United States
Environmental Protection
Agency
Office of Health and
Environmental Assessment
Washington DC 2O460
EPA/600/8-83/012FF
September 1986
Final Report
Research and Development
&EPA
Health Assessment
Document for
Nickel and
Nickel Compounds
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EPA/600/8-83/012FF
September 1986
Final Report
Health Assessment Document
for
Nickel and Nickel Compounds
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 cata-
lysts. 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 rela-
tively 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, kidney, and liver, and, in the case of nickel carbonyl, high levels
are also found in the brain. 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 xn
LIST OF FIGURES xvi
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 2-7
2.3.1 Subcellular and Cellular Aspects of Nickel Toxicity . 2-7
2.3.2 Acute Effects of Nickel Exposure 2-7
2.3.3 Chronic Effects of Nickel Exposure 2-8
2.3.3.1 Dermatological Effects of Nickel 2-8
2.3.3.2 Respiratory Effects of Nickel 2-9
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 2-12
2.4 NICKEL AS AN ESSENTIAL ELEMENT 2-12
2.5 POPULATIONS AT RISK 2-13
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 3-3
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)
3.3
3.4
3.2.5 Sampling for Nickel in Soil
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 Biological
Materi als
SOURCES OF ATMOSPHERIC NICKEL
3.3.1 Nickel Species in Ambient Air ,
3.3.
3.3.
3.3.
3.3.
3.3.
1.1
1.2
1.3
1.4
1.5
3.3.2
NICKEL
3.4.1
Primary Nickel Production
Combustion and Incineration ...
Metal 1urgical Processes
Nickel Chemicals and Catalysts
Miscellaneous Nickel Sources ..
Levels
3.4.2
Ambient Air Nickel
IN AMBIENT WATERS
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 of
Nickel
Concentrations of Nickel in Ambient Waters
3.5 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
3.6 GLOBAL CYCLE OF NICKEL
3.6.1 Atmosphere
3.6.2 Water
3.6.3 Soil and Sediments ..
3.7 REFERENCES
4. NICKEL METABOLISM IN MAN AND ANIMALS
4.1 ROUTES OF NICKEL ABSORPTION
4.1.1 Nickel Absorption by Inhalation
4.1.2 Gastrointestinal Absorption of Nickel
4.1.3 Percutaneous Absorption of Nickel
4.1.4 Transplacental Transfer of Nickel
4.2
TRANSPORT AND DEPOSITION OF NICKEL
ANIMALS
IN MAN AND EXPERIMENTAL
4.2.
4.2.
4.3
4.4
4.5
Nickel in Blood
Tissue Distribution of Nickel
4.2.2.1 Human Studies
4.2.2.2 Animal Studies
Subcellular Distribution of Nickel
RETENTION AND EXCRETION OF NICKEL IN MAN AND ANIMALS
FACTORS AFFECTING NICKEL METABOLISM
REFERENCES
4.2.3
3-14
3-15
3-15
3-15
3-16
3-16
3-17
3-18
3-21
3-23
3-24
3-24
3-26
3-26
3-26
3-27
3-28
3-29
3-30
3-31
3-36
3-36
3-39
3-41
3-41
3-43
3-44
3-46
3-48
3-50
4-1
4-1
4-3
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
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TABLE OF CONTENTS (continued)
5.
NICKEL TOXICOLOGY .-
5.1 ACUTE EFFECTS OF NICKEL EXPOSURE IN MAN AND ANIMALS
5.2
5.1.1
5.1.2
CHRONIC
5.2.1
Human Studies
Animal Studies
EFFECTS OF NICKEL EXPOSURE
Nickel Allergenicity
IN MAN AND ANIMALS
5.2.2
5.2.3
,2.4
,2.5
,2.6
5.
5.
5.
5.2.1.1 Clinical Aspects of Nickel
Hypersensitivity
5.2.1.2 Epidemiological Studies of Nickel
Dermati ti s •
5.2.1.2.1 Nickel Sensitivity and Contact
Dermati ti s
5.2.1.2.2 Sensitivity to Nickel in
Prostheses
5.2.1.3 Animal Studies of Nickel Sensitivity
Respiratory Effects of Nickel
Endocri ne Effects of Nickel
Cardiovascular Effects of Nickel
Renal Effects of Nickel
Other Toxic Effects of Nickel
5.3
5.4
INTERACTIVE RELATIONSHIPS OF NICKEL WITH OTHER FACTORS
REFERENCES ,
6. REPRODUCTIVE AND DEVELOPMENTAL TOXICITY OF NICKEL
6.1
6.2
6.3
6.4
6.5
6.6
REPRODUCTIVE FUNCTION/FERTILITY EFFECTS
MALE REPRODUCTIVE SYSTEM EFFECTS ..
FEMALE REPRODUCTIVE SYSTEM EFFECTS
DEVELOPMENTAL EFFECTS
SUMMARY
REFERENCES
7. MUTAGENIC EFFECTS OF NICKEL
7.1
7.2
7.3
7.4
7.5
GENE MUTATION STUDIES
7.1.1 Prokaryotic Test Systems (Bacteria)
7.1.2 Eukaryotic Microorganisms (Yeast)
7.1.3 Mammalian Cells Ln Vitro
CHROMOSOMAL ABERRATION STUDIES
7.2.1 Chromosomal Aberrations In Vitro
7.2.2 Chromosomal Aberrations In Vivo
SISTER CHROMATID EXCHANGE (SCE) STUDIES IN VITRO
OTHER STUDIES INDICATIVE OF MUTAGENIC DAMAGE
7.4.1 Rec Assay in Bacteria .....
7.4.2 S-Phase-Specific Cell Cycle Block
7.4.3 .Mammalian Cell Transformation Assay .....
7.4.4 Biochemical Genotoxicity
REFERENCES -
8.
CARCINOGENIC EFFECTS OF NICKEL
8.1 EPIDEMIOLOGIC STUDIES
Page
5-1
5-1
5-1
5-2
5-3
5-3
5-3
5-8
5-9
5-13
5-15
5-16
5-19
5-20
5-22
5-23
5-24
5-27
6-1
6-1
6-2
6-4
6-4
6-8
6-10
7-1
7-1
7-1
7-3
7-4
7-7
7-10
7-11
7-13
7-16
7-16
7-17
7-17
7-18
7-20
8-1
8-1
vn
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TABLE OF CONTENTS (continued)
8.1.1 Clydach Nickel Refinery (Clydach, Wales) .
8.1.1.1 Hill (1939, unpublished)
8.1.1.2 Morgan (1958)
8.1.1.3 Doll (1958)
8.1.1.4 Doll et al. (1970)
8.1.1.5 Doll et al. (1977)
8.1.1.6 Cuckle et al. (1980, unpublished)
8.1.1.7 Peto et al. (1984)
8.1.1.8 Summary of Studies on the Clydach Nickel
Refi nery
8.1.2 International Nickel Company, Inc. (INCO) Work
Force (Ontario, Canada)
8.1.2.1 Early Studies
8.1.2.1.1 Sutherland (1959), Mastromatteo
(1967), and INCO (1976)
8.1.2.1.2 Sutherland (1969)
8.1.2.1.3 Sutherland (1971)
8.1.2.1.4 Chovil etal. (1981)
8.1.2.2 Recent Studies
8.1.2.2.1 Roberts and Julian (1982)
8.1.2.2.2 Roberts et al. (1982,
unpublished)
8.1.2.2.3 Roberts et al. (1983,
unpublished; 1984)
8.1.2.2.4 Copper Cliff Medical Screening
(Sudbury, Ontario)
8.1.2.3 Summary of Studies on the Ontario INCO
Mining and Refining Processes
8.1.3 Falconbridge, Ltd., Work Force (Falconbridge,
Ontario)
8.1.4 Falconbridge Refinery Work Force (Kristiansand,
Norway)
8.1.4.1 Pedersen et al. (1973)
8.1.4.2 Hrfgetveit and Barton (1976)
8.1.4.3 Kreyberg (1978)
8.1.4.4 Hrfgetveit et al. (1978)
8.1.4.5 Torjussen et al. (1978)
8.1.4.6 Torjussen and Andersen (1979)
8.1.4.7 Torjussen et al. (1979a)
8.1.4.8 Torjussen et al. (1979b)
8.1.4.9 Hrfgetveit et al. (1980)
8.1.4.10 Magnus et al. (1982)
8.1.4.11 Kotlar et al. (1982).....
8.1.4.12 Summary of Studies on the Falconbridge
Refi nery (Norway)
8.1.5 Hanna Miners and Smelting Workers, Oregon
(U.S.A.)
8.1.6 Nickel Refinery and Alloy Manufacturing Workers,
West Virginia (U.S.A.)
8-1
8-4
8-5
8-6
8-8
8-10
8-11
8-12
8-16
8-18
8-20
8-20
8-22
8-23
8-24
'8-25
8-26
8-27
8-31
8-32
8-33
8-34
8-37
8-38
8-41
8-41
8-42
8-43
8-44
8-46
8-47
8-48
8-49
8-51
8-52
8-53
8-55
vm
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TABLE OF CONTENTS (continued)
8.
8.
8.
1.9
8.1.10
8.1.11
8.1.12
Sherritt Gordon Mines Workers (Alberta, Canada) ...
Nickel Refinery Workers (U.S.S.R.)
Oak Ridge Nuclear Facilities, Tennessee (U.S.A.) ..
8.1.9.1 Oak Ridge Gaseous Diffusion Plant,
Metallic Nickel Powder Exposure
8.1.9.1.1 Godbold and Tompkins (1979) ..
8.1.9.1.2 Cragle et al. (1983,
unpublished; 1984)
8.1.9.2 Oak Ridge Plants, Primarily Nickel Oxide
Exposure to Weiders
Nickel-Using Industries
8.1.10.1 Die-casting and Electroplating Workers
(Scandi navia)
8.1.10.2 Metal Polishing and Plating Workers
(U.S.A.)
8.1.10.3 Nickel Alloy Manufacturing Workers
(Hereford, England)
8.1.10.4 High-Nickel Alloy Plant Workers (U.S.A) .
8.1.10.5 Nickel-Chromium Alloy Workers (U.S.A.) ..
8.1.10.6 Stainless Steel Production and
Manufacturing Workers (U.S.A.)
8.1.10.7 Nickel-Cadmium Battery Workers (England)
8.1.10.8 Stainless Steel Welders (Sweden)
Community-Based Case-Control Studies
8.1.11.1 Hernberg et al. (1983)
8.1.11.2 Lessard et al. (1978)
8.1.11.3 Burch et al. (1981)
Summary of Epidemiologic Studies
8.
8.
8.
8.
1.12
1.12.
1.12.
1.12.
1
2
,3
,4
8.2
Mining of Nickel Ore
Nickel Ore Smelting and Related
Processes
Nickel Matte Refining
Other Nickel-Related Industries .
EXPERIMENTAL STUDIES
8.2.1 Animal Studies by Inhalation and Ingestion
8.2.1.1 Inhalation Studies
8.2.1.2 Oral Studies
Animal Studies of Specific Nickel Compounds
8.2.2
2.2.
2.2.
Nickel Subsulfide
Nickel Metal
Nickel Oxide
Nickel Refinery Dusts
8.2.3
Soluble and Sparingly Soluble Nickel
Compounds
8.2.2.6 Specialty Nickel Compounds
8.2.2.7 Potentiations and Inhibitions of Nickel
Carcinogenesis
Physical, Chemical, Biological, and Toxicological
Correlates of Carcinogenic Activities
8-56
8-57
8-58
8-59
8-60
8-62
8-63
8-67
8-67
8-68
8-69
8-71
8-74
8-77
8-79
8-80
8-81
8-81
8-82
8-83
8-84
8-86
8-90
8-91
8-95
8-95
8-95
8-95
8-104
8-105
8-105
8-109
8-113
8-117
8-121
8-124
8-124
8-126
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TABLE OF CONTENTS (continued)
8.2.
8.2.
8.2.
8.2.3.4
8.2.3.5
8.2.3.6
Solubilization of Nickel Compounds
Phagocytosis of Nickel Compounds
Erythrocytosis Induced by Nickel
Compounds
Interaction of Nickel Compounds with
DMA and Other Macromolecules
Induction of Morphological Transformation
of Mammalian Cells in Culture
Relative Carcinogenic Activity
8.2.4 Summary of Experimental Studies
8.3 QUANTITATIVE RISK ESTIMATION FOR NICKEL COMPOUNDS
8.3.1
8.3.2
8.3.3
Introduction
Quantitative Risk Estimates Based on Animal
Data
8.3.2.1 Description of the Low-Dose Animal-to-
Human Extrapolation Model
8.3.2.2 Selection of the Ottolenghi et al. (1974)
Rat Inhalation Study
8.3.2.3 Calculation of Human Equivalent Dosages
from Animal Data .
8.3.2.3.1 Calculation of Human Equivalent
Dosages Based on Dose/Body
Surface Area Equivalence
8.3.2.3.2 Dosiroetric Considerations
8.3.2.4 Calculation of the Incremental Unit Risk
Estimates
8.3.2.5 Interpretation of Quantitative Risk
Estimates ..';
8.3.2.6 Alternative Methodological Approaches
Quantitative Risk Estimates Based on Epidemidloqic
Data .........;.....
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
8.3.3.1.2 Investigation of Data Sets
8.3.3.1.2.1 Huntington, West
Virginia
8.3.3.1.2.2 Copper Cliff,
Ontario
8.3.3.1.2.3 Clydach, Wales
8.3.3.1.2.4 Kristiansand,
Norway
8.3.3.1.2.5 Conclusion —
Choice of Models ..
8.3.3.2 Calculation of the Incremental Unit Risk
from Human Data
8.3.3.2.1 Huntington, West Virginia
Page
8-126
8-130
8-136
8-139
8-141
8-142
8-144
8-156
8-156
8-156
8-156
8-158
8-160
8-160
8-162
8-179
8-179
8-181
8-182
8-184
8-184
8-186
8-186
8-188
8-192
8-196
8-200
8-200
8-200
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TABLE OF CONTENTS (continued)
8.4
8.3.4
SUMMARY
8.4.1
8.3.3.2.1.3
8.
8.
8.3,
8.3,
8.3.3.2.1.1 Refinery Workers
8.3.3.2.1.2 Non-Refinery
Workers
Use of Estimates
of A to Estimate
Unit Risk
Ontario
Norway
Relative Potency
Copper Cliff,
Kristiansand,
Clydach, Wales
Conclusion and Discussion:
Recommended Unit Risk Estimates
Based on Human Studies
Qualitative Analysis ,
8.4.1.1 Nickel Subsulfide (Ni3S2)
8.4.1.2 Nickel Refinery Dust
8.4.1.3 Nickel Carbonyl [Ni(CO)4] ,
8.4.1.4 Nickel Oxide (NiO) .,
8.4.1.5 Nickelic Oxide (Ni203) ,
8.4.1.6 Soluble Nickel Compounds [NiS04, NiCl2,
Ni(CH3COO)2]
8.4.1.7 Nickel Sulfide (NiS)
8.4.1.8 Nickel Metal (Ni)
8.5
8.6
8.4.2 Quantitative Analysis
CONCLUSIONS
REFERENCES
9. NICKEL AS AN ESSENTIAL ELEMENT
9.1 REFERENCES
Page
8-200
8-205
8-205
8-211
8-214
8-215
8-217
8-219
8-225
8-225
8-226
8-226
8-227
8-227
8-228
8-228
8-229
8-230
8-231
8-231
8-233
9-1
9-4
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LIST OF TABLES
Tab1e Page
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 3-33
3-4 Nickel concentrations in groundwater: 1980-1982 '.'.'.'.'.'.'.'.'.'.'. 3-35
3-5 Natural levels of nickel in selected soil types ! 3-38
3-6 Nickel concentrations in enriched soils '.'.'.'.'.'. 3-38
3-7 Accumulation of nickel in plants '.'.'.'.'.'. 3-40
3-8 Nickel content of various classes of foods in U.S. and Danish
diets 3-42
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 strain 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: j_n vitro chromosomal
aberrations 7-8
7-5 Mutagenicity evaluation of nickel: in vivo chromosomal
aberrations 7777 7-9
7-6 Mutagenicity evaluation of nickel: jri vitro sister chromatid
exchanges 7-14
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
plant 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 8-32
xn
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LIST OF TABLES (continued)
Table
Page
8-7, Mortality (1950 to 1976) by exposure category for lung,
laryngeal, and kidney cancer, at Falconbridge, Ltd., Ontario ... 8-36
8-8 Standardized mortality ratios (SMRs) for selected causes of
death among nickel workers and unexposed workers 8-64
8-9 Possible nickel exposures and levels of exposure by category
of work in the high-nickel alloy industry 8-72
8-10 Industries for which epidemiologic studies of cancer risks
from nickel exposure have been reviewed 8-85
8-11 Summary of cancer risks by nickel industry and worker
groups • 8-87
8-12 24 Factorial design of nickel subsulfide rat inhalation study
of two preexposure subtreatments followed by 78-week exposure .. 8-96
8-13 Hyperplastic and neoplastic changes in lungs of rats exposed
to nickel subsulfide :. 8-98
8-14 Experimental studies of nickel subsulfide carcinogenesis 8-106
8-15 Species differences to nickel subsulfide: intramuscular
injection • • 8-110
8-16 Strain differences in rats to nickel subsulfide intramuscular
injection 8-110
8-17 Strain differences: carcinogenicity of nickel subsulfide after
a single intrarenal injection in four rat strains 8-111
8-18 Route of administration differences and dose-response:
carcinogenicity of nickel subsulfide in male Fischer rats 8-112
8-19 Experimental studies of nickel metal carcinogenesis 8-114
8-20 Experimental studies of nickel oxide carcinogenesis ............ 8-118
8-21 Experimental carcinogenesis studies of nickel refinery and
other dusts , 8-120
8-22 Experimental carcinogenesis studies of soluble and sparingly
soluble nickel compounds , 8-122
8-23 Experimental carcinogenesis studies of specialty nickel
compounds • • 8-125
8-24 Potentiations and inhibitions of nickel compounds with other
agents 8-127
8-25 Rank correlations between chemical and biological parameters
of nickel compounds 8-133
8-26 Biological characteristics of nickel compounds 8-134
8-27 Summary of survival data and sarcoma incidences in carcino-
genesis tests by intramuscular injections of 18 nickel
compounds - 8-135
8-28 Cancers in the injected kidney of rats following intrarenal
injection of nickel compounds 8-137
8-29 Relationship between phagocytosis and induction of
morphological transformation by specific metal compounds 8-142
8-30 Mammalian cell transformation by nickel 8-143
8-31 Summary of animal and in vitro test results of specific
nickel compounds , 8-145
8-32 Relative deposition of monodisperse and heterodisperse
particles in regions of the respiratory tract of rats 8-167
xm
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LIST OF TABLES (continued)
l Page
8-33 Amount of nickel subsulfide deposited daily in regions of the
respiratory tract of rats .............................. . ____ 8-168
8-34 Equilibrium values and accumulation of nickel subsulfide in .....
the nasopharyngeal , tracheobronchial , and pulmonary regions of
rats after 78-weeks of exposure and assuming three different
retention half-times (monodisperse particles) ................ .. 8-169
8-35 Equilibrium values and accumulation of nickel subsulfide in .....
the nasopharyngeal, tracheobronchial, and pulmonary regions of
rats after 78-weeks of exposure and assuming three different
retention half-times (heterodisperse particles) ................ 8-170
8-36 Daily deposited surface area dose, clearance half-time,
equilibrium values at 78-weeks, and total accumulated dose
modeled in rat and in man under exposure conditions of the
Ottolenghi et al. (1974) study: for tracheobronchial,
pulmonary, and combined regions ................................ 8-180
8-37 Incremental maximum likelihood and upper-limit unit risk ....... .'
estimate for rat-to-human extrapolation using the Ottolenghi
et al. (1974) rat inhalation study of nickel subsulfide and
the one-hit model .................. . ........................... 8-181
8-38 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 [[[ 8-187
8-39 Copper Cliff refinery workers: lung cancer incidence'and ........
deaths by seven weighted duration of exposure subgroups,
follow-up from January 1963 to December 1978 ................... 8-190
8-40 Copper Cliff sinter plant: lung cancer mortality 15 to 29 years
since first exposure by workers first exposed before and since
1952, by duration of exposure .................................. 8-191
8-41 Clydach, Wales nickel refinery workers: total mortality and .....
cancer mortality by year of first employment ................... 8-193
8-42 Clydach, Wales nickel refinery workers: lung cancer mortality
by duration of years in calcining furnaces before 1925 -
(chi-square tests) ............................................. 8-195
8-43 Clydach, Wales nickel refinery workers: lung cancer mortality
by type and duration of exposure for men first employed before
T QOC
•Li*" [[[ 8-195
8-44 Clydach, Wales nickel refinery workers: lung cancer mortality
by_time since first exposure for workers exposed before 1925 ... 8-197
8-45 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 ................. 8-198
8-46 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 ............................................ 8-199
8-47 Data used to estimate A and its variance: Enterline and Marsh
-------
LIST OF TABLES (continued)
Table
8-48 Expected lung cancer deaths based on the additive and relative
risk models and bounds fitted to the Enterline and Marsh
refinery data .....
8-49 Data used to estimate A and its variance: Enterline and Marsh
"non-refinery workers" pre-1947 subgroup .. .
8-50 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
8-51 Estimated risks for the additive and multiplicative models
based on the Enterline and Marsh refinery workers data
8-52 Estimated risks for the additive and multiplicative models
based on the Enterline and Marsh non-refinery workers data
8-53 Data on lung cancer deaths used to estimate A and its variance:
Copper Cliff refinery workers (Chovil et al.) relative risk
model only •
8-54 Estimation of fraction of lifetime exposed to nickel in the
workplace, Clydach, Wales
8-55 Estimates of incremental unit risks for lung cancer due to
exposure to 1 p.g Ni/m3 for a lifetime based on extrapolations
from epidemiologic data sets
8-56 Relative carcinogenic potencies among 55 chemicals evaluated by
the Carcinogen Assessment Group as suspect human carcinogens ...
8-206
8-207
8-208
8-210
8-211
8-213
8-217
8-218
8-221
xv
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LIST OF FIGURES
Figure
3-1 Nickel hydrolysis distribution diagram
3-2 Concentrations of nickel in surface waters, by county, 1982
3-3 The global cycle ,of nickel on a one-year frame
7-1
8-2
8-3
8-4
8-5
8-6
. relationship between the lethal and mutagenic effect of
Ni2 by means of the clone method
8-1 Accumulation of Ni3S2 in the nasopharyngeal region of the rat
during chronic exposure of Ni3S2 for 78 weeks with daily depo-
sition of 8.19 ug and different retention characteristics
Accumulation of Ni3S2 in the tracheobronchial region of the
rat during chronic exposure of Ni3S2 for 78 weeks with daily
deposition of 1.29 ug and different retention characteristics ..
Accumulation of Ni3S2 in the pulmonary region of the rat
during chronic exposure of Ni3S2 for 78 weeks with daily
deposition of 2.0 pg and different retention characteristics ...
Predicted Ni3S2 particle deposition on surface area (assuming
even distribution) per airway generation in rat after 6-hour
exposure to 970 pg/m3
Accumulated surface area dose (assuming even distribution) of '
Ni3S2 in pulmonary and tracheobronchial regions of rat and man
during continuous exposure for 78 weeks
Histogram representing the frequency distribution of the potency
indices of 55 suspected carcinogens evaluated by the Carcinogen
Assessment Group
3-6
3-34
3-45
7-5
8-171
8-172
8-173
8-176
8-177
8-220
xvi
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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 Bellies
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
xvn
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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
Dr. Gunter Oberdb'rster
Radiation Biology and Biophysics Division
University of Rochester
School of Medicine
Rochester, New York
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 carcinogenicity chapter was reviewed by the Carcinogen Assessment Group
(CAG) of the U.S. Environmental Protection Agency. Participating members of
the CAG are:
xviii
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Roy E. Albert, M.D.
David L. Bayliss, M.S.
Chao W. Chen, Ph.D.
William H. Farland, Ph.D. (Director)
Charalingayya B. Hiremath, Ph.D.
Robert E. McGaughy, Ph.D.
Charles H. Ris, M.S., P.E.
Dharm V. Singh, D.V.M., Ph.D.
In addition, there are several scientists who contributed valuable informa-
tion and/or constructive criticism to successive drafts of this report. Of spe-
cific note are the contributions of Gerald Akland, Mike Berry, Joseph Borzelleca,
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,
and Stuart Warner.
SCIENCE ADVISORY BOARD
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
xix
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Dr. John Doull, Professor of Pharmacology and Toxicology, University of Kansas
Medical Center, Kansas City, Kansas 66207
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
Consultants
Dr. Seymour Abrahamspn, 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. F. William 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
xx
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The most recent draft of this document was reviewed in public session by
the Metals Subcommittee of the Environmental Health Committee. The following
were members of that Committee:
Chairman, Metals Subcommittee
Dr. Bernard Weiss, Professor, Division of Toxicology, P.O. Box RBB, University
of Rochester, School of Medicine, Rochester, New York 14642
Executive Secretary
Dr. Daniel Byrd, III, Science Advisory Board, A-101F, U.S. Environmental Protec-
tion Agency, Washington, D.C. 20460
Members
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. Philip Cole, Professor of Epidemiology, School of Public Health, Tidwell Hall,
Room 203, 720 20th Street South, University Station, University of Alabama
at Birmingham, Birmingham, Alabama 35294
Dr. Gary Diamond, Assistant Professor of Pharmacology, University of Rochester,
School of Medicine, P.O. Pharmacology, 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. Robert Goyer, Deputy Director, National Institute of Environmental Health
Sciences, P.O. Box 12233, Research Triangle Park, North Carolina 27709
Dr. Marvin Kuschner, Dean, School of Medicine, Health Science Center, Level 4,
State University of New York, Stony Brook, New York 11794
Dr. Gunter Oberdorster, Associate Professor, Radiation Biology and Biophysics
Division, University of Rochester, School of Medicine, 400 Elmwood Avenue,
Rochester, New York 14642
Dr. F. William 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. Ronald Wyzga, Electric Power Research Institute, 3412 Hillview Avenue, P.O.
Box 1041, Palo Alto, California 94303
xxi
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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. Linda Bailey
Ms. Frances P. Bradow
Mr. Doug Fennell
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. Janice Sanchez
Ms. Scottie Schaeffer
Ms. Judy Theisen
Ms. Donna Wicker
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1. INTRODUCTION
In September, 1983, the Environmental Protection Agency'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. Information
within this draft document was presented in regard to total nickel exposures.
At a public meeting in which this document was reviewed, the SAB and general
public advised the Agency, where possible, to assess health risks associated
with exposure to specific nickel compounds, rather than total nickel.
In response to this advice, the Agency undertook to revise the Health
Assessment Document for Nickel to provide analyses of individual nickel com-
pounds based upon existing information. The revised document is organized into
chapters which include an executive 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 com-
pounds in media with which the U.S. population comes into contact (Chapter 3);
information on nickel metabolism, where factors of absorption, tissue distribu-
tion, and excretion are discussed with reference to the toxicity of specific
nickel compounds (Chapter 4); information on nickel toxicity, where acute, sub-
acute, 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).
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 rele-
vant for human health risk assessment purposes. Literature was collected and
reviewed up to April, 1985. Particular emphasis is placed on the delineation
1-1
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of health effects and'risks associated with exposure to airborne nickel com-
pounds. The primary purpose of this document is to serve as a basis for deci-
sion-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 multi-
media risk assessment purposes as well. The background information provided at
the outset on sources, emissions, and ambient concentrations 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.
The Agency recognizes that the regulatory decision-making process is a con-
tinuous one. The present document represents the state-of-ihe-know!edge as
currently exists. To further this knowledge, the Agency has initiated a re-
search project to study the health effects associated with exposure to speci-
fic nickel compounds as determined from reanalysis of epidemiologic studies.
This project, headed by Sir Richard Doll of Oxford University, is a collabora-
tive effort on the part of various epidemiologists, engineers, hygienists, and
medical and data processing experts. Other sponsors of the research project
include the Ontario Ministry of Labour; National Health and Welfare, Canada;
Energy, Mines and Resources, Canada; the Nickel Producers Environmental Research
Association; and the Commission of European Communities. The results of this
research project will hopefully help to clarify the exposures of individual
workers to specific nickel compounds and will yield greater insight into the
association of such exposures with human health effects. Results of the project
are expected to be available by mid-1988. As this and other 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 uniquely resistant to
alkalis, but generally dissolves in dilute oxidizing acids. Nickel may exist in
9+
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 residential use sectors,
and municipal and sewage sludge incinerators); high temperature metallurgical
sources (steel manufacturing, nickel alloy manufacturing, secondary nickel
smelting, secondary nonferrous metals smelting, and iron and steel foundries);
chemical and catalyst sources (nickel chemical manufacturing, electroplating,
2-1
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nickel-cadmium battery manufacturing and catalyst production, use and reclama-
tion); and miscellaneous sources (co-product nickel recovery, cement manufactur-
ing, coke ovens, asbestos mining/milling and cooling towers).
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 ele-
ment. 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 contribu-
tion 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 com-
plex metal oxides containing nickel.
2.1.3 Nickel in Ambient and Drinking Water
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 predominant.
