposure-response is probably a close approximation.  Furthermore,
cumulative exposures are  generally  the only data available.  With respect to
model, assumption (2) leads to a choice of two models:
     (A)  The excess additive  risk  model.   This  model  follows the assumption
that the  excess cause-age-specific  rate due to nickel exposure,  h-^t), is in-
creased by an amount proportional to  the cumulative exposure up  to that time.
In mathematical  terms this is h-^t)  = AXt, where  Xt is the  cumulative exposure
up to time t, and A is the proportional increase.   The total cause-age-specific
rate h(t) is then additive to the background cause-specific rate hQ(t) as  fol-
lows:

                             h(t) =  h0(t) + hx(t)

Under the assumptions of this model, we can estimate the parameter A by summing
the expected rates to yield:
where E.  is  the  total  number of expected cases in the observation period for
the group exposed  to  cumulative exposure X..  EQ. is the expected number of
cases due to background causes; it  is  usually derived from either county,
state, or national death rates, corresponding  to  the same age distribution as
the cohort at  risk.   W. is the number of person-years of observation for the
 th                    •*
j   exposure group, and the parameter A represents the  slope of the dose-
response model.  To estimate A, the  observed number of cause-specific deaths,
0., is substituted for E..
     (B)  The multiplicative or relative  risk model.   This model follows the
assumption that the background cause-age-specific rate at any time is increased
                                   8-164

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by an amount proportional to the cumulative dose up to that time.   In mathema
tical terms this  is  h(t) = hQ(t) •  (1 + AX.).   As above, we can estimate the
parameter A by  summing  over the observed and  expected  experience to yield:
                                       = 1 + AX
E. is estimated  by  the observed deaths 0, and the equation is solved for A.
 J                                       J
O./EQ, is the standardized mortality ratio, or SMR.
     In  many  previous quantitative risk assessments,  the  EPA has used the
relative risk model  in the form

                               BHX = PQ(SMR - 1)

where X  is the average dose  to  which an individual is  exposed  from birth
throughout  life,  and PQ  represents  the lifetime background  cause-specific
risk.  The two formulations are approximately equal  if one sets
                    A = Bu/Pn and X = IX,-N./(70-2N,)
                         H  u           J  J       J
where N. is the number of years exposed at level  X..   The multiplicative model
is one  in  which  the SMR is linearly  related  to  dose.   It assumes that the
time-response relationship is  constant; that is,  at any time since the start of
exposure (after a  latent period),  the SMR for a  set cumulative exposure is
constant.  Likewise,  in  the additive  model,  the excess mortality rate for a
set cumulative exposure  is  constant over time.   Under either  model,  excess
risk remains constant  once  exposure ceases.   As  indicated below, this result
is important in determining which of  these models holds for respective nickel
data sets.
8.3.3.1.2  Investigation of data sets.  Investigated in the following sections
are four data sets for nickel  refinery workers in which there is some evidence
for the  use  of  a  dose-response model   for risk assessment.   In addition to
dose-response,  differences due to exposures to different nickel compounds are
compared.  The  workers at the  Huntington, West Virginia refinery are subdivided
into those with  nickel  subsulfide  exposure vs.  those whose job exposures
should not have included the subsulfide form.   This separation  with dose-response
data does  not exist in the other refineries.  Although  the  Roberts et al.

                                   8-165

-------
(1984) study  clearly shows  refinery  dust with nickel  subsulfide  as  being
carcinogenic,  the analysis  is  confounded by the fact that refinery dust and
nickel subsulfide exposures  were  at such high levels compared to the rest of
the plant.  Only  the Enterline and Marsh (1982) data  appear to have lower
subsulfide levels, by which dose-response can be compared with the non-subsulfide-
exposed workers.  The dose-response curves  for  nasal sinus cancer will not be
investigated,  since  nasal  sinus cancer risk from nickel  is thought to be only
an occupational  hazard associated with the pyrometallurgical  process.
     8.3.3.1.2.1  Huntington, West Virginia.  The  study of  mortality in West
Virginia nickel  (pyrometallurgical) refinery workers by Enterline and Marsh
(1982) showed a  dose-response with cumulative nickel exposure versus lung can-
cer.   These results  are  reproduced (eliminating the nasal sinus cancers) in
Table 8-32.   Although there are only eight respiratory cancer deaths (ICD
161-163; there were also two nasal cancer deaths,  not included) in the refinery
workers (as defined  by employment  of 1+  years in the calcining  or casting and
melting department)  versus  7.55 expected,  the  data represent an important
attempt at finding  a dose-response relationship.   One significant feature of
the data  in Table 8-32  is that the dose is based on a cumulative exposure of
up to 20  years,  while  response  allows  a 20-year  latent period from first
exposure.
     Verification of the above dose-response model  can be  done in several
ways. As  a  first  approach, weighted regression fits  (for the refinery data
only) were attempted on the observed SMRs using the expected deaths as weights.
The weighted  regression  technique  merely allows more weight where there are
more expected deaths.  Statistically,  it stabilizes the variances of the SMRs,
which allows the  standard regression estimation techniques to be used.
     The  results  of the regressions are  presented in  Table 8-32.  For  the
refinery  data,  the  regression of SMR versus  dose  results in a  statistically
significant (p <  0.05) dose-response,  while there was no dose-response relation-
ship  for  the non-refinery workers, whether hired  before 1947  (a  subcohort
comparable in years  of follow-up and expected background rates to the refinery
workers), after 1946 (when the refinery was  torn  down), or  combined.  These
results are  suggestive  of  a linear relationship with the SMR for the  refinery
workers versus the non-refinery workers.  For the  additive risk model, neither
data  set  showed a statistically significant dose-response trend.
      8.3.3.1.2.2   Copper Cliff,  Ontario.   Another  data set  that suggests a
linear  relationship  between SMR and cumulative dose for nickel pyrometallur-
                                   8-166

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00
I
en
—i
                        TABLE 8-32.  WEST  VIRGINIA  NICKEL REFINERY AND  ALLOY WORKERS (NON-REFINERY)  :
                          OBSERVED AND  EXPECTED DEATHS FROM  LARYNX AND  LUNG CANCER  (ICD 161-163)
               AND SMR FOR  MALE NICKEL  WORKERS 20 YEARS AFTER  FIRST EXPOSURE BY CUMULATIVE  NICKEL EXPOSURE
                                            UP TO 20  YEARS FROM  ONSET OF  EXPOSURE
                                         (ALSO INCLUDES REGRESSION FITS FOR TWO MODELS)
Cumulative
nickel
exposure
mg Ni/m3 mo.
(mean X)
<10 (4.20)
10-24 (18.89)
25-49 (39.03)
50-99 (64.37)
100-199 (160.91)
S200 (563.80)
Linear regressions
(all

Ob-
served
0
0
0
3
1
4

Multiplicative model:

Additive model:




Refinery3
hired before 194

Ex-
pected 0/E
0.04 0
0.34 0
1.00 0
3.08 0.974
0.61 1.64
2.48 1.61
(weighted)
SMR = 0.413 + 0.
r = 0.82 (p <
j^ = 0.00017+1.
r = 0.55 N.S.
Non- refinery
7) (hired before 1947b)

0-Ed
PY
-0.00136
-0.00152
-0.001742
-0.0000431
0.0011611
0.001041

Ob-
served
9
15
9
10
4
None

Ex-
pected
13.22
13.26
10.35
4.43
5.35
at risk


0/E
0.681
1.13
0.87
2.26
0.748

(hired after 1946C)

0-E Ob-
PY served
-0.0005279 1
0.0002194 3
-0.0002281 0
+0.0023166 0
-0.0004528 0
None at

Ex-
pected 0/E
2.70 3.71
1.66 181.1
1.24 0
0.53 0
0.14 0
risk
(unweighted)
00259X
.05)
74xlO~6X

SMR
r
0-E
PY
r
= 1.15 - 0.
= -0.019 N.
0002X
S.




= 0.000712+4. lxlO~6X
= -0.232 N.
S.


All non-refinery
workers

Ob-
served
10
18
9
13
5
None at

Ex-
pected
15.92
14.92
11.59
4.96
5 49
risk


0/E
0.628
1.206
0.777
2.621
0 911

(unweighted)
SMR = 1
r = 0
5ii = o
PY u
r = 0
.16 + 0.0012X
.090 N.S.
.000301+1
.079 N.S.

7x!0"6X

    aNumber at risk = 259; person-years at risk = 4,501.4.

     Number at risk = 1,533; person-years at risk = 27,227.8.
    cNumber at risk = 1,287; person-years at risk = 6,359.7.

     See Tables 8-41 and 8-42 for the person-years (PY).

    Source:  Enterline and Marsh (1982).

-------
gical refinery workers  is  that of 495 workers  at  the Copper Cliff, Ontario
plant (Chovil et al., 1981).   The Copper Cliff  refinery, using the  same pyro-
metallurgical process and nickel matte from the same region as that shipped to
the West Virginia  refinery,  operated from 1948 to  1963.  A total of 54 lung
cancer cases and 37 deaths occurred versus 6.38 expected cases and 4.25 expec-
ted deaths.  The standardized  incidence ratio (SIR) and SMR were 8.5 and 8.7,
respectively.
     In analyzing  these  data for dose-response relationships, the  Chovil et
al. (1981)  study provided no measure  of exposure levels, but described condi-
tions as  being  "extremely  dusty."   The authors also  provided  a reference
suggesting that "actual  dust levels might have dropped by half"  after 1951 and
"thus it was thought  that it would be appropriate  to weight exposure for men
employed during the period 1948-51 by multiplying these exposures by a factor
of two for purposes of dose-response analysis."   [Roberts et al.  (1984) analyzed
the 37  lung  cancer deaths also and found  a  highly  significant  linear trend
with unweighted  duration of exposure.  The  authors'  numbers,  however, are
somewhat different than  those  of the Chovil  et al.  study presented here.]
     Table 8-33 presents the lung cancer incidence  and deaths during the study
follow-up  period  from January  1963  through  December 1978.   Since  exposure
ceased  in  1963, both  models assume that excess risk remains constant during
the follow-up period.  Weighted exposure  is presented as cumulative years of
exposure where exposure  during any  of the first 4  years was weighted double.
The authors grouped the  exposure years so that there were roughly equal numbers
of men  (and  hence  approximately equal expected  incidences and deaths) in each
of the  seven groupings.   This  eliminated the need to use a weighted analysis.
     The results of the  analysis show a highly  statistically significant (p <
0.005)  linear regression between both the  SMR and SIR  and cumulative exposure
(since person-years of observation are not given in the paper,  only the multipli-
cative  risk  model  can be investigated).   The results are basically identical
and provide  strong evidence  for the linear dose-response relationship.  Other
factors must be considered in the above analysis.   In addition to the dose-response
analysis,  Chovil and  co-workers (1981) discussed the distribution of cases by
year of  first employment.   They noted that all  but one of the 37 lung cancer
deaths  and  all  of  the nasal cancer cases  occurred  in  the subgroup  first em-
ployed from 1948 through 1951.   This part of the analysis has been extended in
a recent paper by Muir et al. (1985), who presented results on a larger Copper
                                  8-168

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               TABLE  8-33.   COPPER CLIFF REFINERY  WORKERS:  LUNG CANCER INCIDENCE AND  DEATHS (ICD 162)
                 BY SEVEN WEIGHTED EXPOSURE SUBGROUPS,  FOLLOW-UP FROM JANUARY 1963 to  DECEMBER 1978
00
IO
Weighted exposure (years)
<1 (0.5)a
Number of men
in subgroups (N,) 67
Cases of lung cancer
Observed 0
Expected 0.71
0/E 0
Linear regression
(0/E) = a+b- (years)
(0/E - 1) = b- (years)
Lung cancer deaths
Observed 0
Expected 0.47
0/E 0
Linear regression
(0/E) = a+b- (years)
(0/E - 1) = b- (years)
l-(2) 3-(4)

78 82

2 3
0.54 0.81
3.70 3.70

a = 1.07
™ ™.

0 3
0.36 0.54
0 5.56

a = -0.18
""
5-(6.5) 8-(9.5) 11-U2.5) £14(16)

77

7
0.90
7.78

b = 0.87°
b = 0.87C

4
0.60
6.67

b = 1.03b
b = 0.92C

70 66 65

10 16 16
1-02 1.14 1,26
9.80 14.0 12.70

linear correlation coefficient
linear correlation coefficient

6 13 11
0.68 0.76 0.84
8.82 17.11 13.10

linear correlation coefficient
linear correlation coefficient
Total

495

54
6.38
8.46

r = 0.
r = 0.

37
4.25
8.70

r = 0.
r = 0.








953C
983C





921b
96*
         Numbers in  parentheses are  estimated midpoints used in regression calculations.
        bp < 0.005.
        Cp < 0.001.

        Source:   Chovil et al.  (1981).