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
2-2
-------
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).
Specific forms of nickel in ambient waters have not been reported; however,
inferences of species expected to be found in effluents can be made based on the
nature of source processes and the aqueous chemistry of nickel. Nickel species
in wastewaters from the major anthropogenic sources are likely to include
dissolved salts (such as sulfates, chlorides and phosphates), insoluble oxides of
nickel and other metals, and metallic 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 exchange
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
2-3
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has been applied, nickel concentrations have been reported to range from 0.3 to
1150 ppm.
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 has been reported to range from
0.02 ppm (wet weight) in food items such as fresh tomatoes, frozen swordfish and
pork chops to 9.80 ppm in cocoa.
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 of experimental animals is mainly
of importance in assessing the kinetics of nickel transport, distribution and
excretion. Parenteral exposure of humans to nickel from medications, hemodi-
alysis and protheses can be a significant problem to certain sections of the
population.
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
2-4
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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
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 pg daily with absorption on
the order of one to ten percent. Recent studies show that nickel bioavailabil-
ity 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 pg/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,
2-5
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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.
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.
2-6
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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 amino groups with binding
to peptide (amido) and carboxylate ligands also possible.
A number of reports in the literature describe various i_n vivo and i_n 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 are constrictive chest pain,
dry coughing, hyperpnea, cyanosis, occasional gastrointestinal symptoms,
2-7
-------
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.
2.3.3 Chronic Effects of Nickel Exposure
2.3.3.1 Dermatological Effects 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 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.
2-8
-------
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
certain production or use 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 septa! perforations, and chronic rhinitis and sinusitis; and
(2) increased 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 hyperglycemia 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 ischemic myocardial injury
and in burn patients. 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 in 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, it has been demonstrated that a deficiency of dietary
2-9
-------
nickel can also lead to reproductive effects in the form of reduced litter 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 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 Mutagenic 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 mutations
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 mammalian 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 i_n vitro and to interact with DNA
resulting in crosslinks 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 in 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
2-10
-------
acetate, when tested in strain A mice, and nickel carbonyl, at toxic levels,
have also 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 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.
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 the Environmental Protection Agency's classification scheme for evaluating
carcinogens (U.S. Environmental Protection Agency, 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 jin 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 carcinogenic potential of other nickel
compounds remains an important area for further investigation. Some biochemi-
cal and i_n vitro toxicological studies seem to indicate the nickel ion as a
potential carcinogenic form of nickel and nickel compounds. If this is true,
all nickel compounds might be potentially carcinogenic with potency differences
related to their ability to enter and make the carcinogenic form of nickel
available to a susceptible cell. However, at the present time, neither the
bioavailability nor the carcinogenesis mechanism of nickel compounds is 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
incremental unit risks from 1.1 x 10 (ng/m ) to 4.6 x 10 (pg/m )~ has
been calculated. Taking the midpoint of this range, the quantitative
incremental unit risk estimate for nickel refinery dust is 2.4 x 10 (ug/m ) ;
2-11
-------
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 55 other compounds which the Environmental
Protection Agency has evaluated as suspect or known human carcinogens, nickel
subsulfide would rank between the second and third quartiles.
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
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 celjs 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 criterion 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.
2-12
-------
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 placental
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
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, since various studies have presented conflicting
information.
Nickel crosses the placental barrier in animals and apparently in man, thus
exposing the conceptus to nickel. There is no information at present that
nickel exposure i_n utero under conditions of nickel exposure encountered by
pregnant women in the U.S. population leads to adverse effects.
2-13
-------
-------
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 minerals is relatively high (up to 70 percent for heazlewoodite), nickel
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)gSi4010(OH)g], nickeliferous limonite [(Fe,Ni)0(OH)-NH20]
(Warner, 19845), and pentlandite [(FeNi)gSg] (Duke, 1980). Native metallic
nickel in a pure form is rarely 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 corro-
sion 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
R
turbochargers. Copper-nickel and nickel-copper alloys, such 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 transition
metal series and exhibits the properties presented in Table 3-1. Nickel is
resistant to alkalis, but reacts with dilute 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 by formation of a
surficial oxide film (Tien and Howson, 1980).
* MONEL is a registered trademark of INCO, LIMITED.
3-1
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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, +1, +2,
+3, or +4 oxidation states (Antonsen, 1980). The most prevalent form, however,
is nickel II. The lower oxidation states usually occur in situations not nor-
mally 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 refracto-
ry. 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 ferrite, NiFe204, 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). When heated, the salt loses water and, above 800°C, decomposes into
nickel oxide and sulfur trioxide (Antonsen, 1980). The sulfate is extremely
soluble in water and sparingly soluble in ethanol.
Nickel nitrate hexahydrate, Ni(N03)2 • BH^O, 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, NiC03, is only slightly soluble in water, but is soluble
in acids and ammonium salt solutions. Commercially, the basic salt, 2NiC03 •
3Ni(OH)p • 4HLO, is the most important form. Nickel carbonate has been used as
a glass colorant, in catalysts, and in electroplating baths. It has also been
used to prepare specialty nickel compounds (Antonsen, 1980).
3-3
-------
Nickel hydroxide, Ni(OH)2, is insoluble in water but reacts with acids and
aqueous ammonia (Cotton and Wilkinson, 1980). When placed in aqueous ammonia,
the hydroxide forms the complex hexaamminenickel (II) hydroxide, [Ni(NH3)g](OH)2,
which is soluble (Cotton and Wilkinson, 1980). 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
hexahydrate, Nid2 • 6H20, and nickel chloride, NiCl2; 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 sulfide ions
2+
(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). Other sulfides,, Ni^S*, NiySg, and NigSp, are also known.
Nickel subsulfide, Ni3S2, is insoluble in water but soluble in nitric acid.
Nickel carbonyl, Ni(CO)4, is a colorless volatile liquid formed by passing
carbon monoxide over freshly formed metallic nickel in the presence of an
oxidant. The vapor density of nickel carbonyl is about four times that of air
(Antonsen, 1980), indicating that nickel carbonyl in ambient air would tend to
settle and not disperse. The compound decomposes at high temperatures, depo-
siting 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 configurations
of nickel complexes are octahedral or tetrahedral. For example, [Ni(NHo)g](C10/,,)2
exhibits octrahedral configuration; the [NIC!,] ion is tetrahedral in struc-
ture. The rate of formation of nickel complexes is relatively slow compared to
other divalent cations (Nieboer, 1981). The difference in the rate of complex
formation in solution is due in part to the high energy of formation of the
3-4
-------
trigonal pyramidal intermediates from the original octahedral configuration. In
2+
aqueous solutions, the Ni ion is surrounded by six water molecules forming
2+
octahedral [NHHLO),.] ; the loss of a water molecule has been determined to be
the rate limiting step (Nieboer, 1981). 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 suspend-
ed 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 may lead to the emission of nickel sulfate-containing particulates
from 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,
oxides of nickel and other metals may be formed during high temperature process-
es involving these metals.
3.1.2.2 Water. Nickel is usually found as nickel 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
ion (or more likely
The divalent 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
o- -
form at this pH with the likelihood of formation as follows: OH > SO, > Cl
> NHQ (Richter and Theis, 1980). However, in aerobic environments, at pH less
2+
than 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.
2+
example, in natural fresh waters at pH 5 to 9, the Ni
2+
) is the dominant form (Richter and Theis, 1980).
,.•2+
The hydrolysis reaction, Ni + 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.
3-5
-------
100
90-
80-
70-
60-
50-
40-
30-
20-
10-
14
PH
Figure 3-1. Nickel hydrolysis distribution diagram.
Source: Richter and Theis (1980)
3-6
-------
Sulfate is a relatively weak nickel complex form (Richter and Theis, 1980),
but at relatively high sulfate concentrations, nickel sulfate may be the domi-
nant soluble form.
Based on a computer model, Sibley and Morgan (1975) report that in seawa-
ter, 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
f) i ^-4- +
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, 69 picometers, may facilitate its substitution for magnesium
O-i- *} -\"
(Mg ) (radius 65 picometers) or iron (Fe ) (radius 74 picometers) (Duke,
1980). As mentioned earlier, nickel compounds are often octahedrally coordi-
nated. 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). Such ferromagnesium minerals are fairly suscep-
tible to weathering, and the nickel released is usually held in the weathered
material in association with clay particles (Duke, 1980). Therefore, 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~
complexes with free organic or inorganic ligands present, including SO* , Cl ,
- 9-
OH , C03 , humic/fulvic acids. Under anaerobic conditions and in the presence
of sulfur, the insoluble sulfide, NiS, may form (National Academy of Sciences,
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
3-7
-------
greater than 9, the.carbonate or hydroxide may precipitate. As the pH increas-
es, nickel adsorption by iron and manganese oxides increases because of greater
?+
electrostatic attraction between the negative oxide surface and positive Ni
cation (Richter and Theis, 1980).
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 association
with particulate 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 compo-
nents 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
a!., 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 organometal-
lic 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 e'nables the collection of volatile species that can
3-8
-------
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).
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
3
greater than 300 psig. The detection limit is 60 |jg/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 (National Academy of Sciences) has
used a high-volume filtration sampler to collect 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 unstable compounds such as nickel
carbonyl.
3.2.2 Analytical Procedures for Nickel in Air
The determination of nickel, as the element, can be satisfactorily accom-
plished 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 identification 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 [jg/m in 1982, see
Table 3-2) complicates this identification.
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 0.05 jjg/ml (Sachdev and West,
1970; Pickett and Koirtyohann, 1969). The linear range for accurate measurement
3-9
-------
TABLE 3-2. CUMULATIVE FREQUENCY DISTRIBUTION OF INDIVIDUAL 24-HOUR AMBIENT AIR NICKEL LEVELS
Year
1977
1978
1979
1980
1981
1982
Network9
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
Type0
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
Percentile0
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
0.007
NCd
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 jjm 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 |jm, F* <2.5 urn, and C* is the difference, -i.e., greater than 2.5 urn and less than 10 urn.
=*
"Values 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
-------
is reported as 0.2 to 0.5 |jg/ml for a 232.0 nm wavelength setting. 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 hundredfold excess of iron, manganese, chromi-
um, 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 (National Institute of
Occupational Safety and Health, 1977; National Academy of Sciences, 1975).
Atomic absorption spectrophotometry without flame is also a viable analyti-
cal 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
|jl of injected fluid, flameless 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 analytical procedure does not destroy the sample, thereby allowing
o
reanalysis. The detection limit for XRF is 0.01 ng/cm (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 com-
pounds (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 comprehensive
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 concen-
trations at the microgram level. However, the detection limit of NAA is only
3-11
-------
0.7 |jg/g. A final method for nickel determination is flame emission spectropho-
tometry (FES); this method is sensitive to 0.03 pg/ml of nickel in solution
(Pickett and Koirtyohann, 1969).
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 speciation 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. A lack of reference information complicates the
identification 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). Secon-
dary 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 interpreta-
tion 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 detect-
ed, and the applicability to trace nickel concentrations is questionable
(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
3-12
-------
to interferences from background, particle mass, and interelement effects
(Henry, 1979).
Inorganic compounds containing nickel in the vapor phase are readily
speciated based upon the volatility of the compound. Brief 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 M9/9-
The chemiluminescence method is faster and more specific 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
(02). 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 concentration.
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. Three sampling 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 ten percent. The
sample is drawn through a clean Teflon line inserted into the sampling bottle.
A valve is used to regulate the flow. Heat exchange sampling works in precisely
the same 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 procedure 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
-------
period. Significant loss of trace elements during storage has been identified
by several investigators (Owens et a!., 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 (National
Academy of Sciences, 1975). Sachdev and West (1970) recommend a concentration
step using a mixed ligand. With preconcentration, there is also a potential for
loss and contamination (Cassidy et al., 1982).
3.2.4 Analytical Procedures for Nickel in Water
Analysis of 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, as
reported by the U.S. Environmental Protection Agency (1979), is 0.15 mg/1 and
the detection limit is 0.05 mg/1. More recently, Greenberg and co-workers
(1985) reported a detection limit of 0.02 pg/ml for nickel by flame AA and 0.001
fjg/ml by graphite furnace AA.
Other analytical procedures for nickel in liquid samples are also employed.
Multi-element techniques such as inductively coupled plasma emission spectrome-
try (ICPES) and spark source mass spectrometry (SSMS) 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 chroma-
tography (HPLC). This procedure is capable of detecting nickel at pg/ml and
ng/ml concentrations. A problem with this technique is the significant poten-
tial 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
3-14
-------
greater than three 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).
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 procedure;
(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 Materi-
als, 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 unrepre-
sentative 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. Anodic-stripping voltametry and isotope-
dilution mass spectrometry are also used. Acid extraction is required before
3-15
-------
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 adsorption
losses on the walls of the combustion chamber (dry-ashing) and additions through
leaching from container walls (wet-ashing) (Stoeppler, 1980). A typical extrac-
tion procedure involves subjecting the samples to acid digestion and then
separating the nickel from interfering elements by chloroform extraction of
nickel dimethylglyoximate at alkaline pH. A similar extraction procedure
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, 1967, 1965). Potential sources of error in the analy-
sis of biological materials for nickel using acid extraction and atomic absorp-
tion spectrophotometry are: (a) contamination of the sample; (b) background
absorbance; and (c) nonspecific absorbance caused by the presence of inorganic
salts (Sunderman, 1984; Stoeppler, 1981, 1984; Nomoto and Sunderman, 1970). An
International Union of Pure and Applied Chemistry (IUPAC) reference method for
nickel in serum and urine using electrothermal atomic absorption spectrometry
has been published (Brown et al., 1981).
3.3 SOURCES OF ATMOSPHERIC NICKEL
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 treat-
ment 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, available 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,
3-16
-------
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 incineration,
electroplating, nickel-cadmium battery manufacturing, nickel chemicals manufac-
turing, cooling towers, cement manufacturing, coke ovens, asbestos mining/
milling, and nickel catalyst manufacture and reclamation. From these 19 individ-
ual source categories, five organizational groupings exist that generally
describe the major species of nickel emitted into ambient air by 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. 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 process-
es. 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 Environmental Quality, 1981).
The AMAX Nickel Refining Company in Braithwaite, Louisiana is the only
facility in the U.S. that refined imported nickel matte to produce nickel. This
facility closed in late 1985. The discussion presented here describes emissions
of nickel or nickel-containing substances associated with past practices at
AMAX/Braithwaite.
3-17
-------
Nickel emissions to ambient air from the AMAX refining operation were
likely to have been in the forms of nickel subsulfide, metallic nickel, and to a
much lesser extent, nickel oxide. Nickel subsulfide exists in particulate
emissions associated with matte handling and preparation parts of the refining
process because the processed mattes are sulfidic in nature (Page, 1983; Warner,
1983). XRD tests by the matte refining plant verified the existence of nickel
subsulfide emissions (Gordy, 1984). Metallic nickel powder was generated by the
matte refining plant as a final product and was emitted during drying, packag-
ing, and briquetting operations. Nickel oxide could also have been emitted from
the plant sintering operation as some metallic nickel was likely to have been
oxidized in the high temperature sinter furnace (Warner, 1983). Total nickel
emissions from the matte refining facility have been estimated to be approxi-
mately 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 which is 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 informa-
tion, it can be postulated that the form of nickel in the fly ash emissions and
ambient air from oil-fired combustion is predominantly 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(NH^)2 (S04)2'6H20] (Bla'ha 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
distinguish between pure nickel oxide and complex metal oxides involving nickel.
Potentially, the nickel component of the insoluble fraction could exist as
3-18
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nickel oxides, such as ferrites, aluminates, and vanadates; a combination of
metal oxides, including 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) postulat-
ed 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 insolu-
ble nickel components of the oil combustion fly ash were reported to be simple
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 may 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) 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 combustion,
nickel probably exists as nickel sulfate. Various metal sulfates were identi-
fied 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 anions. Eatough et
+2
al. (1981) confirmed the existence of Ni associated with sulfate in the
soluble portion of emissions from an oil-fired power plant.
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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 Fe3_xNix°4- Hansen et al. (1981) substantiated
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 emitted 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 or oxides of nickel and other metals.
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 estimated to
account for 60 to 98 percent (Krishnan and Hellwig, 1982; Systems Applications
Incorporated, 1982; Baig et al., 1981). The American Petroleum Institute (API),
however, has recently estimated lower emissions of nickel from petroleum fuel
combustion, ranging from 1,725 Mg to 2,400 Mg (1,900 to 2,640 tons/yr) (API, 1986).
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 urn) 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 partic-
ular 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 the work by Cawse
(1974). Cawse (1974) measured the bulk deposition of many elements, including
nickel, at seven nonurban ambient air monitoring sites in Great Britain. The
soluble nickel component as a percentage of total nickel deposition ranged from
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47 to 80 percent, with the average level being 59 percent. The major am"on
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 ammoni-
um 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
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; howev-
er, 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 nonferrous
metals smelting, and iron and steel foundries. In the high temperature
processes occurring in metallurgical furnaces, the majority of nickel in emis-
sions would be expected to be oxidized. Data from the steelmaking industry and
3-21
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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 a!., 1981).
In one test of nickel emissions from an electric arc furnace (EAF) producing
stainless steel, only five 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 showed nickel oxide to constitute from zero
to three percent of the total particulate emissions. Similar work on the
emissions from a refining vessel handling specialty steel showed one sample
where nickel oxide was reported to constitute 3.1 percent of total particulate
emissions (Emission Standards and Engineering Division, 1983; Andolina, 1980).
It was not clearly documented in these studies whether the emission samples
contained pure nickel oxide or another oxide of nickel, possibly involving
additional metals. The data suggest that instead of being pure nickel oxide,
the reported values likely represented total nickel present, expressed in terms
of calculated percentages of pure oxides (i.e., nickel oxide).
Several dust samples have been collected during the manufacture of differ-
ent 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 temper-
ature 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 metal-
lurgical environments is predominantly oxidized and combined with other metals
present (if stoichiometry permits) to form complex oxides of nickel and other
3-22
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metals. Nationwide nickel emissions from steelmaking and nickel alloy manufac-
turing,, the dominant emission categories of the metallurgical group, have been
estimated to be 71 Mg (79 tons)/yr and 66 Mg (73 tons)/yr, respectively (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 nickel 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 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
hydroxide (Radian Corporation, 1983; Radakovich, 1978). No specific data are
available to indicate which form nickel emissions may take during the produc-
tion, use, and reclamation of nickel catalysts. During catalyst preparation,
nickel can be emitted as fugitive dusts of the raw material such as nickel
carbonate, hydroxide, nitrate, or acetate (McNamara et al. , 1981). Nickel is
used, in finely divided form, as a catalyst in the hydrogenation of oils;
however, no data were found to indicate the magnitude of nickel emissions from
this source. During the recycling of nickel catalysts, nickel may be emitted as
an oxide since the metal is subjected to high temperatures required for thermal
3-23
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decomposition. 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 manufacturing,
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 processes.
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 (Ni3S2 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 hydroxides, sulfates, or chlorides, 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.
3-24
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In the NAMFS network, ambient air participate 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 dichotomous
(dichot) filter samples are taken. Inhalable Particulate network HiVol samples
are analyzed using ICAP spectrometry, while XRF spectroscopy is used on dichoto-
mous filter samples. Further discussions of analytical procedures are found 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 National Academy of Sciences (NAMFS) data there appears to be a general
downward trend as the 1977 mean of 0.012 fjg/m3 fell to 0.008 ug/m3 in 1982. In
1977, 99 percent of the National Academy of Sciences data points were less than
0.062 ug/m , but in 1982 the level at which the 99th percentile was gauged at
being less than was only 0.030 ug/m3. The IP network HiVol data show a similar
downward trend. The mean IP HiVol value in 1979 was 0.021 pg/m3 but was only
0.007 ug/m in 1982. The 99th percentile value for the IP network HiVols had an
even greater decrease than the National Academy of Sciences 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/m3). There
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 ana-
lysis 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
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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 pro-
cesses. The concentration of nickel in U.S. surface waters recorded in the U.S.
Environmental Protection Agency's Storage and Retrieval (STORET) data base
ranges from less than 5 (jg/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 (National Academy of Sciences, 1975). About 90 percent of the samples
taken in this survey contained less than 10 ug/1.
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.
3.4.1 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. Refining of imported nickel-
containing matte was performed by the AMAX Nickel Division in Braithwaite,
Louisiana, until late 1985.
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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 included 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, dis-
charges of nickel from the AMAX facility were probably small. Hoppe (1977)
reported that greater than 99 percent of the nickel contained in initial
feedstock (matte) was recovered.
Nickel in tailing pond discharges may have been present as the ion, Ni'
or the dissolved sulfate from electrolyte solutions. A small amount of the
insoluble nickel subsulfide may have been present due to dusts from matte
handling and storage. Likewise, small amounts of metallic nickel powder may
have been 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.
3-27
,,2+
-------
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 bil-
lets. 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 incinera-
tion of municipal refuse and sewage sludge release nickel into all environmental
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,
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 combus-
tion 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
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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 incinera-
tor 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 incinera-
tor 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 exten-
sive 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 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 solubility
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. Depending on
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the concentration of the nickel salt in the bath, nickel is likely to be
2+
discharged as the Ni ion or as the 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 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 battery
2+
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 the hydrogenation of fats and oils,
the hydrotreating of petroleum, and in various ammonolysis and methanation
reactions. They are also used in the catalytic combustion of organic compounds
in automobile exhausts. Wastewater sources were not definitively identified,
D
but may include 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 chlorides, acetates, nitrates, or
sulfates (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 process-
es 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.
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
a!., 1974). Any nickel present would most likely be, held in the mineral lattice
of the parent raw material (limestone, sand, etc.).
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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 temperatures
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.
Environmental Protection Agency, 1976). Twenty percent is discharged to a
settling pond; eight 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 ug more dissolved nickel per kilogram than intake
waters after a two-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 complex-
es, be adsorbed, or precipitate out of solution.
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
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15 major river basins in the continental U.S. were retrieved for 1980 to 1982.
As shown in Table 3-3, mean total nickel concentrations for these river basins
ranged from less than 5 pg/l to greater than 700 |jg/l during the three-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 pg/l 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/1. 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 concentration,
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 ug/1.
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 percentiles, meaning that 85 per-
cent 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 compar-
isons 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.
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
three-year period. From Table 3-4 it is apparent that groundwaters from the
Ohio River basin show substantially higher nickel concentrations for all three
3-32
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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 ug/1. The California basin also has rela-
tively 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 2,500 ug/1
but 85 percent of the remaining samples contained less than 130 [jg/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 (National Academy
of Sciences, 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 concentrations 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
literature.
3.5.1 Nickel in Soils
The level of naturally occurring nickel in soils depends upon the elemental
composition of rocks in the upper crust of the earth. These rocks provide 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
3-36
-------
6,000 ppm (National Academy of Sciences, 1975; Vaneslow, 1966). Various re-
searchers (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; (d) emissions from electric
power utilities deposited on soils downwind of the facility; (e) municipal waste
incineration emissions deposited on soils; and (f) emissions from coal and oil
combustion for water and space heating deposited on soils. The most significant
anthropogenic nickel inputs to soil result from metals smelting 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 prob-
lems in plants (Webber, 1972). In sludge from more than 300 sewage treatment
plants studied by Page (1974), the recorded nickel concentrations ranged from 10
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
3-37
-------
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 arid 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 (197.4)
Lagerwerff and Specht
,(1970) > ,
Hutchinson (1972)
3-38
-------
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 exceeded 5 ppm, concentrations as high as 100 ppm
could 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 (Schauer et
al., 1980; Mitchell et al., 1978; Clapp et al., 1976; Giordano and Mays, 1976;
Anderson and Nilsson, 1972; LeRiche, 1968). Higher concentrations occurred in
soils with low pH. A study by Beavington (1975) showed that concentrations of
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
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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 a!., 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 1 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 humans 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), Vaneslow (1966)
and, more recently, Nielsen and Flyvholm (1984) are given in Table 3-8. The
level of nickel rarely exceeds 1 ppm, but in some specialty foods, such as soya
beans and cocoa, it has been measured as high as 5.2 and 9.8 ppm, respectively.
Food processing methods may add to the nickel levels naturally present in
foodstuffs by (1) the leaching of nickel from food-processing equipment made
from stainless steel, (2) the milling of flour, and (3) the catalytic hydrogen-
ation of fats and oils with nickel catalysts (National Academy of Sciences,
1975). Daily nickel intake may also become elevated after the replacement and
supplementation of specialty items, such as soya beans and chocolate, in the
average diet. Calculations show that nickel intake may reach levels as high as
900 ng Ni/day through such means (Nielsen and Flyvholm, 1984).
3.5.4 Nickel in Cigarettes
Cigarette smoking may contribute to man's daily nickel intake by inhala-
tion. Early studies suggested that nickel in mainstream smoke was in the form
of carbonyl (Szadkowski et al. , 1970; Sunderman and Sunderman, 1961); however,
recent data have not supported these earlier findings (Alexander et al., 1983).
The amount of nickel in mainstream smoke is a topic of some controversy and
3-41
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TABLE 3-8. NICKEL CONTENT OF VARIOUS CLASSES OF FOODS
IN U.S. AND DANISH 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
Rice
Rye flour
Rye bread
Oatmeal
Fruits and vegetables
Potatoes, raw
Peas, fresh frozen
Peas, canned
Peas
Beans, frozen
Beans, canned
Soya beans
Lettuce
Cabbage, white
Tomatoes, fresh
Tomato juice
Spinach, fresh
Spinach
Celery, fresh
Apples
Bananas
Pears
Hazel nuts
Seafood
Oysters, fresh
Clams, fresh
Shrimp
Scallops
Crabmeat, canned
Sardines, canned
Haddock, frozen
Swordfish, frozen
Salmon
0.54
1.33
0.70
0.47.
0.33°
0.23
0.21.
1.20°
0.56
0.30
0.46.
0.37C
0.65
0.17.
5.20C
0.14
0.32
0.02
0.05
0.35.
0.06C
0.37
0.08
0.34
0.20.
1.90C
1.50
0.58
0.03
0.04
0.03
0.21
0.05
0.02
1.70
(continued on following page)
3-42
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TABLE 3-8 (continued)
Food Class and Examples
Nickel Content,
ppm, wet weight
Meats
Pork (chops)
Lamb (chops)
Beef (chuck)
Beef (round)
Chocolate
Cocoa
Milk chocolate
Dark chocolate
0.02
Not detected
Not detected
Not detected
9.80!
0.57C
1.80C
Value is that of Danish diet.
Source: Adapted from National Academy of Sciences (1975) and Nielsen and
Flyvholm (1984).
further research is needed before definitive conclusions can be reached (see
Chapter 4).
3.6 GLOBAL CYCLE OF NICKEL
Nickel in all environmental compartments (air, water, and soil) is continu-
ously 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 continuous,
however, because nickel may leave the ocean as sea spray aerosols, burst, and
release minute particles containing nickel and other elements into the atmo-
sphere. 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 affecting naturally occurring nickel,,and accounts for
increased ambient nickel concentrations in all environmental media.
In the atmosphere, nickel-containing particulates are subject to dispersion
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 water
bodies, nickel is transported by stream flow and can be removed from the water
3-43
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column by sedimentation, precipitation from solution, or adsorption onto sus-
pended 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 anthropogen-
ic sources, as shown in Figure 3-3. Estimates of the portion of the total
atmospheric burden of nickel attributed to either source category vary, depend-
ing 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 sourc-
es, 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
sources, 2.8 x 10 Mg (3.1 x 10 tons)/year, but report emissions from
anthropogenic 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 vegeta-
tive exudates (Schmidt and Andren, 1980). Up to 80 percent of anthropogenic
emissions of nickel may be generated by fossil fuel combustion and nonferrous
metals production (Nriagu, 1980). Other researchers have estimated that combus-
tion of oil alone accounts for 83 percent of atmospheric nickel from anthropo-
genic sources (Lee and Duffield, 1979). Although the resolution of differences
in these worldwide emissions is beyond the scope of this document, 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, most anthropogenic
3-44
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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/
o
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 pro. Galloway et al. (1982) reported wet deposition rates of 2.4 to
114 ug/1 nickel in urban areas (median 12 ng/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
fallout of 2.2 x 10 Mg (2.4 x 10 tons) nickel per year are received by ocean
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
3-46
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nickel-containing material that was introduced into the atmosphere by 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; National Academy of Sciences, 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 concentrations 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. Nevertheless,
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
fi c
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 104 Mg (1.2 x 104
tons)/year input from rivers as dissolved nickel. Industrial and municipal
3-47
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wastes may contribute 3.8 x 10 Mg (4.2 x 103 tons) nickel/year (Nriagu, 1980),
80 percent of which is estimated to be soluble forms of the metal (Snodgrass,
1980).
The transport of nickel to the oceans depends on stream velocity, channel
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 transported
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 10 years (Nriagu, 1980). Nickel may
be taken up by marine flora and fauna or deposited in oceanic muds and sedi-
ments. Accumulation of the metal in these sediments, the ultimate sink for
nickel, is estimated to exceed 1.5 x 10 Mg (1.7 x 106 tons)/year (Nriagu,
o
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 environment each year by
deposition of atmospheric nickel-containing particulates, and that waste dispos-
al (sewage sludge, fly ash) and fertilizers add 1.4 x 10 Mg and 1 x 10 Mg (1.5
4 3
x 10 and 1.1 x 10 tons), respectively. Litter fall from vegetation may
provide an additional 7.8 x 10 Mg (8.6 x 10 tons) of nickel on an annual basis
(Nriagu, 1980).
3-48
-------
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 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 manga-
nese oxides break down, thereby remobilizing any nickel present (Rencz and
Shi Its, 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 avail-
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Insoluble or less soluble nickel species may deposit and add to riverbed
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.
3-49
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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. -Paren-
teral administration of nickel is of interest to experimental studies and is
particularly helpful in assessing the kinetics of nickel transport, distribu-
tion, and excretion. Parenteral exposure of humans to nickel from medications,
hemodialysis, and protheses can also be a significant problem to certain sectors
of the population. 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 JH vitro studies have described the relationship of chemi-
cal composition and such properties as crystallinity of nickel compounds to
their relative solubility in biologically relevant media. In the most compre-
hensive 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 comparison, 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.
While i_n vitro solubilization half-times determined in this manner are
useful to know, they must be cautiously used in predicting iji vivo solubility.
Furthermore, examination of the solubilization half-times for all 17 nickel
forms in the Kuehn and Sunderman study indicates that solubilization cannot be
the only factor operating in the carcinogenicity of various nickel compounds.
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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.
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 reli-
ability 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 approximately
1000-fold higher than generally accepted values.
Lee and co-workers (1983) found that 1 to 10 mM levels (59 to 590 mg/1) of
nickel II in a biological solution were obtained after incubation of a-nickel
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
subsulfide nickel is central to solubilization, which supports earlier data of
Kasprzak and Sunderman (1977).
In the more complex i_n vitro cellular test systems, where the end point is
relative phagocytosis of nickel compounds as a prelude to cell transformations,
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 nega-
tive charge density on particulate surfaces (Heck and Costa, 1982). Crystalline
nickel monosulfide 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 reduction
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.
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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.
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 National Academy of Sciences report
on nickel (National Academy of Sciences, 1975) as well as a review by Sunderman
(1977).
Studies of nickel carbonyl metabolism by Sunderman and co-workers
(Sunderman and Selin, 1968; Sunderman et al. , 1968) indicate that pulmonary
absorption is both rapid and extensive, with the agent passing the alveolar wall
intact. Sunderman and Selin (1968) observed that rats exposed to nickel carbon;;
yl at 100 mg Ni/1 air for 15 minutes excreted 26 percent of the inhaled amount ~
in the urine by 4 days postexposure. 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 Radiologi-
cal Protection (ICRP) Task Group on Lung Dynamics (1966) has advanced detailed
deposition and clearance models for inhaled dusts of various chemical origins as
a function of particle size, chemical properties, and compartmentalization
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 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 particulate matter in the ICRP model is based on
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chemical homogeneity of the participates, 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 ob-
tains a total absorption (clearance) of approximately 6 percent, with major
clearance, 5 percent, calculated as taking place from the pulmonary compartment.
Further complicating the issue of pulmonary absorption from particulate
matter is the finding of Hayes et al. (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 as 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 care-
fully 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 30 pg Ni/m3. The
authors' 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 about 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 on 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 ug/1 (2 to 160 mg/m3) and
particle size of 1.0 to 2.5 pm MMAD led to a deposition of 20 percent of the
4-4
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total amount inhaled. Six days postexposure, 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. It is possible that the relatively high exposure concentrations
used may have affected lung clearance mechanisms and led to a decrease in lung
clearance of particles (see Section 5.2.2). 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
3
(MMAD range, 0.6 to 4.0 pm) at a concentration of 0.4 to 70 mg/m for a maximum
period of 90 days (6 to 7 h/d, 5 d/wk). In addition to an exposure-lung deposi-
tion 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
elimination rate of the element from lungs of these animals at about 100 |jg
Ni/year.
Wehner et al. (1979) exposed Syrian hamsters to nickel-enriched fly ash
aerosol (respirable concentration, approximately 185 to 200 pg fly ash/1) for
either 6 hours or 60 days and found that, in the short exposure, about 90
percent of 80 pg deposited in the deep tract remained 30 days after exposure,
indicating very slow elimination. In the two-month study, the deep tract
deposition was approximately 5.7 mg enriched fly ash, or 510 [jg 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 pg/1 respirable nickel-enriched fly ash (NEFA) aerosol (6 percent
nickel), 17 pg/l NEFA (6 percent nickel), or 70 (jg/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 pg after 20 months exposure compared to 91, 42, and 6
fjg for the low-NEFA, FA, and control groups, respectively) was due to reduced
pulmonary removal.
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
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particle size versus nickel content was known precisely, highest nickel levels
being determined in particles 0.5 to 1.0 urn in diameter at an air level of 8.4
pg Ni/m . While the authors did not determine the total nickel deposition in
the lungs of these animals, they observed that essentially no elimination 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. (1983b), 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
the fume was 0.4 percent, the measured nickel retention rate was 0.3 ug 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 elimination from the lungs of these
animals was 30 ± 10 days.
Kalliomaki and co-workers (1983a) also demonstrated, in experimental
animals, that the deposition and elimination 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 approximately 20-fold when animals were exposed to fumes from the
former process (6.1 versus 0.29 ug/g/h). A corresponding maximum lung nickel
level (130 versus 7.1 ug/g) 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/d, 15
days) to fly ash generated at a coal-fired power plant (0.2 to 0.4 mg/1, 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 (liv-
er), 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
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material was sufficiently bioavailable 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), using
o
mice and nickel chloride aerosol (<3 urn diameter, 110 mg Ni/m ), found about 75
percent elimination by day 4 postexposure. The rapid elimination 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
relate to pulmonary elimination, with inert compounds having relatively slower
removal, the relationship of elimination to toxic manifestations is less cer-
tain. 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 pathologi-
cal 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 [jg/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 differences in lung reten-
tion (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. It is important to note that these various studies employed different
nickel compounds that likely have different effects on elimination kinetics.
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 less than 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 Ni-labeled nickel chloride solution
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
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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 (jg/ml), a retention half-time of roughly
72 hours for the carbonate can be calculated. This assumes that urinary excre-
tion parallels that of instilled nickel absorption from lung, which is clearly
the case in the Corvalho and Ziemer (1982) report on rats.
In the study of English and co-workers (1981), where both 63Ni-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 elimination of particulate 63Ni-labeled nickel subsulfide in
mice (1.7 pm, mass median diameter) has been described by Valentine and Fisher
(1984). Following intratracheal instillation, elimination 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 post-
instillation. 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 elimination 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, demon-
strating a significant degree of solubilization of particulate subsulfide by
the mouse lung. As described earlier, the data of Kuehn and Sunderman (1982)
showed dissolution half-times for the subsulfide of 34 and 21 days in serum and
tissue cytosol, respectively. Hence, both i_n vitro and jji vivo bioavailability
data suggest that there is a higher level of mobilization of the element in this
form into the blood than might be expected based on simple kinetics of solubil-
ity.
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
4-8
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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 in 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
and testing representative commercial cigarette samples via the "vacuum-smoking"
method, Alexander et.al. (1983) reported that no measurable amounts of nickel
carbonyl could be found at a detection level of 0.1 pi carbonyl/1 smoke. An-
other study showed that the amount of nickel in mainstream smoke from cigarettes
with a high nickel content is low (Gutenmann et al., 1982). However, the to-
bacco used in this study was grown on sludge-amended soil which might have
affected the pyrolytic behavior of the test leaf versus that of ordinary tobacco.
Further research is needed on the topic.
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, moder-
ate clearance of the carbonate with a half-time of around three 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 the lung involves both direct absorp-
tion 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 contributions of
nickel from utensils and equipment in processing and home preparation of food.
4-9
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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 (National
Academy of Sciences, 1975; Nielsen and Flyvholm, 1984). Collectively, the data
of Horak and Sunderman (1973), Nodiya (1972), 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 differ from 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
gastrointestinal intake is probably 250 to 300 pg 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
63
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 pro-
files were compared to those obtained when the same amount of nickel was given
in beverages and two test meals, including an average American breakfast. All
beverages except soft drink suppressed nickel absorption, as did the two test
diets. When the chelating agent, EDTA, was added to the diet, nickel in serum
was suppressed to a point below even fasting baseline levels.
4.1.3 Percutaneous Absorption of Nickel
Percutaneous absorption of nickel is mainly considered to be important in
the dermatopathologic effects of this agent, such as contact dermatitis, and
4-10
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such absorption is restricted to the passage of nickel past the outermost layers
of skin deep enough to bind with apoantigenic factors.
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. Spruit 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) reported that the relative extent of nickel penetration is enhanced
by sweat and detergents.
Mathur and co-workers (1977) 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 testi-
cular lesions were observed in rats, while hepatic effects were seen after 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 of 22 to 30 ppm when the
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 placenta! tissue with peak
accumulation having occurred by eight hours postexposure (Lu et al., 1976).
co
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. Within the fetus, the highest nickel
levels were seen in the kidney, and the lowest levels were recorded in the
CO
brain. Furthermore, Olsen and Jonsen (1979) used Ni whole body radiography in
mice to determine that placenta! transfer occurs throughout gestation.
A similar study is that of Sunderman et al. (1978), who administered
63Ni-labe!ed solution to pregnant rats intramuscularly. Embryo and embryonic
4-11
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membrane showed measurable label by day eight of gestation, while autoradiograms
demonstrated label in yolk sacs of placentae one day postinjection (day 18 of
gestation).
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 stillbirths and neonatal deaths.
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 (ng 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 ng/100 ml 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 signifi-
cance 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 route by which absorbed nickel is delivered to other
tissues. 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
4-12
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limited extent, exposure status (National Academy of Sciences, 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.
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. Furthermore,
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 elimination 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 modeling 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 the kinetics of nickel
elimination from plasma or serum in experimental animals are characterized by a
two-compartment distribution, with corresponding half-times which can be calcu-
lated 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 (National Academy of
Sciences, 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 metallo-
protein identified as an ou-macroglobulin (nickeloplasmin) in rabbits and as a
9.5 S a-,-glycoprotein in man. Sunderman (1977) has suggested that nickelo-
plasmin may be a complex of the a-,-glycoprotein with serum a-,-macroglobulin.
_
4-13
-------
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 an important factor in the
transfer of nickel from blood to other tissues.
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 condi-
tions, suggesting that nickel transfer from HSA to histidine may facilitate the
movement of nickel from the serum into other tissues. 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 radio-labeled nickel in human serum
was bound mainly to two proteins: albumin and an alpha-2-protein, possibly
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 may 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 popula-
tions 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 al., 1962;
Tipton and Cook, 1963; Tipton et al., 1965) indicate that many autopsy tissues
4-14
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TABLE 4-1. SERUM NICKEL IN HEALTHY ADULTS OF SEVERAL SPECIES
Species (N)
Domestic horse (4)
Man (47)
Jersey cattle (4)
Beagle dog (4)
Fischer rat (11)
British goat (3)
New Hampshire chicken (4)
Domestic cat (3)
Guinea pig (3)
Syrian hamster (3)
Yorkshire pig (7)
New Zealand rabbit (24)
Maine lobster (4)
Nickel concentration,
Mg/la
2.0 (1.3-2.5)
2.6 (1.1-4.6)
2.6 (1.7-4.4)
2.7 (1.8-4.2)
2.7 (0.9-4.1)
3.5 (2.7-4.4)
3.6 (3.3-3.8)
3.7 (1.5-6.4)
4.1 (2.4-7.1)
5.0 (4.2-5.6)
5.3 (3.5-8.3)
9.3 (6.5-14.0)
12.4 (8.3-20.1)
Mean (and range)
Source: Sunderman et al. (1972).
evaluated in the respective laboratories of these workers were below the detec-
tion limits available 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 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 |jg/g in most cases. Higher levels in skin, intestine, and lung reflected
some fraction of the unabsorbed element. Of importance to nickel pharmaco-
kinetics was the demonstration by these workers that the accumulation of the
element does not increase with increasing age except in the lung. Lung accumu-
lation 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
ug Ni/g wet weight) of all tissues. Andersen and Hogetveit (1984) found that
autopsied lung samples from former nickel refinery workers in Norway have nickel
contents ranging from 2 to 1350 (jg/g, depending on worksite classification
within a nickel operation.
Bern.stein 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
4-15
-------
0.23 and 0.81 ug Ni/g wet weight, respectively. The relatively high values in
lymph nodes indicated that lymphatic clearance of participate nickel lodged in
lung also occurs in humans, such clearance being demonstrated in experimental
animals (vide supra).
Sumino et al. (1975) analyzed nickel in autopsy samples from 30 non-exposed
Japanese and also found highest levels in lung (0.16 jjg/g wet weight), followed
by liver (0.08) and kidney (0.1 pg/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
(National Academy of Sciences, 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 tiss.ues appears to occur only
in the lung, other soft tissues showing no accumulation. Such accumulation may
be associated with highly insoluble forms of inhaled nickel. 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) pg/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 mg/g) than in dentine (31.4 pg/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 (National
Academy of Sciences, 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 observed elevated, rapidly eliminated 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
CO
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
4-16
-------
take up an appreciable amount of nickel. Nickel carbonyl has also been shown to
be excreted in breath following its intravenous administration in rats (Kasprzak
and Sunderman, 1969; Sunderman et al., 1968; Sunderman and Selin, 1968).
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. Retained nickel carbonyl appears to undergo decompo-
sition to carbon monoxide and possibly zero-valent nickel in erythrocytes and
other tissues, followed by intracellular oxidation of the element to the diva-
lent form and subsequent release into serum (National Academy of Sciences, 1975).
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 (NiClp)
to induce the metal binding protein, metallothionein (MT), in livers and kidneys
of Fischer rats. Nickel II was moderately active as an inducer at dosing
levels of 6.3 and 47 mg/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 copper/zinc uptake. However, nickel may
induce MT synthesis through either hormonal disturbances or stimulated transla-
tion 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. Schroe-
der et al. (1974) could find no uptake of nickel in rats chronically exposed to
nickel in drinking water (5 ug/ml) 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
4-17
-------
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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 pg/g.
While levels of nickel were somewhat elevated in pancreas, testis, and bone at
250 (jg/Qj pronounced increases in these tissues were seen at 1000 pg/g. Whanger
(1973) exposed weanling rats to nickel (acetate) in the diet at levels up to
1000 [jg/g. As nickel exposure was increased, nickel content of kidney, liver,
heart, and testis was also elevated, with greatest accumulation in the kidneys.
CO
Spears et al. (1978) observed that lambs given tracer levels of Ni orally with
or without supplemental nickel 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 absorption, e.g., 5 pg/g, but such
regulation 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 RNA 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 microsom-
al 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
nig/kg, i.p., single dose). The relative amount of nickel bound to whole chroma-
tin 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 hi stone octamer proteins from kidney.
A number of recent studies indicate that subcellular partitioning of nickel
in vivo or in vitro is markedly different between insoluble nickel compounds and
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soluble nickel salts. Herlant-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
subselenide are all actively phagocytized and enter Syrian hamster embryo or
Chinese hamster ovary cells with subsequent transfer of nickel to cell nuclei.
Harnett 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
should be given to the observation that some process, possibly endocytosis,
delivers the particles adjacent to the nucleus, as determined by ultrastructural
observation. Eventual dissolution would likely permit 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, less than 2000 daltons. The remainder was
partitioned among molecules of 10,000 to less than 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-
performance size-exclusion chromatography (Sunderman et al., 1983). Abdulwajid
and Sarkar (1983), on the other hand, have claimed that their method of purifi-
cation 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
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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 an elimination half-time of 1200 days
(approximately 3.3 years) based upon a daily net retention of around 30 percent
of the amount absorbed from a rather high daily ingestion 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 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 ug/g bone,
30 to 40 ug/g dentition) lead to a body nickel burden closer to the ICRP esti-
mate. If it is assumed that the current daily nickel intake is closer to 200 |jg
(Myron et al., 1978; Clemente et al., 1980) than the ICRP value of 400 ug, then
the biological half-time is increased, being entirely determined by mineral
tissue burden. Since nickel in bone is relatively constant with age, it presum-
ably is constantly being resorbed and deposited in the mineral matrix. The
daily net retention figure of 30 percent for absorbed 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 to 500 jjg/day in man.
Urinary excretion in man and animals is usually the major excretory route
for absorbed nickel. Reported normal levels in urine vary considerably in the
literature, and earlier value variance probably reflects both methodological
limitations as well as inherent biological variation. More recent studies
suggest values of 2 to 4 ug/1 (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), employing relatively accurate methodology, observed that
biliary excretion of nickel in the rat, when administered in single subcutaneous
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doses, only amounted to approximately 0.3 percent of the total dose over a
24-hour period, thereby constituting a rather minor route for excretion.
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 jjg/1 for men and 131 ± 65
ug/1 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
(1969) have reported sex-related differences in nickel levels of human hair
samples, female subjects having nickel levels (3.96 jjg/g, S.E.M. = ±1.06) about
fourfold those of men (0.97 |jg/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.
Several studies have demonstrated that excretion of nickel in human milk is
quite low and should be considered a minor route of excretion in lactating women
(Feeley et al. 1983; Mingorance and Lachica, 1985).
In experimental animals, urinary excretion is the main excretion route for
nickel compounds introduced parenterally. Onkelinx et al. (1973) studied the
CO
kinetics of injected Ni metabolism in rats and rabbits. In both species, a
two-compartment model of excretion 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 comparable excretion in the rat required 3 days. In a
later study, Onkelinx (1977) reported whole body kinetics of 63Ni 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 elimination was
accounted for by renal excretion.
Chausmer (1976) has measured exchangeable nickel in the rat using 63Ni
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, the 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.
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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 in vivo to. divalent nickel, and carbon monoxide with nickel
eventually undergoing urinary excretion (Mikheyev, 1971; Sunderman and Selin,
1968).
The time course of labeled-nickel urinary excretion in rats given a single
CO
injection (4 mg/kg, 12.5 |j Ci Ni/mg cold Ni, as chloride) was studied by Verma
et al. (1980) who reported nickel to be excreted as a mixture of complexes
within 24 hours of dosing, the binding species having a molecular weight of 200
to 250.
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 experi-
mental animals. Furthermore, in vivo movement of nickel may be deliberately
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 myocar-
dial infarction (AMI) (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 eight hours on day one and daily for the second and third days. Hyper-
nickel emi a 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 con-
cluded that elevated nickel may be associated with the pathogenesis of ischemic
myocardial injury.
4-23
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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 fivefold (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 inexplicable.
Several recent studies demonstrate an association of serum nickel with
chronic renal failure and hemodialysis. According to Drazniowsky and co-workers
(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). Simi-
larly, 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-glucosaminidase.
Other stresses appear to have an effect on nickel metabolism. Significant
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
4-24
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rose to normal at parturition, and a 20-fold, transitory rise in serum nickel at
5 minutes postparturition. By 60 minutes, serum values were normal. Unfortu-
nately, several problems have been noted with this study including the reliabil-
ity of the analytical methods employed and-the inability of others to replicate
the results (Nomoto et al., 1983).
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
elsewhere (Sunderman, 1977; National Academy of Sciences, 1975), and will only
be summarized in this section.
On the basis of reported clinical experience, sodium diethyldithiocarbamate
(dithiocarb) is presently the drug of choice in the management of nickel carbon-
yl poisoning, being preferable overall to EDTA salts, 2, 3-dimercaptopropanol
(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 suggests
that the dithiocarbamates may serve to markedly alter the distribution of
nickel as well as its retention jji vivo (Oskarsson and Tjalve, 1980). Similar
results have been reported using alkyl thiuram sulfides, agents which readily
undergo in vivo reduction to the dithiocarbamates (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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5. NICKEL TOXICOLOGY
Both acute and chronic effects of exposure to various nickel compounds have
been extensively documented over the years. The following chapter discusses
these non-mutagenic/carcinogenic effects of exposure to various nickel com-
pounds. 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 HUMANS 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)4, 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 industri-
al 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, sweat-
ing, visual disturbances, and severe weakness. Aside from the weakness and
hyperpnea, the symptomatology strongly resembles that of viral pneumonia.
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The lung is the target organ in nickel carbonyl poisoning in humans 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.
In humans, 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 one hour of exposure. There is subsequent
proliferation and hyperplasia of bronchial epithelium and alveolar lining cells.
By several days postexposure, 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 prolif-
eration 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.
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5.2 CHRONIC EFFECTS OF NICKEL EXPOSURE IN HUMANS 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 (National
Academy of Sciences, 1975). Originally considered to be a problem in occupa-
tional medicine, the 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, extrac-
tion, and refining of the element as well as such operations as plating, cast-
ing, grinding, polishing, and preparation of nickel'alloys (National Academy of
Sciences, 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 (National Academy of Sciences, 1975).
Nonoccupational exposure to nickel potentially leading to dermatitis in-
cludes nickel-containing jewelry, coinage, tools, cooking utensils, stainless
steel kitchens, prostheses, and clothing fasteners. Women appear to be parti-
cularly at risk for dermatitis of the hands and their continuous contact with
many of the nickel-containing commodities noted above has been implicated by
Malten and Spruit (1969) as a factor in dermatitis.
Nickel dermatitis usually begins as itching or burning papular erythema in
the web of fingers and spreads to the fingers, wrists, and forearms. Clinical-
ly, the condition is usually manifested as a papular or papulovesicular dermati-
tis 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 rela-
tion 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
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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 significant
increases of IgE in patients having nickel and atopic dermatitis histories.
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) reported that pustular patch test reac-
tions to five percent nickel sulfate were regularly produced in patients with
atopic dermatitis, but only when applied to areas of papulae, erythema, lichen-
ification, 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 Mb'ller (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 erythema
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 influ-
enced by any steps taken to minimize external exposure. Subsequently, these
workers (Christensen and Moller, 1975b) discovered that oral administration 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 compari-
son 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 manifested as hand eczemas of dyshi-
drotic morphology. Of 17 subjects in the clinical trial, nine showed signifi-
cant improvement during a period of six weeks on a low nickel diet. Of these
nine showing improvement, seven had a flare-up in their condition when placed
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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 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 following oral
challenge with nickel and other salts and were subsequently placed on low-metal
allergen diets showed clearing or improvement of the condition after approxi-
mately four weeks.
The association between endogenous nickel and nickel sensitivity has
prompted study of the known nickel chelant diethyldithiocarbamate, in the form
R
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 six 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 of
P
Christensen and Kristensen (1982), 11 patients given Antabuse (200 mg/day,
5-5
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8 weeks) showed healing in two cases and improvement in eight 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.
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 five and six 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; National Academy of
Sciences, 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 generally
range between 10 to 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 (National Academy of Sciences, 1975;
Samitz and Katz, 1975). Apparently, sufficient solubilization of nickel from
the surface of the material appears to trigger an increase in dermatitis activi-
ty. 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, counseled caution in interpreting the reports
and recommended specific criteria for proof of nickel dermatitis from a foreign
body to include evidence of surface corrosion art'd sufficient corrosion to give a
positive nickel spot test.
Nickel dermatitis has been described in a patient undergoing hemodialysis
(Olerud et al., 1984). Exposure occurred through blood contaminated 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 poten-
tial problem in these individuals.
5-6
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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 a patch test
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 a!., 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 (National Academy of Sciences,
1975).
The effect of nickel on lymphocyte transformation and the utility of this
phenomenon as an In vitro alternative to conventional patch testing with its
attendant ambiguity and dermatological hazards merit discussion.
Transformation of cultured human peripheral lymphocytes as a sensitive in
vitro screening technique for nickel hypersensitivity versus the classical patch
testing has been studied in a number of laboratories, and the earlier conflict-
ing studies have been reviewed (National Academy of Sciences, 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 y.M) stimulated
both immunologically immature thymocytes and immunocompetent peripheral lympho-
cytes in children of different ages. Nickel-stimulated DNA synthesis in both
of 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. Later, Vandenberg
and Epstein (1963) successfully sensitized nine percent (16 of 172) of their
clinical subjects.
5-7
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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 (National Academy of Sciences,
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 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 (National Academy of Sciences, 1975). In the
section on nickel metabolism, 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-alanine) was a better sensitizer than nickel alone,
while Thulin (1976) observed that inhibition of leukocyte migration in ten
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 DR 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
5-8
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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 fragmen-
tary that they will not be considered.
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 (National Academy of Sciences,
1975). Originally considered to be a problem in occupational medicine, the more
recent clinical and epidemiological 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 clini-
cal 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 significantly 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 practice of
surveying patient samples to surveying subjects more representative of the
general population.
5-9
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5-10
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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.
The North American Contact Dermatitis Group study (1973) permits examina-
tion 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-
tive persons 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-sensitive 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
hairdressers; they showed a positive reaction rate of 40 percent to nickel
sulfate (5 percent) solution. Wahlberg's 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 individu-
als. 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 pg Ni /I.
Edman and Moller (1982) reported on a University of Lund patient population
of 8,933 who had been patch tested at the University clinic over a 12-year
period. The authors found that nickel sensitivity increased during that period
5-11
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TABLE 5-2. NORTH AMERICAN CONTACT DERMATITIS GROUP PATCH TEST RESULTS
FOR 2.5 PERCENT NICKEL SULFATE IN 10 CITIES
Subject
Black
White
All
Total
Females
Males
Total
Females
Males
Total
Females
Males
Positive Reactions
Total No.
79
64
143
612
445
1057
691
509
1200
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).
5-12
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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 aller-
gy. 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 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 preven-
tive 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, and so forth. Some prepara-
tions used in hairdressing contain nickel, and consequently hairdressers exhibit
nickel dermatitis. The consequences of nickel contact dermatitis seem to vary
with the surrounding social factors. Male factory workers appear not to be han-
dicapped by it (Spruit and Bongaarts, 1977b) and continue in their work; hair-
dressers leave their occupation when they develop dermatitis (Wahlberg, 1975).
The impact of nickel dermatitis on the health of the total U.S. population
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 severi-
ty, 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 orthope-
dic implants.
5-13
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The alloys, contrary to general assumption, appear not to be biologically
inert and produce adverse reactions in some of the individuals sensitive to
nickel. A number of cases have been reported in which individuals developed
malignant soft-tissue tumors near the implantation sites of bone plates or joint
protheses containing nickel, chromium or cobalt (Linden et al., 1985).
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 implants
which included loosening of total joint prostheses. The authors studied the
preoperative sensitivity status of 212 patients scheduled for total hip replace-
ment 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 prostheses. 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 postopera-
tive period of the study which was approximately two years. This represented a
5-14
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postoperative conversion rate of six 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, addition-
al reports have appeared augmenting the list of items which have created sensi-
tization and symptoms.
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 applications of nickel sulfate in detergent solu-
tion. Samitz and Pomerantz (1958), however, 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 statistically
greater than with control animals. Turk and Parker (1977) reported sensitiza-
tion 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 ng of the salt after
two weeks. Delayed hypersensitivity reactions developed in two of five animals
at five 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.
Mb'ller (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 three-week interval. The resulting dermatitis was moderate, as indicated
by a weak wet weight increase in inflamed skin tissue.
5-15
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5.2.2 Respiratory Effects of Nickel
Effects of nickel in the human respiratory tract, other than
carcinogenicity, 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
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 nickel carbonyl 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, breath!essness, anorexia, and 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 electroplating
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
(Tolat et a!., 1956; McConnell et a!., 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 antigenie 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.
5-16
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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.
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 patho-
logical changes included bronchial epithelial hyperplasia, focal proliferative
pleuritis and adenomatosis.
Wehner and co-workers (1981) studied hamsters inhaling nickel-enriched fly
ash (aerosol, 17 or 70 |jg/l) for up to 20 months. Lung weights and volumes were
significantly increased in the higher (70 jjg/1) fly ash exposure groups. The
severity of anthracosis, interstitial reaction, and bronchiolization was
dose-dependent.
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 the lung
response in rabbits inhaling metallic nickel dust (1 mg/m Ni) for three and six
months. In addition to responses similar to those noted above for soluble
nickel aerosol, the six-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, particu-
larly 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).
5-17
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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).
Spiegel berg and co-workers (1984) exposed adult Wistar rats to nickel oxide
aerosols for either four weeks or four months. Exposure levels for the short-
term study were 50, 100, 200, 400, and 800 pg Ni /m3, while exposure levels for
the long-term study were either 25 or 150 p.g Ni/m3. Short-term effects on
alveolar macrophages included altered size at the 100 jjg Ni/m3 level, increased
phagocytic activity (elevated to 141 percent of controls) at the 400 |jg Ni/m3
level, and increased numbers of polynucleated cells, also at the 400 (jg Ni/m3
level. After four months of exposure, the number of macrophages was signifi-
cantly increased at 25 ug Ni/m3, but slowly decreased at 150 jjg Ni/m3. Increase
in size and number of polynucleated macrophages was observed at both the 25 and
150 pg 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 threefold increase in phosphatidyl choline
(Casarett-Bruce et al., 1981). Lundborg and Camner (1982) reported that signif-
icant 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 three months. Hydrolytic enzymes in macrophages
were significantly reduced in content, whereas the opposite occurred in macro-
phages of rats inhaling nickel oxide (120 ug/m3) or nickel chloride (109 pg/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 pm to 8
pm. 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 mechanisms
appear to resemble the pathological picture presented by both human pulmonary
alveolar proteinosis and animals inhaling quartz dust.