-------
Cliff cohort  (all  workers  with any exposure versus workers  with at least 5
years total service with the company in the Chovil et al.  study).  The results
of the Muir  et al. (1985) analysis, presented in Table 8-34, show  increased
lung cancer mortality not only by duration of exposure, but also for the early
exposure  cohort  versus the  late  exposure cohort.  For the  cohort  exposed
before 1952,  the SMRs  by duration of exposure are from 2.1 to 5.1 times those
of the later cohort.
     A partial explanation  for these  differences lies in  the  fact  that the
earlier cohort was followed longer (28 vs. 25 years  mean follow-up since first
exposure), and that the average length of exposure was 33 percent higher  (2.4
years vs.  1.8 years).   Even more significant is  the average amount of nickel
exposure  before and after  1952.   Chovil   et al.  (1981) hypothesized that  the
                                          o
exposure  of  the early  subcohort on a mg/m basis was twice as high  as that of
the  later cohort,  but examination of  a  chart  in a recent paper by Warner
(1984) appears to  put  that  ratio closer to three and possibly as high as  5 or
6.   Factoring  in  all  these data in a  qualitative way  further supports the
dose-response relationship of SMR as being linear with  cumulative dose.
     The  Copper Cliff  results  can be compared with those of the West Virginia
refinery  subcohort, since both subcohorts comprised workers exposed solely in
the higher risk nickel subsulfide areas.   While the  lung cancer relative risks
were much  higher  in  the Copper Cliff plant,  both dose-response relationships
appear linear, indicating that the functional  relationship spans a broad range
of nickel (subsulfide) exposure.
     8.3.3.1.2.3   Clydach. Wales.  The Copper Cliff results must also be  com-
pared with results for the refinery workers in Clydach, Wales.   The similarity
between Copper Cliff  and Wales in very high lung cancer relative risks  (about
10 for workers starting before 1915, and  about 6 for workers starting between
1915 and 1924), and in the apparent termination of exposure to the carcinogens
in both plants, allows for comparisons of the effect of decreased exposure and
for  investigation of the effect of stopping exposure on the relative risk.  In
Copper Cliff,  exposure ceased  by 1963, whereas in Clydach, the  relative risks
decreased  significantly for cohorts  entering after 1925 and were not statis-
tically elevated  for  those  entering after 1930,  indicating that exposure to
the  carcinogen ceased.  These  reductions seem to be concurrent with better
industrial hygiene conditions.
                                   8-170

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00
                                              TABLE 8-34.  COPPER CLIFF SINTER  PLANT:
                                   LUNG CANCER MORTALITY 15-29 YEARS SINCE  FIRST  EXPOSURE
                                          BY WORKERS FIRST EXPOSED BEFORE AND SINCE  1952,
                                                      BY DURATION OF EXPOSURE

Years of
sinter
exposure Obs.
<5 23
5-9 11
10+ 18
All 52
Mean
Age at entry
Years of exposure
Years of follow-up
First sinter
Before 1952
Exp. SMR
7.76 296
0.64 1730
1.51 1197
9.91 525
Before 1952
27
2.4
28
plant exposure
After 1952
Obs. Exp. SMR
3 2.15 139
1 0.30 339
1 0.23 431
5 2.68 187
After 1952
24
1.8
25
SMR ratio
r 1952 or later -,
1 before 1952 J
2.1
5.1
2.8
2.8
            Source:   Muir  et  al.  (1985).

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     Dose-response data from Clydach are presented several  ways, and inferences
can be made from these.  Data by Doll et al. (1977), Table 8-35, present lung
cancer mortality by year  of first employment.   As can be seen, the relative
risk steadily declines  from 10.0  for the subcohort first exposed before 1910
to 2.5 for the subcohort first exposed between  1925 and 1929.   This is consis-
tent with the relative  risk functionally related to cumulative dose,  since
each subcohort is probably  exposed for 5 years longer than the  one succeeding
it. It is also consistent with the Copper Cliff results (Table 8-34) where  the
early subcohort exhibited higher  lung cancer mortality than  the  later one.
     The other Clydach  data suitable for analysis of dose-response relation-
ships come from Peto et al.  (1984).   These data,  taken  from a slightly different
cohort than those of earlier studies on Clydach refinery workers,  categorize men
by duration of exposure in  the calcining furnaces.  The results, presented in
Table 8-36, show that  lung  cancer deaths rise significantly  (p < 0.05) in a
linear way with increasing years in the calcining furnaces.
     Peto  et  al.  (1984) present  dose-response  relationships  for  lung
cancer mortality in  terms  of low versus high  exposure,  with breakdowns of
each.   The results, shown in Table 8-37, clearly show increased relative risk
with increased duration of exposure.
     Peto et al.  (1984) also attempt  to combine data so that  many factors are
introduced simultaneously into  a  dose-response model.   In order to do this,
they had to review individual records, not only for vital status but also for
four other factors:  age  first  exposed,  year first exposed,  time since first
exposure, and exposure in high-risk jobs.   The  factors  were put into a Poisson
model  in which the  expected values, the expected cause-specific death rates,
were defined as a multiplicative function of the four factors (see Table 8-3).
Based on this additive  form of the risk model, Peto and co-workers found both
time-since-first-exposure and  the high  exposure categories  to be highly
significant (p < 0.001) after adjusting for the other factors.   The analysis
also found  age  at, and period of,  first exposure  not  significant.   The
nonsignificance of period of first exposure is  a curious and probably misleading
result, considering the lung cancer relative risk ratios in Table 8-35.  It is
quite probable that period of first exposure is just too highly correlated  with
exposure level as defined by duration in high-risk categories, and that if  one
factor is dropped from the model,  the other shows high statistical significance.
Since this is a survivor cohort starting in 1934, those first employed earlier
should be the same people with longer and probably higher cumulative exposure.
                                   8-172

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  TABLE 8-35.   CLYDACH, WALES NICKEL  REFINERY WORKERS:   TOTAL  MORTALITY  AND CANCER MORTALITY BY  YEAR OF FIRST EMPLOYMENT
oo
i
CO

Year of
first
employment
Before 1910
1910 - 1914
1915 - 1919
1920 - 1924
1925 - 1929
All periods
before 1930
1930 - 1944
All periods

Number
of men
119
150
105
285
103
762
205
967

Person-years
at risk
1980.0
2666.5
2204.0
7126.5
2678.0
16,655
4,538.0
21,193.5

Average
years
at riskd
16.6
17.7
21.0
25.0
26.0
21.9
22.1
22.0
of
Observed
(%)
117(98)
137(91)
89(85)
209(73)
60(58)
612(80)
77(38)
689(71)
Number
deaths
Expected
102.01
92.84
55.44
146.25
51.91
448.45
60.42
508.87
Lung
Observed
(%)
24(20)
34(23)
20(19)
50(18)
9(9)
137
8
145
cancer deaths
Expected
2.389
3.267
3.070
9.642
3.615
21.983
5.463
27.446

Ratio
10.0
10.4
6.5
5.2
2.5
6.2
1.5
5.3
    Between the years 1934 and  1971.  For  the two early subcohorts,  the person-years at risk start after the  20-year latent period.



   Source:  Doll  et al.  (1977).

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              TABLE 8-36.   CLYDACH,  WALES NICKEL REFINERY WORKERS:
                  LUNG CANCER MORTALITY BY DURATION OF YEARS
             IN CALCINING FURNACES BEFORE 1925 (CHI-SQUARE TESTS)
Years in calcining furnaces
Lung cancer deaths
Yes
No
Total
(percent)
Total chi square
Test for linear trend
Departure from linearity
0 1-2 3+
116 13 8
489 39 14
605 52 22
(19.2) (25.0) (36.4)
X2 =4.71 0.05 < p < 0.10
2
X2 =4.53 p < 0.05
i
X2 = 0.18 N.S.
i
Total
137
542
679
(20.2)



Source:   Adapted from Peto et al.  (1984).
              TABLE 8-37.   CLYDACH, WALES NICKEL REFINERY WORKERS:
            LUNG CANCER MORTALITY BY TYPE AND DURATION OF EXPOSURE
                      FOR MEN FIRST EMPLOYED BEFORE 1925

Low
exposure

High
exposure



Total
Years
in
furnaces
0
0
0
<2
2-5
5+

Years
in
CuS04
0
<5
5+
0
0
0

Number
of
men
404
99
50
63
45
18
679
Lung
Observed
64
21
15
17
14
6
137
cancer deaths
Expected
19.00
4.12
1.08
1.51
0.80
0.32
26.83

0/E
3.4
5.1
13.9
11.2
17.5
18.8
5.1
Source:  Peto et al. (1984).
                                   8-174

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     One factor that  is  consistent for the Clydach lung cancer data is that
relative risk decreased with time since entry.   While  the possible confounding
of these time  factors has been discussed above and in  section 8.1.1.7, we
discuss it at  this point  vis-a-vis the dose-response model.  The  significance
of this time-si nee-entry  factor  is that the relative risk (or proportional
hazards) model assumes  that (and is only valid if) the risk ratio (SMR)  is
constant over  time.   The  results,  shown in Table 8-38 for  the  Peto and  Kaldor
data, are similar to  results first shown by Doll et al.   (1970), who discussed
this decline.  Doll's explanations were:   (1)  that the men most heavily exposed
would die sooner, so  that the  survivors would actually  be  those who were less
heavily exposed; and  (2)  that  the effect of nickel is  lessened over time.
However, an  additional explanation is  related to the fact  that (a) the  nickel
concentration was so  high that 20 percent of the  cohort died of lung cancer,
and (b) the normal  age-specific incidence of lung  cancer (for cigarette smokers)
rises to the  fourth  power of age, anyway (Doll  and Peto, 1978).   With such a
high  nickel  exposure causing  such a large rise in lung cancer mortality,
maintaining such a high relative risk into old age would be close to impossible,
especially if  the  competing risks of  the  older ages  are  considered.   This
decreasing relative  risk  over  time-since-first-exposure might  not be observed
if  the  nickel  concentration were  not  so  high;  also,  the  decrease  was not
statistically significant until 40 years after first exposure.
     In contrast to the decreasing relative risk (Table  8-38),  the excess  risk
increases with time,  since  exposure is statistically  increased over the 0-19
years-si nee-entry group after adjusting for exposure.    If the additive (excess
risk) model  were the proper model, then the excess risk should be constant
over time after  adjusting for  exposure.   Again, however, an argument similar
to the one above can explain the rise to a peak in the 30-39 year group followed
by  a  decline.   Neither model  is completely supported or contradicted  by the
Clydach lung cancer data.
     8.3.3.1.2.4  Kristiansand, Norway.  The final  data set for which infer-
ences about  a  model  can be made is from the nickel refinery at Kristiansand,
Norway, the most recent update being that of Magnus et al.  (1982).  Although the
data provide neither  person-years  nor dose-response relationships, there  are
three points worth discussing.   The first is that, unlike the decrease seen in
the Clydach data, the relative risk for lung cancer remained essentially constant
                                   8-175

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               TABLE 8-38.   CLYDACH,  WALES NICKEL REFINERY WORKERS:
              LUNG CANCER MORTALITY BY TIME SINCE FIRST EXPOSURE
                        FOR WORKERS EXPOSED BEFORE 1925a



Years
since
entry
0-19
20 -
30 -
40 -
50+
Total



Person-
years
at risk
2,564.3
4,757.1
4,326.2
2,461.4
1,076.4
15,185.4



Lung cancer

Observed
6
35
55
31
10
137



deaths

Expected
0.55
3.14
7.59
9.20
6.37
26.85



Relative
risk
0/E
10.9
11.1
7.2
3.4b
1.6b
5.1
Excess
risk
0 - E

Person-
years
0.0021
0.0067°
0.0110b
0.0089b
0.0034
0.0073
 First year of observation was 1934,  or 10 years after the last person was
 first exposed.   Thus, the 6 deaths in the 0-19 years-si nee-entry group all
 occurred before 1945 and the 0-19 years category cannot possibly include
 any of the subcohort whose first employment was before 1915.
 Significantly different (p < 0.01) vs.  0-19 years after adjusting for
 exposure, year, and age at first employment.
cSame as b, but with p < 0.05.
Source:  Adapted from Kaldor et al. (1985, unpublished).   According to one of
the authors (Morgan), this paper is being revised, but the above information
has been verified.   Since other material was inaccurate pending this revision,
Dr. Morgan requested that the review of this paper be removed from Section 8.1.
(around 4)  from 15 years after first employment (Table 8-39).  Although these
figures are unadjusted  for  nickel  exposure, they do support a relative risk
model.  When these  figures  are  adjusted for smoking,  the  relative risk in-
creases until  35+ years post-exposure, after which  it decreases but still
remains significantly above  the  3-14 year time-since-first-employment group.
     The second point pertains to the authors'  attempt to adjust for the effect
of smoking and nickel exposure on lung cancer.   The results shown in Table 8-40
indicate that  the combined effect of nickel and smoking  is greater  than addi-
                                   8-176

-------
oo
                TABLE 8-39.  KRISTIANSAND, NORWAY DATA:  RATIO BETWEEN OBSERVED AND EXPECTED NUMBER OF CASES
                OF LUNG CANCER AMONG NORWEGIAN NICKEL WORKERS BEFORE AND AFTER ADJUSTMENT FOR SMOKING HABITS
Number of years since first employment
Year of
first
employment
1916-1929
1930-1939
1940-1949
1950-1959
1960-1965
Total
3-14
Unadj.
ratio
-
-
1.8
2.7
1.6
2.3
years
Adj.
ratio
-
-
1.8
3.2
2.7
2.7
15-24
Unadj.
ratio
-
-
2.7
5.1
4.2
4.0
years
Adj.
ratio
-
-
2.7
6.5
7.9
6.7
25-34
Unadj.
ratio
22.6
4.4
3.1
2.5
-
4.1
years
Adj.
ratio
22.6
5.6
5.0
4.8
-
8.0
35+
Unadj .
ratio
3.9
4.9
-
-
-
4.3
years
Adj.
ratio
3.9
6.7
-
-
-
5.6
      Source:  Magnus et al. (1982).

-------
CO
I
CO
           TABLE 8-40.  KRISTIANSAND, NORWAY DATA:  AGE-STANDARDIZED INCIDENCE OF CANCER OF THE  LUNG
                  AMONG NONSMOKERS AND SMOKERS IN A SAMPLE OF THE GENERAL POPULATION OF NORWAY
                                   AND AMONG EMPLOYEES AT THE NICKEL REFINERY
Group
Controls
Nickel
workers
Controls
Nickel
workers
Exposure
to
nickel
No
Yes
No
Yes
History
of
cigarette
smoking
No
No
Yes
Yes
Number
of lung
cancer
cases
9
5
116
39
Age-ad j.
lung
cancer
rate
0.19
1.60
1.13
3.27
Difference
vs.
controls
0.0
1.41
0.94
3.08
Ratio
vs.
controls
1.0
8.4
5.9
16.2
       Sample covered cases from 1966-1977.
       Per 1,000 person years.

      Source:   Adapted from Magnus et al.  (1982).

-------
tive but less than multiplicative.  Again, these analyses are not adjusted for
nickel exposure within the refinery; it is assumed that smokers and nonsmokers
within the  refinery  both experienced the same nickel exposure.  Finally, the
number of  nonsmoking cases is small and  no  firmer conclusions can  be  drawn.
     8.3.3.1.2.5   Conclusion -  Choice  of models.   All  analyses  for  which
dose-response estimates  for lung cancer  can be  calculated show a  positive
relationship, based  on either an  additive or multiplicative model,  and can be
considered  to support either model.  When time relationships are introduced,
there is evidence both supporting and contradicting both models.   The analyses
by Peto et al. (1984) and by Kaldor et al. (1985, unpublished) supported a model
less than  multiplicative over background, in the sense  that the relative risk
decreases with time-since-first-exposure.  On the other hand,  both their analyses
also showed that the  (additive) excess risk  increased with time-since-first-exposure.
The Norwegian data reported by Magnus et al.  (1982) also supported a model  which
was less than multiplicative but greater than additive when smoking was factored
in as being the most  important agent for non-nickel-induced lung cancer.  However,
in a separate analysis, Magnus et al. (1982) also reported a constant or increasing
relative risk  with  time-since-first-exposure, which can be interpreted as
supporting  a  relative risk model.  In this  part of  the analysis, Magnus and
co-workers did not report person-years exposed, so no estimates of excess risk can
be derived.  Therefore, for the four data sets analyzed below, both the additive
and multiplicative excess risk models will be fit whenever possible.
8.3.3.2  Calculation of the Incremental Unit Risk from Human Data
8.3.3.2.1  Huntington, West Virginia.
     8.3.3.2.1.1  Refinery workers.   In extrapolating from occupational to low
environmental risks  due  to nickel exposure,  the search for the best data set
focuses not on one that provides the greatest risk,  but on one that might best
approximate environmental  conditions.  This  usually  translates to choosing a
data set (or  sets)  which shows dose-response at low exposures, and for which
there is some reasonable measure  of exposure.  For the nickel refinery data,
we have chosen  the  Huntington,  West Virginia data set  (Enterline and  Marsh,
1982) as the primary data set for several reasons.   First, INCO (1976) reported
that dust  concentrations  around the calciners were  much  lower than those at
Clydach, Port Colborne,  or Copper Cliff.  Enterline and  Marsh  (1982)  cited
this and suggested that  nickel  exposures may have,  thus,  been considerably
                                   8-179

-------
lower.   Second, the Huntington refinery was similar to the other refineries in
operation and type of matte refined.   Third, it was the only U.S.  refinery, so
that background  rates were  more  relevant to an extrapolation  to  the  U.S.
environment. Fourth,  nasal cancer rates were elevated, certainly indicating a
significant exposure.  Fifth, Enterline and Marsh's breakdown of the data  and
their analyses were  more  conducive  to risk extrapolation than the  other data
sets.  Enterline and  Marsh  broke  their data set into three groups, with the
refinery group being well-defined  both by work location and time (the calciners
were removed in  1947).  Enterline and Marsh's refinery subcohort consisted of
266 men; 109 had worked in the calcining department for a year or more, and an
additional  157  had worked  in  the physically adjacent melting  and casting
department, comprising 6,738.9  person-years  at  risk (average follow-up 25.3
years) after exposure  had ceased.   Enterline and Marsh also presented their
data to adjust  for a 20-year latent period from first exposure and to count
exposure  only  up to  20  years  from  onset of  exposure.   These adjustments
resulted  in a  subcohort comprised of 259  men and 4,501.4 person-years of risk
after a 20-year  latent period.  Finally,  the authors presented their exposure
           3
as mg Ni/m months,  units in which both amount and duration are incorporated.
     The 259 refinery workers subcohort can be considered to have been exposed
to nickel  subsulfide.  These can be  compared directly with the 1,533 non-refin-
ery workers who  were assumed to have been  exposed  to nickel  oxide but not
nickel subsulfide.
     Enterline and Marsh's data for  lung cancer have already been presented in
Table 8-32.  The two basic  models,  the excess and the relative risk models,
have also  been  presented  above.  The additive or  excess  risk model can be
written as follows:

                                  Ej = Eoj + AXjWj                         (1)

where E.  is the number of  expected lung cancer deaths  in the  observation
                 th
period for  the  j   group  with  cumulative exposure  X.,  EQ. is the number of
expected  background  lung  cancer deaths, and W. is the person-years  exposed in
     th                                      ^
the j   group.   The multiplicative model does not use person-years of observa-
tion directly in its formulation.   It is

                              Ej = Eoj(l + AXj)                            (2)

                                  8-180

-------
Under either assumed model, the observed number of deaths in the j   exposure
group is a Poisson random variable with mean E..
                                              J
     Solution for the  estimate  of A will  be by the maximum likelihood method
and will follow closely the development of the risk assessment model  presented
in the  Updated  Mutagenicity  and Carcinogenicity Assessment of Cadmium (U.S.
EPA, 1985).   For the additive risk model,  the likelihood is
               L -
The maximum likelihood estimate (MLE) of the parameter A is obtained by solving
the equation

                                           n v w
                    d In L =  I - X.W. +   UJXjWj    _ n                   (3)
                    -dA—   j=l   J J   E0j + AXjWj - °

for A.

     The asymptotic variance for the parameter A is

                      2             c    y2 U2
                  , rd  In L,-l _ , °    X JW j    -,-1                     (4)
                                -
                            -I   ~
                                        p
                                        E
                            -                 .
                       d2A         j=l   0j     jj

This variance  can  then be used to  obtain  approximate 95 percent upper and
lower bounds for A.  The refinery worker data used to obtain the estimate of A
and  its  variance  are presented in  Table 8-41.   The cumulative exposure is
changed to a 24-hour equivalent times years  exposure  by the following factor:

l(mg/m3)' months =  l(mg/m3) -months x  1  year/12  months x 103ug/l mg  x  8/24
x 240/365
                = 18.26 |jg/m3  continuous equivalent exposure
                                   8-181

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                                   TABLE 8-41.   DATA USED TO ESTIMATE A AND ITS VARIANCE:
                                       ENTERLINE AND MARSH "REFINERY WORKERS" SUBGROUP
CO
CO
ro
Group
cumulative
exposure
(mg Ni/m3) mo.
(mean worker
exposure)
4.20
18.89
39.03
64.37
160.91
563.80
Continuous
|jg/m3
equivalent x
years
xi
76.69
344.93
712.69
1,175.40
2,938.22
10,294.99
15,542.92

Number
at
risk
KJ
2
14
36
106
21
80
259
Person-
years
obser-
vation
wi
29.4
223.4
574.2
1,858.1
355.9
1,460.5
4,501.4

Background
expected
Ew
0.04
0.34
1.00
3.08
0.61
2.48
7.55
Observed
lung
cancer
deaths
°,i
0
0
0
3
1
4
8

x.iwi
2,254.68
77,057.68
4.09 x 10s
2.184 x 106
1.046 x 106
1.5036 x 107
1.8759 x 107

X.iwi0i
0
0
0
6.552 x 106
1.046 x 106
6.0143 x 107
6.774 x 107
      aFactor:  1 (mg/m3) • months = 1 (mg/m3) •  months x years/12 months x 103ug/l mg x 8/24 x 240/365 = 18.26 (ug/m3)
       years continuous exposure, for 20 years.

      bZE0--X.   = 31,777.16.


      Source:   Enterline and Marsh (1982).

-------
An estimate of A = 9.66 x 10"8 is obtained by rewriting equation (3) filling
in the numbers from Table 8-41:

i R7CiQ v in? -     6.552 x 106     =     1.046 x 106     =    6.0143 x 107
i.o/sy x lu  - 3.08 + A(2.184xlOe)   0.61 + A(1.046xlOB)   2.48 + A(l. 5036x10"')

The Var (A) is estimated from equation (4) as 1.6 x 10    so that the S.E. (A)
= 1.28  x  10   and the 95 percent upper and 5 percent lower confidence limits
(UCL and LCL, respectively) are approximately AUCL = 3.07 x 10   and ALCL = 0,
respectively.

     Alternatively, the estimate of A derived from the multiplicative model is
obtained by solving the equation


                    d In L _  I -En.X. +   °JXJ   _ n                     (5)
                    ~^~ ~ J=1   J J    i + «xj "
for (A), which reduces to

             c -    3,526.2       ,    2,938.22          41,179.96
            lD — 	f	 "•" 	1	 T 	yy
                 1 + 25(1,175.40)   1 + A\2,938.22)   1 + S(10,294.99)
                                      A            -5
The solution to the above equation is A = 5.70 x 10  .

     The asymptotic variance for the estimate A of the multiplicative model is
           - E [d  1" Lj  -1 = c       Ojj   ]-l = 5.725 x ID'9
                  d2A         j=l  1
and  the  standard error is 7.57 x 10  ,  so that the 95 percent lower and upper
                          -4
bounds are 0 and 1.81 x 10  .
     It  becomes  obvious  from both  of the above analyses  that the asymptotic
variances of  the estimates are  quite large for both  models,  leading to upper
and  lower bounds which  encompass a broad range  of values, including zero
excess risk.   This  is due not  only to  the choice  of models  but  also to the
choice of the data set.   Even though we expect  it  to  provide  the  best low-exposure
                                   8-183

-------
estimates of the various data sets because its exposures are closest to environ-
mental exposures, the  small  sample size and relatively few person-years lead
to large variances.
     The fit of  each model is shown in Table 8-42 and the likelihood ratio of
the estimates, A, are  evaluated for each model.  Neither estimate is signifi-
cantly different from zero.
     8.3.3.2.1.2  Non-refinery workers.   The Enterline "non-refinery" subcohort
excludes the refinery workers from the calcining, melting,  and casting depart-
ments, essentially the areas  shown to be responsible for the  significant lung
and nasal  cancer excess in the large studies of  the Canadian  nickel  refiners.
As such, we  can  use  the pre-1947  Enterline  subcohort  to extrapolate to low
environmental exposures  under the assumption that the  actual nickel species
differences by department, and not the actual exposure levels, are responsible
for the differences in cancer responses.  The "refinery" cohort is presumed to
be exposed to a  much  higher proportion  of the  nickel subsulfide species.  The
pre-1947 non-refinery  subcohort is used  instead  of the  total  non-refinery co-
hort  because the pre-1947 subcohort1s background expected  lung cancer death
rates  and  years  of follow-up (indicative of  a similar  age  distribution) are
nearly identical to those of the pre-1947 refinery cohort,  while the background
rates  of the post-1946 cohort are considerably  lower.  Furthermore, the ear-
lier  group has 27,228  person-years of follow-up  after a 20-year latent period,
while  the  later  group  has only 6,360.
      Table 8-43  shows  the data from the Enterline pre-1947  non-refinery cohort
used  to  estimate the  parameters from  both  the additive  and  the multiplicative
models.  The results  corresponding to  those of the  refinery workers above  are
presented  in Table 8-44.  The estimate of A in the additive model is A = 6.055
x  10"8 (additive)  with standard  error  =  2.42 x  10~7,  so that the 95 percent
lower and  upper bounds are 0 and 4.58 x 10   .   For the multiplicative model,
the  estimate of A is  3.74 x  10"5 with standard  error = 2.23 x 10"  , so that
the  95 percent lower  and  upper bounds are 0 and  2.60 x  10   .  These  values are
used  below to estimate incremental unit risks  for cancer.
      8.3.3.2.1.3  Use of  estimates of A to  estimate unit risk.  Mathematically,
the  risk due to a constant  lifetime exposure  of x ug/m of nickel  in  air, in
the  presence of  all other competing risks,  may be expressed as
                                   8-184

-------
CO
I
CO
en
          TABLE 8-42.   EXPECTED LUNG CANCER DEATHS BASED ON THE ADDITIVE AND RELATIVE RISK MODELS

                         AND BOUNDS FITTED TO THE ENTERLINE AND MARSH  REFINERY DATA
Exposure Interval
mg Ni/m3 months
(24-hour/pg/m3
equivalent
• years
median)
<10
10-24
25-49
50-99
100-199
£200
(76.69)
(344.93)
(712.69)
(1,175.40)
(2,938.22)
(10,295)
Number of lung cancer deaths predicted under models
Additive3 Multiplicative13
Person-
years
29.4
223.4
574.2
1,858.1
335.9
1,460.5
4,481.5
Lower
Observed bound
0
0
0
3
1
4
8
0.04
0.34
1.00
3.08
0.61
2.48
7.55
MLE
0.040
0.347
1.040
3.291
0.711
3.933
9.36
Upper
bound
0.041
0.364
1.126
3.750
0.931
7.096
13.31
Lower
bound
0.04
0.34
1.00
3.08
0.61
2.48
7.55
MLE
0.040
0.347
1.041
3.286
0.712
3.935
9.36
Upper
bound
0.041
0.361
1.129
3.735
0.934
7.101
13.30
'Predicted = E
                   Q.
                          ...
= 9.66 x 10
"8
         =  3.07 x 10
                                                                 "7
      Likelihood ratio test for MLE slope: x2 = 0.76 N.S.



     'Predicted = En4[l +AX.].   &,. c =  5.70 x 10"5; £lir.  = 1:81 x
                   UJ      J      Hit                 ULL


      Likelihood ratio test for MLE slope: x2 = 0.41 N.S.
                                                                          = 0.
                             = 0.

-------
00
I
00
01
                                    TABLE 8-43.   DATA USED TO ESTIMATE A AND ITS VARIANCE:
                                         ENTERLINE AND MARSH "NON-REFINERY WORKERS"
                                                      PRE-1947 SUBGROUP
Cumulative
exposure
(mg Ni/m3) mo.
(mean worker
exposure)
4.20
18.89
39.03
64.37
160.91
563.80
24-hour
ug Ni/m3
equivalent
• years
xi
76.69
344.93
712.69
1,175.40
2,938.22
—
5,247.93
Number
at
risk
459
432
327
153
162
—

Person-
years
obser-
vation
W.
7,993.8
7,929.6
5,918.9
2,404.4
2,981.2
None at risk
Lung and
larynx cancer deaths
Expected
Eo.i
13.22
13. 26
10.35
4.43
5.35
—
46.61
Observed
°.i
9
15
9
10
4
—
47
X.iWi
613,044.5
2.7352xl06
4.2183xl06
2.8261xl06
8.7594xl06
—
1.9152xl07
X.iWi°.i
5.5174xl07
4. 1027xl07
3.7965xl07
2.8261xl07
3.8541xl08
—

°.iX.i
690.21
5,173.95
6,414.21
11,754.00
11,752.88

      aFactor:  1 (mg/m3) •  months = 1 (mg/m3)
       x years continuous exposure.

      bZEQ.-X.  = 33,890.45.