5-18
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Respiratory tract cytotoxicity of nickel species i_n 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.
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
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, adrenalectomized, and
hypophysectomized rats. Injection of nickel chloride (2 or 4 mg/.kg) produced
prompt elevations in plasma glucose and glucagon levels with a return to normal
two to four hours afterwards, suggesting that hyperglucagonemia may be responsi-
ble 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 significant depres-
sion of serum prolactin without any affect on growth hormone or thyroid-
5-19
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stimulating hormone. The jri 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 pro! act in over the short term,
but resulted in a sustained elevation of the hormone after one day, lasting up
to four days (demons and Garcia, 1981). Elevation was due to reduced levels of
pro!actin-inhibiting factor. A later study by Carlson (1984), demonstrating
that nickel II antagonizes the stimulation of both prolactin and growth hor-
mone by barium II, suggested that the basis of antagonism may be competi-
tive inhibition of calcium uptake.
Dormer and co-workers (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 to 5.0 mg/kg/day, 2 to 4
weeks) or by inhalation (0.05 to 0.5 mg/m3) 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 i_n vitro conditions, has
a number of effects on the heart, including coronary vasoconstriction, myocardi-
al depression, and subcellular injury.
Ligeti and co-workers (1980) reported that administration of nickel II
ion at rather low levels (20 pg/kg body weight) to anesthetized dogs induced a
significant decrease of coronary vascular conductance. Higher nickel dosing
(200, 2000, and 20,000 ng/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.
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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,
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 al., 1982). As a follow-up to their earlier studies,
Rubanyi and co-workers (1984) evaluated the effect of nickel on the |n situ
heart of anesthetized open-chest dogs. Soluble nickel (NiCl2) was administered
either intravenously (20 |jg Ni/kg bolus injection) or via intracoronary infusion
(40 MO 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. Accord-
ing 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 pM.
Human data relating nickel to the pathogenesis of cardiovascular disease
states are meager. As noted above, Balogh et al. (1983) observed significant
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nickel accumulation in postmortem myocardium of carbon monoxide victims, paral-
leling the observation in experimental animals. Leach et al. (1985) 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 the
pathogenesis of ischemic myocardial injury. The existence of hypernickelemia in
burn patients (see Chapter 4) and other traumatic states parallels the experi-
mental 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. As noted in the study of Rubanyi and co-workers (1982)
(Chapter 4), a huge transitory rise in serum nickel attending childbirth may be
related to a minimizing of atonic bleeding. Care should be exercised in inter-
preting this study, however, owing to possible problems of analytical methodol-
ogy and failure of other researchers (Nomoto et al., 1983) to replicate the
results. Whether excessive nickel exposure in occupational or non-occupational
populations exacerbates ischemic heart disease or enhances the risk of myocardi-
al infarction in subjects with coronary artery disease is unknown. The present-
ly 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 hyperten-
sion and hyperlipidemia.
5.2.5 Renal Effects of Nickel
Nickel-induced nephropathy in man or animals has not been widely document-
ed. 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
5-22
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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 dysfunc-
tion being dose-dependent. Proteinuria was observed at a dose of 2 nig/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 rabbits,
Foulkes and Blanck (1984) found that the nephrotoxic action of injected nickel
salt (N1C12, 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 hyperemia 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 (National Institute for Occupational Safety
and Health, 1977; National Academy of Sciences, 1975). Neural tissue lesion
formation in the latter case is profound, including diffuse punctate hemorrhages
in cerebral, cerebellar, and brain stem regions, degeneration 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, crNi^, Ni^FeS^,
NiSe, Ni' Se9, NiAsS, NiO, and Ni dust. Rank correlation (p <0.0001) was
O (_
obtained between erythrocytosis and renal cancers. Erythrocytosis in this
animal model of nickel toxicity appears to be mediated by enhanced erythropoie-
tin production (Hopfer et al., 1985).
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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 nonspeci-
fic defense against certain types of infection and tumors, were seen to be sig-
nificantly suppressed in activity within 24 hours of a single intramuscular in-
jection of nickel chloride (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 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 chlo-
ride, 400 or 800 |jg/g) on retarding growth in chicks over the range of 10 to 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). Presum-
ably, the existence of any interactive mechanism is overwhelmed at large levels
of agents employed in the former study.
Using lethality of injected nickel chloride (95 or 115 |jmol/kg) in rats as
an effect index, Waalkes et al. (1985) demonstrated that co-administration of
zinc II (multiple doses, 300 (jmol/kg) at different times significantly increased
5-24
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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
metal!othionein, 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 hemato-
crit 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.
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 protec-
tion 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 nickel chloride-suppression of NK cell activity which
might provide important clues to understanding the antagonism of manganese for ,
nickel-induced carcinogens!s.
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 ng/ml nickel salt and 0.78 M9/ml
benzofa).pyrene. Furthermore, in a mutagenesis system using hamster embryo cells,
as described by Barrett et al. (1978), a comutagenic effect between nickel
sulfate and benzo(a)pyrene has also been observed (Rivedal and Sanner, 1980;
1981). These observations, supported by cocarcinogenic effects between nickel
compounds and certain organic carcinogens (Toda, 1962; Maenza et al., 1971;
5-25
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Kasprzak et al., 1973), are of considerable importance in evaluating the enhanc-
ing effect of cigarette smoke on the incidence of lung cancer in nickel refinery
workers (Kreyberg, 1978).
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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, Fla and Flb, derived from the single FQ generation.
For the second and third generations, breeding pairs from dams and sires
exposed to nickel in Flb or F2b, 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 off-
spring.
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 genera-
tions, although the authors note that the animals "recovered considerably" by
the time they were mated. Unfortunately, statistical analysis of this and the
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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 po.ints
and the reduced parental body weight at this dose, the effect of nickel expo-
sure on postnatal growth cannot be assessed. Other observations included an
increase in fetal death in both groups of the first generation (but not subse-
quent generations) and a possible decrease in litter size and postnatal surviv-
al. However, the authors do not discuss these data relative to reproductive
toxicity, 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 paren-
tal animals during eight weeks exposure prior to mating at 1000 ppm. Due to
deficiencies in the experimental design relative to sample size and statistical
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 have been 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,
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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
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. Histologically,
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)1. Mathur and co-workers (1977) 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 sacrificed,
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
Original manuscript not available during this review.
6-3
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which were incapable of developing into blastocysts. Cleaved eggs from this
same dose group were capable of developing into blastocysts. 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.
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 de-
creased rate of pregnancy and an increase in the preimplantation loss of em-
bryos. 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 endometriurn 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 LDrg of 22 mg/kg was established for treatment on gesta-
tion day 8, and the authors reported an LD5 of 17 mg/kg. However, none of
the three doses in the developmental toxicity study led to maternal death or
6-4
-------
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 eight
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; how-
ever, 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 reduction
in fetal weight and placenta! 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
6-5
-------
weight, reduced mean birth weights of pups, and increased incidence of spon-
taneous abortions. Using a short-term, i_n vivo screen, Chernoff and Kavlock
(1982) treated pregnant CD-I mice with 30 mg/kg of nickel chloride intraperi-
toneally on gestational day 8. They concluded that nickel chloride was feto-
toxic based on a decreased mean number of pups per litter compared to controls.
In addition, the pregnancy rate for nickel-treated dams was significantly
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 administration 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 four of incubation, via the
yolk sac, or day eight 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
teratogenic. The time of administration in this study was relatively late,
however. In studies by Gilani (1982) and Gilani and Marano (1980), 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 eight of incubation and examined grossly for malformations.
Under these conditions, nickel chloride was found to induce a series of mal-
formations 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 i_n 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 uM NiClp • 6hLO). When exposure was not initiated
until the 4- to 8-cell stage, higher concentrations (200 to 300 uM) were re-
quired to cause an effect on development; no effect was observed at 100 uM.
6-6
-------
In a subsequent jn vivo study (Storeng and Jonsen, 1981), a single intraperi-
toneal injection of nickel chloride hexahydrate (20 mg/kg body weight) was
administered to pregnant mice on one of gestational days one through six. The
dams were sacrificed on gestational day 19 and gestational and embryotoxicity
data were ascertained. The data presentation and statistical approach do not
permit a clear interpretation of dose- and time-related effects. However, it
does appear that jm 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^)
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 intrarenal
injection of nickel subsulfide did successfully induce maternal polycythemia
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.
6-7
-------
Finally, in a series of experiments, Sunderman and co-workers (1983, 1980,
1979, 1978b,c) 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 inhalation on
gestation day 7 to 0.16 mg/liter for 15 minutes resulted in decreased fetal
viability and fetal weight, and an increased number of litters with malforma-
tions. Similar effects were seen at 0.30 mg/liter, but this level was also
associated with significant maternal death. Lower exposure levels on day seven
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 increased numbers
of litters (and fetuses) with malformations. Exposure on days six, seven or
eight did not have a significant effect on development. Among the teratogenic
effects noted were anophthalmia and microphthalmia in rats and exencephaly 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 (See
Chapter 9).
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 ef-
fects on the reproductive process. However, studies should be designed to
cover a wider range of exposure levels and durations, in order to better de-
fine 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.
6-8
-------
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
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 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
humans relative to effects on embryo/fetal development, following exposure to
this form of nickel.
6-9
-------
6.6 REFERENCES
Ambrose, A. M. ; Larson, P. S. ; Borzelleca, J. F. ; Hennigar, G. R. , Jr. (1976)
Long term toxi col ogic assessment of nickel in rats and dogs. J. Food Sci
Techno I. 13: 181-187.
Berman, E.j Rehnberg, B. (1983) Fetotoxic effects of nickel in drinking water
in mice. Research Triangle Park, NC: U. S. Environmental Protection
rifn£&/ Health Ejects Research Laboratory; EPA report no
EPA-600/1-83-007. Available from: NTIS, Springfield, VA; PB83-225383.
Chang, C. C. ; Tatum, H. J. ; Kincl, F. A. (1970) The effect of intrauterine
copper and other metals on implantation in rats and hamsters. Fertil.
oteri I . c.i.\ 274~ 278.
Chernoff, N. ; Kavlock, R. J. (1982) An in vivo teratology screen utilizinq
pregnant mice. J. Toxicol. Environ, "ReaTtlTlO: 541-550.
Deknudt, G. H. ; Leonard, A. (1982) Mutagenicity tests with nickel salts in the
male mouse. Toxicology 25: 289-292.
Perm, 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 cardioqenesis.
Teratology 25: 44A.
Gilani, S. H.; Marano, M. (1980) Congenital abnormalities in nickel poisoning
in chick embryos. Arch. Environ. Contam. Toxicol. 9: 17-22.
Hoey,_M. J (1966) The effects of metallic salts on the histology and function-
ing of the rat testis. J. Reprod. Fertil. 12: 461-471.
Jacquet, P.; Mayence, A. (1982) Application of the In 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. a>y
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
-------
Ridgway, L. P.; Karnofsky, D. A. (1952) The effects of metals on the chick
embryo: toxicity 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 i_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) Teratogenicity
and embryotoxicity of nickel carbonyl in Syrian hamsters. Teratog.
Carcinog. Mutagen. 1: 223-233.
Sunderman, F. W.; Reid, M. C.; Shen, S. K.; Kevorkian, C. B. (1983)
Embryotoxicity 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.; pp. 399-416.
von Waltschewa, W.; Slatewa, M.; Michailow, I. (1972) Hodenveranderungen bei
weissen Ratten durch chronische Verabreichung von Nickelsulfat [Testicular
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 genotoxicity 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 (NiCl?) 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 evaluation 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, 10, and 25 ug/ml, mutation frequencies
7-1
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were similar to those of control groups. In the experimental groups there were
51, 42, and 27 turbid tubes, respectively, for the above doses. Controls showed
44} 44 s and 51 turbid tubes. Two hundred tubes were scored for each concentra-
tion with 200 concurrent control tubes.
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 |jg/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 incu-
bated 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 (jg/ml. However, concentrations
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
7-3
-------
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
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25.2
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96.3
100
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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).
tryptophan and isoleucine, respectively. Nickel sul fate 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.
7.1.3 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 transf erase (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 MS/ml) induced 7.1 ± 0.2 and 15.6 ±
2.0 mutants per 10 survivors, respectively. The control mutation rate was
7-4
-------
logN(
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log N
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m
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Figure 7-1. The relationship
between the lethal and muta-
genic effect of Ni2+ (//g/ml) by
means of the clone method:
IMC, number of surviving cells
(open symbols); Nm mm
(closed symbols) in 1 ml of
culture.
Source: Pikalek and Necasek
(1983).
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5.8 ± 0.8 per 106 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 per-
cent), the mutation frequency (7.1 ±0.2 per 10 survivors) was almost similar
to that of the control rate (5.8 ± 0.8 per 106 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 Paillet (1980) reported that nickel chloride was mutagenic in
mouse lymphoma L5178Y cells. Nickel chloride at concentrations of 1.69 x 10 M
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
(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-resistant mutants
per 104 survivors. The cell survival at these concentrations ranged from 32 ± 2
to 22 ± 3 percent. These results demonstrate a dose-related response and trans-
late into a 4- to 5-fold increase in the mutation frequency over the control
level (0.38 ± 0.06). Cultures treated with one 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 Paillet (1980) is the only study that indicates
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 i_n vivo induction of chromosomal aberra-
tions are summarized in Table 7-5.
7-7
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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 chromosomal
preparations for aberrations. Nickel chloride and nickel acetate induced no
aberrations at concentrations of 1.0 x 10"3, 6.4 x 10~4, and 3.2 x 10~4 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 (2 percent)
at 48 hours of treatment. The concentration of 1.0 x 10"3M 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 period
using the flame-drying method, and 100 metaphases for each interval we.re
analyzed for chromosomal aberrations. Nickel acetate at a concentration 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 reincubation
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 noted. Nickel
acetate at a concentration of 8 x 10~4 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 concentration of 6 x 10"4 M,
aberrations were also observed after 24 hours of reincubation. Nickel chloride,
nickel sulfide, and potassium cyanonickelate induced similar clastogenic
7-10
-------
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 aberrations. 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-
tration of 1.9 x 10"5 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 three 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. Unfortunately, this study is limited because only one concentration was
tested by these investigators.
Clearly, well designed i_n 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 relationships 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.
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 LD5Q, was provided for dosage selection.
Waksvik and Boysen (1982) analyzed blood lymphocytes for chromosomal abnor-
malities and sister chromatid exchanges from workers exposed to nickel in a re-
finery. Three groups of workers were studied. According to these investigators,
7-11
-------
the subjects were nonsmokers and nonalcohol users and did not use drugs regular-
ly. The workers had not received any form of therapeutic irradiation. Of the
three groups, two 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/m3) from 7 to 29 years, with an average of
21.2 years. The plasma concentration of nickel in blood ranged from 1 to 7
(|jg/l). 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/m3 air, a range of 0.1 to 0.5 mg Ni/m3. 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 (jg/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 chromosomal
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.
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
LD5Q) were used. One thousand polychromatic erythrocytes from bone marrow cells
of five male mice were scored for each test compound. The yields of
micronucleated 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 four weeks covering the entire sperma-
togenic cycle. Pregnant mice were sacrificed and the incidence of pre- and
7-12
-------
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 implantations,
indicating the toxicity of the metal for the preimplantation zygotes. The
.authors indicated that since dominant lethalIs are generally a result of chromo-
somal 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 i_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 leading 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.
7.3 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 increase in
SCE. At a concentration of 2.33 x 10~4M/1 (55 ng/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-Ma/ml), the SCE frequency was 7.24 ± 0.38
7-13
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7-14
-------
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 cultures.
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 |jg/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
concentration of 1.19 x 10 M (28 ug/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. Concentrations 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
7-15
-------
10"6M (2.5 ug/ml) and 1.9 x 10~5M (5.0 po/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 10~6M (1 ng/ml), 9.5 x 10~6M (2.5
and 1.9 x 10"M (5.0 |jg/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 i_n 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.
Kanematsu et al. (1980) exposed Bacillus subtil is strains H17 (rec+) and
M75 (rec-) to 0.05 ml of 0.005 to 0.5 M 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 be
indicative of a negative response.
7-16
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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 (Ni-3S2), -crystalline-nickel monosulfide (NiS),
crystalline, nickel selenate (Ni'3Se2), 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
i_n vitro. Nickel subsulfide (NigS,,) induced a positive response in these
studies, whereas amorphous nickel monosulfide gave negative results in the
transformation 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 et
al. (1982b) found that soluble nickel chloride (NiCl2) induced morphologic
transformation of Syrian hamster embryo cells. Saxholm et al. (1981) found that
nickel subsulfide (Ni3S2) induced morphologic transformation in C3H/10T1/2
cells. Hansen and Stern (1982) studied the activity of nickel dust, nickel
subsulfide, nickel trioxide (Ni'203), nickel oxide (NiO), and Ni(C2H302)2 for
in 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).
7-17
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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 (1981, 1980). Costa and
Mollenhauer found that pretreatment of cells with BP enhances cellular uptake of
nickel subsulfide particles. Rivedal and Sanner found that a combined treatment
of nickel sulfate 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) reviewed the biochemical genotoxicity of nickel compounds.
Sigee and Kearns (1982) demonstrated that nickel in the chromatin of dinoflagel-
lates associated with hj^h-moJLecular-weight proteins and nucleic acids. Kovacs
and Darvas (1982) demonstrated the localization of nickel in centrioles of HeLa
cell cultures. Hui and Sunderman (1980) found 0.2 to 2.2 mol 63Ni/mol of DNA
nucleotides in DNA isolated from liver and kidney of rats treated with 63NiCl2
or Ni(CO)4. Ciccarelli and Wetterhahn (1983) demonstrated nickel-nucleic
acid-histone complexes in liver and kidney of nickel carbonate-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 nickel carbonate. In
Chinese hamster ovary cells, crystalline nickel monosulfide 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 com-
pounds, since strand breaks can also be produced by indirect, nonspecific ef-
fects, such as intracellular 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 in vitro from synthetic
polynucleotide templates by microbial polymerases.
7-18
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The effects of nickel cations on transcription of calf thymus DMA and phage
t^ DMA by RNA polymerase from E. coli B were studied by Niyogi and Feldman
(1981) under carefully controlled conditions. These studies demonstrated 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) In 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 DMA 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. 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 ui 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. D.; 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 ijn 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) _In vitro and transformation potency of nickel
compounds. Copenhagen, Denmark; Danish Welding Institute, report no. 82/22;
pp. 1-10.
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
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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 NiC]2 and the analysis of
mutagenicity of metal ions in a bacterial fluctuation test 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.
Tokyo, 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. -
Niyogi, S. K. ; Feldman, R. P. (1981) Effect of several metal ions on misincor-
poration during transcription. Nucleic Acids Res. 22: 9-21.
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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 jn 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 DMA 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 dinoflage!late 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.
Zakour, R. A.; Tkeshelashvili, L. K.; Sherman, C. W.; Koplitz, R. M.; Loeb,
L. A. (1981) Metal-induced infidelity of DNA 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. A Bessemer matte from Canada 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. 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
8-1
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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
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 practically
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 sulfuric
acid. This resulted in a matte which had a relatively high concentration 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 was 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 noted 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
8-2
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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
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 five
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.
8-3
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TABLE 8-1. EXPOSURES BY WORK AREA (CLYDACH, WALES)
Work area
Exposures
Level
Changes
Crushing, grinding,
and calcining shed
Copper extraction
Reduction, volatil-
ization,
Dust, nickel, oxides, Very high
S02, copper, sulfur
Copper sulfate,
arsenic (contaminant)
Nickel powder, nickel
carbonyl, CO decomposition
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 practi-
cally free of
arsenic.
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 refinery.
It provides no risk estimates by species of nickel.
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
8-4
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almost exclusive to process workers; no nasal cancer deaths occurred among
nonprocess workers.
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 process
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 one 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 independently,
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 approximately
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,
8-5
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269 between 1910 and 1914, 667 between 1915 and 1919, 602 between 1920 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 one 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 ten years had
the highest rate, 20 percent, as compared to those entering during other
periods and working less than ten years. All subsequent cohorts, defined by
year of entry and working for one to ten 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 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 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
8-7
_
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was higher for process (defined as "processman" or "process worker" on the
death certificate) versus nonprocess workers. The lung cancer PMR for process
workers was 700 versus 340 for nonprocess workers. The nasal cancer PMR was
30,000 for process workers versus 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 five 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 five 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 five 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 exposure, 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
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
8-8
-------
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 youngest
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
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 explanation
for the pattern noted in the Doll et al. (1970) study (which assumes an
additive effect for nickel and smoking).
8-9
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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 correspondence 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 five 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 five 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 proportion
of the cohort started their employment before 1925 (68 percent versus 66
percent) due to the change in the cohort definition between this and the 1970
report (Doll et al., 1970).
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
8-10
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identified 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 250, higher than that reported
in 1970 (Doll et al. , 1970).
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
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
8-11
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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 versus 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 I I 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 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
8-12
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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 and volatilization area of the plant, where the ambient nickel
carbonyl 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
ten 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 five 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 five or more years in the copper sulfate ar.ea. The low-exposure
group was further divided into two ordinal categories, and the high-exposure
group was divided into four ordinal categories.
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 five 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
8-13
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than two years in the furnaces and five 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-expo-
sure 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 cerebrovascular disease is ad-
justed for local rates, the excess risk completely disappears.
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
nonprocess 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
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 increased
up to 40 years after first exposure for lung cancer and 50+ years for nasal
cancer.
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 FACTORSd
Risk factor
. Significance
Lung cancer level p
Nasal cancer
Significance
level p
Age first exposed (A)
<25
25-34
35+
1.00
1.27 NS
1.26
1.00
2.96
10.03
<0.001
Period first exposed (P)
<1910
1910-1914
1915-1919
1920-1924
1.00
1.33 NS
0.89
1.70
1.00
1.81
1.31
0.60
<0.05
Time since first exposure (T) (years)
<20
20-29
30-39
40-49
50+
Job category (J):
Time in Time in
0.21
0.61
1.15 <0.001
1.25
1.00
0.06
0.28
0.37
0.75
1.00
<0.01
copper sul- furnaces
fate (years) (years)
0 0
<5 0
5+ 0
<5
5+
1.00
1.59
3.23 <0.001
3.16
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.
bValue of constant: 0.0048.
°For improvement in fit, based on change in log likelihood when each factor
is removed from the full (Poisson) model.
dValue of constant: 0.0026.
Source: Adapted from Peto et al. (1984).
8-15
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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 addition,
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 variables 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 to 1924 cohort who died within
10 to 14 years after first exposure were not ascertained. 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 rela-
tive 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.
8.1.1.8 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.
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
Year of
first employment
Minimum
number of years
of employment
Minimum
number of years
between
first 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
The studies of workers at the Clydach Nickel Refinery reveal the following
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 five
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 1910 and 1914. Doll et al. (1977) showed that lung cancer risk
was still in excess among workers starting between 1925 and 1929 and, in
fact, appeared to be increasing with continued follow-up.
(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 to 1923, 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 penetrating the
respiratory system. A single gauze pad was found to have a filtering efficien-
cy of 60 to 85 percent, while two in tandem had 85 to 95 percent efficiency.
8-17
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Particles most effectively screened were those ranging in size from 5 to 15 urn
(International Nickel Company, Inc., 1976). (Typically, particles ranging from
5 to 30 |jm 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 to 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 employ-
ment 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 the National
Institute for Occupational Safety and Health.
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.
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. (Epidemiologic
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 (NiFeS2), with smaller amounts of nickeliferous
pyrrhotite (Fe7Sg). Copper is also present, as are precious metals. Primary
8-18
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processing of the ore is carried out at INCO's Copper Cliff Smelter; until
1972, the Coniston Smelter also conducted some primary processing (Roberts et
al., 1983, unpublished). The resulting metallic matte contains primarily
nickel subsulfide (Ni3S£) and copper sulfide (Cu2S).• Before 1948 (Dr. Stuart
Warner, INCO, personal communication), this matte was sent to INCO's refineries
in Port Col borne, 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 Col borne workers are reviewed in this section on INCO's
Ontario operations.
At Port Col borne, 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 (International Nickel Company, Inc., 1976). The calcining/
sintering area of Port Col borne 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).
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).
8-19
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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 the National Institute for Occupational Safety
and Health (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 five 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 five 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-ascertainment to be minimal, "since the study was restricted to
'term-long1 employees ... 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 International
Classification of Disease (ICD) 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.
Ontario male death rates specific for age and five-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.
8-20
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Men were classified into eight 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 five 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 three 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 reelassification of several cases into the "dusty" categories,
which does not change the interpretation of the results.
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 (Inter-
national Nickel Company, Inc., 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
8-21
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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. 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
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 mortality
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 five 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 six months in the sinter plant. Deaths through
8-22
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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 six 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
and chronic respiratory disease risk among nickel workers was related to the
levels of airborne sulfur dioxide generated in the work areas, Sutherland stud-
ied workers at INCO's Copper Cliff smelter. A sample was selected by INCO
(using an unspecified method) of men who had had at least five 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, 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.
8-23
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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 three 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 plant workers with five years of company experience (not all spe-
cifically stated to have been in Copper Cliff), including workers who had not
been identified in the original cohort of 483 men in the study by Sutherland
(1969). This group was stated by the authors to be "not a complete roll of
all the sinter plant workers, but a somewhat stratified random selection that
included all durations of exposure." 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 composed of 495 men who had sur-
vived to 1963, were known not to be lost to follow-up, and had been exposed at
Copper Cliff sometime 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 (WCBO); this may have led to under-
ascertainment of cases who were not in the files of the Compensation Board.
The authors identified a total of 54 cases and 37 deaths of lung cancer with
expected cases and deaths being 6.38 and 4.25, respectively. To estimate
incident lung cancer cases the author multiplied the expected numbers of deaths
fay 1.5. Eight cases and five deaths of sinus cancer (two of the cases subse-
quently developed primary lung cancer) were identified in the cohort; expected
numbers of cases and deaths for this disease were not reported.
Only 75 percent of 495 men were followed successfully through 1977 or 1978.
For the purpose of analysis, the authors counted those lost to follow-up as sur-
vivors who did not have lung cancer. This means that the lung cancer risks of
8-24
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8.5 and 8.7 estimated by the Standardized Mortality Ratio (SMR) and Standardized
Incidence Ratio (SIR), respectively, would have been underestimated. The
authors found a lung cancer dose response by duration of exposure. They did .
not find an association between duration of exposure or year of first employment
and lung cancer latency.
The poor follow-up, the use of WBCO records to identify incident lung can-
cer cases, the derivation of expected incident cases, and a somewhat ambiguous
cohort definition, are limitations of the study. However, the high overall lung
cancer risks among the workers in this study and the lung cancer dose response
observed are suggestive of a causal association between employment at the Copper
Cliff Nickel Sinter Plant and excess lung cancer risk.
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 McMaster
University. Several reports on the results of this study have been reviewed
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.
8-25
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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 Col borne Nickel Refinery
in southern Ontario. The men were classified into 14 occupational subgroups.
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 increased 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 duration 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
Enter! ine 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 is a study of Sudbury
workers and Port Colborne workers, in which each group was analyzed separately.
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 subsequent papers (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 (Ni3S2). 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.
8-27
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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 Colborne, 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 Colborne 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 five years of exposure, but was lower
for those with less than five years of exposure (SMR = 3,297, p <0.001). The
8-28
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dose-response relationship of duration of exposure to nasal cancer death risk
at Port Col borne, 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 Col borne 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 five 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
Col borne was that of a man who had worked for 20 years in the electrolytic
department at Port Col borne. Of particular interest is the fact that he had
worked previously for 20 years at INCO's New Jersey plant and had been involved
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 problem
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 problem
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 have increased the
extent of the problem in these studies. Generally, such misclassification
8-30
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problems tend to obscure risks and underestimate SMRs related 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."
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.
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 Colborne'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).
8-31
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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
Sinter
plant
Sudbury
Port Col borne
<5 years
Number of
deaths 1000
1
3
Duration of
Rate per
person-years
0.067
0.26
exposure
5+
Number of
deaths
1
18
years
Rate per
1000 person-years
0.31
3.44
Source: Adapted from Roberts et al. (1983, unpublished).
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 finding 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.
Of the men who worked in the sintering plant at sometime 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
8-32
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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
to 1974 sputum cytology screening program. Of these, 12 showed positive cytol-
ogy by the end of 1978 (11 men were current smokers, while 1 was a former
smoker). Ten of the 12 developed lung cancer (squamous cell type), 1 developed
maxillary sinus cancer (squamous cell), and 1 developed microinvasive 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-
lytic refining (Port Col borne). 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.
8-33
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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. Three reports of this study have been reviewed here. The first is the
unpublished version which was presented at the International Agency for
Research on Cancer conference on nickel in Lyon, France in 1983 (Shannon et al.,
1983, unpublished). The second was published in the proceedings of that confer-
ence (Shannon et al., 1984a). The third was published in a peer-reviewed jour-
nal in 1984 (Shannon et al., 1984b). All are reviewed because each presents
some material which is not included in the others. Most importantly, the un-
published version (1983) presents many statistical tables which are not included
in the other versions, although the conclusions of those analyses of cancer risk
remain essentially unchanged. The 1984a 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.