      Source:   Enterline and Marsh (1982).
months x 1 year/12 months x 103ug/mg x 8/24 x 240/365 = 18.26  (pg/m3)

-------
           TABLE 8-44.  EXPECTED LUNG CANCER DEATHS BASED ON THE ADDITIVE AND RELATIVE RISK MODELS

              AND BOUNDS FITTED TO THE ENTERLINE AND MARSH PRE-1947 "NON-REFINERY WORKERS" DATA
CO
I
CO
Exposure Interval
mg Ni/m3 months
(24- hour ug/m3
years-
equivalent Person-
median) X. years
<10 (76.69) 7,993.8
10-24 (344.93) 7,929.6
25-49 (712.69) 5,918.9
50-99 (1,175.40) 2,404.4
100-199 (2,938.22) 2,981.2
5,247.99 27,227.9
X2 goodness-of-flt (Neyman)
4 p value
Predicted = EQ. + AX.W.. A^LE =
Predicted = En,[l +AX.]. /L c =
Number of lung cancer deaths
Additive3
Observed
lung
cancer
deaths
9
15
9
10
4
47


6.055 x 1
3.74 x 10


Lower
bound
13.22
13.26
10.35
4.43
5.35
46.61
5.94
N.S.
O"8; Auc
* 1 IP 1



MLE
13.26
13.43
10.61
4.60
5.88
47.78
6.27
N.S.
L = 4.58 x
= 2.60 x


Upper
bound
13.50
14.51
12.28
5.72
9.36
55.37
12.48
<0.025
104\*LCL = 0.
10 ; A, p. = 0.
predicted under models
Multiplicative1*


Lower
bound
13.22
13.26
10.35
4.43
5.35
46.61
5.94
N.S.





MLE
13.26
13.43
10.63
4.62
5.94
47.87
6.31
N.S.




Upper
bound
13.48
14.45
12.27
5.78
9.44
55.42
12.62
<0.025



-------
               P(x) =
where hu(x,t)  is the age-specific death rate at age t due to a constant  life-
time exposure  at  level  x,  and h(t)  is  the  age-specific death rate for  all
other causes.  The  result  is derived by Gail  (1975).   The  upper limit « is
approximated by the median age of the 1978 U.S. Life Table stationary population.
The age-specific "competing  causes"  rates  h,(t) are also taken from the 1978
U.S. Vital Statistics rates.   For the refinery workers,  the age-specific death
ho(x»t) are those estimated as

                            h2(x,t) =9.66 • 10~8xt

for the additive model  with the MLE, and

                    h£(x,t) = hQ(t)  • (1 + 5.70 • 10"5xt)
for the multiplicative  model,  with the MLE.   The  results  of the unit risk
calculations  are  presented in Table 8-45,  based  on the estimates from  the
Enterline  refinery  cohort  and in Table 8-46 for  the  Enterline non-refinery
cohort estimates.  The results for the refinery workers (Table 8-45), show for
                                                                             -4
the additive model, the MLE estimate of the incremental  unit risk as 2.8 x 10
     3 -1                                                                  -4
(ug/m )    and  the  95 percent upper-limit incremental  unit risk as 8.8 x 10
(Mg/m3)"1; for the multiplicative model, the MLE estimate is 1.5 x 10"5  (Mg/m3)"
with the  95  percent UCL as  4.7  x  10  .  For. either model computed  under the
assumptions  of 10-  or 20-year latent periods,  the  results change  very  little.
For the  non-refinery workers, the estimates are  about  30 percent lower  than
those of  the refinery workers under either  the additive or  the multiplicative
model.  None of the parameter estimates are statistically significant.
     Table 8-45  also presents an estimate of  the incremental unit risk  under
the average  relative risk model used by CAG in cases where there is only one
dose-response  data  point.   This is  the same model  used below for estimates
based on  the Clydach and Kristiansand studies.  The model is
                              BH =  PQ(R-1)/X
                                    8-188

-------
    TABLE 8-45.   ESTIMATED RISKS FOR THE ADDITIVE AND MULTIPLICATIVE MODELS
            BASED ON THE ENTERLINE AND MARSH REFINERY WORKERS DATA
Incremental risk due to a constant lifetime
exposure of 1 ug/m3
Model S
Additive risk
Upper bound 3.07 x 10
MLE 9.66 x 10"8
Lower bound 0
Relative risk
-4
Upper bound 1.81 x 10
MLE 5.70 x 10"5
Lower bound 0
Average relative risk3

No lag
time
8.8 x 10"4
2.8 x 10"4
0
4.7 x 10"5
1.5 x 10"5
0
4.8 x 10"5
10-year
lag time
8.6 x 10"4
2.7 x 10"4
0
4.2 x 10"5
1.3 x 10"5
0
--
20-year
lag time
8.2 x 10"4
2.6 x 10"4
0
3.7 x 10"5
1.2 x 10"5
0
—
aBH = P0 (R-1)/X, where PQ =0.036, R = 8/7.55, and X = 57.4 ug/m3
 average continuous exposure for a 70-year lifetime.


where B^ =  the  incremental  unit risk estimate; PQ = the background lifetime
risk for lung cancer  = 0.036; R =  observed  divided  by expected lung cancer
deaths = 8/7.43  = 1.077 (subtracting expected nasal cancer  deaths)  and X =
average exposure  for  the  refinery cohort on a lifetime  continuous exposure
basis.   For the refinery workers:

              ZX.N./IN.            -
          X = —	»*• = 57.4 ug/m  continuous exposure equivalent
(see Table 8-41).   The  estimate of the incremental  unit  risk,  Bu, is 4.8 x
  _ c      o _ 1                                   _ c              n
10   (ug/m )  ,  close to the estimate of 1.5 x 10   derived above.  It is also

close to  the estimates  derived from the Clydach, Wales  and Kristiansand,

Norway study below.

     For the  non-refinery workers,  the  exposures were less than those of the
                                   8-189

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    TABLE 8-46.   ESTIMATED RISKS FOR THE ADDITIVE AND MULTIPLICATIVE MODELS
          BASED  ON THE ENTERLINE AND MARSH NON-REFINERY WORKERS DATA
Incremental risk due to a constant lifetime
exposure of 1 ug/m3
Model
Additive
Upper bound
MLE
Lower bound
Multiplicative
Upper bound
MLE
Lower bound
Average relative

ft
4.58 x 10"7
6.055 x 10"8
0
2.60 x 10"4
3.74 x 10"5
0
risk

No lag
time
1.3 x 10"3
1.8 x 10"4
0
6.6 x 10"5
9.5 x 10"6
0
3.2 x 10"5
10-year
lag time
1.3 x 10"3
1.7 x 10"4
0
6.1 x 10"5
8.6 x 10"6
0
--
20-year
lag time
1.2 x 10"3
1.6 x 10"4
0
5.2 x 10"5
7.7 x 10"6
0
—
refinery workers.   For these non-refinery workers,  the average continuous
                                              o
exposure lifetime equivalent was X = 30.0 pg/m ,  while R = 47/45.75 (subtract-
ing the  0.87 expected nasal cancer  deaths)  = 1.027.
before, the estimate of the incremental  unit  risk is
ing the  0.87  expected nasal  cancer deaths) =  1.027.   Since PQ = 0.036  as
                                                      -5
                            = 0.036 (0.027) = 3.2 x 10
                                30 ug/m3
8.3.3.2.2  Copper Cliff, Ontario.   Unlike the low exposure/low response of the
Huntington refinery, the Copper Cliff refinery was among the dustiest and most
hazardous, with  relative  risks  for lung cancer deaths  averaging  8.7 (Table
8-33).  These data  can  be analyzed the  same  way  as  those of the Huntington
refinery workers above,  except  that only the relative  risk model can be  fit
since the person-years experience is not available.
                                   8-190

-------
     In view of  the  excellent fit to the relative risk model, however, it is
most unlikely that a better fit could be established with the excess additive
risk model.
     In estimating exposure,  we  refer to Roberts et al.  (1984) who stated,
"High-volume exhaust-air samples at Copper Cliff indicate airborne nickel sul-
                              o                                     3
fide levels of  about  400 mg/m  in 1950, falling to around 100  mg/m towards
the end of  the plant's  productive  life  in 1958."  Following,  also,  the Chovil
et al.  (1981) organization of data, where they considered early exposure about
                                                                         3
double that of exposure after 1951, we  preserve the estimate  of 100 mg/m  for
                                     3
the later years but estimate 200 mg/m  as the early exposure.   These estimates
are also  consistent with those of Warner (1985),  who reported, from a single
40-hour sample on the floor of the sinter plant, a total dust concentration of
          o
46.4 mg/m .  An  accompanying  figure shows estimates of nickel concentrations
                        3           3
decreasing from 200 mg/m  to 50 mg/m  over time.
     The  results  of  the analysis are presented in  Table 8-47.   The maximum
likelihood  estimate AM|_E = 4.19 x lo"5  for  the relative  risk model, with  95
percent limits  of ALC|_  = 2.94 x 10"5  and AUCL = 5.44 x  10"5,  all  fit the data
satisfactorily.  These  estimates  translate to an incremental unit risk for 1
|jg/m3 nickel  refinery  dust exposure of 1.1  x 10    with  lower and  upper con-
fidence  limits  of  7.6  x 10   and 1.4 x 10   .  These narrow confidence limits
result from the excellent fit by the relative risk model to the data.
     For comparison, we fit the data to the  average relative risk model.   From
Table 8-33, it can be seen that
                           o                          P   ?ftn    i
     R = 8.70; X = 100(mg/nO • (IN.. • years ../IN..)  ' 2?  ' 3B3 ' 7U
                  3
       = 2.24 mg/m  continuous lifetime equivalent exposure,
PQ = 0.036 and
                              B      0.036(7.7)    =1.2xlo-4
                               H            o    O
                                   2.24 x 10Jug/nr

The  order  of magnitude difference in estimate  between these  two models proba-
bly  reflects the greater sensitivity  of  the  likelihood model  to  the  lower
exposure-response data.
                                   8-191

-------
                    TABLE 8-47.   DATA ON LUNG  CANCER DEATHS USED TO ESTIMATE A AND  ITS VARIANCE-
                       COPPER CLIFF REFINERY WORKERS (CHOVIL ET AL.)  RELATIVE RISK  MODEL ONLY
Weighted
cumulative
exposure
(mg/m3)
• years
50
200
400
650
oo •""
E 1250
ro
1600
Total
24-hour
mg Ni/m3
equivalent
• years
"j
10.95
43.80
87.60
142.35
208.05
273.75
350.40
2
X goodness-of-f1t (Neyman)
p-value

Lung cancer deaths
Number
at
risk
67
78
82
77
70
66
65
495
- First

Expected
Eoj
0.47
0.36
0.54
0.60
0.68
0.76
0.84
4.25d
four exposures

Observed
0 0
0 0
3 262.8
4 569.4
6 1248. 3
13 3558.8
11 3854.4
37
grouped:


2. 95x10" 5
0.62
0.82
1.93
3.11
4.84
6.88
9.49
27.74
3.35
N.S.
Fit of model0
with
A
4.19xlO"5
0.67
1.02
2.52
4.18
6.61
9.48
13.17
37.65
1.72
N.S.

A
5.44xlO"5
0.75
1.22
3.11
5.25
8.38
12.08
16.85
47.64
5.70
N.S.
a!00 mg/m3  estimated as average after 1952.  Before 1952 estimate  is 200 mg/m3.
 Conversion factor: I(mg/m3)*years = I(mg/m3)years x 103 pg/mg x 8/24 x 240/365 = 0.219 (mg/m3)-years continuous
 exposure.
 Units of A presented in (pg/m3) l for comparison with other studies.
dlE0.-X.  =  797.20.
Source:   Chovil et al. (1981); see also Table 8-33.

-------
8.3.3.2.3  Kristiansand, Norway.   The  latest  update  of this study (Magnus et
al., 1982) showed increased but differential  risks among different occupational
groups, specifically the  roasting-smelting and  electrolysis workers.   Nickel
compounds associated with the roasting  process include nickel subsulfide,
nickel oxide, and nickel dust.   Exposure in the  electrolysis process is mainly
to nickel chloride and  nickel  sulfate.  While measurements  taken  in the early
1970s showed  levels averaging  from  below 0.1 to 0.8 ug/m ,  earlier exposures
must have been considerably higher.   Determination of an estimate can be based
on a  modification  of the International Nickel  Company  (INCO) estimates from
                                                               3
the Clydach,  Wales plant which ranged from 20 mg to 50 mg Ni/m  between 1902
and 1930, and from 3 mg to 50  mg Ni/m3 in the mid to  late 1940s (INCO, 1976),
the higher exposures occurring in  the calciner sheds.  Based on these uncer-
tainties, we choose as  a range of estimates 3 mg to 35 mg Ni/m .  Estimates of
unit risk will be based on this range.
     The  study did not  record the number of  years  worked;  therefore  it  is
estimated that exposure lasted for about one quarter of a lifetime.
     For the  low end of the exposure range, we can estimate an average lifetime
exposure for workers as:

     exposure = 3 mg/m3 x ^f hours x ^ days x ^ lifetime x 10  ug/mg
                        3
              = 164 ug/m
                                                                         3
For  the high end  of the range,  average lifetime  exposure  is 1,918 ug/m .
     The  estimated unit lifetime probability, Bu, of  dying from  cancer from
                                                      3
exposure  to  these  airborne nickel  compounds at 1 ug/m  over 70 years  of con-
tinuous exposure is given by

                             BH = PQ(R - 1)/X

     The  total  relative risk for all  categories  estimated  for the Norwegian
workers  in  the  1982  update was  3.7  for  lung  and larynx cancer.   PQ = 0.036.
     The  estimated lifetime  probability of death from  lung and larynx cancer
                                  3
from  nickel  at  the rate of  1  ug/m   of continuous exposure  for  70 years  is
estimated as:
                                   8-193

-------
     BH = 0.036(2.7)7164 = 5.9 x 10   for the low exposure estimate and
                  -5
     BM = 5.1 x 10   for the high exposure estimate.

8.3.3.2.4  Clydach, Wales.   A risk assessment can also be made from the epide-
miologic data at  Clydach,  Wales (Doll et a!., 1977).  The lung cancer rates
prior to 1930 will  be used to calculate the  risk, because the observed cancer
risk declined dramatically after 1925; this reduction in risk was statistically
significant after  1930.   As  discussed in the epidemiology section, it is be-
lieved that the refining procedure used after 1925 led to the carcinogen being
drastically reduced  in  the environment.   INCO estimates that prior to 1930,
the concentration  of airborne nickel  dust in areas of high exposure was  20 mg
to 50 mg  Ni/m  .   Morgan (1985) estimated that exposure  in 1932 ranged from
                          3
approximately 8 to 42 mg/m  during a period when the plant was operating below
capacity.  Because not all workers were in high risk areas and those who were,
                                                                       3
probably were exposed for less than 8 hours/day,  we estimate 10 mg Ni/m  as the
lower bound to the range.
     Because the  exposure  estimate  used describes conditions between  1900 and
1930 only,  the  fraction of lifetime  exposed should  reflect  exposure before
1930 only.  This can be estimated as  shown in Table 8-48.
     Average number  of  years exposed 8,032.5/762 =  10.5 years,  or 0.15  of a
70-year lifetime.
     The average lifetime exposure for the workers, X, was:
          X = 10 mg/m3 x -   hours x     days x 0.15 lifetime x 103 pg/mg
                    3
          = 329 |jg/m  for the low exposure estimate and
          X = 1,644 pg/m  for the high-exposure estimate.
     The relative risk estimated by Doll was 6.2 for lung cancer (ICD 161-163).
The  lifetime  lung cancer  risk,  PQ,  to the  general  U.S.  population  is  approxi-
mately  0.036.
     The  range  of estimated incremental risk  of  death  from lung cancer from
nickel  at the rate of 1 ug/m  for 70  years of  continuous exposure  is:

                BH = (0.036) (5.2) = 5.7 x 10"4 (ug/m3)'1
                       329
                                    8-194

-------
      TABLE 8-48.  ESTIMATION OF FRACTION OF LIFETIME EXPOSED TO NICKEL
                       IN THE WORKPLACE, CLYDACH, WALES
Period
starting
employment
1902-1909
1910-1914
1915-1919
1920-1924
1925-1929
Total
Number
of men
119
150
105
285
103
762
Average number
of years exposed
x prior to 1930
x 25
x 17.5
x 12.5
x 7.5
x 2.5
2.5
Person-
years
= exposed
2975
1875
787.5
2137.5
257.5
8032.5
Source:  Adapted from Doll et al. (1977).
for the low exposure limit and
                       -4      3 -1
             = 1.1 x 10   (pg/m )   for the high exposure limit.
8.3.3.2.5  Conclusion and discussion:  Recommended unit risk estimates based on
human studies.  The  results  of  the  analyses  from  the  various models  and  human
data sets are presented in Table 8-49.  The estimates for the refinery workers
                   -5            -4
range from 1.5 x 10   to 5.9 x 10  .  The estimates from the Huntington refin-
ery are  somewhat  lower,  but this may be  merely a result of the  small  sample
size.   We note that if the two nasal cancer deaths are added to the eight lung
                                                                    -4
cancer deaths, the  incremental  unit-risk estimate becomes 2.0  x 10  , well
within the  range of  the  other  estimates.  If a  more specific  estimate is
                                                       "4
needed, we recommend  the  median  of  the range,  3.0 x 10  .  This  is  very  close
to the estimate derived from the additive risk model  for the Huntington refin-
ery workers.
     For the  Huntington  non-refinery workers,  the MLE estimates are about 30
percent  less  than those of  the  Huntington  refinery workers,  regardless of
which model  is used,  but neither of these estimates  is statistically significant.
                                  8-195

-------
                TABLE 8-49.   ESTIMATES OF INCREMENTAL UNIT RISKS
                        FOR  LUNG CANCER DUE TO EXPOSURE
                         TO  1 ug Ni/m3 FOR A LIFETIME
             BASED ON EXTRAPOLATIONS FROM EPIDEMIOLOGIC DATA SETS
Study Additive risk model
Huntington, W. Va.a
-4
Refinery workers 2.8 x 10
-4
Non-refinery workers 1.8 x 10
Copper Cliff, Ontario

Clydach, Wales

Kristiansand, Norway
Relative

-5
1.5x10 °
9. 5x10" 6
l.lxlO"5
-d
1.1x10 *
-^
5.1x10 °
risk model

™ Tl) f*
- 4.8x10 '
- 3.2x!0"5c
- 1.2xlO"4c
-4
- 5.7x10 H
-4
- 5.9x10 ^
          Median of range for                    ,
            refinery workers            3.0 x 10

aMLE estimates only.
b                                           -4
 Incremental unit risk increases to 2.0 x 10   if the two nasal  cancer deaths
 and expected nasal cancer deaths are included.

cAverage relative risk model.

In fact, an incremental risk estimate of zero fits the data (by the x2 goodness-
of-fit) as well as the MLE estimate for either model.  This is consistent with
the qualitative finding of no data supporting an excess risk for the non- refinery
nickel workers.  On the other hand, we cannot say that these non-refinery data
support a  zero increased  risk either,  since  the  estimates  are also  consistent

with those from the refinery workers.
     We conclude that:
     (1)   For  the  refinery  workers exposed to refinery  dust, an  incremental

unit risk  of


                               BH = 3.0 x 10"4 (ug/m3)'1


is consistent  with  results from the four data sets.
     Since nickel  subsulfide is a major component  of the refinery dust and
nickel  subsulfide  has been shown to be the most  carcinogenic nickel compound
                                   8-196

-------
in animals (supported by j_n vitro studies), this incremental unit risk estimate
might be  used for nickel  subsulfide  with a multiplication factor  of  2 to
account for the roughly 50 percent Ni^Sp  composition.  While nickel oxide and
nickel sulfate are two other important nickel compounds in  the refinery dust,
their carcinogenic potencies relative to the subsulfide have not been established
and the above  estimate  cannot  be used for  either  the oxide or the sulfate
form.
     (2)  For the non-refinery  workers,  those not exposed to nickel  subsulfide,
we are unable  to  estimate an incremental  unit risk.   The low exposure/low re-
sponse of these non-refinery workers  do not provide a sufficient data  base to
support a quantitative  estimate of the carcinogenicity of  these  compounds.
The wide range of quantitative  estimates,  including zero,  reflects this uncer-
tainty.

8.3.4  Relative Potency
     One of the uses of the concept of unit risk is to compare the potency of
carcinogens.   To  estimate  the  relative  potency on a per mole basis, the unit
risk slope factor is multiplied by the molecular weight and the resulting num-
ber expressed in terms of (mmol/kg/day)   .  This is called the relative potency
index.
     Figure 8-1 is a histogram  representing the frequency distribution of the
potency indices of 55 chemicals evaluated by the CAG as suspected carcinogens.
The actual  data  summarized by  the histogram are presented in  Table 8-50.
Where human data are available  for a compound,  they have been used to calculate
the index.  Where no human data are available, animal  oral  studies and animal
inhalation studies  have  been  used in that  order.   Animal  oral  studies are
selected over  animal inhalation studies because animal oral studies have been
conducted on  most of these  chemicals;  this allows potency comparisons by
route.
     The potency index for nickel refinery dust based on lung cancer in occupa-
                                                      +2
tional studies of nickel  refinery workers is 2.5 x 10  .   This is derived as
follows:   the range  of unit risk estimates based on both additive and relative
risk models is 1.5 x 10"5 - 5.9 x 10"4 (ug/m3)'1 (Table 8-48).  We first take
the midpoint of the  range 3.0  x 10   (ug/m )  .   This is converted to units of
           -I                                   3
(mg/kg/day)   , assuming a breathing rate of 20  m  of air per day and 70 kg per-
son.
                                   8-197

-------
u
UJ
20
18
16
14
12
10



6
4

2
0

4th QUARTILE
1 X
3rd QUARTILE 2nd QUARTILE. 1st QUARTILE
I I
I0+1 4X10+2 2X10+3

III I 1 1 1 I 1 1
— —



—
12
—
8


—
_


~~ 0
I





\








\



7




J
16






W ;


,

f

—

—
^^^

7
• —
___
3

:•:•:•:•:•:•:•:•: —
1 x:::-:.-:x::::: 1
i iiii ;iS ? tei:l
               -1
  2345
LOG OF POTENCY INDEX
Figure 8-1.  Histogram representing the frequency distribution of the potency indices of 55 suspect
carcinogens evaluated by the Carcinogen Assessment Group.
                                      8-198

-------
      TABLE  8-50.   RELATIVE  CARCINOGENIC POTENCIES AMONG  55  CHEMICALS EVALUATED BY THE CARCINOGEN ASSESSMENT GROUP

                                             AS  SUSPECT  HUMAN  CARCINOGENS
00
I
I—»
to
Level
of evidence
Compounds
Acrylonitrile
Aflatoxin B,
Aldrin
Ally! chloride
Arsenic
B[a]P
Benzene
Benzidene
Beryllium
1,3-Butadiene
Cadmium
Carbon tetrachloride
Chlordane
CAS Number
107-13-1
1162-65-8
309-00-2
107-05-1
7440-38-2
50-32-8
71-43-2
92-87-5
7440-41-7
106-99-0
7440-43-9
56-23-5
57-74-9
Humans
L
L
I

S
I
S
S
L
I
L
I
I
Animals
S
S
L

I
S
S
S
S
S
S
S
L
Grouping
based on
IARC
criteria
2A
2A
3

1
28
1
1
2A
2B
2A
2B
3
Slope , Molecular
(mg/kg/day)" weight
0.24(W)
2900
11.4
1.19xlO"2
15(H)
11.5
2.9xlO~2(W)
234(W)
2.6(W)
1.0xlo"1(I)
6.1(W)
1.30X10"1
1.61
53.1
312.3
369.4
76.5
149.8
252.3
78
184.2
9
54.1
112.4
153.8
409.8
	 T-? 	 > —
Order of
magnitude
Potency (log-,-,,
indexc inde^
lxlO+1
9xlO+5
4X10"1"3
9x10" l
2xlO+3
3xlO+3
2x10°
4xlO+4
2xlO+1
5x10°
7xlO+2
2xlO+1
7xlO+2
	 TT 	 f _ 1 -t _.
+ 1
+6
+4
0
+3
+3
0
+5
+1
+1
+3
+1
+3

-------
TABLE 8-50.   (continued)
Level
of evidence









00
i
ro
o
o









Compounds
Chlorinated ethanes
1,2-Dichloroethane
Hexachloroethane
1,1,2,2-Tetrachloro-
ethane
1,1,2-Trichloroethane
Chloroform
Chromium VI
DDT

Dichlorobenzidine
1,1-Dichloroethylene
(Vinylidene chloride)
Dichloromethane
(Methylene chloride)
Dieldrin
2,4-Dinitrotoluene
Diphenlhydrazine
Epichlorohydrin
Bis(2-chloroethyl)ether
CAS Number

107-06-2
67-72-1

79-34-5
79-00-5
67-66-3
7440-47-3
50-29-3

91-94-1
75-35-4

75-09-2

60-57-1
121-14-2
122-66-7
106-89-8
111-44-4
Humans

I
I

I
I
I
S
I

I
I

I

I
I
I
I
I
Animals

S
L

L
L
S
S
S

S
L

S

S
S
S
S
S
Grouping
based on
IARC
criteria

28
3

3
3
28
1
28

28
3

28

28
28
28
28
28
Slope ,
(mg/kg/day)

9.1xlO~2
1.42x10 *•

0.20 ,
5.73x10"^
7xlO~2
41(W)
0.34

1.69
1.16(1)

1.4xlO"2(I)

30.4
0.31
0.77
9.9xlO~3
1.14
Molecular
weight

98.9
236.7

167.9
133.4
119.4
100
354.5

253.1
97

84.9

380.9
182
180
92.5
143
Potency
i ndex

9x10^
3x10°

3x10
8x10°
8x10°
4xlO+3
lxlO+2

4xlO+2
lxlO+2

1x10°

lxlO+4
6xlO+1
lxlO+2
9X10"1
2xlO+2
Order of
magnitude
(lognn
index'

+1
0

+1

+1
+4
+2

+3
+2

0

+4
+2
+2
0
+2
                                          (continued on the following page)

-------
TABLE 8-50.   (continued)
Level
of evidence







00
i
IN3
0
t '*










Compounds
Bis(chloromethyl)ether
Ethylene dibromide (EDB)
Ethyl ene oxide
Heptachlor
Hexachl orobenzene
Hexach 1 orobutadi ene

Hexachl orocycl ohexane
technical grade
alpha isomer
beta isomer
gamma isomer
Hexachl orodi benzo-
dioxin
Nickel refinery dust
Nickel subsulfide
Ni trosami nes
Dimethyl ni trosami ne
Di ethyl ni trosami ne
Di butyl ni trosami ne
CAS Number
542-88-1
106-93-4
75-21-8
76-44-8
118-74-1
87-68-3



319-84-6
319-85-7
58-89-9

34465-46-8

0120-35-722

62-75-9
55-18-5
924-16-3
Humans
S
I
L
I
I
I



I
I
I

I
S
S

I
I
I
Animals
S
S
S
S
S
L



S
L
L

S
S
S

S
S
S
Grouping
based on
IARC
criteria
1
2B
2A
2B
2B
3



2B
3
3

2B
1
1

2B
2B
2B
Slope _,
(mg/kg/day)
9300(1)
41
3.5x10 (1
3.37
1.67
7.75xlO~2


4.75
11.12
1.84
1.33

6.2xlO+3
1.05(W)
2.1 (W)

25.9(not by
43.5(not by
5.43
Molecular
weight
115
187.9
:) 44.1
373.3
284.4
261


290.9
290.9
290.9
290.9

391
240.2
240.2
*
q*) 74.1
q*) 102.1
i 158.2
Order of
magnitude
Potency (log,n,
indexc index ;
lxlO+6
8xlO+3
2xlO+1
lxlO+3
5xlO+2
2xlO+1

+ ..
1x10 ,
3xlO+|
5xio.;
4x10 e-

2xlO+6
2.5xlO+2
5.0X10"*"2

2xl0^3
4xlO+J
9x10 c
+6
+4
+1
+3
+3
+1


+3
+3
+3
+3

+6
+2
+3

+3
+4
+3
                                       (continued on the following page)

-------
                                                        TABLE 8-50.   (continued)
00
ro
o
ro
Level
of evidence
Compounds CAS Number
N-nitrosopyrrolidine 930-55-2
N-nitroso-N-ethylurea 759-73-9
N-nitroso-dimethylurea 684-93-5
N-nitroso-diphenylamine 86-30-6
Humans
I
I
I
I
Animals
S
S
S
S
Grouping
based on
IARC
criteria
28
28
28
28
Slopeb ,
(mg/kg/day)
2.13
32.9
302.6 ,.
4.92x10
Molecular
weight
100.2
117.1
103.1
198
Potency
i ndex
4xXj
3x10 *
1x10°
Order of
magnitude
(log1Q)
index
+2
+4
+4
0
            PCBs                     1336-36-3

            Phenols
             2,4,6-Trichlorophenol    88-06-2

            Tetrachlorodibenzo-
28
28
4.34
1.99x10
                   -2
324
197.4
1x10
4xl(T
                                                                                                                    +3
p-dioxin (TCDD)
Tetrachl oroethy 1 ene
Toxaphene
Trichloroethylene
Vinyl chloride
1746-01-6
127-18-4
8001-35-2
79-01-6
75-01-4
I
I
I
I
S
S
L
S
L/S
S
28
3
28
3/28
1
1.56x10 3
5.1xlO"2
1.13
l.lxlO*2
1.75xlO"2(I)
322
165.8
414
131.4
62.5
5xlOT'
8x10°
5xlO+2
1x10°
1x10°
+8
+1
+3
0
0
            S = Sufficient evidence; L = Limited evidence; I = Inadequate evidence.