The cohort was identified (Shannon et al., 1983, unpublished) as 11,594
men who had been employed by the company for at least 6 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 two years of exposure at
8-34
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Falconbridge, These men were followed for mortality and cause of death from
1950 through 1976, using the Canadian National Mortality Data Base as well as
independent tracing. The capabilities of the Canadian National Mortality Data
Base have been described by Smith and Newcombe (1982). Follow-up was completed
on 10,342 men, or 89.2 percent of the total cohort of 11,594.
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, thus elevating the SMR in several categories. The number of deaths
observed in all of the exposure groups combined totals 996, a marked increase
over the reported total of 804. Person-years were contributed to more than one
category, increasing the number of expected deaths for each category and thus
decreasing the SMR. Analyses of time since first exposure were based on time
since exposure began, regardless of whether prior exposure had occurred in
another category.
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 significance
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TABLE 8-7. MORTALITY (1950 TO 1976) BY EXPOSURE CATEGORY FOR LUNG, LARYNGEAL,
AND KIDNEY CANCER, AT FALCONBRIDGE LTD., ONTARIO
Cause of Death
Exposure category
Mines Mills Smelter Service Administration
Lung cancer
Laryngeal cancer
Kidney cancer
Prostate cancer
Obs.
Exp.
SMR
Obs.
Exp.
SMR
Obs.
Exp.
SMR
Obs.
Exp.
SMR
28
19.65
142D
4
iboo
400°
1
1.82
55
2
2.58
78
5
3.81
131
1
0.20
507
1
0.37
274
2
0.54
370
13
9.92
131
1
0.59
196
0
0.92
0
4
1.83
219
20
12.34
162b
0
0.63
0
0
1.13
0
1
2.07
48
0
1.40
0
0
0.07
0
0
0.13
0
0
0.14
0
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.
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
subgroup was 302, p <0.05 (Shannon et al., 1983, unpublished). As pointed out
by Shannon et al.- in the 1984a publication, this excess among smelter workers
was consistent with the observation by Enterline and Marsh (1982) of an increase
8-36
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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. (1984a,b),
the increase in lung cancer mortality among these workers (SMR = 214), although
not statistically significant, was consistent with the similar increase among
INCO's Coniston sinter plant workers.
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 sinter
workers (SMR = 214), 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 biological monitoring.
The refining process begins with Bessemer matte containing approximately
48 percent nickel, 27 percent copper, 22 percent sulfur, and trace metals
(Hrfgetveit and Barton, 1976). The process is divided into five steps:
crushing, roasting, leaching of the calcine, 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
8-37
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worker exposures to dust and fumes. Unfortunately, these changes are not speci-
fied in the literature. Nonetheless, efforts have been made to characterize
the range and types of nickel exposures by category of work. Workers in roast-
ing and smelting operations are primarily exposed to "dry dust," containing
nickel subsulfide and 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 average ambient nickel concentration of about 0.2 mg Ni/m3.
Other process workers are exposed to miscellaneous nickel composites at an aver-
age level of 0.1 mg Ni/m . However, the species are not defined for this latter
group. Data in these studies on the level of exposure are based on atomic
absorption analysis of relatively recent air samples (Torjussen 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 (Pedersen
et al., 1973; Kreyberg, 1978; Magnus et al., 1982). Two studies reported on
the relationship between histopathology of the nasal mucosa, nickel exposure,
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 three years at sometime 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 nonprocess job, he was classified as a process worker. The exposure groups
and size of each were as follows: roasting and smelting (462); electrolysis
8-38
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(609); other processes (299); other and unspecified work (546). The last cate-
gory included laborers, plumbers, fitters, technicians, and administrative per-
sonnel. 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 mortality rates by 5-year
age groups for each calendar year during the period 1953 to 1970. Expected num-
bers of cancer cases were based on age-specific incidence rates for 1953 to
1954, 1955 to 1959, 1960 to 1964, and so forth.
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 distribu-
tion 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
8-39
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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 electrolysis
departments, and to the cohort starting between 1910 and 1940, all of the nasal
cancer cases are confined to those with more than 15 years of employment.
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 roasting and
8-40
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smelting department are related to the changing risks in nasal and laryngeal
cancer, and whether there has been a change in the size and concentration of
particulate matter.
8.1.4.2 H^getveit 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 students.
Nickel levels were measured using flameless absorption spectrophotometry. The
average plasma nickel level was higher in electrolysis workers as compared to
R/S workers (7.4 p:g/l 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.
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. Subsequent
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
8-41
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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,
where the relative risk or SMR declined with calendar time of first employment.
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 declines,
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 exposure, or
to a decreasing attributable risk for lung cancer from nickel exposure.
8.1.4.4 Hrfgetveit et al. (1978). This is a follow-up to the 1976 publication
on biological 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
(four samples times two 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
8-42
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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 nonprocess 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
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 yg/1 and 129.2 |jg/l), followed by R/S workers
(7.2 pg/1 and 65 ug/1), and other process workers (6.4 pg/l and 44.6 pg/1). In
contrast, the electrolysis workers were exposed to by far the lowest mean air
concentration of nickel (0.23 ng/m3), followed by other process department
q o
workers (0.42 ng/m ) and by R/S workers (0.86 |jg/m ).
This evidence supports the conclusion of Htfgetveit 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
relatively 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 6 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.
8-43
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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. However,
no statistical test was conducted.
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 nonpro-
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 nonprocess 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
nonprocess 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 Mg/100 g), and, surprisingly, the electro-
lysis workers had the lowest mucosal nickel levels. The plasma, urine, and
8-44
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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.
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 mucosal
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 ten 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 sometime 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 pattern
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is consistent with the expected deposition pattern in the upper respiratory
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 aerosols 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-L4-7 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 workers.
Three of the seven were diagnosed during the study as having nasal carcinomas.
Exposed workers were divided into three groups: crushing, roasting, and
smelting (n = 55), electrolysis department (n = 28), and other process workers
(n = 15). Individuals were divided into groups defined by work area of longest
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 eight-point scale ranging from normal
respiratory epithelium to carcinoma. Two readings were made on each biopsy,
presumably by different readers. There was exact agreement in 148 of 159
samples (93 percent). Three histologic groups were defined: normal (0), limit-
ed 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
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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 six. 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, although
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 Tor.jussen et al. (1979b). This was a study of the relationships
between histopathology of the nasal mucosa and exposure to nickel, age, smoking
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 etal., 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 five, i.e., epithelial dysplasia or carcinoma. Twelve per-
cent of the R/S workers, 11 percent of the electrolysis workers, ^and 10 percent
of the nonprocess workers exhibited epithelial dysplasia, i.e., a score of 6.
All but one of the nonprocess workers with dysplasia were former process workers.
Two percent of the R/S workers (n = 25) had carcinoma iji situ, i.e., a score of
seven. No other active workers had a score greater than six. Fifty-three per-
cent 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 five. The average histologic score was highest for
retired workers (4.93), followed by R/S workers (3.25), electrolysis workers
(3.01), and nonprocess 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
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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 eight 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.
8'1-4-9 Hrfgetveit et al. (1980). The purpose of this study was to investigate
the diurnal variation in urine and plasma nickel levels and its relationship 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
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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 8 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,
calendar 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-
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 cancer.
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
8-49
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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, and so
forth. For a fixed number of years since first employment (i.e., 3 to 14, 15
to 24, 25 to 39, and 35+), there was a consistent decrease in the SMR as the
year of first employment increased. This suggests that exposure to the car-
cinogen 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
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
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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 al. (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.
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 concluded 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,
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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 biological moni-
toring, 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 frequency 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. The nasal mucosal levels of nickel were the lowest in
the electrolytic tankhouse 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 associated risks.
The occurrence of laryngeal cancer and the disappearance of nasal cancer
appear to have been associated. Four of the 5 laryngeal cancer cases were
first employed during or after 1940, whereas only 1 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
8-52
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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 tfie 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
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 the National Insti-
tute for Occupational Safety and Health in 1976. According to Cooper and Wong,
the ambient nickel levels measured were relatively low for both periods.
Twenty-two samples were collected in 1967 in the smelting building. All were
o
below the threshold limit value (TLV) of 1.0 mg/m as a time-weighted average.
o
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 nickel ranged from 0.004 to 0.420
o 3
mg/m . Six percent of the samples were above 0.1 mg/m , and 22 percent were
o
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 fil-
ters installed on the melting furnaces, crusher house, and storage bins in 1958,
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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 were 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 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 employment in
high-exposure groups resulted in relatively low exposures, even among those
defined as the high-exposure group.
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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 sometime 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 calciners
(20 to 350 mg Ni/m3 and 5 to 15 mg Ni/m3, 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 five-year age- and calendar
time-specific mortality rates by cause for white males nationally and locally.
Exposure groups were defined in several ways: by the cohort definitions noted
above, by duration of employment, and by cumulative nickel exposure.
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
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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' personnel
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 four 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. Enter!ine 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 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 Alberta
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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 to
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.
The authors concluded that no association was seen between nickel exposure
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 processes
used included drying-and-pressing, smelting, roasting-reduction, and
briquetting, but not electrolysis. Exposures included sulfide and oxide nickel
_
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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
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.
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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 barrier
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 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 National Institute for Occupational Safety and Health (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 evi-
dence 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 sometime between January 1, 1948 and December
31, 1953 were included in the study. The study cohort of exposed "barrier"
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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 1 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.
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 remaining
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 underlying
cause of death was performed by comparing the observed numbers of deaths with
the numbers expected based on age group-, calendar time-, and cause-specific
rates for U.S. white males. An SMR and its 95 percent confidence interval was
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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.
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 of 24 to
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90). The SMR for this cause among unexposed workers was 89 (no confidence
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 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.
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 five 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
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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 of 21 to 128, with
6 observed deaths). The directly adjusted death rate for respiratory 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
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
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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 No.
All causes 137
Disease of the 56
circulatory system
Disease of the 6
digestive system
Respiratory disease 6
Malignant neoplasms 29
Cancers:
Buccal cavity and 3
pharynx
Digestive organs 8
and peritoneum
Respiratory system 6
Prostate 1
Kidney 0
All lymphopoietic 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 98
(94-102)
984 98
(92-104)
68 65
(51-83)
101 93
(76-114)
352 92
(83-102)
3 23
(5-67)
79 73
(58-91)
151 116
(98-136)
21 104
(65-159)
12 121
(62-211)
41 105
(75-142)
ijExpected deaths based on overall
95% confidence interval assuming
distribution.
U.S. white males.
that the observed deaths follow the Poisson
Source: Adapted from Cragle et al. (1983, unpublished).
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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 facilities
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.
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 regarding
duration of employment. The scanty data on smoking habits suggest that the
proportion of K-25 welders who were heavy smokers was Tower 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
attributed mainly to emphysema.
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In the separate analyses of K-25 and other welders, the only statistically
significant SMR was that seen among K-25 welders for deaths due to diseases of
the circulatory system: SMR = 70, 95 percent confidence interval of 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 considerations, as
well as the observation pointed out by Gibson (1982) that respiratory 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.
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 oeen 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.
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In summary, this study does not provide evidence of an association between
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 exposures to
nickel in industries other than mining and refining.
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
die-casting; 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 ten 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 employment 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
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increased with length of time worked in those departments. The trend was most
significant for Department 5, in which the major activity was die-casting 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 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 five-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
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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, pancreas,
and larynx, as well as from non-Hodgkin's lymphoma and Hodgkin's disease. No
excess of lung cancer deaths was seen (62 observed versus 58.7 expected). 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, combrned 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 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
' 2
concentration of airborne nickel between 1975 and 1980 ranged from 0.84 mg/m in
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Q
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 five 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 (mg/m3). There
is no discussion of the possibility that exclusion of 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 0 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
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.
However, 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
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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
1 to laryngeal cancer (SMR not given). Despite the very low numbers of
deaths, subgroup 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 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 Administration 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.
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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
Artnri ni Qf*v*pi"i \/o
Pipklinn anH fl oani nrr
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
Q
(mg Ni/m )
Average
0.064
0.111.
0.083
0.298
0.071
0.098
1.5
Source: Adapted from Redmond et al. (1983, unpublished).
The levels of exposure to nickel were relatively low, ranging from an average
low of 0.064 mg/m in the cold working area to a high of 1.5 mg/m3 in the powder
metallurgy area.
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
contributed 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.
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The results of this study were predominantly negative. The few
statistically 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 significant..
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 us-ing length of employment as a measure of
dose. However, the excess risk could reflect differences in the jobs held by
short- and long-term workers, e.g., unskilied 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 (SMR = 172,
p <0.05); for kidney cancer in the melting area, for those working 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 can-
cer are based on a very small number of observed cases (three and two, respec-
tively), and are only significant for those with shorter, but not longer, term
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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 discussion 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.
8-1-10-5 Nickel-Chromium Alloy Foundry Workers (U.S.A). Landis and Cornell
(1981, unpublished) and Cornell and Landis (1984) conducted a proportionate mor-
tality ratio (PMR) study of 992 male deaths (out of 1,018 total deaths) among
nickel-chromium alloy workers from 26 plants. Of these plants, 6 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.
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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 any given foundry is divided into a number of departments, 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 ng/m to 233 ng/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 five-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 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.
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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 proportionate
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 (4 groups) and age (3 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
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 increasing length
of employment." In fact, the patterns seem to be different. The exposed
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workers showed an increasing ratio with increasing length of employment, 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 proportion of
deaths from cancer, and specifically from cancer of the lung and cancer of the
kidney, than would be expected from the age-specific proportional 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 employment. 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
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
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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 nonexposed. None of the PMRs for any cancer site were
above unity for those exposed. The PMR for other neoplasms was statistically
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.
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
categories 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
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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
1 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 ventilation," 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.
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 respiratory
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
8-79
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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 discussion 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 nor 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 8 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 five 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 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
carcinogenesis.
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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 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
8-8.1
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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 pathologically, 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
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.
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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 nonsmokers among cases would be
underestimated. The very high relative odds for ever smoking and lung cancer
(RO = 22) suggests that proportionately more nonsmoking 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 Caledonia
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 neighborhood
controls were selected. Cases and controls were interviewed about smoking
history, alcohol consumption, and occupational history. Specific probes were
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 nine
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
8-83
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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 epidemiologic
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 publication 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, electroplating operations, and
other end use activities with nickel. These investigations 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 related
substances. In addition, in most of the available studies, the epidemiologic
data have not been analyzed to determine if changes in process corresponded to
changes in risk. Hopefully, results of the nickel speciation research project,
mentioned in the Introduction of this report, will help to clarify the exposures
of individual workers to specific nickel compounds. Nevertheless, within the
limitations of the information available, an effort has been made herein to
discuss health risks in relation to selected nickel species.
8-84
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TABLE 8-10. INDUSTRIES FOR WHICH EPIDEMIOLOGIC STUDIES OF CANCER RISKS
FROM NICKEL (Ni) EXPOSURE HAVE BEEN REVIEWED
Industry
Year of most recent
report reviewed
I. Ni ore mining
Sulfide ore
Falconbridge, Ontario
Sudbury, Ontario
Oxide ore
Hanna, Oregon
New Caledonia
II. Ni ore refining
Sulfide ore - Pyrometallurgical processes
Coniston, Ontario
Copper Cliff, Ontario
Falconbridge, Ontario
Sulfide ore - Hydrometallurgical processes
Fort Saskatchewan, Alberta
Oxide ore
Hanna, Oregon
Noumea, New Caledonia
RSFSR, Soviet Union
III. Ni matte refining
Clydach, Wales
Copper Cliff, Ontario
Port Col borne,. Ontario
Falconbridge, Norway
Huntington, West Virginia
IV., Electrolytic refining
Falconbridge, Norway
Port Col borne, Ontario
V. Ni metal use
Die-casting and electroplating
Polishing, buffing, and plating
High Ni alloy manufacturing
Ni alloy manufacturing
Ni/chromium alloy manufacturing
Stainless steel and low Ni
alloy manufacturing
Ni "barrier" manufacturing
Ni-cadmium battery manufacturing
Ni alloy welding
1984
1982
1981
1978
1984
1984
1984
1984
1981
1978
1973
1984
1984
1984
1982
1982
1982
1959
1981
1980
1984
1981
1984
1984
1984
1983
1981
8-85
-------
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 processing
have yielded results which are in apparent contradiction. However, in such
cases, a number of factors must be considered: differences in the definition 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 associated 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 (International
Nickel Company, Inc., 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
(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
8-86
-------
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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 sometime 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 maximum
of 24 years of follow-up from first exposure, only 1,192 person-years of
observation were accumulated in workers with more than 20 years after first
exposure.
8-1-12.2 Nickel Ore Smelting and Related Processes. Sulfide nickel ore is
processed at INCO's Copper 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 in exposure that could account for the slight differences in
risks are likely to be subtle.
8-90
-------
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 refinery 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 considerably
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
8-91
-------
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 contrast
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 and
polycyclic aromatic hydrocarbons (International Nickel Company, Inc., 1976).
At Port Colborne 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 al.
8-92
-------
(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
(International Nickel Company, Inc. , 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 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 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 5 laryngeal cancer cases were first employed on
or after 1940, whereas only 1 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
8-93
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1945. It would be of interest to know the relationship of such control 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 possibly
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 Colborne, 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 primarily to smelter
8-94
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workers. The electrolytic tankhouse workers at Falconbridge, Norway, showed a
large excess risk of nasal cancer (Magnus et al., 1982) while tankhouse exposure
at Port Colborne was not associated with lung cancer (International Nickel
Company, Inc., 1976, unpublished).
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 the manufacture of the nickel-containing products, 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; Nation-
al 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 physi-
cal 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 indica-
tors, 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 (NigS^ concentration of 0.97 trig nickel/m (70
8-95
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TABLE 8-12. 24 FACTORIAL DESIGN OF NICKEL SUBSULFIDE RAT INHALATION
STUDY OF TWO PREEXPOSURE SUBTREATMENTS FOLLOWED BY 78-WEEK EXPOSURE*
(16 SUBGROUPS)
Preexposure
Treatment
Control
Ni3S2
Injection
M F
29
29
28
28
Subtreatment
No Injection
M F
28
22
30
26
No Preexposure
Injection
M F
32
39
32
24
No Injection
M F
31 31
32 26
Preexposure subtreatment for one month to Ni,S9 followed by subtreatment of
intravenous injection with hexachlorotetrafmofobutane.
Source: Ottolenghi et al. (1974).
percent particles smaller than 1 pm) 6 hours/day, 5 days/week, for 78 to 80
weeks. The animals were observed for an additional 30 weeks thereafter. The
design of the study, matrixed in Table 8-12, included two subtreatments in a
A
2 factorial arrangement: a total of 467 rats of both sexes (factor 1) were
used in the design which incorporated a preexposure subtreatment for one month
to nickel subsulfide (0.97 mg Ni/m3, 6 hrs/d, 5 d/wk), followed by the second
subtreatment of intravenous injection with hexachlorotetrafluorobutane (HTFB),
an agent used to induce pulmonary infarction. The fourth factor was the actual
treatment (after the injection factor) with nickel subsulfide for 78 to 80
weeks. Following the exposure period, the animals were observed for an addi-
tional 30 weeks before terminal sacrifice.
The design of the 2 arrangement, resulting in the 16 subgroups (Table
8-12), allowed simultaneous estimation of the effect of each of the four factors
(sex, pretreatment, HTFB injection, Ni3$2 treatment) in a combined analysis
using an additive effects model. This analysis appears to have been done only
partially, using a Mantel-Haenzel procedure. Some of the reported results are
noted below.
(1) With respect to mortality, there was no difference between males and
females or between the injection versus the no injection subgroups; preexposure
to nickel subsulfide caused a slight increase in early deaths among male rats.
For the nickel subsulfide treatment group, the results were clear-cut; all eight
nickel subsulfide groups showed a higher mortality when compared with their
corresponding control groups. This difference first appeared during the 52-
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to 78-week exposure period (p <0.05 for males; p <0.10 for females), and was
accentuated (p <0.01) during the final 30 weeks before sacrifice. Combining
sexes and pretreatment groups, fewer than 5 percent of the nickel subsulfide-
treated rats were alive at the end of 108 weeks, as compared with 31 percent
of the controls.
(2) Body weight changes were reported to be similar to mortality effects,
with all eight nickel subsulfide-treated subgroups showing a time-related
reduction versus the corresponding control groups. None of the pretreatments
had a consistent effect.
(3) The lungs were most affected by nickel subsulfide treatment, but no
differences in response were attributed either to sex differences or to the in-
jections of HTFB. Of the rats receiving HTFB, 15 percent had lung tumors com-
pared with 13 percent of the untreated 'animals. Also, the injections of HTFB
produced lung infarctions in 32 percent (35 of 109) of the controls, compared
with only 14 percent of the nickel subsul fide-treated rats (35 of 109), so
that there appears to be no synergistic effects of HTFB and nickel subsulfide
on lung tumors.
The major lung effects of nickel subsulfide are presented in Table 8-13,
combining the subtreatment groups taken from the Ottolenghi et al. (1974) paper.
Here it is seen that nickel subsulfide treatment causes hyperplasia, metaplasia,
adenomas, and adenocarcinomas equally in both males and females. Furthermore,
these changes and tumors were in both the bronchiolar and alveolar regions.
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
o
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 elemental
nickel in the form of 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?/
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consistency with which organs other than the lungs were examined histopatholog-
ically. The author indicated that the mice had hyperemic to hemorrhagic
8-97
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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 lymphosarcomas. Thirty-seven guinea pigs were evaluated histopatho-
logically. Seven of 8 guinea pigs dying in the first 6 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 "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 poor survival times of the animals in this study (less
than two 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 pro, was administered with sulfur dioxide
and powdered limestone. (The limestone was added to prevent the nickel parti-
cles 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 cocarcinogen.) 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 irri-
tant 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 fibrosing changes with bronchiectasis, squamous cell metaplasia,
8-99
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and peribronchial adenomatosis, they did not consider these changes to be
malignant or premalignant as in the previous study.
Wehner and co-workers (1984) 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 concentrations of nickel oxide
dust (count median diameter 0.3 urn) at a concentration of 53.2 mg/m3 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 ten 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 inflammatory
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 pneumoco-
niosis) developed from chronic exposure to nickel oxide, "neither a significant
carcinogenic effect of the nickel oxide nor a cocarcinogenic effect of ciga-
rette smoke" was found. However, it is noteworthy that three malignant muscu-
loskeletal 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
LAKrLVG). 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 impactor. 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
8-100
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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 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 com-
pared 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. (1981, 1975) for
determining carcinogenic potential is questionable, however, because of the
possible lack of sensitivity of the hamsters as experimental animals to carci-
nogenic materials. Hueper and Payne (1962) observed a lack of pathological
response of hamsters to airborne nickel as compared to rats. Similarly, Furst
and Schlauder (1971) 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 exposed
to nickel powder at a concentration of 87.3 HQ/ft3 (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 ng/ft (2.1
mg/m3), and the iron concentration averaged 53.2 ug/ft (1.9 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 concen-
tration of 85.0 ng/ft3 (3.0 mg/m3). Within each group, subgroups were exposed
8-101
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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 granulo-
matous response as compared to the controls or to the rats exposed to iron. In
group I, 3 of 60 rats evaluated histopathologically had lung tumors (2 carcino-
mas and 1 lymphosarcoma). This group had the greatest nickel exposure. Among
the 61 rats evaluated histopathologically from group II, there was only 1 lung
tumor, a squamous cell carcinoma. The group III rats, exposed to an iron mix-
ture, developed 2 carcinomas and 1 papillary adenocarcinoma among the 58 evalu-
ated histopathologically. Among the 55 control rats evaluated histopathologi-
cally there was only 1 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 1 month to nickel oxide concen-
Q
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 six animals examined. There were no
cancers among the four 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 carcin-
ogenic responses in rats variably exposed to nickel carbonyl [Ni(CO)4] by
inhalation. Sunderman et al. (1959) exposed 3 groups of male Wistar rats
to nickel carbonyl: 64 rats were exposed to 0.03 mg/1 3 times weekly for
one year; 32 rats were exposed to 0.06 mg/1 3 times weekly for 1 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 two 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
8-102
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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
adenocarcinomatous 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
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, 3 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, 3 animals of
the 80 surviving the 2-year exposure and/or observation period showed pulmonary
carcinomas with metastases, 1 with papillary adenocarcinoma, 1 with anaplastic
carcinoma, and 1 with adenocarcinoma. No pulmonary neoplasms were noted in any
of the 44 animals remaining in the control groups.
The two studies cited above, taken in the aggregate, reveal that 6
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
(3 animals) or chronic time-graded exposure (2 animals, exposed for 1 year;
1 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
8-103
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survivors, it should be noted that spontaneous pulmonary malignant neoplasms in
Wistar rats 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 and Mitchener,
1975; Schroeder et al., 1974, 1964). 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
(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-deficient, 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 (jg/rat for the con-
trols and 37.6 ug/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 (NiS04 • 6H?0;
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 3 dogs of each sex assigned to each dose group. A
similar number of untreated animals were maintained and served as controls.
8-104
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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 hemoglo-
bin values, and increased kidney/body weight and liver/body weight ratios. Two
of the six dogs showed marked polyuria. There were no other signs of toxicity
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 granulo-
cytic 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. 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 nickel sub-
sulfide 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 nickel subsulfide intra-
tracheally. 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 ex-
ception 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 8-14 summarizes
some of the many studies on nickel subsulfide. These data are more comprehen-
sively reviewed by Sunderman (1984b,c, 1983, 1981, 1976) and the International
8-105
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Agency for Research on Cancer (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 car-
cinogenesis, have also been performed (Gilman and Yamashiro, 1985; Sunderman et
a!., 1979b, 1978; Hildebrand and Biserte, 1979a; Friedman and Bird, 1969;
Daniels, 1966; Gilman, 1962). These data have been reviewed by Sunderman
(1983) and Gilman and Yamashiro (1985), and are presented in Tables 8-15 through
8-18. While there are definite differences in tumor response between species/
strain and route of administration, different experimental conditions among
laboratories make cross comparison difficult. Gilman's analysis (Table 8-15)
seems to indicate that rats are more susceptible than mice, rabbits, or ham-
sters. 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 nickel subsulfide
following intrarenal and intramuscular injections (Table 8-18). Gilman and
Yamashiro (1985) suggested a relative strain susceptibility ranking of Hooded >
Wistar > Fischer > Sprague-Dawley rats when nickel subsulfide was administered
intramuscularly (Table 8-16). Sunderman (1983), on the other hand, reported a
relative strain susceptibility of Wistar > NIH Black > Fischer > Hooded, when
nickel subsulfide was administered via the intrarenal route (Table 8-17). Com-
parison of the routes of administration on organ susceptibility of Fischer rats
to nickel subsulfide carcinogenesis gave a relative ranking of eye > muscle >
testis ~ kidney > liver (Sunderman, 1983; Table 8-18).
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
8-109
-------
TABLE 8-15. SPECIES DIFFERENCES TO NICKEL SUBSULFIDE: INTRAMUSCULAR INJECTION
Species and
Dose (mg)
Syrian
Hamster
Mice?
i< • D
Mice _
Rabbit0
Ratd
Rat
Rate
(5)
(10)
(2.5)
(5)
(80)
(5)
(10)
(10)
No. Animals
(% Tumors)
15
202
163
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
JDBA/2 and C57>BL/6; 2C3H and Swiss outbred
3Bilateral injections; exact numbers not stated
aSunderman (1983); Ail man (1962); cHildebrand and
Biserte (1979a); uSunderman (1979); eYamashiro
et al. (1980).
Source: Gilman and Yamashiro (1985).
TABLE 8-16. STRAIN DIFFERENCES IN RATS TO NICKEL SUBSULFIDE-
INTRAMUSCULAR INJECTION .
Strain and
Dose (mg)
Sprague -
Dawley (20 )a
Hooded (10)
Fischer (10)
Wistar (10)
% Tumors
Sited
37
96
78
82
Rhabdomyosarcomas
82
91
87
86
% Other
Sarcomas
18
9
13
14
Friedmann and Bird (1969)
Source: Gilman and Yamashiro (1985)
8-110
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induction. The data are summarized in Table 8-19. Intrafemoral injections
induced tumors in rats and rabbits (Hueper, 1955, 1952). Intravenous injections
produced tumors in rats but not in rabbits and mice (Hueper, 1955). Intramus-
cular injection was the route most studied, and tumors were observed in rats
and possibly hamsters but not in mice (Sunderman, 1984a; Jasmin et al., 1979;
Sunderman and Maenza, 1976; Furst et al., 1973; Furst and Schlauder, 1971;
Haro et al., 1968; Heath and Daniel, 1964; Hueper, 1955). 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,
and the observation (albeit somewhat questionable) of adenomatoid lesions of the
respiratory tract from inhalation studies, metallic nickel should be considered
as having carcinogenic potential in animals. However, tests are presently
inadequate to support any definitive conclusions regarding its carcinogenicity.