            Animal slopes are 95% upper-bound slopes based on the linearized multistage model.   They are calculated based on
            animal oral studies, except for those indicated by I (animal inhalation), W (human occupational exposure), and H
            (human drinking water exposure).  Human slopes are point estimates based on the linear nonthreshold model.  Not all
            of the carcinogenic potencies presented in this table represent the same degree of certainty.   All are subject to
            change as new evidence becomes available.   The slope value is an upper bound in the sense that the true value (which
            is.unknown) is not likely to exceed the upper bound and may be much lower, with a lower bound approaching zero.
            Thus, the use of the slope estimate in risk evaluations requires an appreciation for the implications of the upper
            bound concept as well as the "weight of evidence" for the likelihood that the substance is a human carcinogen.

            The potency index is a rounded-off slope in (mmol/kg/day)   and is calculated by multiplying the slopes in
            (mg/kg/day)   by the molecular weight of the compound.

-------
     3.0 x 10"4 ((jg/m3)"1 x 1 day x  1 U9   x 70 kg = 1.05 (mg/kg/day)'1
                            20 m3   103 mg

For  current  purposes,  we  multiply this estimate  by  240.25,  the molecular
weight of  nickel subsulfide,  the principal component  of nickel refinery dust.
Multiplying by the  molecular weight of 240.25 gives a potency index of 2.5 x
  +2
10   . Rounding off  to  the nearest order of  magnitude gives a value of +2,
which is the  scale  presented  on the horizontal  axis of Figure 8-1.  The index
           +2
of 2.5 x 10   lies in the third quartile of the 55 substances that the CAG has
evaluated  as  suspect carcinogens.  For nickel subsulfide  the  estimate of
                                                                        +2
potency is adjusted  by  a factor of 2,  giving a potency index of 5 x  10   .
     Ranking of the  relative  potency  indices  is subject to  the uncertainty of
comparing  potency  estimates  for  a number of  chemicals based  on different
routes of  exposure  in  different species using  studies whose  quality  varies
widely.   Furthermore, all  of the  indices are  based on estimates of low-dose
risk  using linear  extrapolation from the observational range.   Thus,  these
indices are not valid  to compare potencies  in  the experimental  or observa-
tional range if linearity does not exist there.  Finally,  the index for nickel
refinery dust is subject to the additional  uncertainty of  not being able to
accurately quantify  the  potencies  of  the specific nickel carcinogens  in the
refinery other than nickel subsulfide.
8.4  SUMMARY
8.4.1  Qualitative Analysis
     Nickel, at  least in some forms,  should  be considered carcinogenic to
humans when  inhaled.   Evidence  of a cancer risk is strongest in the sulfide
nickel matte  refining industry.  This evidence includes  a  consistency of
findings across different studies in different countries, specificity of tumor
site (lung  and nose),  high relative risks, particularly  for nasal cancer, and
a dose-response relationship by length of exposure.   There are also animal  and
rr\ vitro studies  on  nickel  compounds which support the concern that at least
some forms  of  nickel  should be considered carcinogenic.  The animal studies
employed mainly injection as  the route of exposure, with some studies  using
inhalation as the exposure route.  While the majority of the compounds  tested
in the  injection .studies caused tumors at the  injection site only, nickel

                                  8-203

-------
acetate, a soluble  salt,  and  nickel  carbonyl  have caused distal  site primary
tumors.   The  relevance of  injection  site  only tumors in animals  to human
carcinogenic hazard via inhalation,  ingestion,  or cutaneous  exposure is uncer-
tain.    Thus,  the  bulk of the evidence  from  injection studies on different
nickel  compounds, which  is  summarized in the following sections, constitutes
only  limited  evidence for  carcinogenicity.  Three low-dose drinking water
studies and one  diet  study  with soluble nickel compounds have not shown any
increase in tumors of the dosed animals.
     It is possible that it  is the nickel ion that is carcinogenic once inside
the cell, and that potential differences in carcinogenic activity of different
nickel compounds are a function of the particular nickel  compound's ability to
enter the cell.   Following this hypothesis, experiments have been conducted to
correlate carcinogenicity via injection with  physical,  chemical, and bio-
logical activities.   While it is suggested from such studies that, on a quali-
tative  basis, some  nickel  compounds  may have  higher carcinogenic potential
than  others,  the relationships  between physical,  chemical, and biological
indices  are  not currently well  enough  established to allow a quantitative
comparison.    Following  the  reasoning  that there  may  be  differences among
nickel  compounds with  regard  to  carcinogenic potency,  the following  summaries
present  the  qualitative evidence for  the  most-studied nickel compounds or
mixtures of compounds.
8.4.1.1  Nickel  Subsulfide (Ni0Sp).   The evidence for carcinogenicity among
the different nickel compounds is strongest for nickel subsulfide.   Workers in
the areas of refineries where nickel  subsulfide is believed  to have constituted
most  of the  nickel exposure  have  increased  risks of  cancers  of the nasal
cavity  and  lung.  Nickel subsulfide has  also been  shown to  be  carcinogenic by
numerous routes  of  administration in  several animal  species and  strains.  The
observation of  adenomas  and adenocarcinomas in rats  exposed to nickel  subsul-
fide  by inhalation  and when injected  into  heterotopic  trachea  grafts  supports
the concern of human carcinogenicity when nickel  subsulfide  is inhaled.
     The observation  of  injection-site sarcomas  from  the various studies on
several  species  of  animals, the  induction  of morphological  transformations of
mammalian cells  in  culture,  the induction of sister chromatid exchanges, the
inhibition  of DNA  synthesis,  the  induction  of DNA  strand  breaks,  and the
observation of  nickel  concentrating  in the cell  nucleus  all  further support
the carcinogenicity of nickel subsulfide.   Furthermore, in  terms of potency,
nickel  subsulfide has been  shown to be  either the most potent or among the
most potent of the  nickel compounds in all the comparative tests.
                                   8-204

-------
8.4.1.2  Nickel Refinery Dust.   Based on large excesses  of lung and nasal
cancer in  several  epidemiologic  studies  in  different countries, including
strong exposure response relationships, nickel  refinery dust from pyrometallurgical
sulfide nickel matte refineries can be classified  as a known human carcinogen.
The excess risks are  greatest in the  dustier parts  of the refinery (e.g.,
calcining  and  sintering).   Nickel  compounds  in the  dustier  areas  include
nickel subsulfide,  nickel  sulfate, and nickel  oxide.
     Nickel refinery  dust also has  been studied for potential carcinogenicity
in animals.  Nickel refinery flue dust containing  68 percent Ni3$2,  20 percent
NiSO., and 6.3 percent NiO gave  either negative  or equivocal results  from
inhalation studies  in rats.   However, intramuscular injections produced strong
tumor responses in both rats  and  mice.  The observation of  pulmonary squamous
cell carcinomas in two of five surviving  rats that were exposed  by  inhalation
to  feinstein  dust  (an intermediate  product of nickel  refining containing NiS,
NiO, and metallic  Ni) further supports nickel refinery dust  as  a potential
human carcinogen.   These dusts have not been studied using jn vitro short-term
test systems or tests for macromolecular interactions.
8.4.1.3  Nickel Carbonyl [N1(CO)^].  Nickel  carbonyl was the first nickel com-
pound suspected of causing  cancer in  humans.  Detailed analysis  of  the  epide-
miologic data  from a  study  of workers  at  the sulfide  nickel matte refinery  at
Clydach, Wales, however,  did not find that workers  in the reduction area,
where  nickel  carbonyl exposure was present, had  an  excess risk of cancer.
With  respect  to animals,  however, nickel  carbonyl administered  to  rats via
inhalation produced pulmonary adenocarcinomas, and intravenous injections into
rats  gave  malignant  tumors  at various sites.   Biochemical studies have shown
that the nickel from  nickel carbonyl is bound to DNA and inhibits RNA polymerase
activities.  The data taken together provide sufficient evidence that  nickel
carbonyl is an animal carcinogen and  should be considered a probable  human
carcinogen.
8.4.1.4  Nickel Oxide (NiO).  The evidence  for the carcinogenic potential of
nickel oxide is equivocal and, in general, the study designs have been  inadequate
for a  determination  of carcinogenicity specific to  nickel  oxide.  With  regard
to  epidemiologic studies, nickel  oxide generally  occurred  as  one component  of
the refinery dust in  the very dusty calcining and sintering areas of pyrometal-
lurgical sulfide nickel matte refineries where the lung and nasal cancer risks
were  high.  Yet in other occupational  settings, such  as nickel alloy manufac-
                                   8-205

-------
taring and nickel oxide ore refining,  where nickel  oxide exposure was believed
to occur without  nickel  subsulfide  exposure,  increased cancer risks were not
found.  This latter finding, however,  may be simply a function of the intensity
of nickel exposure, as these latter occupational settings were far  less dusty
than the nickel matte  refineries.  Exact comparisons of the ambient  levels of
nickel in these  dustier  areas  with  ambient levels of nickel  in occupational
settings where nickel  oxide,  nickel  dust,  or nickel  compounds other than the
subsulfide are believed  to be  the primary exposure are difficult because of
possible improvements in industrial  hygiene prior to the time when the measure-
ments were taken  and  because of presumed differences in sampling techniques.
     In  animals,  while nickel  oxide was carcinogenic  in  five intramuscular
injection studies  and one  intrapleural  injection study,  it  produced only
injection site tumors.   The response  by the intrapleural  route,  however, was
strong and  approached the response  produced by  Ni'3S?.   The results of one
inhalation study  with Syrian  golden  hamsters, a  strain  resistant  to lung
tumors,  showed  neither a  carcinogenic  effect alone nor  a co-carcinogenic
effect with  cigarette  smoke.   An  inhalation study  with  rats was  inconclusive.
Responses from the various intramuscular injection studies varied depending on
the dose and animal  species and strains used.  To the  extent that  injection
studies  can  be used to compare carcinogenic potency, the  injection  site tumor
results  indicate  that  NiO is most likely less carcinogenic than Ni^^.  Cell
transformation assays  give equivocal  results:   negative  with SHE  cells  and
positive with BHK-21  cells with an activity about  one tenth of that of Ni-S^.
8.4.1.5  Nickelic Oxide  (Ni,,03).  Nickel (III) oxide (Ni'203)  has neither been
evaluated in human studies,  nor been  tested sufficiently  in animal  studies to
allow  any definite conclusions to be drawn about  its carcinogenic potential.
In animals,  nickelic  oxide gave a marginal tumor  response by intracerebral
injection, but intramuscular injections of the same animals produced no injec-
tion-site sarcomas.  It produced no tumors in a second  intramuscular injection
study.   However, Ni^O., is  more  active in the induction of morphological trans-
formations of mammalian cells  in culture than is 'NiO.  The transforming activ-
ity in BHK-21 cells approximates that of N13S2, but in  SHE cells it  shows only
about  one tenth the activity of Ni3S«.
8.4.1.6  Soluble Nickel Compounds [NiSOvNiC12,Ni(CH3COO)2].  The evidence for
three  soluble nickel compounds, nickel sulfate (NiS04), nickel chloride (NiCl,,),
and  nickel  acetate [NiCCH3COO)2], is summarized here as  a class both  because
of  hypothesized  similar modes  of action of the soluble compounds and  because
                                   8-206

-------
of limited testing  of  the different compounds.   The results from four intra-
muscular Injection  studies and one  ingestion study on nickel sulfate were
negative. Two  low-dose drinking water studies with nickel  acetate and one
low-dose diet study with nickel sulfate were also negative.   The only study on
nickel chloride was  an intramuscular implantation study, which gave negative
results.   Both  the  sulfate and the  chloride, however,  Induce morphological
transformations of  mammalian cells  1n  culture,  sister chromatid exchange,
chromosomal  aberrations iji vitro, gene mutations 1n yeast, and mammalian cells
in culture, and decrease  fidelity of DNA synthesis.  The observation of pul-
monary tumors in  strain A mice from the administration of  nickel acetate  by
intraperitoneal  injections  and the  ability  of  nickel  acetate to transform
mammalian cells  in  culture  and to inhibit RNA  and DNA  synthesis provides
limited  evidence  for the carcinogenicity of  nickel acetate and supports  a
concern  for  the carcinogenic potential  of  other soluble nickel  compounds.
However, testing of  these soluble nickel compounds is too limited to support
any definitive judgment regarding their carcinogenic potential.
     With respect to humans,  the evidence is somewhat contradictory and must
be examined carefully.  Electrolysis workers at  the refinery  in  Kristiansand,
Norway experienced the highest lung cancer risk in the refinery.   Nickel expo-
sures  in the  electrolysis  area were predominantly  to nickel  chloride and
nickel sulfate, both soluble  nickel  salts.   Other  nickel exposures may also
have occurred,  however, due to the proximity of the electrolysis process  to
other parts of  the  plant  and because of the  removal of impure nickel waste
from the electrolysis cells by the electrolysis workers.
     Lung cancer risk was not found among electrolysis workers at Port Colborne,
Ontario, but  it is  unclear whether the study had  sufficient  power to  detect
such an  increase.   It is also possible that there were qualitative and quanti-
tative differences 1n exposure between the electrolysis workers at Port Colborne
and those at Kristiansand.
8.4.1.7  Nickel  Sulfide (NiS).  Significantly elevated mortality from pancreatic
and prostate cancer was found among  30,000 nickel  workers employed by  INCO in
the Sudbury region  of  Ontario.   These workers had mining but no sinter plant
or office experience.   In the mines, the workers were reported to be exposed
to nickel/Iron  sulfide,  not  exposed to asbestos,   and exposed to only low
levels of radon daughters.  It was not indicated what other exposures may have
been present.   Both  pancreatic  and prostate cancer  mortality  showed a dose-
response by duration of employment.

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     Elevated lung and  laryngeal  cancer was found among a different group of
nickel workers with mining experience who also worked in the Sudbury region of
Ontario but were  employed  by Falconbridge,  Ltd.   Presumably, this  group  of
workers had  similar exposures to  those of the INCO workers; however,  the
Falconbridge workers  included individuals  who had  sinter plant experience
which may have produced the elevations in lung and laryngeal cancer mortality.
     The individual results  from  these two studies provide some suggestions
that  the  nickel  mining occupation and  perhaps nickel  sulfide exposure are
associated with an  excess  risk of cancer.  This  suggestion of  an increased
risk  is weakened,  however, by the  lack  of consistency  in  tumor site mortality
between the two studies, the  inclusion  of workers as miners,  in both studies,
who  had  occupational  experience  other than nickel  mining,  and  the "lack  of
complete exposure data for  the  mining operations.  As  a  result,  the human
evidence for  an association  of nickel sulfide or the  mining  occupation with
excess cancer risk is considered inadequate.
      In  animals,  crystalline nickel  sulfide has been  found to  be a potent
carcinogen by  the intramuscular  and intrarenal injection routes of exposure.
Its  carcinogenic  activity  equals  that  of N13$2 by the  intramuscular  route and
is more active than Ni^Sp by  the intrarenal route.  It also induces morpholog-
ical  transformations  of mammalian cells in culture with an activity equal to
that  of  NioSp.   In the same  sets  of experiments,  however, amorphous nickel
sulfide  was  inactive  both as  an  animal  carcinogen  by the  intramuscular  or
intrarenal  injection  routes  of exposure and in the  induction  of morphological
transformations of mammalian  cells in culture.
      X-ray powder diffraction of insoluble  crystalline material  present in the
tumors of  Ni^S^-injected mice indicated that a  conversion of Ni3$2 to  Ni^Sg
and  NiS  had occurred.  The conversion  of  nickel  subsulfide to  NiS and  other
nickel sulfide forms  heightens the  concern for  the carcinogenicity of NiS.
      In  summary,  the  evidence from animals  for the  carcinogenicity of crystal-
line nickel  sulfide is limited.    There  is  no evidence that amorphous nickel
sulfide  is carcinogenic.
8.4.1.8   Nickel Metal (Ni).   In  most of the epidemiologic studies where there
was  believed to be exposure  to nickel  metal,  statistically significant  excess
cancer risks were not found.  In studies of workers believed to be exposed to
metallic nickel  dust where significant excess risks were found  (e.g.,  nickel/
chromium alloy manufacturing  and  nickel/cadmium battery  workers),  there was
                                    8-208

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concurrent exposure to  other  known or suspected lung carcinogens which con-
found the results.
     In animals, nickel  metal,  in the form of dust or pellets, leads to the
induction of malignant sarcomas at the site of injection in rats,  rabbits,  and
possibly  hamsters.  However,  the few inhalation studies on  metallic nickel
have not shown that it produces lung tumors.   Based on the strong tumor response
from intramuscular injection  studies,  the observation of adenomatoid lesions
of the  respiratory tract from inhalation  studies, and the ability of powdered
nickel   to  induce morphological  transformation of mammalian cells in culture,
metallic  nickel  should be  considered  to have limited animal  evidence  for
carcinogenicity.

8.4.2  Quantitative Analysis
     The  results  of  the analysis  of  lung cancer data in  four sulfide  ore
nickel   refineries suggest  a range of carcinogenic potency for nickel  matte
                                   -5           -4         3 -1
refinery dust  in workers  of 1 x 10    to  6 x 10   (ug Ni/m  )   .  As a best
                                                     -4         3-1
estimate, we take the  median  of the range,  3.0  x  10   (ug  Ni/m )   as the
incremental unit risk  due  to a  lifetime  exposure  to  nickel  matte  refinery
dust.   Since the major component in this refinery dust is nickel  subsulfide,
which has  been  shown  to be the  most carcinogenic nickel compound in animals
(supported by |n vitro studies), this incremental unit risk might also be used
for  extrapolating risks  due to  nickel  subsulfide exposure.   If this is done,
increasing the  unit risk by a factor of 2 to adjust for the approximately 50
percent  Ni^S^  in the  refinery  dust is appropriate.  For  nickel  oxide  and
nickel   sulfate, two other  important nickel compounds in the refinery dust,
their carcinogenic potencies  relative  to the subsulfide have not been estab-
lished and the above unit risk estimate cannot be used for either the oxide or
the sulfate form.
     An upper-limit incremental  unit  risk for nickel  subsulfide exposure has
                                                                -3      3 -1
also been  estimated from a  rat  inhalation  study  as q? = 4.8  x  10    (ug/m)   ,
                                                -3       3-1
with a  maximum likelihood  estimate of 3.2 x  10    (ug/m )  .  The  estimate
based on  subsulfide exposure  to human refinery workers is about one-fifth of
this estimate.   The lower estimate based on human studies is recommended for a
quantitative extrapolation.
     For the non-refinery workers, those  not  exposed to nickel  subsulfide, we
are unable to estimate an incremental  unit risk.   The low exposure/low response
of these  non-refinery  workers  do not provide a  data  base  sufficient for a
                                   8-209

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quantitative estimate.  The animal data base of relative carcinogenic activi-
ties of the  various  nickel  compounds is also not  sufficient to estimate a
quantitative potency  of these  compounds  relative to either nickel  subsulfide
or nickel  refinery dust.
8.5  CONCLUSIONS
     There are only three compounds or mixtures of nickel compounds which can
currently be classified as either Group A or B, according to EPA's classifica-
tion scheme for evaluating carcinogens (U.S. EPA,'1984).   Nickel refinery dust
from pyrometallurgical sulfide nickel matte refineries is classified as Group
A. Nickel  subsulfide  is  believed to be the major  nickel  component of this
refinery dust.  This,  along  with the evidence from animal  studies on nickel
subsulfide, is sufficient to conclude that  nickel subsulfide is also in Group
A.  While  there is inadequate evidence from epidemiologic studies with regard
to evaluating the carcinogenicity of  nickel  carbonyl,  there is  sufficient
evidence from animal  studies to classify it as Group B2.   The available evidence
for other  nickel  compounds  is  insufficient to evaluate their carcinogenicity
or to  calculate quantitative unit risk estimates for them.  However, there is
a reasonable  probability that the ultimate  carcinogenic form of nickel is the
nickel  ion.   On this  basis, all  compounds of nickel might be  regarded as
potential  human  carcinogens, with  potency differences among the compounds
based  on their physical  and/or  chemical  properties which  determine their
ability to enter the cell and be converted to the nickel  ion.   At the present,
the bioavailability  of different nickel  compounds  is  not  well understood.
     Estimates of carcinogenic risk to humans  from exposure via inhalation of
nickel  refinery dust  and nickel  subsulfide have been  calculated  from cancer
epidemiology  studies.   The  quantitative  incremental  unit  risk for nickel
                         -4      3 -1
refinery dust is 3.0 x 10   (ug/m )  ; the quantitative unit risk estimate for
nickel  subsulfide is  twice  that for nickel  refinery  dust.  Comparing the
potency  of nickel subsulfide to 54 other compounds.which the EPA has evaluated
as suspect or known  human carcinogens, nickel  subsulfide would rank in the
third  quartile.
                                   8-210

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Cooper, W.  C.; Wong, 0.  (1981)  A  study of mortality  in a population of nickel
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Cornell, R. G.  (1979)  A report on mortality patterns  among stainless steel
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Costa,  M.;  Mollenhauer, H. H.  (1980a)  Carcinogenic  activity of  particulate
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Costa, M.;  Nye, J.;  Sunderman, F. W., Jr.  (1978)  Morphological transformation
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Costa, M.; Abbracchio,  M.  P.; Simmons-Hansen, J.  (1981a) Factors  influencing
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Cragle, D.  L.; Hollis,  D.  R. ; Shy, C.  M.;  Newport,  T. H.  (1983)  A retro-
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DeMeester, P.;  Goodgame,  D.  M.  L.;  Skapski, A.  C.;   Smith, B. T.  (1974)
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Doll, R. (1970) Practical steps towards the prevention of bronchial carcinoma.
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Ededahl, R.;  Rice, E.  (1983)  Cancer incidence at a hydrometallurgical nickel
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Eichhorn, G.  L.; Shin, Y. A.  (1968)  Interaction of metal ions  with polynucleotides
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Evans,  R.  M.;  Davies,  P.  J.  A.;  Costa,  M. (1982)  Video time-lapse microscopy
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Farrell, R. L. ; Davis, G. W. (1974) The effects  of participates  on  respiratory
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Gitlitz, P. H.;  Sunderman,  F.  W., Jr.; Goldblatt, P. J.  (1975)  Aminoaciduria
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Harris, C.  C.   (1973)   The  epidemiology of different  histologic types of
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Heck, J. D.;  Costa,  M.  (1982)   Surface reduction of amorphous NiS particles
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Hernberg,  S. ;  Westerholm,  P.;  Schultz-Larsen,   K. ;  Degerth, R.;  Kuosma, E. ;
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Hildebrand,  H. F. ; Biserte,  G.   (1979a) Nickel  sub-sulphide-induced leiomyosar-
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     metastasizing  pulmonary tumors  in rats induced  by the inhalation of
     nickel carbonyl. Am. J.  Pathol. 46: 1027-1038.

Sunderman, F.  W., Jr.; Hopfer,  S. M. (1983) Correlation between carcinogenic
     activities of  nickel compounds and their potencies  for  stimulating  erythro-
     poiesis  in rats.  In: Sarkar,  B.,  ed. Biological aspects of metals and
     metal-related  diseases.  New York,  NY:  Raven  Press;  pp.  171-181.

Sunderman, F.  W. , Jr.; Maenza,  R. M. (1976) Comparisons of  carcinogen!cities
     of  nickel  compounds in  rats. Res. Commun.  Chem.  Pathol.  Pharmacol. 14:
     319-330.

Sunderman, F.  W., Jr.; Lau,  T.  J. ;  Minghetti,  P. F.;  Maenza, R.  M.;  Becker,
     N.;  Onkelix, C.; Goldblatt,  P.  J.  (1975)  Effects  of manganese on tumori-
     genesis  and metabolism  of  nickel  subsulphide.  Proc. Am.  Assoc. Cancer
     Res.  16: 554.

Sunderman, F. W., Jr.;  Kasprzak,  K.  S.; Lau, T. J.  (1976)  Effects  of  manganese
     on  carcinogen!city and  metabolism of  nickel  subsulfide.  Cancer Res.  36:
     1790-1800.

Sunderman, F. W., Jr.;  Maenza, R. M.; Allpass,  P.  R.;  Mitchell, J.  M.; Damjanov,
     I.;  Goldblatt,  P.  J.  (1978) Carcinogenicity of nickel subsulfide in
     Fischer  rats and Syrian hamsters after administration by various routes.
     In:  Schrauzer, G. W. , ed.  Inorganic  and  nutritional  aspects of cancer.
     New York,  NY:  Plenum Press;  pp.  55-67.

Sunderman, F.  W., Jr.;  Maenza, R. M.;  Hopfer,  S.  M.; Mitchell,  J.  M. ; Allpass,
     P.  R.;  Damjanov, I. (1979a)  Induction of renal cancers  in rats by  intra-
     renal  injection of  nickel subsulfide.  J.  Environ. Pathol. Toxicol.  2:
     1511-1527.

Sunderman,  F.  W.,   Jr.;  Taubman,  S.  B.; Allpass,  P.  R.  (1979b)  Comparisons of
     the carcinogenicities  of  nickel  compounds  following intramuscular ad-
     ministration to rats. Ann. Clin.  Lab.  Sci.  9: 441.

Sunderman,  F.  W., Jr.; Albert,  D. M.;  Reid,  M.; Dohlman, H.  0.  (1980) Induction
     of  amelanotic  uveal  melanomas  in Fischer  rats by  an intraocular injection
     of  nickel  subsulfide. Fed. Proc.  Fed.  Am.  Soc.  Exp. Biol.  39:  330.
                                    8-224

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Sunderman, F. W. ,  Jr.;  McCully,  K.  S.;  Rinehimer, L. A. (1981) Negative test
     for transplacental carcinogenicity of  nickel  subsulfide  in  Fischer  rats.
     Res.  Commun. Chem.  Pathol.  Pharmacol.  31: 545-554.

Sunderman, F. W.,  Jr.;  McCully,  K.  S. ;  Hopfer, S. M. (1984) Association bet-
     ween erythrocytosis and renal cancers in rats following intrarenal injec-
     tion of nickel compounds.  Carcinogenesis 5:  1511-1519.

Sutherland,  R.  B.  (1959)  Summary of  report  on respiratory cancer mortality
     1930-1957.   Port Colborne, Ontario,  Canada:  International Nickel Company
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Sutherland,  R.  B.  (1969)  Mortality  among sinter  workers.  Copper Cliff,  ON,
     Canada: International Nickel Company of Canada, Ltd.

Sutherland,  R.  B.  (1971)  Morbidity  and mortality  in selected occupations  at
     the  International  Nickel Company of Canada,  Ltd.,  Copper Cliff,  Ontario,
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Swierenga, S. H.  H. ;  Basrur, P.  K.  (1968)   Effects  of  nickel on cultured  rat
     embryo muscle cells.   Lab.  Invest.  19:   663-667.

Theiss, J. C. (1982) Utility of injection site tumorigenicity in assessing the
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     2: 213-222.

Toda,  M.  (1962) Experimental studies  of occupational lung cancer.  Bull.  Tokyo
     Med. Dent.   Univ.  9: 440-441.

Torjussen,  W.;  Anderson,   I. (1979)  Nickel  concentrations  in  nasal  mucosa,
     plasma, and urine  in active and retired nickel workers. Ann. Clin. Lab.
     Sci. 9: 289-298.

Torjussen, W.;  Haug, F.-M.S.; Andersen, I.  (1978)  Concentration  and distribution
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     studied  with atomic  absorption  spectrophotometric  analysis  and with
     Timm's  sulphide silver method.  Acta Otolaryngol. 85:  449-463.

Torjussen, W.;  Solberg, L. A.; Hjdgetveit, A.  C. (1979a) Histopathologic  changes
     of  nasal mucosa  in nickel  workers. A pilot  study. Cancer (Philadelphia)
     44:  963-974.

Torjussen,  W.;  Solberg,  L.  A.;  Hrfgetveit,   A. C.  (1979b) Histopathological
     changes of the nasal  mucosa in active  and retired nickel workers.  Br. J.
     Cancer  40:   568-580.