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 (NiO) in experi-
mental 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 expo-
sures alone or in conjunction with cigarette smoke, it is difficult to deter-
mine if this was a consequence of the animal model used (Syrian golden ham-
sters). Horie et al. (1985) reported the observation of one lung adenocar-
cinoma out of 6 rats sacrificed 20 months after a 1-month exposure to 0.6
mg/m3 of nickel oxide aerosol. The significance of this later study is uncer-
tain because of the limitations of the experiment design. Intratracheal injec-
tion studies (Saknyn and Blohkin, 1978; Parrel! and Davis, 1974) gave negative
to equivocal results. However, nickel oxide was tested to be carcinogenic in
five intramuscular injection studies (Suderman, 1984a; Gilman, 1966, 1965, 1962;
Payne, 1964) 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
8-113
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controls were not used in some of these studies. Nickel oxide was also carcin-
ogenic by intrapleural injections, with an activity that approached that of
nickel subsulfide (Skaug et al., 1985). It has not been tested to be carcino-
genic by intrarenal injections (Sunderman et al., 1984). These data are
summarized in Table 8-20. Taken together, the data support the evaluation of
nickel oxide as having limited evidence as an animal carcinogen. Nickel(III)
oxide (Ni203) has not been found to be carcinogenic in two intramuscular
injection studies (Payne, 1964; Sosinski, 1975). However, 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 NiS04,
57 percent Ni3$2, 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
refinery dust (59 percent Ni3S2, 20 percent NiS04, 6.3 percent NiO) in rats by
inhalation. The refinery dust was one of 6 types of dust exposures adminis-
tered 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 1 lung cancer in 60 rats exposed by inhalation
to a combination of nickel and iron dusts.
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 two of five rats which
survived the treatment. Saknyn and Blohkin (1978) also treated albino rats by
intraperitoneal 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
NioS2, 33.4 percent NiO + Si02 and oxides of iron and aluminum). At 80 to 100
mg/m , 5 hours/day for 12 months, no tumors were found. A summary of these data
is included in Table 8-21. 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.
8-117
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8.2.2.5 Soluble and Sparingly Soluble Nickel Compounds. The soluble nickel
compounds—nickel sulfate (NiS04), nickel chloride (NiCl2), and nickel acetate
(Ni(CHoOO)9)--have received a limited amount of study, and the findings are
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summarized in Table 8-22.
Nickel acetate was studied for carcinogenic potential by Stoner et al.
(1976), Schroeder et al. (1974, 1964), Haro et al. (1968), and Payne (1964).
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 the
observation indicates the potential of soluble nickel compounds in inducing
tumors in animals. However, the validity of .using lung tumor response data in
Strain A mice as an indicator of carcinogenicity is uncertain. 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, nickel sulfate, has been tested, mainly
via the intramuscular route (Kasprzak et al. , 1983; Gilman, 1966, 1962; Payne,
1964), and no treatment-related tumors have been observed. Payne (1964) did
report 1 sarcoma of 35 rats receiving nickel sulfate 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 (NiCOg)
(Payne, 1964) and nickel hydroxide (Ni(OH)2) in the crystalline, dried, and
colloidal forms have been studied (Kasprzak et al., 1983; Gilman, 1966, 1965).
Payne (1964) observed 4 of 35 rats with sarcomas after muscle implants of 7 mg
nickel carbonate/rat.
Gilman (1966, 1965) observed the development of local sarcomas in 48 per-
cent of rats receiving nickel hydroxide (form not specified) intramuscularly.
Kasprzak et al. (1983) further studied the effect of the physical state of
nickel hydroxide on carcinogenic activities and found that intramuscular injec-
tion 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.
8-121
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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 judgment 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 (Furst
and Schlauder, 1971; Haro et a!., 1968). Fibrosarcomas, in particular, were
observed in rats and hamsters in these studies (see Table 8-23).
Nickel carbonyl was used as an intermediate in the refining of nickel by
the Mond process (International Agency for Research of Cancer, 1976), but it
is also a specialty reagent for the fabrication of nickel alloys and in the manu-
facture of catalysts. Nickel carbonyl has been tested by inhalation (Sunderman
and Donnelly, 1965; Sunderman et al., 1959, 1957) to be carcinogenic, producing
lung neoplasms. Because of the high toxicity of nickel carbonyl, the testing
regimen was around the LD5Q 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 car-
cinogenic 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-
gate the potential for synergism and antagonism were also performed. Maenza et
al. (1971) observed that nickel subsulfide, co-administered with benzpyrene,
significantly reduced (30 percent) the latency period for sarcoma induction by
the intramuscular route. Kasprzak et al. (1973) studied the effects of co-
administering nickel subsulfide and benzpyrene to rats by intratracheal injec-
tions. They found that none of the rats receiving nickel subsulfide alone devel-
oped bronchial metaplasia, while 62 percent of rats receiving nickel subsulfide
and benzpyrene and 31 percent of those receiving benzpyrene alone developed
bronchial metaplasia.
Sunderman et al. (1976, 1975) observed a dramatic reduction of sarcomas
(from 73 percent to 7 percent) in Fischer rats when manganese powder was
co-administered with nickel subsulfide by intramuscular injections. Further-
more, Sunderman et al. (1979a) observed the inhibitory effects of manganese on
nickel subsulfide carcinogenesis 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
8-124
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to the production of injection site sarcomas by nickel subsulfide 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
8-24.
The results of the studies on nickel subsulfide indicate the synergistic
and antagonistic effects of nickel subsulfide 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 predom-
inant 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 died 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
8-126
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hamster embryo (SHE) cells. In contrast, no active phagocytosis was observed
in cells exposed to amorphous nickel monosulfide. Costa et al. (1981b) ob-
served 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, phago-
cytosis. Costa et al. (1981a) showed that particles of crystalline nickel mono-
sulfide having mean diameters of 2 to 4 urn were phagocytized six times more than
nickel monosulfide particles having mean diameters of 5 to 6 urn. In contrast,
the size of the particle had no effect on the phagocytosis of amorphous nickel
monosulfide. Studies by Costa and Mollenhauer (1980a,b) demonstrate that cry-
stalline cobalt monosulfide is similarly a potent inducer of morphological
transformation in CHO cells, while amorphous cobalt monosulfide lacks such
activity. Since crystalline cobalt monosulfide is actively phagocytized and
amorphous cobalt monosulfide 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 nickel subsulfide, nickel monosulfide, and nickel subsele-
nide were significantly more active in inducing cell transformations and were
more actively phagocytized than amorphous nickel monosulfide, metallic nickel,
nickel (III) oxide, and nickel oxide. Intracellular uptake and distribution of
crystalline nickel monosulfide 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 nickel monosulfide in CHO cells.
Crystalline nickel monosulfide 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 gen-
erally required only seven to ten minutes. Endocytosed crystalline nickel
monosulfide particles exhibited saltatory motion. Lysosomes were observed to
8-129
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repeatedly interact with the nickel monosulfide particles in a manner similar
to the digestion of macropinosomes. Nickel monosulfide 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 par-
ticles. The observed lysosomal interaction with phagocytized cytoplasmic
nickel monosulfide may accelerate dissolution of particulate nickel, allowing
the entry of ionic nickel into the nucleus. Studies by Abbracchio et al. (1982)
suggest that the dissolution of phagocytized crystalline nickel monosulfide
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 nickel monosulfide particles.
Kuehn and Sunderman (1982) determined the dissolution half-times of 17
nickel compounds in water, rat serum, and renal cytosol. Concentrations
of dissolved nickel were analyzed by electrothermal atomic absorption spectro-
photometry, and dissolution half-times were computed using a Weibull distribu-
tion. Nickel, NiS, amorphous NiS, Ni3$2, NiSe, Ni3Se2, Nile, NiAs, Ni1:LAs8,
Ni5As2, and Ni^FeS^ dissolved more rapidly in serum or cytosol than in water.
No detectable dissolution was observed for NiO, NiSb, NiFe alloy, or NiTiOo in
O
any of the media. The dissolution half-times of nickel subsulfide in serum
and cytosol are in close agreement with the excretion half-time of 24 days in
CO
urine following intramuscular injection of Ni3S2 in rats (Sunderman et al.,
1976). These data suggest that i_n vitro' dissolution half-times of nickel
compounds may be used to predict iji vivo excretion half-times, since the dis-
solution 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 nickel monosulfide particles were actively phagocytized and induced
morphological transformation in Syrian hamster embryo (SHE) cells in a concen-
tration-dependent manner. In contrast, amorphous nickel monosulfide was not
actively phagocytized by SHE cells and was relatively inactive in inducing
morphological transformation at both cytotoxic and noncytotoxic concentration
levels. Chemical reduction of positively charged amorphous nickel monosulfide
with lithium aluminum hydride (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, nickel monosulfide caused strand breaks ,in ,DNA.
Phagocytized inert particles such as latex beads did not induce transformation
8-130
-------
or DNA damage, suggesting that genotoxic dissolution products such as nickel II,
rather than the phagocytized particles, are responsible for the observed cellu-
lar transformation and damage to DNA. In these experiments, nickel chloride was
one-third to one-half as potent in inducing cellular transformation as compared
to crystalline nickel monosulfide on a weight basis. These results suggest a
correlation between selective phagocytosis of nickel compounds and their ability
to induce cellular transformation.
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 nickel monosulfide
particles was significantly greater than that following a similar exposure to
amorphous nickel monosulfide particles. They attributed the differences in
potency to the selective phagocytosis of crystalline nickel monosulfide parti-
cles into the SHE cells, since no uptake of amorphous nickel monosulfide was
observed. Chemical reduction of amorphous nickel monosulfide and lithium
aluminum hydride 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 nickel monosulfide was
also increased by reduction with lithium aluminum hydride. 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. (1982, 1981) have demonstrated that crystalline nickel mono-
sulfide particles have a negative surface potential (-28 mV), while amorphous
nickel monosulfide particles have a positive surface charge (+9 mV). The nega-
tive surface charge of crystalline nickel monosulfide appears to be directly
related to cellular uptake by phagocytosis. The extent of phagocytosis of
crystalline nickel monosulfide particles is not affected by the components of
the tissue culture medium used (Abbracchio et al., 1981). Altering the particle
surface of both crystalline and amorphous nickel monosulfide by reduction with
lithium aluminum hydride enhanced phagocytosis by CHO cells and, in the case of
amorphous nickel monosulfide, resulted in induction of morphological transfor-
mation of SHE cells. Heck and Costa (1983) have found that crystalline nickel
monosulfide, nickel subsulfide, and nickel oxide, which are carcinogenic by the
intramuscular injection route, exhibit strongly negative surface charges in
distilled water and enter CHO cells readily by phagocytosis. Under similar
8-131
-------
experimental conditions, amorphous nickel monosulfide, which appears to be non-
carcinogenic, is positively charged and not extensively phagocytized. The
greater dissolution rate of amorphous nickel monosulfide, in comparison to
crystalline nickel monosulfide, 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 sub-
stances (size <10 urn, with known X-ray patterns) according to hemolytic ability
correlated with the external roughness of the particulates as characterized 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 re-
action sequence: colloidal Ni(OH)2 (568 ± 13) > NiO (8.0 ± 0.5) > Ni powder,
non-spherical and rough (4.3 ± 0.4) > ofNiS, pNiS (3.4 ± 0.2); dried Ni(OH)2
(2.9 ± 0.1); aNi3S2 (2.2 ± 0.4) > Ni powder, smooth spheres (0.4 ± 0.1). The
authors concluded that surface passivity of relatively insoluble nickel com-
pounds might be an important determinant in nickel carcinogenesis.
Kuehn et al. (1982) measured the relative phagocytosis of 17 nickel com-
pounds iji vitro in monolayer cultures of rat peritoneal macrophages. The
macrophages were exposed to nickel particles (median diameter 1.5 urn) at con-
centrations of 2 (jg/ml of medium for 1 hour at 37°C. The phagocytic index,
the percentage of macrophages with one or more engulfed particles, ranged from
69 percent for nickel oxide to 3 percent for amorphous nickel monosulfide. In
order of decreasing phagocytic indices, the 17 nickel compounds were ranked:
NiO > Ni4FeS4 > NiTiOg > NiSe > Ni3S2 > Ni > Ni'5As2 > NiS2 > NiFe alloy > NiSb >
NinAs8 > Ni3Se2 > NiS > NiTe > NiAs > NiAsS > amorphous 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 8-25). The
biological data are summarized in Table 8-26. Data from carcinogenicity
bioassays of 18 of the compounds tested i_n vitro do not exhibit any rank
correlation between the phagocytic indices of nickel compounds and the inci-
dences of injection site sarcomas after intramuscular administration to rats
(Sunderman, 1984a). These data are summarized in Table 8-27.
Costa et al. (1981b) performed X-ray fluorescence spectrometry measure-
ments of metal levels in subcellular fractions isolated from CHO cells treated
with crystalline nickel subsulfide, crystalline nickel monosulfide, and amor-
phous nickel monosulfide. Amorphous nickel monosulfide did not significantly
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enter the cells as either phagocytized nickel particles or 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 nickel subsulfide is no
longer part of a sedimentable particle with the same particle size and solu-
bility properties as the parent compound. A substantial portion of the nickel
associated with the nuclear fraction co-precipitates 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
17 nickel compounds. Erythrocytosis (defined as peak hematocrit values
that averaged >55 percent) occurred in 9 of 17 nickel-treated groups (NiS?,
p-NiS, crNi3S2, Ni4FeS4, NiSe, Ni3Se2, NiAsS, NiO, Ni dust). Renal cancers
developed in 9 of 17 nickel-treated groups (NiS2, (3-NiS, crNi^, Ni4Fe$4,
NiSe, Ni3Se2, NiAsS, NiAs, NiFe alloy) within 2 years after the injections.
The results of their studies are presented in Table 8-28. 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 intra-
muscular 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 phagocytic 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 nickel sub-
sulfide (Hopfer et al., 1978; Jasmin and Riopelle, 1976; Morse et al., 1977).
Erythrocytosis induced by intrarenal injection of nickel subsulfide is appar-
ently 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 nickel subsulfide in rats induced pronounced
8-136
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erythrocytosis. They observed a 1.5-fold increase in blood erythrocyte count
and a 2.4-fold increase in erythrocyte mass 5 months following administration.
Nickel subsulfide-induced erythrocytosis was not accompanied by alteration of
erythrocyte 2,3-diphosphoglycerate levels. Jasmin and Solymoss (1975) specu-
lated 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 development of erythropoiesis in female Fischer 344
rats. Nickel chloride was administered by a single intrarenal injection.
Nickel subsulfide was administered by continuous intraperitoneal infusion from
an implanted osmotic minipump. Infusion of nickel chloride (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 nickel subsulfide 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 nickel subsulfide was admini-
stered intravenously, no polycythemia or renal neoplasms were observed. Intra-
renal administration of nickel subsulfide, in either glycerin or saline, rapidly
caused erythrocytosis. Hemoglobin and erythrocyte values were significantly
increased in the rats receiving nickel subsulfide intrarenally. Renal car-
cinomas were observed in approximately 40 percent of the treated animals. In
general, erythrocytosis subsided approximately eight months after intrarenal
injection of nickel subsulfide, 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 erythrocyto-
sis induced by nickel subsulfide was dose-related. Female Fischer rats received
single intrarenal injections of nickel subsulfide at dosages ranging from 0.6
to 10 mg per rat. Administration of nickel subsulfide induced marked erythro-
cytosis 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 intramus-
cular injection of nickel subsulfide did not cause erythrocytosis at a dose of
10 mg/rat. The failure of erythrocytosis to develop after intramuscular injec-
tion is consistent with kinetic studies which show that after intramuscular
8-138
-------
injection of 63Ni3$2 in rats, 63Ni 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 nickel chloride in dosages of
2 to 5 mg/kg. Generalized craminoaciduria was found after a single intra-
peritoneal injection of 4 to 5 mg/kg of nickel chloride. Amino acids in the
plasma were normal or slightly diminished from 1 to 48 hours after administra-
tion of nickel II. Electron microscopy of kidneys of five rats sacrificed 48
hours after receiving 68 pmol/kg of nickel II revealed fusion of foot pro-
cesses 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 amino
acid transport systems located in the luminal and/or peri tubular membranes of
the renal tubules and increased excretion of nickel-histidine chelate, one of
several ultrafilterable complexes involved in the renal excretion of nickel II.
8.2.3.4 Interaction of Nickel Compounds with DNA 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 DNA strand breaks. The work of Si rover and Loeb
(1976) showed that metals can cause a decrease in the fidelity of DNA tran-
scription. Robison et al. (1982) showed that nickel chloride and crystalline
nickel monosulfide produce DNA strand breaks in CHO cells, while amorphous
nickel monosulfide has no effect on DNA. Exposure to activated charcoal, which
was actively phagocytized, had no effect on the DNA of CHO cells. The effect
of nickel chloride and crystalline nickel monosulfide was both time- and con-
centration-dependent. Robison and Costa (1982) found that both nickel chloride
and crystalline nickel monosulfide induced strand breaks in the DNA of CHO
cells at concentrations which did not significantly impair normal cellular
division. Crystalline nickel subsulfide, nickel chloride, and nickel mono-
sulfide have been shown to induce concentration-dependent DNA repair in CHO
cells (Robison eta!., 1983). In contrast, amorphous nickel monosulfide 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,
8-139
-------
undine, and thymidine uptake during exposure showed that the synthesis of
protein and DNA was more extensive than that of RNA. Nickel chloride, nickel
acetate, nickel sulfide, and potassium cyanonickelate induced chromosomal aber-
rations 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 nickel carbonate. DNA strand
breaks and DNA-protein crosslinks were observed. 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 nickel carbonate.
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. Nickel carbonate 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 orgahotropic effects on DNA jn 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 multi-
functional, 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 con-
tractile 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) found a strong interaction between nickel II and
the amino-terminal residues and imidazole groups of histidine residues, and a
weak interaction between nickel II and the sulfhydryl groups of cysteine
residues. Lee et al. (1982) reported that solubilized nickel II is bound to
DNA with an apparent equilibrium constant of 730 M"1 and with a saturation
binding value of 1 nickel per 2.4 nucleotides. Spectroscopic and equilibrium
binding studies of the interaction of nickel with DNA are consistent with the
8-140
-------
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-51-phosphate,
guanosine-51-phosphate, and adenosine-51-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 nickel sulfate enhanced SA7
viral transformation of Syrian hamster-embryo cells. Treatment with crystalline
nickel subsulfide and nickel sulfate 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. (1982, 1981a,b, 1979) and Costa and Mollenhauer (1980a,b) studied
the morphological transformations 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 in vitro transformation abil-
ity of insoluble particulate nickel compounds are determined by their poten-
tial to be endocytosed. The data supporting the above reasoning have been
summarized by Costa and Heck (1982) and Heck and Costa (1982), and are pre-
sented in Table 8-29.
Hansen and Stern (1983) compared the transformation activities of five
nickel compounds (nickel welding fume, nickel subsulfide, nickel (III) oxide,
nickel oxide, and nickel acetate) 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 bioavail-
ability of nickel II. They concluded that it takes ten times as much nickel
oxide as nickel subsulfide to induce the same degree of transformation of
BHK-21 cells.
Synergistic effects of nickel compounds with benzopyrene (BP) were ob-
served by Costa and Mollenhauer (1980b) and Rivedal and Sanner (1981). The
combined treatment of nickel sulfate and benzopyrene in Rivedal and Sanner's
8-141
-------
TABLE 8-29. RELATIONSHIP BETWEEN PHAGOCYTOSIS AND INDUCTION
OF MORPHOLOGICAL TRANSFORMATION BY SPECIFIC METAL COMPOUNDS
Metal compound
(<5 |jm particle size)
Crystalline NiS
Crystalline Ni3S2
Crystalline Ni3Se2
Amorphous NiS
Metallic Ni
11 * /\
Ni000
NiO 3
NiCl?
Latex beads
Phagocytosis
activity
24%!;
22%c
27%c
3%
4%
5%
2%
ND
ND
Incidence of
transformation (percent
relative to crystalline NiS)
100%c
_LW V//O
118%
115%
oo/
o/o
18%
17%
9%
•S/Q
41%
8%
Determined in cultured Chinese hamster ovary cells [10 yg ml x exposure
(1.27 |jg cm ^), 24 h]. Number of cells with metal particles/total number
of cells examined.
Number of transformed colonies/total number of surviving colonies.
Standardized to the incidence of transformation produced by crystalline
NiS. (10 pg ml x exposure, 4 days).
p <0.01 vs. amorphous metal sulfide X2 test. ND, not determined.
Source: Costa and Heck (1982).
(1981) study showed a transformation frequency of 10.7 percent, as compared to
0.5 and 0.6 percent for nickel sulfate and benzopyrene alone. The cell trans-
formations studied have been summarized by Sunderman (1984c), and the results
are presented in Table 8-30.
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 nickel subsulfide-induced erythrocytosis and carcinogenesis
are both inhibited by manganese dust (Hopfer and Sunderman, 1978; Sunderman
et al., 1979a, 1976) provide indirect evidence that these effects are related.
Dissolution half-times and indices of phagocytosis, summarized in Table 8-26,
8-142
-------
TABLE 8-30. MAMMALIAN CELL TRANSFORMATION BY NICKEL
Authors
Cells
Results
DiPaolo and Casto (1979) SHE cells
Costa et al. (1979, 1978) SHE cells
Costa and Mollenhauer
(1980a,b)
Costa et al. (1982)
Saxholm et al. (1981)
SHE cells
SHE cells
C3H/10T
1/2 cells
Hansen and Stern (1983) BHK-21
cells
Rivedal and Sanner (1981) SHE cells
NiS04, Ni3S2 pos.; amorph. NiS neg.
Ni3S2 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
Ni3S2 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).
have been proposed as indirect measures of carcinogenic potency of nickel com-
pounds due to correlations observed between these variables and the incidence
of injection site sarcomas. The results of Sunderman and Hopfer (1983) appar-
ently 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, 1980a,b). No significant rank correla-
tions were observed between dissolution half-times or phagocytosis and the in-
cidence 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 are better 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.
Sunderman (1984a) reported the incidence of injection site sarcomas in
male Fischer rats administered nickel compounds by the intramuscular route.
8-143
-------
Eighteen nickel compounds were tested at equivalent doses of 14 mg Ni/rat.
Results from this study are presented in Table 8-27. 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 S =
pNiS cryst = Ni^FeS^. > NiO > Ni3$e2 > NiAsS > NiS2 > Ni5As2 > Ni dust > NiSb >
NiTe > NiSe = Ni-^ASg > NiS amorphous > NiCr04. NiAs, NiTi03 and NiFe;L g were
not carcinogenic under the conditions of this study. Based on the results of
this study, the earlier observation of Gilman (1962) that nickel subsulfide is
more active than nickel oxide in the induction of injection site sarcomas when
injected intramuscularly, and the observation of Payne (1964) that nickel sub-
sulfide is the most active among eight nickel compounds studied, with the
following order of carcinogenic activities: Ni3$2 > NiC03 > NiO > Ni(CH3COO) ,
it can be stated that nickel subsulfide is most active when administered intra-
muscularly.
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 >
N13S2 > NiS2 = NiAsS > Ni3Se2 = NiSe = NiFeS4 > NiFe-,^ 6 > NiAs. It is apparent
that the relative carcinogenic activities of different nickel compounds may be
route-specific. Based upon the intrarenal studies, however, nickel subsulfide
was still more active than other nickel compounds, with crystalline pNiS the
most active.
To a more limited extent, Gilman1s (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 sub-
sulfide to be the most potent of all nickel compounds studied by intramuscu-
lar injections.
8.2.4 Summary of Experimental Studies
Experimental nickel carcinogenesis test results and short-term jn vitro
test results that have evolved out of various laboratories are summarized in
Table 8-31. 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 8-14 through
8-24.
8-144
-------
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The significance of tumors resulting from the 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 nic-
kel 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 and Mitchener, 1975; Schroeder
et al., 1974, 1964). All three studies produced negative results; however, all
three used the same relatively low dose level of 5 ppm of nickel in the drink-
ing water.
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 3 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 nickel subsulfide and observed no tumors.
Nickel carcinogenesis by inhalation has not been adequately studied. The
Ottolenghi et al. (1974) study using nickel subsulfide and Fischer 344 rats is
of adequate design to determine the carcinogenicity of nickel subsulfide by
inhalation. The observed neoplasms were predominantly adenomas (8/110 male;
7/98 female) and adenocarcinomas (6/110 male; 4/98 female). Additional tumors
were squamous cell carcinomas (2/110 male; 1/98 female) and a fibrosarcoma (one
male). Inhalation studies using nickel carbonyl (Sunderman and Donnelly, 1965;
Sunderman et al., 1959, 1957) 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 is either
very limited or are nonexistent. In general, the results from animal inhala-
tion studies for these compounds tend to be negative or equivocal. The Nation-
al Toxicology Program is in the process of conducting inhalation carcinogenesis
bioassays on nickel oxide, nickel sulfate, and nickel subsulfide. The studies
on these compounds are in the subchronic dose-setting stage. The chronic
inhalation studies will probably be complete by 1989. These studies, together
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with other biochemical and toxicological investigations of the scientific com-
munity, will provide a better database for the evaluation of the carcinogenicity
of nickel compounds in the near future.
Nickel subsulfide (Ni3$2) is the most studied nickel compound. In a study
of the carcinogenicities of various metal compounds, Gilman (1962) noted that
nickel subsulfide was a potent inducer of rhabdomyosarcomas when given intra-
muscularly. Later studies of the carcinogenicity of nickel subsulfide demon-
strated 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 nickel subsulfide will induce sarcomas when injected subcutaneously into
nude mice. In the study of Yarita and Nettesheim (1978), tracheas grafted onto
isogenic rats showed mainly sarcomas but also a low yield of carcinomas with
nickel subsulfide implantation as early as six months. Sunderman et al. (1980)
extended the site tumorigenicity of nickel subsulfide to the eye, where injec-
tion of 0.5 mg into the vitreous cavity in rats led to a high incidence of ocu-
lar tumors by 8 months.
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 DNA synthesis and induction of DMA
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 and Donnelly, 1965; Sunderman et al., 1959, 1957)
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 has been studied for potential
carcinogenicity. Nickel refinery flue dust containing 68 percent nickel sub-
sulfide, 20 percent nickel sulfate, and 6.3 percent nickel oxide produced either
negative results (Kim et al., 1976; Belobragina and Saknyn, 1964) or equivocal
results (Fisher et al., 1971) from inhalation studies. However, intramuscular
8-150
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injections produced strong tumor responses in rats and mice (Oilman and
Ruckerbauer, 1962). The presence of squamous cell carcinomas in two of five
surviving rats exposed to feinstein dust (Saknyn and Blohkin, 1978), an inter-
mediate product of nickel refining containing-nickel monosulfide, nickel oxide,
and metallic nickel, lends credence to the concern that nickel refinery dusts
are potential human carcinogens. These dusts have not been studied using In
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) produced sarcomas in five intramuscular injection
studies (Sunderman, 1984a; Gil man, 1966, 1965, 1962; Payne, 1964) and one
intrapleural injection study (Skaug et al., 1985). As in the 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 nickel subsulfide. One inhala-
tion study (Wehner et al., 1975) conducted on Syrian golden hamsters showed
neither a carcinogenic effect of nickel oxide alone nor a cocarcinogenic 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,
nickel oxide has been shown to have a lower carcinogenic potential than nickel
subsulfide. 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 nickel subsulfide.
Nickel (III) oxide (Ni£03) has not been tested sufficiently to allow any
conclusions to be drawn. Intracerebral injection (Sosinski, 1975) of nickel
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(Ill) oxide produced a marginal tumor response in rats, but intramuscular in-
jections did not. Furthermore, no tumors were produced in another intramus-
cular injection study (Payne, 1964). However, nickel (III) oxide has proven
to be more active in the induction of morphological transformations of mammalian
cells in culture than nickel oxide. The transforming activity in BHK-2.1 cells
approximates that of nickel subsulfide, but in SHE cells it is only about one-
tenth the activity of nickel subsulfide.
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 (Kasprzak et a!., 1983; Gilman, 1966,
1962; Payne, 1964) 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, chromosomal
aberrations .in vitro, and gene mutations in yeast and mammalian cells in cul-
ture; 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 con-
cern that soluble nickel compounds may have carcinogenic potentials. However,
tests on these soluble nickel compounds are too limited to support any defini-
tive judgment.
The above discussion has focused on the ability of nickel compounds alone
to induce carcinogenic responses. An equally important aspect of carcinogeni-
city is the interaction of nickel with other agents, since environmental situa-
tions 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 hydrocar-
bons. 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 sub-
sulfide and benzopyrene that were greater than for either agent alone. However,
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Wehner et al. (1975) did not find a significant carcinogenic response of nickel
oxide 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 |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 |jg/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 comutagenic effect between
nickel sulfate and benzo(a)pyrene was also observed (Rivedal and Sanner, 1981,
1980). These observations are supported by cocarcinogenic effects between
nickel compounds and certain organic carcinogens (Kasprzak et al., 1973; Maenza
et al., 1971; Toda, 1962).