Traul,  K.  A.;  Kachevsky,  V.; Wolff,  J.  S.  (1979) A rapid in vitro assay for
     carcinogenicity of chemical  substances  in mammalian cells  utilizing an
     attachment -  independence endpoint.  Int. J.  Cancer  23:  193-196.

Treagan,  L.;  Furst, A.  (1970)  Inhibition  of interferon synthesis in mammalian
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Van Soestbergen,  M.;  Sunderman,  F.  W. (1972) Ni-63 complexes in rabbit serum
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Warner, J.  S. (1984) Occupational exposure to airborne nickel in producing and
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Warner, J.  S. (1985) Estimating past exposures to airborne nickel compounds  in
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     eds.  Progress in nickel toxicology.  Oxford, United Kingdom: Blackwells,
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Webb, M. ;  Heath,  J.  C.;  Hopkins, T.  (1972)  Intranuclear  distribution  of  the
     inducing metal in primary rhabdomyosarcomata induced in the rat by nickel,
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Wehner, A.  P.; Busch, R.  H.; Olson, R. J.; Craig, 0.  K. (1975) Chronic inhala-
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Wehner,  A. P.;  Dagle,  G. E.; Milliman, E. M. (1981)  Chronic inhalation expo-
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     30:   9-22.
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     Pathol.  Jpn.  33:  45-58.             J *

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     compounds by  reaction  with heavy metals.   Naturwissenschaften 59:  82.
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                    9.  NICKEL AS AN ESSENTIAL ELEMENT
     Nickel has been established as an essential element in prokaryotic organisms
and  experimental  animals,  and there is  suggestive  evidence  that the element
may  also play an essential role in humans (National Academy of Sciences, 1975;
Thomson, 1982; Nielsen, 1980).
     Mertz  (1970)  has  established  criteria  for  essentiality  of trace elements
as micronutrients, and this discussion will focus primarily on one of the most
critical  of these:  demonstration  of  specific  deficiency-related syndromes
which are prevented or cured by the element alone.
     Earlier studies in  trace-element  nutritional  research could  not demon-
strate any consistent effects of nickel deficiency (Spears and Hatfield, 1977;
NAS, 1975)  owing  in part to the technical difficulties of controlling nickel
intake  because  of  its  ubiquity.   Later  studies have demonstrated adverse
effects  of  nickel deprivation  in  various animal  models, including  chicks,
cows, goats, minipigs,  rats, and sheep.
     Nielsen and  Higgs (1971)  have shown  a  nickel-deficiency  syndrome in
chicks fed nickel  at levels of 40 to 80 ppb (control diet:   3 to 5 ppm) charac-
terized by swollen hock joints, scaly dermatitis of the legs, and fat-depleted
livers.  Sunderman  et al.  (1972)  observed  ultrastructural  lesions such as
perimitochondrial  dilation of  rough endoplasmic reticulum in hepatocytes of
chicks fed  a diet having 44 ppb nickel.   Nielsen  and Ollerich  (1974) also
noted  hepatic  abnormalities  similar to  those reported by  Sunderman et al.
(1972).
     Growth  responses  to  nickel   supplementation  have been  reported for
rats (Nielsen et al., 1975; Schnegg and Kirchgessner, 1975a;  Schroeder et al.,
1974) and pigs  (Anke et al., 1974; Spears, 1984;  Spears et al.,  1984).   Rats
maintained  on  nickel-deficient diets  through  three successive  generations
showed a 16 percent and 26 percent weight loss in  the first and second genera-
tions,  respectively, when  compared to  nickel-supplemented  controls  (Schnegg
and  Kirchgessner,  1975a).   Pigs fed a diet containing 100  ppb nickel also
showed signs of decreased growth rate.  However, body weight gain was not
affected in  neonatal pigs fed supplemental concentrations of 5  and 25 ppm
nickel  (NiCl2)  in  milk-based diets  (Spears et  al.,  1984).   Spears and co-workers
noted that the discrepancy between their study and that of  others may  have
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been due to  the  higher nickel  content (0.12 and 0.16 ppm) in the basal  diets
of animals, this level  being adequate for growth of pigs fed milk-based  diets.
     Effects on  reproduction  have  been documented in  rats  (Nielsen  et  al.,
1975) and  swine  (Schnegg  and  Kirchgessner,  1975a; Anke et al.,  1974), mainly
in terms of  increased mortality during the  suckling period  (rats) and smaller
litter size (both species).
     Nickel also appears  to be essential for ruminants, the requirements of
which are  higher than  for other animal  species  (Spears  and Hatfield, 1977;
Spears, 1984).   Spears  and Hatfield (1977) demonstrated disturbances  in  metab-
olic parameters  in  lambs  maintained on a low-nickel  diet (65 ppb),  including
reduced oxygen consumption in  liver homogenate preparations, increased activity
of alanine transaminase,  decreased  levels  of  serum  proteins,  and enhanced
urinary nitrogen excretion.  In a follow-up study, Spears et al. (1978) found
that these animals  had  significantly lower microbial  urease activity.
     Schnegg and Kirchgessner  (1976; 1975b)  demonstrated that nickel  deficiency
in rats leads  to reduced  iron content in organs  and  iron deficiency anemia,
resulting  from markedly impaired iron absorption.  Spears et al. (1984) found
that additional  nickel may  also improve the iron and zinc status of  neonatal
pigs.  The mechanism through  which nickel might  enhance  iron  absorption  is
still  unclear.   While  nickel  might  act  enzymatically to convert ferric to
ferrous iron (a  form more soluble for absorption), it might also promote  the
absorption of  iron  by  enhancing its complexation  to  a molecule that can  be
absorbed (see below) (Nielsen, 1984).
     Nickel  also appears  to adhere  to other criteria  for  essentiality (Mertz,
1970), e.g.,  apparent  homeostatic  control, partial   transport  by specific
nickel-carrier proteins (see Chapter 4), and specific requirements in a  number
of proteins  and  enzymes.   Fishbein et al.  (1976) have reported that jackbean
urease is  a natural nickel metalloenzyme.   It is possible that rumen bacterial
urease may also  have a specific nickel  requirement (Spears  et al., 1977).  In
this connection, Mackay and Pateman (1980)  have  found that  a mutant  strain of
Aspergillis  nidulans,  which is  urease-deficient, requires nickel (II) for
restoration of urease-activity.  In particular, the strain carrying a mutation
in the ure-D locus was responsive to nickel.
     More  recently,  King  et al. (1985)  have  studied the activation of the
calmodulin-dependent phosphoprotein phosphatase,  calcineurin, by various diva-
lent cations.   Activation of  calcineurin by nickel(II)  was observed in the
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presence and absence of calmodulin despite the presence of high concentrations
of chelators.  Their  study  results suggested to the authors that  nickel(II)
may play a physiological role in the structural stability and  full activation
of the calcineurin enzyme.
     To date, the most extensive evidence for identified, specific biochemical
functions of  nickel  has come  from studies of microbial  systems.   In such
systems, the element  is  presented in:  (1) the hydrogenases from several bac-
teria  that  mediate the  Knall  gas reaction  (2H2  + Op  —>  2H20) (Albrecht
et al., 1982), (2) the sulfate-reducing  bacterium  Desulfovibrio  gigas  (Legall
et al., 1982), and (3) the  enzyme  carbon monoxide  dehydrogenase  in acetogenic
bacteria (Drake,  1982).   Furthermore,  a number of  studies  have established
that nickel  is the core metal in the tetrapyrrole, Factor F-30 (see reviews of
Thauer, 1982 and Nielsen, 1984), the cofactor for methanogenic bacteria enzymes
mediating methane formation.
     Evidence for the  role  of  nickel  in human physiology is not conclusively
established.   The  study  of  Rubanyi and  co-workers  (1982)  showing profound,
transitory increases  in  circulatory nickel shortly  after parturition  has been
linked to a  possible  role in control of  atonic bleeding and placental  separa-
tion (see Chapter 4).   In  a recent review of trace elements,  Nielsen  (1984)
postulated that  nickel  was  likely required by humans  and suggested that  a
dietary requirement of 35 ug daily (based upon extrapolation from animal data)
could be reasonably expected.
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9.1  REFERENCES
Albrecht, S.  P.  J. ;  Graf, E. G. ;  Thauer,  R.  K.  (1982)  The EPR properties of
     nickel   in  hydrogenase from methanobacterium thermo-autotrophicum.  FEBS
     Lett. 140:  311-313.

Anke, M.; Grun,  M.;  Dittrich, G.; Groppel,  B.;  Hennig, A.  (1974) Low nickel
     rations for growth and reproduction in pigs. In: Hoekstra, W. G.; Suttie,
     J.  W.;  Ganther, H. E.; Mertz, W. eds. Trace element metabolism  in animals.
     Baltimore,  MD: University Park Press; pp. 715-718.

Drake, H. L. (1982) Occurrence of  nickel in carbon monoxide dehydrogenase from
     Clostridium pasteurianum and Clostridium thermoaceticum.  J.  Bacteriol.
     149: 561-566.

Fishbein, W.  N.; Smith, M. J.;  Nagarajan,  K. ;  Scurzi,  W.  (1976)  The first
     natural nickel metalloenzyme: urease (abstract). Fed.  Proc.  Fed. Am.  Soc.
     Exp. Biol.  35: 1680.

King, M.; Lynn,  K.  K.;  Huang, C. (1985) Activation of the  calmodulin-dependent
     phosphoprotein phosphatase  by nickel  ions.  In: Brown, S.  S.; Sunderman,
     F.  W.,  Jr., eds. Progress in  nickel toxicity. Oxford,  England:  Blackwells
     Ltd.; pp. 117-120.

Legal!,   J.;  Ljungdahl,  P. 0.; Maura, I.;  Peck,  H.  D., Jr.;  Xavier, A.  V.;
     Maura,  J.  J.  G. ;  Teixera, M.;  Huynh,  B.  H.;  DerVartanian, D.  V. (1982)
     The  presence  of redox-sensitive nickel  in  the periplasmic  hydrogenase
     from Desulfovibrio gigas.  Biochem.  Biophys. Res.  Commun.  106:  610-616.

MacKay,   E.  M.;  Pateman, J.  A.  (1980) Nickel  requirement of a  urease-deficient
     mutant in Aspergillus midulans. J. Gen. Microbiol. 116:  249-251.

Mertz,  W.  (1970) Some  aspects  of nutritional trace element  research.  Fed.
     Proc. Fed.  Am. Soc.  Exp. Biol. 29: 1482-1488.

National  Academy of Sciences.  (1975) Nickel.  Washington,  DC:  National Academy
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Nielsen,  F.  H.  (1980)  Evidence  of the  essentiality of arsenic,  nickel  and
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Nielsen,  F.  H.  (1984)  Ultratrace  elements  in nutrition.   Ann. Rev.  Nutr. 4:
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Nielsen,  F.  H.; Higgs,  D.  J.  (1971)  Further  studies  involving a nickel  deficiency
     in  chicks.  In:  Hemphill, D.  D., ed.  Trace  substances in  environmental
     health - IV. Columbia,  MO:  University of Missouri; pp. 241-246.
                                     9-4

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Nielsen, F. H.; Ollerich,  D.  A.  (1974) Nickel:  A new essential trace element.
     Fed.  Proc. Fed. Am. Soc. Exp. Biol. 33:  1767-1772.

Nielsen, F. H.; Myron,  D.  R.; Givand,  S. H.; Zimmerman,  T.  J.;  Dillerich, D.
     A. (1975) Nickel deficiency  in rats. J.  Nutr.  105:  1620-1630.

Rubanyi, G.;  Burtalan,  I.; Gergely, A.; Kovach,  A.  E.  B.  (1982)  Serum nickel
     concentration  in women during pregnancy, parturition and post partum. Am.
     J. Obstet. Gynecol. 143: 167-169.

Schnegg, A.;  Kirchgessner, M.  (1975a) The  essentiality of  nickel  for the
     growth  of  animals.  Z.   Tierphysiol.   Tierernaehr.   Futtermittelkd.
     36: 63-74.

Schnegg, A.;  Kirchgessner, M.  (1975b)  Veranderungen des Hamoglobin - gehaltes
     der Erythrozytenzahl  und des Hamatokrits  bei  nickelmangel.  Nutr.  Metab.
     19: 268-278.

Schnegg, A.,  Kirchgessner, M. (1976)  Zur  absorption und verfrig barkeit  von
     Eisen bei nickelmangel.  Int. J. Vitam.  Nutr.  Res.  46:  96-99.

Schroeder,  H.  A.;  Mitchner,  M.; Nason, A.  P.  (1974)  Life-term  effects of
     nickel in  rats:  survival, tumors, interactions with trace elements  and
     tissue levels. J.  Nutr.  104: 239-243.

Spears, J.  W.  (1984) Nickel  as  a "newer trace element"  in the  nutrition of
     domestic animals.  J. Anim.  Sci.  59: 823-834.

Spears, J.  W.;  Hatfield,  E.  E.  (1977) Role of nickel  in animal nutrition.
     Feedstuffs 49: 24-28.

Spears, J.  W.;  Smith,  C.  J.;  Hatfield, E.   E.  (1977)  Rumen bacterial urease
     requirement  for  nickel.  J.  Dairy  Sci.  60:  1073-1076.

Spears, J. W.; Hatfield, E. E.;  Forbes, R.  M.;  Koenig,  S.  E.  (1978) Studies on
     the role of  nickel  in the ruminant. J.  Nutr.  108:  313-320.

Spears, J. W.; Jones, E. E.;  Samsell,  L. J.; Armstrong, W.  D. (1984) Effect of
     dietary  nickel  on  growth, urease  activity,  blood parameters and  tissue
     mineral  concentrations  in  the  neonatal pig.   J. Nutr.  114:  845-853.

Sunderman,  F.  W., Jr.;  Nomoto,  S.;  Morang,  R.; Nechay, M. W.; Burke,  C.  N.;
     Nielsen, S.  W. (1972) Nickel deprivation in  chicks.  J.  Nutr.  102:  259-268.

Thauer, R. K.  (1982)  Nickel tetrapyrroles  in methanogenic bacteria:  structure,
     function  and biosynthesis.  Zentralbl.  Bakteriol.  Abt.  1 Or1g.  Relhe C.
     3: 265-270.

Thomson, A. J. (1982) Proteins containing  nickel.  Nature (London) 298:  602-603.
                                                         US GOVERNMENT PRINTING OFFICE 1985- 559-111/20704

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