Comparative carcinogenicity of various nickel compounds has been studied
and demonstrated in various laboratories (Sunderman et al., 1984, 1979b;
Sunderman and Maenza, 1976; Jasmin and Riopelle, 1976; Payne, 1964; Oilman,
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
nickel-containing powders: metallic nickel, nickel sulfide, crnickel
subsulfide, 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 nickel subsulfide was one of the
most potent carcinogenic nickel compounds, crystalline nickel sulfide (NiS) was
8-153
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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 noncarcinogenic. 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 8-26,
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 dissolution half-times
or phagocytosis and the incidence of injection site sarcomas after administra-
tion of equipotent doses of nickel compounds by the intramuscular route. Until
the mechanism of nickel carcinogenesis and associated processes are more clearly
understood, there is no a priori basis for using indices of phagocytosis, dis-
solution 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 jn
V1'tro 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. Reviews
by Sunderman (1984b,c, 1983, 1981, 1979) have summarized much of the pertinent
literature.
Several authors have noted the enrichment of the nucleus with nickel when
different nickel compounds are employed in various experimental systems. Webb
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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 nickel
carbonyl and rat hepatocytes, and Heath and Webb (1967), in nuclei from nickel
subsulfide-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 Sirover and Loeb (1977) and Miyaki et al. (1977) demon-
strate the ability of nickel ion (nickel sulfate) to increase the error rate
(decreasing the fidelity) of DNA polymerase in E. coli and avian myeloblastosis
virus.
Studies using test systems of varying complexity (Table 8-30) have demon-
strated both the direct cellular neoplastic transformation potency of soluble
nickel compounds (nickel sulfate, nickel choride), insoluble nickel compounds
(Ni3S2, Ni20o, 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
with carcinogenic activities can induce damage to DNA and form DNA-protein
crosslinks.
While the mechanism of nickel carcinogenesis is not well understood, bio-
chemical 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.
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8.3 QUANTITATIVE RISK ESTIMATION FOR NICKEL COMPOUNDS
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-
Q
out their lifetimes to a concentration of 1 mg/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 Description of the Low-Dose Animal-to-Human Extrapolation Model. 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.
There is no solid scientific basis for any mathematical extrapolation model
that 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 epidemiologic and animal cancer studies, and
because most dose-response relationships have not been shown to be supra!inear
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.
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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.
Let P(d) represent the lifetime risk (probability) of cancer at dose d.
The multistage model has the form
P(d) = 1 - exp C-(q0
qRdk)]
where
Equivalently,
where
qn- I 0, i = 0,-1, 2, ..., k
Pt(d) = 1 - exp [-(q^ + q2d2 + ... + qkdk)]
- P(Q)
- P(0)
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
L»
maximizing the likelihood function of the data. (In the section calculating the
risk estimates, Pt(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 experiment
including the control group. For nickel subsulfide, the only compound for which
the data have been deemed suitable for animal-to-human dose-response extrapola-
tion, the polynomial reduces to k = 1 or a one-hit model, since the only availa-
ble 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
8-157
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the dose producing a given risk are determined from a 95 percent upper
confidence limit, q*, on parameter qr 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.
8.3.2.2 Selection of the Ottolenghi et al. (1974) Rat Inhalation Study. 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, 1975)
because survival of the test animals was too poor. Only 9 of 96 (9 percent) of
the exposed animals survived for 2 years. The toxicity can be attributed to
the administration 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 1 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 chroni-
cally 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 litera-
ture and found among control animals.
In the Ottolenghi et al. (1974) study, 110 male and 98 female Fischer 344
o
rats were exposed to 970 ng/m nickel subsulfide via inhalation for 78 weeks (5
d/wk, 6 h/d). 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 have been shown in Table 8-13.
The results show signicant increases in adenomas and in combined adenomas/
adenocarcinomas for both male and female rats 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
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development of a single proliferative lesion," a unit risk assessment can be
calculated which includes combined adenomas and adenocarcinomas. This is also
consistent with the Environmental Protection Agency's policy as stated in the
Proposed Guidelines for Carcinogen Risk Assessment (U.S. Environmental Protec-
tion Agency, 1984). Three other areas of concern with this study are: (1) the
effects of the pretreatment injections of hexachlorotetrafluorobutane (HTFB) on
lung tumors, (2) the low survival rates in the control groups, and (3) the dif-
ferential survival between the control and nickel subsulfide-treated groups.
Each of these factors must be either adjusted for or dismissed in carrying out
the risk extrapolation procedure.
With respect to the issue of the effect of the injections of HTFB as a lung
infarcting agent, the results showed that there were actually more infarcts in
the controls (32 percent) than in the nickel subsul fide-treated rats (14
percent). However, no significant differences were seen in the injected versus
the noninjected rats with respect to mortality, body weight gain, or lung tumor
development. Of the rats receiving the injections, 15 percent had lung tumors
compared with 13 percent of those not injected. Based on this analysis it is
felt that no adjustment was needed for the injected animals.
With respect to the issue of low survival rates in the control groups, it
is noted that only 31 percent of the controls survived until the end of the
study. This compares with normal 104-week survival rates in the 50 to 60 per-
cent range for many bioassays using the Fisher 344 rat. In comparing this
difference, however, note must be taken that this bioassay actually lasted 114
wee|
-------
group (versus 20 percent in the controls, not statistically significant), the
additional mortality due to tumors in the nickel subsulfide group was approxi-
mately 20 percent (29/145). Based on this analysis, nearly all of the dif-
ference in survival between the control animals (31 percent) and the treated
animals (5 percent) can be explained by lung tumors. Therefore, no adjustment
would be needed.
8.3.2.3 Calculation of Human Equivalent Dosages from Animal Data. Two methods
are presented for the human equivalent dosage based on the Ottolenghi et-al.
(1974) rat inhalation study. The first method (Section 8.3.2.3.1) assumes dose
n f-3
equivalence in units of mg/bw ' for equal tumor response in the two species.
The support for this method is that the ratios of lung mass to body weight are
roughly equal in rat and man, that the lung is the only affected organ in rats,
and that the general distribution, metabolism, and clearance of nickel subsul-
fide in the lung and cells is uncertain enough to be described in general terms.
o /o
The equivalence of mg/bw has been used in most of the Environmental Protec-
tion Agency's quantitative risk assessments.
The second method of calculating rat-to-human equivalence dose (Section
8.3.2.3.2) is based on mg/surface area of the lung dose equivalence between the
two species. In this analysis adjustment is made for particle size, deposition
(bronchiolar versus the alveolar regions), and clearance. As might be expected,
attempts to model dose with increased detail can lead to more areas of uncer-
tainty. Nevertheless, this analysis is included both as a comparison with the
first method and as an attempt to further knowledge in the field.
8.3.2.3.1 Calculation of human equivalent dosages based on dose/body surface
equivalence. 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 approximation, 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 animal experiment, this equivalent dose is computed in the
following manner. Let
L = duration of experiment
le = 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
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Then, the lifetime average exposure is
1 x m
When exposure is via inhalation, agents that are in the form of particulate
matter, such as nickel subsulfide, can reasonably be expected to be absorbed pro-
portionally to the breathing rate. In this case the exposure in mg/day may be
expressed as
m = I x v x r
q q
where I = inhalation rate per day in m , v = mg/m of the agent in air, and r =
the absorption fraction.
The inhalation rate, I, for rats can be calculated from the observations
(Federation of American Societies for Experimental Biology, 1974) that rats
weighing 113 g breathe 105 liters/day. For rats of other weights, W (in kilo-
grams), the surface area proportionality can be used to find breathing rates
3
in m /day as follows:
I
= 0.105 (W/0.113)273 m3/day
For the 300 g rats in the Ottolenghi et al. study, the daily inhaled amount of
nickel subsulfide is as follows:
,m = I x 6/24 x 970 M9/m3 =48.8 pg/day
For humans, the value of 20 m3/day* is adopted as a standard breathing rate
(International Commission on Radiological Protection, 1977).
The equivalent exposure in mg/W2/3 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 Commission on Radiological1Protec-
tion- page 9. The average breathing rate is 10 m per 8-hour workday and
20 m 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
Man
Rats
W
70
0.35
i = I/W
0.29
0.67
Therefore, for particulates or completely absorbed gases, the equivalent expo-
sure in mg/W ' is
- m -
vr
_ iWvr _ ,.,,1/3,
- - -- IW
w
273
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. This would be the case for nickel subsulfide. Thus, rearranging the
above equation and solving for v, gives
-i /o
vhumans ~ Brats'1humans •> ^rats^humans^ vrats
Filling in the numbers gives
1/3
vh = (0.67/0.29)(0.30/70r/0 x 122.8
i3 = 46.1
as the human equivalent continuous exposure, since the daily equivalent exposure
in the Ottolenghi et al. study is
970 (jg/m x — hours x - days x — weeks = 122.8 ug/m3
24 7 110
8.3.2.3.2 Dos i metric considerations. When extrapolating results from animal
inhalation studies to humans several factors have to be considered:
1. The deposition of the inhaled chemical throughout the respiratory tract.
Deposition in nasopharyngeal , tracheobronchial and alveolar regions should
be separated. The deposition in these regions depends on respiratory
8-162
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parameters (respiratory geometry, breathing volume and frequency) and
particle parameters (aerodynamic size, hygroscopicity, and heterodisper-
sity). However, not only is total regional deposition of importance but
the dose deposited per unit surface area of a specific region should also
be evaluated. Although this delivered dose may not be equivalent to the
dose to a target site in the respiratory tract—clearance mechanisms having
to be taken into account—it may give an indication of where possible
effects can be expected to occur.
2. Retention half-time of the inhaled particles. This is dependent on many
factors, e.g., solubilization in the lung, uptake by macrophages, and
uptake into epithelial cells. Retention may also be affected by chronic
exposure to the substance itself if this substance influences lung
clearance. The i_n vivo solubility of different nickel compounds seems to
differ considerably, with water soluble nickel salts being rapidly
solubilized and nickel oxide being solubilized much more slowly in the lung
(although still to a much higher degree than in water). Nickel subsulfide,
also insoluble in water, seems to be solubilized in the lung to a higher
extent than nickel oxide, as judged by its short pulmonary retention
half-time of about 12 days in mice (Valentine and Fisher, 1984) and from
nickel excretion rates in urine. Accumulation of nickel in the respiratory
tract during chronic exposure conditions depends on all of these
parameters.
3. Metabolism of the inhaled compound. After solubilization in the lung,
possibly inside macrophages, the retention could be influenced by tissue
binding in the lung and by elimination rates via feces and urine. While
this may be different in humans and small laboratory animals for the same
compound, it has yet to be determined for nickel.
4. Differences in sites of tumor induction. The sites of tumor induction may
be different in man and animals, e.g., bronchogenic versus alveologenic
tumors. Thus, the region of the target cells in the respiratory tract has
to be considered when extrapolating from animal studies.
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These four points will be discussed in the following section dealing with
extrapolating results from the inhalation study by Ottolenghi et al. (1974). In
this study, male and female Fischer 344 rats were exposed for 78 weeks to 970 ug
Ni3S2/m , 6 hours/day, 5 days per week. From the sparse information on particle
sizes given in the paper (70 percent of the mass smaller than 1 urn and 25 percent
between 1 and 1.5 urn geometric diameter), the following particle parameters can
be deduced, assuming that the particle size distribution was log-normal: the
density, rho, of nickel subsulfide is 5.82 g/cm3, i.e., a particle with geo-
metric diameter, Dg, of 1 u, would have an aerodynamic diameter, D , of 2.41
|jm ^Dae = Dg * rn°)' Under the above mentioned assumption of a log-normal
distribution, the mass median aerodynamic diameter (MMAD) and geometric standard
deviation (GSD) of the particles used in the Ottolenghi et al. study were: MMAD
= 2.0 urn, GSD = 1.47.
Under the exposure conditions of the study, both benign and malignant
tumors of the respiratory tract developed to a significant degree in the
animals. There was no clear distinction between tumors of bronchogenic and
alveolar origin; tumors of both types were induced. Since nickel concentrations
in the lungs were not reported, the question about the levels of nickel having
accumulated in the lungs can only be approximated. In the following cases,
respective calculations are performed assuming different respiratory tract
retention behavior of the inhaled nickel subsulfide.
Case 1: The retention half-time of nickel subsulfide in the alveolar region is
12.4 days as determined for the mouse lung by Valentine and Fisher (1984)
after a single intratracheal instillation. Bronchial clearance is assumed
not to be disturbed and to occur with a retention half-time of 1.2 days
(Valentine and Fisher, 1984). Nasopharyngeal clearance is also assumed to
be undisturbed with a half-time of 0.5 days.
Case 2: The retention half-time is significantly longer, because the species
is different (rat, Ottolenghi; mouse, Valentine and Fisher) and because a
chronic continuous exposure to nickel subsulfide may lead to an impairment
of alveolar clearance mechanisms for the compound. The latter is indicated
in hamster studies by Wehner et al. (1981) who found that chronic exposure
to fly ash with high nickel content considerably increased retention of
nickel in the lung compared to fly ash with low nickel content. Oberdorster
8-164
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and Hochrainer (1980) also observed a decrease in alveolar particle clear-
ance during continuous exposure to nickel oxide particles at a concentra-
tion of 50 (jg/m3 in the rat. Particle retention half-time was 520 days
under these conditions, whereas a single exposure to nickel oxide resulted
in a pulmonary retention half-time for nickel of 36 days (Hochrainer et
a!., 1980). This represents an almost 15-fold increase in retention half-
time. Whether lung clearance of nickel oxide particles and other particles
is affected in the same way by chronic nickel exposure has not been deter-
mined; however, the studies by Wehner et al. (1981) and Tanaka et al.
(1985) support this assumption. Nickel subsulfide appears to have a more
rapid i_n vivo solubility than nickel oxide (Kuehn and Sunderman, 1982).
However, without experimental data it is impossible to determine whether
under the chronic exposure conditions of the Ottolenghi et al. study,
nickel subsulfide solubility would be different from nickel oxide. Thus,
for this case, an increased pulmonary retention half-time of 500 days will
be assumed. Bronchial clearance is also assumed to be affected due to
development of bronchitis, the retention half-time increasing to 30 days.
Nasal clearance is assumed to be affected, as demonstrated in humans
(Torjussen and Andersen, 1979), and has a long half-time of 100 days.
Case 3: The assumption is made that nickel subsulfide is not cleared at all
from the respiratory tract; hence, the total deposited dose is delivered to
the respiratory tract.
Since no data for nickel clearance in the nasopharyngeal area in rodents
are available, the retention data used for this region are only provided to
illustrate the outcome under the assumed different retention characteristics.
The following calculations on respiratory tract deposition are derived by
using a lung model described by Schum and Yeh (1980) and Yeh and Schum (1980).
The deposition calculations are based on anatomical models reflecting the
asymmetrical branching of the bronchial tree present in the mammalian lung. The
model uses a typical path which particles follow when inhaled. Particle size
and density and respiratory pattern (e.g., total lung capacity, functional
residual capacity, tidal volume, and breathing rate) can be adjusted
independently in the mathematical model to reflect realistic values. The
dimensions for the anatomical model were determined from silicone rubber casts
of the bronchial tree of rats and humans and include diameter, length, branching
8-165
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angles, and gravity angle of the airways. The model represents a system of
cylindrical tubes connected in a typical branching pattern for each airway
generation starting at the trachea (generation 1) to the acini (generation 17 to
25). Deposition of inhaled particles is assumed to occur by diffusion, sedimen-
tation, and impaction during inhalation, and by diffusion and sedimentation
during exhalation (Schum and Yeh, 1980; Yeh and Schum, 1980). As shown by the
authors, predicted depositions from the model agree quite well with experimental
studies in rats (Raabe et al., 1977) and humans (Lippmann, 1977).
The inhaled minute volume and respiratory frequency for the rats in the
Ottolenghi et al. study are predicted according to Stahl (1967):
Minute Volume:
Respiratory Rate:
Tidal Volume:
- u.,.0.8
VM = bwu'° x 379 (ml) (1)
FR = bw~°'26 x 53.5 (min'1) (2)
VT == VFR
(3)
As an approximation for mean body weight (bw, in kilograms) of the rats in the
Ottolenghi et al. study, a value of 0.3 kg is assumed. This gives VM = 144.66
ml, FR = 73.16 min , and Vy = 1.98 ml.
The amount At of nickel accumulated at time t is determined by:
At = B (1 ' e"bt> (4>
where a is the amount being deposited each day and b is the elimination rate
b = lH_2
(Task Group on Metal Accumulation, 1973). For retention in the tracheobronchial
tree, only the accumulation of the newly deposited nickel subsulfide.particles
is calculated. Nickel subsulfide particles cleared from the alveolar region and
passed through the tracheobronchial region are not included; no data are
available for this portion of nickel subsulfide.
Since the rats were only exposed for five days each week, a was adjusted to
(5)
8-166
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to account for the two days of no exposure. This changes the accumulation to:
_ a1
(1-e
-bt>
(6)
The equilibrium or steady state value is given by
A ' =
H
—
b
(7)
In addition, the influence of heterodispersity is included in the following
calculations and deposition both for a monodisperse nickel subsulfide aerosol
and for one with a geometric standard deviation of 1.47 is calculated.
Since the geometric standard deviation of the nickel subsulfide particle
size distribution of the Ottolenghi et al. study is rather low, the influence on
regional deposition is expected to be small. This is shown in Table 8-32, where
the percent predicted regional deposition according to the model by Schum and
Yeh (1980) is given. With bigger geometric standard deviations, differences can
become larger, in particular with regard to deposition within a given generation
of the respiratory tract.
The amount, M, of nickel subsulfide inhaled daily by the rats in the
Ottolenghi et al. study is given by:
M=VMxTxCx 10
"6
(8)
TABLE 8-32 RELATIVE DEPOSITION OF MONODISPERSE AND HETERODISPERSE PARTICLES
IN REGIONS OF THE RESPIRATORY TRACT OF RATS.
Region
Monodisperse
Heterodisperse
GSD = 1.47
Nasopharyngeal
Tracheobronchial
Pulmonary
16.14
3.78
6.02
22.69
3.59
5.54
aValues given are percent of inhaled particle mass deposited in respective
regions. MMAD =2.0 pm; GSD =1.47
8-167
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where T is the exposure time in minutes (360 min) and C is the exposure
concentration in (jg/m3 (970 M9/m3)- This gives a daily inhaled amount of 50.5
MO, which compares with 48.8 ug in Section 8.3.2.3.1.
Based on the deposition data (Table 8-32) and on the amount of nickel
subsulfide inhaled, the amount of nickel subsulfide deposited daily in these
regions of the respiratory tract in the rat [a in equation (4)] is shown in
Table 8-33. Also shown is the amount adjusted for seven days per week exposure
(a1).
TABLE 8-33. AMOUNT OF NICKEL SUBSULFIDE (|jg) DEPOSITED DAILY IN REGIONS
OF THE RESPIRATORY TRACT OF RATS
Region
Monodisperse
Heterodisperse
GSD = 1.47
Nasopharyngeal
Tracheobronchial
Pulmonary
8.15
1.91
3.04
5.82
1.36
2.17
11.46
1 81
2.80
8.19
1 29
2.00
a = daily deposition during 5 day/week exposure; a1
for 7 day/week exposure.
= daily deposition adjusted
Calculation of nickel subsulfide accumulation in regions of the respiratory
tract according to equation (6) after 78 weeks of exposure is exemplified for
Case 1, monodisperse particles. (Calculations for Cases 2 and 3 were performed
in the same way using the respective values, and all results are summarized in
Table 8-34.)
Case 1: Pulmonary retention half-time, 12.4 days; bronchial retention half-
time, 1.2 days; monodisperse particles:
a) Pulmonary region:
A'alv
(a1
alv
= 2'17 ^g; b
alv
_ In 2 _
= 546
A1
alv=38.8Mg
8-168
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TABLE 8-34 EQUILIBRIUM VALUES AND ACCUMULATION OF NICKEL SUB/SULFIDE IN
THE NASOPHARYNGEAL (NP), TRACHEOBRONCHIAL (TB), AND PULMONARY/(P) REGIONS
OF RATS AFTER 78 WEEKS OF EXPOSURE AND ASSUMING THREE DIFFERENT RETENTION
HALF-TIMES (MONODISPERSE PARTICLES)
'Retention
T1/2, days
NP
TB
P
(Db
(2)
(3)
(1)
(2)
(3)
(1)
(2)
(3)
0.5
100
infinite
1.2
30
infinite
12.4
500
infinite
Clearance
rate, day
In 2/T,/9
LI L
1.3863
0.0069
0
0.5776
0.0231
0
0.0559
0.0014
0
Accumulation at
78 weeks /' equilibrium
4.20'
823.98
3177.72
2.35
58.87
742.56
38.82
828. 30
1184.82
4.20
843.48
no eqilibr.
2.35
58.87
no equilibr.
38.82
1550.00
no equilibr.
j\ig/region
D(l) = Case 1; (2) = Case 2; (3) = Case 3.
MMAD = 2.0 urn-
text.
Due to the short half-time, this is already the equilibrium value.
b) Tracheobronchial region:
(a'tb = 1.36-
btb =
2 _
= 0.5776; t = 546 days)
A'tb = 2.35 MO
This is also the steady state value; however, as indicated before, it does
not include nickel subsulfide cleared via the mucociliary escalator from the
tracheobronchial tree.
Table 8-35 shows the amount of the accumulated nickel subsulfide after 78
weeks of exposure, as well as the equilibrium values, for heterodisperse
8-169
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TABLE 8-35. EQUILIBRIUM VALUES AND ACCUMULATION OF NICKEL SUBSULFIDE3
IN THE NASOPHARYNGEAL (NP), TRACHEOBRONCHIAL (TB), AND PULMONARY (P) REGIONS
OF RATS AFTER 78 WEEKS OF EXPOSURE AND ASSUMING THREE DIFFERENT RETENTION
HALF-TIMES (HETERODISPERSE PARTICLES)
Retention
T1/2, days
NP
TB
P
(Db
(2)
(3)
(1)
(2)
(3)
(1)
(2)
(3)
0.5
100
infinite
1.2
30
infinite
12.4
500
infinite
Clearance
rate, day
In 2/T1/2
1.3863
0.0069
0
0.5776
0.0231
0
0.055
0.0014
0
Accumulation at
78 weeks equilibrium
5.91
1159.52
4471. 74
2.23
55.84
704.34
35.78
763.41
1092.00
5.91
1186.96
no eqilibr.
2.23
55.84
no equilibr.
35.78
1428.57
no equilibr.
[jg/region
D(l) = Case 1; (2) = Case 2; (3)
MMAD =2.0 urn; GSD = 1.47.
= Case 3. See text.
particles. Figures 8-1 through 8-3 depict accumulation behavior for the
heterodisperse nickel subsulfide particles in the different regions of the
respiratory tract, calculated for three different retention half-times. A
steady state or equilibrium value is reached within the exposure period of 78
weeks in all cases except when the retention half-time is assumed to be 500 days
(pulmonary region, Figure 8-3). In this case, the amount accumulated after 78
weeks of exposure is 764 ug, whereas the equilibrium value is 1429 ug.
Since none of the assumed retention half-times have, been experimentally
proven for nickel subsulfide, the tables and figures are not intended to give
exact values for nickel accumulation in the respiratory tract, but mainly show
the differences in accumulation of nickel for the different cases. Approximate
equilibrium values are reached after about ten half-times.
In the study by Ottolenghi et al. (1974), tumors developed in both the
bronchial and alveolar regions of the lung. The surface area of a respective
lung region is conceivably an important factor for dosimetric considerations
because the total dose deposited in a certain region is not equivalent to the
8-170
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8-173
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dose per surface area. For example, although only 3 percent of inhaled
nickel subsulfide may deposit in the tracheobronchial region and 6 percent in
the alveolar region of the respiratory tract of the rat, the respective surface
areas are about 40 cm for the tracheobronchial region and about 4,000 cm2 for
the pulmonary region. Thus, although twice as much nickel subsulfide may have
been deposited in the alveolar region than in the bronchial region, the surface
area dose for the tracheobronchial region is about 50 times greater than for
that of the pulmonary region. For humans, regional deposition differs from that
in the rat and the surface area dose will also be different from the rat.
In the following section, lung surface areas of rat and man are compared, as
well as the deposited surface area dose for the tracheobronchial region and for
the pulmonary region under the exposure conditions of the Ottolenghi et al.
study. In addition, the deposited surface area dose per airway generation in
the two species is compared. Finally, the total dose per surface area of the
human lung under these exposure conditions is calculated, both for discontinuous
exposure (6 hrs/d, 5 d/wk), and for continuous exposure (24 hrs/d, 7 d/wk).
Lung surface area and deposited surface area dose are predicted using the
anatomical dimensions for the airways given by Schum and Yen (1980) and Yeh and
Schum (1980). The following surface areas can be calculated for a 300 g rat
with a tidal volume of 1.98 cm3 and a normal man with a tidal volume of 750 m3
(ICRP Task Group on Lung Dynamics, 1966):
Rat: Tracheobronchial surface (cm2): 45.7
Pulmonary surface (cm2): 4,453
Man: Tracheobronchial surface (cm2): 4,060
Pulmonary surface (cm ):
548,789
The predicted percent deposition of the inhaled particles for the rat is 3.59
percent for the tracheobronchial region and 5.54 percent for the pulmonary
region (Table 8-32). For man, the respective percentages are 3.94 and 18.18
percent for particles with MMAD of 2.0 urn and GSD of 1.47.
With these data, the amount deposited during a 6-hour exposure to 970
can be calculated (rat: tidal volume = 1.98 cm3; respiratory frequency =
73 min ;
man: tidal volume = 750 cm3; respiratory frequency = 15 min"1; amount
of nickel subsulfide inhaled daily during 6 hours by human: 3928.5 Hg). The
8-174
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daily deposited surface area dose of nickel subsulfide in rat and man, under the
conditions of the Ottolenghi et al. study, are as follows:
2
Rat: Tracheobronchial surface area dose (ng/cm ): 39-52
Pulmonary surface area dose (ng/cm ):
0.63
2
Man: Tracheobronchial surface area dose (ng/cm ): 38.12
Pulmonary surface area dose (ng/cm ):
1.30
The tracheobronchial region receives an approximately 30-fold higher dose
(man) and 60-fold higher dose (rat) per surface area than the pulmonary region.
The amount deposited per cm2 of tracheobronchial surface is essentially the same
in both the rat and man, whereas deposited pulmonary surface area dose in man is
twice that of the rat. However, since clearance mechanisms are effective in
both regions, the deposited dose must be adjusted to reflect the accumulated
long-term dose.
Before this long-term dose is calculated, differences in the deposited
surface area dose per airway generation will briefly be compared between the^two
species. Figure 8-4 shows the predicted deposited nickel subsulfide per cm of
each airway generation in rat and man. Deposits onto airway generation areas 16
through 25 are considered to be in the pulmonary region. In general, specific
surface area deposition is higher in both the proximal airway generations and in
the pulmonary region in man than in the rat during the six-hour exposure. As
noted above, clearance of nickel subsulfide over the six-hour exposure period
will occur to a certain extent, particularly in the tracheobronchial region, but
is not considered here.
The accumulated surface area dose in rat and man of nickel subsulfide under
the conditions of the Ottolenghi et al. study is shown in Figure 8-5. Because
of the lack of retention data for inhaled nickel subsulfide in either species,
available retention half-times for nickel oxide in rats and for slightly soluble
particles in humans were used. This assumes, however, that clearance mechanisms
were not influenced by chronic exposure, an assumption which is probably not
justified for low concentrations of environmental exposure. Thus, the tracheo-
bronchial clearance rate is assumed to be 0.8664 0"1/2 = 0.8 days) for rat and
man, and pulmonary clearance is assumed to be 0.0193 (T1/2 = 36 days) for the rat
8-175
-------
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8-176
-------
8-177
-------
and 0.0116 ai/2 = 60 days) for man. Although there is evidence that inert parti-
cles are cleared in two phases from the pulmonary region (Bailey et al., 1985a,b;
Philipson et al., 1985), this is not considered for nickel subsulfide in these
calculations.
Figure 8-5 shows that under these assumptions and the exposure conditions
of the study by Ottolenghi et al., steady state levels are reached for both the
tracheobronchial and pulmonary regions within the 78-week period. Equilibrium
levels for the tracheobronchial region are very similar for the rat (32.6
ng/cm ) and for man (31.4 ng/cm2). The main difference between the rat and man
is in the accumulated surface area dose of the pulmonary region which is
considerably higher in man (equilibrium value = 80.2 ng/cm2) than in the rat
(equilibrium value =23.3 ng/cm2).
Calculation of a nickel subsulfide exposure concentration for humans for 6
hours/day, 5 days/week that would accumulate to the same equilibrium as that for
the rat (23.3 ng/cm ) gives a value of 282 Mg/m3. This means, under the
assumptions made for pulmonary retention of inhaled nickel subsulfide in rats
and man, that humans will reach the same pulmonary surface concentration when
exposed to a 3.5-fold lower concentration than rats (at a nickel subsulfide
particle size of 2.0 urn). Even if it is assumed that rats and man have the same
pulmonary retention half-time, the human exposure concentration necessary to
reach the same equilibrium value would still be only half (470 pg/m3) of the 970
ug/m used in the rat study.
If the exposure of humans is continuous, i.e., 24 hours/day for a lifetime,
then-the exposure concentration decreases to 70.5 Mg/m3 in reaching a pulmonary
equilibrium value of 23.3 ng/cm2. This is about 1/14 of the concentration used
in the study by Ottolenghi et al. (1974).
Figure 8-5 shows that tracheobronchial surface area accumulation is very
similar in rat and man for this particle size and a GSD of 1.47, i.e., the
exposure concentration to reach equilibrium (32 ng/cm2) is about the same in
both species (970 |jg/m3 for rat versus 1005 Mg/m3 for man). Under constant
24-hour exposure conditions, the equilibrium value for tracheobronchial surface
area dose (32 ng/cm2) would be reached at a fourfold lower exposure
concentration of about 250 Mg/m3. This is about 3.5 times higher than the
predicted inhaled concentration necessary to reach the equilibrium of the
pulmonary surface area dose calculated in the preceding paragraph.
8-178
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Table 8-36 summarizes the above results and presents the equivalent
exposure values for humans to receive the same daily deposited dose, per surface
area and equilibrium values per surface area as the rat. As can be seen, the
human and rat exposures are nearly equal for tracheobronchial dose, but humans
require significantly less exposure for equal pulmonary dose. In order to
combine the tracheobronchial and pulmonary regions (the Ottolenghi et al. study
described tumors in both regions), the assumption was made of dose/surface area
equivalence between the two regions. Regions were then combined on the basis of
combined dose/combined surface area. The results show 636 ug/m and 284 ug/m
as human equivalent exposures for daily deposited dose/surface area and
equilibrium dose/surface area, respectively.
8.3.2.4 Calculation of the Incremental Unit Risk Estimates. The incremental
unit risk extrapolations from rat to man using the human equivalent exposures
calculated in the two previous sections, are presented in Table 8-37. The unit
risks are calculated using GLOBAL83. The human equivalent continuous exposure
for the deposited daily dose/surface area and the equilibrium dose/surface area
are calculated from data provided in Section 8.3.2.3.2 as follows:
636 ug/m x
xf x
= 80.5
The results are close for all three methods, with the general method of
dose equivalence on a mg/bw2/3 basis providing an estimate between the other
two. The maximum likelihood estimates range from 1.8 x 10 to 4.1 x 10
(jjg/m3)"1, with the upper limits ranging from 2.7 x l.o"3 to 6.1 x 10 (ug/m ) .
As will be shown next, these estimates are approximately one order of magnitude
greater than those obtained based on human studies.
8.3.2.5 Interpretation of Quantitative Risk 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
8-179
-------
8-180
-------
TABLE 8-37. INCREMENTAL MAXIMUM LIKELIHOOD AND UPPER-LIMIT UNIT RISK
ESTIMATES FOR RAT-TO-HUMAN EXTRAPOLATION USING THE OTTOLENGHI et. al (1974)
RAT INHALATION STUDY OF NICKEL SUBSULFIDE AND THE ONE-HIT MODEL
Equivalence
method
mg/bw273
Deposited
Human
equivalent
continuous
exposure
(pg/m3)
46.1
80.5
Incremental un
Maximum
likelihood
(Ijg/m3)'1
3.2 x 10 3
1.8 x 10"3
it risk, estimates
Upper-
limit -,
(ug/rnY1
4,8 x 10 3
2.7 x 10"3
daily dose/SAa
Equilibrium
dose/SAa
36.0
4.1 x 10
-3
6.1 x 10
-3
aSurface area of the lung.
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.
8.3.2.6 Alternative Methodological Approaches. The methods presented in the
Proposed Guidelines for Carcinogen Risk Assessment (U.S. Environmental Protec-
tion Agency, 1984) and followed by the CAG for quantitative assessment are
8-181
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consistently conservative, i.e., avoid underestimating risks. The most im-
portant 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 would give lower risk estimates. In
other documents, other models have been used for comparative purposes only. How-
ever, the animal inhalation data for nickel have only one dose group plus a con-
trol; 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.
8-3-3 Quantitative Risk Estimates Based on Epidemiologic Data
Epidemiologic studies have shown strong evidence that secondary smelting
and refining 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 sufficient 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 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 a!., 1981; Cragle et al., 1984; Redmond et al.,
1983, 1984). Conclusions from these studies, however, were limited by other
considerations 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 Col borne and Sudbury, Ontario, isolated all the
increased lung cancer among the sinter workers.
8-182
-------
The one apparent contradiction to the hypothesis that the pyrometallurgical
process and nickel subsulfide exposures are responsible for the observed cancer
increase 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, nickel metal, copper-nickel oxides, 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; International Nickel Company, Inc., 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.
Public comments to a draft of this document suggested that the electrolysis
operation at Kristiansand "probably created a much higher concentration of
nickel sulfate aerosols than would have existed in the Port Colborne tankhouse"
(International Nickel Company, Inc., 1986). In additional comments submitted
by Falconbridge Ltd., a table (Falconbridge, 1986) showed that the concentrations
of fine solids per unit volume of nickel-bearing electrolytes in Kristiansand
was about eight times that in the electrolysis department at Port Colborne in
1954. Factoring in the information that the total tonnage of electrolytes at
Kristiansand was nearly three times that of Port Colborne, the commentators sug-
gest that this increased concentration may provide "a possible explanation for
the apparent divergence in frequency of respiratory cancer in the two plants."
Furthermore, the comments of Falconbridge presented a reading of 40 mg Ni/m
in one area of the Kristiansand electrolysis department which the commentators
attributed to a 50 percent insoluble and 50 percent soluble form. The Environ-
mental Protection Agency is presently further analyzing these tankhouse data,
but the results are not yet available.
The following is an analysis of the epidemiologic data available for a
quantitative assessment of risk from exposures to nickel refinery dusts. 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, the models are 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 Kristian-
sand, 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
8-183
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not presented here because its analysis produces results very similar to that
of Copper Cliff.
8<3-3-1 Choice of Epidenriologic 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 extra-
polation from human studies always involves many assumptions, primarily because
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 particulates such as nickel subsulfide and nickel refinery dust with
relatively long lung clearance times;,_ Jhe .J.ssumgtion _of a.cumulative exposure-
response is probably a close approximation to actual lung" burden. FurSiemor^
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, h1(t), is in-
creased by an amount proportional to the cumulative exposure up to that time. In
mathematical terms this is h1(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 hn(t) as
follows: °
h(t) = h0(t) +
Under the assumptions of this model, we can estimate the parameter A by summing
the expected rates to yield:
where Ej is the total number of expected cases in the observation period for the
group exposed to cumulative exposure X... EOJ is the expected number of cases
8-184
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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 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
J (B) The multiplicative or relative risk model. This model follows the
assumption that the background cause-age-specific rate at any time is increased
by an amount proportional to the cumulative dose up to that time. In mathema-
tical terms this is h(t) •= h0(t) x (1 + AXt). As above, we can estimate the
parameter A by summing over the observed and expected experience to yield:
J- = .1 + AXj
E0j
E. is estimated by the observed deaths, Qj, and the equation is solved for A.
O./EQ. is the standardized mortality ratio (SMR).
J In many previous quantitative risk assessments, the Environmental Protec-
tion Agency 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 = B,,/Pn and X = IX.-N,/(70-ZNO.
H U J J J
where N- is the number of men exposed at level X... The multiplicative model is
one inJwhich 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 the multiplicative or
additive model, excess risk (SMR or mortality rates, respectively) remains
8-185
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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 com-
pared. The workers at the Huntington, West Virginia refinery are subdivided into
those with nickel subsulfide exposure versus 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. (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
Enter!ine 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 asso-
ciated with the pyrometallurgical process.
8.3.3.1.2.1 Huntingdon, West Virginia. The study of mortality in West
Virginia nickel (pyrometallurgical) refinery workers by Enter!ine 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 8-38. 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 in one of the less dusty of the
nickel refineries. One significant feature of the data in Table 8-38 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 models 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.
8-186
-------
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8-187
-------
The results of the regressions are presented in Table 8-38. 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 pyrometallurgical
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 expected
deaths. The standardized incidence ratio (SIR) and SMR were 8.5 and 8.7,
respectively.
The shortcomings of the Chovil et al. study, which provide potential
biases, have been discussed in Section 8.1.2.1.4. The methods used for
obtaining the observed and deriving the expected lung cancer cases make the
incidence data less reliable than the mortality results. The poor follow-up of
only 75 percent of the cohort biases the results toward underestimating the
risk, since all those lost to follow-up were considered survivors for the
mortality analysis and noncancer cases for the incidence analysis. The emphasis
in the following analyses is on the mortality data, which are considered the
more accurate because of reasons discussed above. The group most biased by the
large percentage lost to follow-up is felt to be those exposed earliest and to
the dustiest conditions. Counting these as survivors would tend to bias the
slope estimate downwards. Thus, the risk estimates derived from the Chovil et
al. data would have to be considered a lower limit of the risks that did occur.
In analyzing these data for dose-response relationships, the Chovil et al.
(1981) study provided no measure of exposure levels, but described conditions 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
8-188
-------
the period 1948 to 1951 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 8-39 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 four years was weighted double
(see below). 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
multiplicative risk model can be investigated). The results are basically
identical; either one provides strong evidence for the linear dose-response
relationship, with the deviations from linearity not statistically significant.
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 employed 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 Cliff cohort (all workers with any exposure versus a stratified
random sample of workers with at least five years total service with the company
in the Chovil et al. study). The results of the Muir et al. (1985) analysis,
presented in Table 8-40, 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 versus 25 years mean follow-up since first
8-189
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exposure), and that the average length of exposure was 33 percent higher (2.4
years versus 1.8 years). Even more significant is the average amount of nickel
exposure before and after 1952. Chovil et al. (1981) hypothesized that the
exposure of the early subcohort on a mg/m3 basis was twice as high as that of
the later cohort, but examination of a chart in a paper by Warner (1984) appears
to put that ratio closer to three and possibly as high as five or six. Calcu-
lating a weighted linear regression (with the square root of expected as weights)
of SMR versus years of exposure (with years of exposure before 1952 counted as
double), the slope is significant at the p = 0.05 level, while deviations from
linearity were not statistically significant. 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 mostly in
the higher risk nickel subsulfide areas. While the dust levels and 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 was, at least, drastically reduced. These reductions seem to be
concurrent with better industrial hygiene conditions.
Dose-response data from Clydach are presented several ways, and inferences
can be made from these. Data by Doll et al. (1977), Table 8-41, 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 consistent with
8-192
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the relative risk functionally related to cumulative dose, since each subcohort
is probably exposed for five years longer than the one succeeding it. It is also
consistent with the Copper Cliff results (Table 8-40), where the early subcohort
exhibited higher lung cancer mortality than the later one.
The other Clydach data suitable for analysis of dose-response relationships
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 8-42, 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 8-43, 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 8-41. 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.
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
8-194
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TABLE 8-42. 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)
0
116
489
605
(19.2)
1-2
13
39
52
(25.0)
3+
8
14
22
(36.4)
Total
137
542
679
(20.2)
Total chi square
Test for linear trend
Departure from linearity
X = 4.71 0.05
-------
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 8-44 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 soonen, 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 8-44), the excess risk
increases with time, since exposure is statistically increased over the 0 to 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- to 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 inferences
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
(around 4) from 15 years through 35 years after first employment (Table 8-45).
If conditions remained dusty through the early 1960s, then these figures
do support a relative risk model despite the fact that they are unadjusted for
nickel exposure. When these figures are adjusted for smoking, the relative
8-196
-------
TABLE 8-44. CLYDACH, WALES NICKEL REFINERY WORKERS:
LUNG CANCER MORTALITY BY TIME SINCE FIRST EXPOSURE
FOR WORKERS EXPOSED BEFORE 1925d
Excess
risk
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
0 -
Relative
risk
0/E
10.9
11.1
7.2
3.4b
1.6b
5.1 .
• E
Person-
years
0.0021
0.0067C
0.0110b
0.0089b
0.0034
0.0073
aFirst year of observation was 1934, 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.
bSignificantly 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.
risk increases until 35+ years postexposure, after which it decreases but
still remains significantly above the 3 to 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 8-46
indicate that the combined effect of nickel and smoking is greater than additive
but less than multiplicative. Again, these analyses are not adjusted for
nickel exposure within the refinery; it is assumed that smokers and nonsmokers
8-197
-------
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8-199
-------
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 (Enter!ine and Marsh, 1982)
as the primary data set for several reasons. First, International Nickel Com-
pany, Inc., (1976) reported that dust concentrations around the calciners were
much lower than those at Clydach, Port Col borne, or Copper Cliff. Enter!ine
and Marsh (1982) cited this and suggested that nickel exposures may have, thus,
been considerably lower.
8-200
-------
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 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 8-38. 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:
where E- is the number of expected lung cancer deaths in the observation period
for the jth group with cumulative exposure X-, EQ. is the number of expected
background lung cancer deaths, and W, is the person-years exposed in the j
group. The multiplicative model does not use person-years of observation
directly in its formulation. It is
EJ =
(2)
8-201
-------
Under either assumed model, the observed number of deaths in the jth exposure
group is a Poisson random variable with mean E-.
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. Envi-
ronmental Protection Agency, 1985). For the additive risk model, the likeli-
hood is
L =
The maximum likelihood estimate (MLE) of the parameter A is obtained by solving
the equation
d In L = I [- X W +
dA j=l j j
j + A¥j
] = 0
(3)
for A.
The asymptotic variance for the parameter A is
= [ I
-
EOJ+AXJWJ
(4)
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 8-47. The cumulative exposure is changed to a
24-hour equivalent times years exposure by the following factor:
1 (mg/m ) • months = 1 (mg/m3) • months x 1 year/12 months x 103|jg/l mg x 8/24
X 240/365
o
= 18.26 mg/m continuous equivalent exposure
8-202
-------
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8-203
-------
An estimate of £ = 9.66 x l(f8 is obtained by rewriting equation (3) filling in
the numbers from Table 8-47
1.8759 x 107 =
6.552 x 1Q
1.046 x 10
6.0143 x 10
3. 08 + A(2. 184X106) 0. 61 + A(l. 046xl06) 2.48 + A(1.5036xl07)
The Var (fc is estimated from equation (4) as 1.6 x 10"14 so that the S.E. (A)
1.28 x 10 and the 95 percent upper and lower confidence limits (UCL and LCL
respectively) are approximately AUCL = 3.07 x 10'7 and ALC[_ = 0, respectively.'
Alternatively, the estimate of A derived from the multiplicative model is
obtained by solving the equation
d In L _ z -En.X
dA ~ 1=1 UJ •
AX.
= 0
(5)
for (A), which reduces to
31.777.16= 3>526-2
2,938.22
41,179.96
1 + A(l,175.40) 1 + £(2,938.22) 1 + £(10,294.99)
The solution to the above equation is £ = 5.70 x 10~5.
The asymptotic variance for the estimate A of the multiplicative model
is
and the standard error is 7.57 x lo'5, so that the 95 percent lower and upper
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
8-204
-------
the data set. Even though we expect it to provide the best low-exposure
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 8-48, 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 and Marsh "non-refinery"
subcohort excludes the refinery workers from the calcining, melting, and casting
departments. As such, we can compare the results of the pre-1947 non-refinery
subcohort with those of the refinery subcohort under the assumption that the
actual nickel species differences by department are responsible for the differ-
ences 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 cohort, because the
pre-1947 subcohort's 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 earlier group has 27,228
person-years of follow-up after a 20-year latent period, while the later group
has only 6,360.
Table 8-49 shows the data from the Enterline and Marsh pre-1947 non-refinery
cohort used to estimate the parameters from both the additive and the multipli-
cative models. The results corresponding to those of the refinery workers above
are presented in Table 8-50. The estimate of A in the additive model is A =
so that the 95 per-
6.055 x 10"8 (additive) with standard error = 2.42 x 10 .
cent 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"4. 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 ng/m of nickel in air, in the
presence of all other competing risks, may be expressed as
P(x) = / (h2(x,t)ej -[h (x,v) + h (v)]dv}dt
8-205
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8-208
-------
where h2(x,t) is the age-specific death rate at age t due to a constant lifetime
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 approxi-
mated 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
h2(x,t) are those estimated as
h£(x,t) =9.66 • 10"8xt
for the additive model with the MLE, and
h2(x,t) = h0(t) • (1 + 5.70 • 10"5xt)
for the multiplicative model, with the MLE. The results of the unit risk
calculations are presented in Table 8-51, based on the estimates from the
Enter!ine and Marsh refinery cohort, and in Table 8-52 for the Enter!ine and
Marsh non-refinery cohort estimates. The results for the refinery workers
(Table 8-51), show, for the additive model, the MLE estimate of the incremental
unit risk as 2.8 x 10"4 (ug/m3)"1 and the 95 percent upper-limit incremental
unit risk as 8.8 x 10"4 (ug/m3)'1; for the multiplicative model, the MLE esti-
mate is 1.5 x 10"5 (ug/m3)'1 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 sta-
tistically significant.
Table 8-51 also presents an estimate of the incremental unit risk under the
average relative risk model used by the CAG in cases where there is only one
dose-response data point and where the more detailed information, such as
person-years and time since first exposure, are not available. This is the same
model used below for estimates based on the Clydach and Kristiansand studies.
The model is
BR = P0(R-D/X
8-209
-------
RFnM,, ADDITIVE AND MULTIPLICATIVE MODELS
BASED ON THE ENTERLINE AND MARSH REFINERY WORKERS DATA
=
Incremental risk due to a constant lifetime
exposure of 1 uq/m
Model
Additive risk
Upper bound
MLE
Lower bound
Relative risk
Upper bound
MLE
Lower bound
Average relative
A
A
3.07 x 10"7
9.66 x 10"8
0
1.81 x 10"4
5.70 x 10~5
0
risk9 -
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
3.1 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
= PQ (R~1)/X> where P0 = °-023> R = 8/7-43, and X = 57.4 ug/m
eragS continuous exposure for a 70-year lifetime.
where BH = the incremental unit risk estimate; PQ = the background lifetime risk
for lung cancer = 0.036 in the general U.S. white male population (1976)*; 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:,
- ZXJNJ/ZN.1 _ 3
X Ij~ - - 57-4 M9/m continuous exposure equivalent
(based on the numbers_1n Table 8-47). The estimate of the incremental unit
"
_
risk, BH, is 3.1 x 10" ((jg/m )"1, close to the estimate of 1.5 x 10"5 derived
This value is adjusted to PQ = 0.023 when the increasing lung mortality rates
from 1948 to 1977 are taken into account.
8-210
-------
TABLE 8-52. 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
A No 1 ag
Model A time
Additive
-7 ~3
Upper bound 4.58 x 10 1.3 x 10
MLE 6.055 x 10"8 1.8 x 10"4
Lower bound 0 0
Multiplicative
Upper bound 2.60 x 10"4 6.6 x 10"5
MLE 3.74 x 10"5 9.5 x 10"6
Lower bound 0 0
' i v- _
10-year 20-year
lag time lag time
1.3 x 10"3 1.2 x 10"3
1.7 x 10"4 1.6xlO"4
0 0
6.1 x 10"5 5.2 x 10"5
8.6 x 10"6 7.7 x 10"6
0 0
Average relative risk
_
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
refinery workers. For these non-refinery workers, the average continuous
exposure, lifetime equivalent was X = 30.0 Mg/m3> while R = 47/45.75 (subtracting
the 0.87 expected nasal cancer deaths) = 1.027. Since PQ = 0.036 as before, the
estimate of the incremental unit risk is
B.. = 0.023 (0.027) = 2.1 x 10"5
H 5
30 [jg/m
'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
8-39). 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.
8-211
-------
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-
fide levels of about 400 mg/m3 in 1950, falling to around 100 mg/m3 towards the
end of the plant's productive life •••.." [Public comments by International
Nickel Company, Inc., (1986) state that these levels were actually total dust
concentrations.] Following, also, the Chovil et al. (1981) organization of
data, where they considered early exposure about double that of exposure after
1951, we^preserve the estimate of 100 mg/m3 for 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 46.4 mg/m3. An accompanying
figure shows estimates of nickel concentrations decreasing from 200 mg/m3 to
50 mg/m over time.
The results of ^the analysis are presented in Table 8-53. The maximum
likelihood estimate AML£ = 4.19 x 10"5 for the relative risk model, with 95
percent limits of ALC|_ = 2.94 x 10~5 and A\jCL = 5.44 x 10'5, all fit the data
satisfactorily.
nickel refinery dust exposure of 1.1 x 10
These estimates translate to an incremental unit risk for 1
"5
fidence limits of 7.6 x 10"6 and 1.4 x 10"5
with lower and upper con-
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 8-39, it can be seen that
R = 8.70; X = 100(mg/m3) - (IN, • years./IN.) • -§ . 280
J J J
24 365 70
= 2.24 mg/m continuous lifetime equivalent exposure.
Adjusting for the Canadian workers and the rates from 1963 through 1978 yields
value of PQ = 0.026 (see next section).
B 0.026(7)
" 2.24 x l
8.9xlQ
-5
8-212
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8-213
-------
The order of magnitude difference in estimates between these two models probably
reflects the greater sensitivity of the likelihood model to the lower
exposure-response data.
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, while exposure in the electrolysis process includes
nickel chloride -and nickel sulfate. Exposure estimates for the Kristiansand
refinery before 1952 are lacking. All estimates below are based on a review of
an analysis by Thornhill (1986). For two of the roasting and smelting opera-
tions, Thornhill reports total dust measurements of 5 to 18 mg/m3 (whole shift
samples) in 1952 and 3 to 18 mg/m3 in 1953 (day shift samples). These are con-
sistent with some earlier measurements, but are slightly higher than several
measurements reported later. Thornhill, citing "a steady trend towards im-
proving working conditions following WWII", concludes "that dust levels around
the Mond Reducers frequently ranged between 15 and 20 mg/m3 as estimated by
foremen who worked there" (in the early 1950s). If we make minor adjustments
based on two assumptions that (1) earlier levels were probably dustier, and (2)
The Mond Reducers were among the dustier operations in the process, then a range
of 3 to 30 mg/m should provide a reasonable range for which to calculate a unit
risk.
For the electrolysis workers, Thornhill estimates that the range of nickel
exposures varies from 0.03 to 0.04 mg Ni/m3 as nickel sulfate for the Copper
Electrodispersion tanks (1960, no dust) to 40 mg Ni/m3 as nickel-copper sulfide
and oxide complexes (1974, 80 mg/m3 total dust). Both the wide range and the
nickel species differences seem to preclude a unit risk estimate for these elec-
trolysis workers without individual exposure information. Thus, the calcula-
tions that follow are based on the roasting and smelting operations.
The study did not record the number of years worked; therefore, it is
assumed that exposure lasted for about one quarter of a lifetime. The meager
evidence suggests that this may be a slight overestimate. The corresponding
estimate for Clydach was 10.5 years before 1930, when exposure to the carcinogen
was drastically reduced. In Norway, there is no corresponding cutoff date.
For the low end of the exposure range, we can estimate an average lifetime
exposure for workers as
8-214
-------
exposure = 3 mg/m3 x — hours x — days x - lifetime x 10 |jg/mg
24 365 4
o
= 164 |jg/m
o
For the high end of the range, average lifetime exposure is 1644 |jg/m .
The estimated incremental unit risk, BH, of dying from cancer due to
exposure to these airborne nickel compounds at 1 ng/m over 70 years of
continuous exposure is given by
BH = PQ(R -
The relative risk, R, for roasting and smelting workers in the 1982 update
was 3.9 for lung and larynx cancer. The background lung cancer risk for
Norwegian males, PQ, has been estimated as approximately 45 percent that of the
U.S. White males based on 1976-77 age-adjusted death rates (Page et al. , 1985),
or 0.016. This is consistent with the figures of Warner (1986) for Norwegian
males, if we accept the background rates of 1976 as valid figures for
comparison. If we consider that the U.S. age-adjusted death rates for lung
cancer rose from 25.9 in 1953 (the first year of the study; Grove, 1968) to 68.1
in 1976, and attribute a similar trend to the Norwegian population, then the
background rate of PQ = 0.011 applies.
The incremental unit risk of death from lung and larynx cancer from nickel
Q •
per increment of 1 yg/m °f continuous exposure for 70 years is estimated as:
Bn = 0.011(2. 9)/164 = 1.9 x 10~4 ((jg/rn3)'1
n
3
based on the low exposure estimate of 3 mg/m
and
BH = 1.9 x 10"5 (ijg/m3)"1
3
based on the high exposure estimate of 30 mg/m .
8.3.3.2.4 Clydach, Wales. A risk assessment can also be made from the epide-
miologic data at Clydach, Wales (Doll et al., 1977). The lung cancer rates
prior to 1930 will be used to calculate the risk, because the observed cancer
8-215
-------
risk declined dramatically after 1925; this reduction in risk was statistically
significant after 1930. As discussed in the epidemiology section, it is
believed 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
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
probably were exposed for less than 8 hours/day, we estimate 10 mg Ni/m3 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 8-54.
Average number of years exposed is 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 ug/mq
24 365 y
o
= 329 ug/m for the low exposure estimate and
o
X = 1,644 ug/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, adjusted to the population of England and
Wales from 1934 to 1977, is approximately 0.029.
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:
B (0.029) (5.2) =4.6xlQ-4
329
for the low exposure limit and
BH = 8.1 x 10"
(ug/m ) for the high exposure limit.
8-216
-------
TABLE 8-54. 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
X
X
X
X
X
X
Average number
of years exposed
prior to 1930
25
17.5
12.5
7.5
2.5
2.5
Person-
years
exposed
2975
1875
787.5
2137.5
257.5
8032.5
Source: Adapted from Doll et al. (1977).
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 8-55. The estimates for the refinery workers
range from 1.1 x 10"5 to 4.6 x 10~4. The estimates from the Huntington refinery
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 cancer
deaths, the incremental unit-risk estimate becomes 1.3 x 10 , well within the
range of the other estimates. If a more specific estimate is needed, we
recommend the midpoint of the range, 2.4 x 10"4. This is very close to the
estimate derived from the additive risk model for the Huntington refinery
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.
In fact, an incremental risk estimate of zero fits the data (by the x 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.
8-217
-------
TA5tLSr,55' ESTIMATES QF INCREMENTAL UNIT RISKS FOR LUNG CANCER DUE TO
EXPOSURE TO 1 ug Ni/nT FOR A LIFETIME BASED ON EXTRAPOLATIONS FROM
EPIDEMIOLOGIC DATA SETS
Study
Huntington, W.
Refinery
Va.
Additive risk model
~a
workers 2.8 x 10~4
Non-refinery
Copper
Clydach
Cliff,
, Wales
Kristiansand,
workers 1.8 x 10~4
Ontario
—
Norway
Relative
1.
9.
1.
8.
1.
5 x
5 x
1 x
1 x
9 x
10"5 -
10
10
10
10
-6
-5
-5
-5
risk model
3.
2.
8.
4.
1.
1 x
1 x
9 x
6 x
9 x
10
10
10
10
10
-5b,c
-5c
-5c
-4
-4
Midpoint of range for
refinery workers
2.4 x 10"
MLE estimates only.
Incremental unit risk increases to 1.3 x 10"4 if the two observed nasal cancer
deaths and expected nasal cancer deaths are included.
cAverage relative risk model.
We conclude that:
(1) For the refinery workers exposed to refinery dust, an incremental unit
risk of
BH = 2.4 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 in
animals (supported by jjn 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 nickel subsulfide composition. While nickel oxide
and nickel sulfate are two other important nickel compounds in the refinery
dust, their possible 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-
s' 218
-------
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 uncertainty.
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 number
expressed in terms of (mmol/kg/day)"1. This is called the relative potency
index.
Figure 8-6 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 8-56. 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-
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 1.1 x 10"5 - 4.6 x 10~4 (pg/m3)"1 (Table 8-54). We first take
the midpoint of the range 2.4 x 10"4 (mg/m3)"1. This is converted to units of
(mg/kg/day)"1, assuming a breathing rate of 20 m of air per day and 70 kg
person.
2.4 x 10"4 (pg/m3)'1 x ^-^ x 1^9 x 70 kg = 0.84 (mg/kg/day)"1
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 2.0 x
10+2. Rounding off to the nearest order of magnitude gives a value of +2, which
is the scale presented on the horizontal axis of Figure 8-6. The index of 2.0 x
10+2 lies in the third quartile of the 55 substances that the CAG has evaluated
as suspect carcinogens. For nickel subsulfide the estimate of potency is
adjusted by a factor of 2, giving a potency index of 4 x 10 .
8-219
-------
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8-220
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8-224
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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 observational 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 In
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 acetate, when tested
in Strain A mice, and nickel carbonyl, at toxic levels, have also 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
uncertain. 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 stu-
dies and one diet study with soluble nickel compounds have not shown any in-
crease 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
8-225
-------
enter the cell. Following this hypothesis, experiments have been conducted to
correlate carcinogenicity via injection with physical, chemical, and biological
activities. While it is suggested from such studies that, on a qualitative
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 (Ni^So). 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 subsulfide 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 DMA 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 of the comparative tests.
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 nickel subsulfide, 20
percent nickel sulfate, and 6.3 percent nickel oxide gave either negative or
equivocal results from inhalation studies in rats. However, intramuscular
8-226
-------
injections produced strong tumor responses in both rats and mice. The observa-
tion 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 nickel) further supports nickel
refinery dust as a potential human carcinogen. These dusts have not been stu-
died using i_n vitro short-term test systems or tests for macromolecular inter-
actions.
8.4.1.3 Nickel Carbonyl [NKCO)^]. 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 DMA 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 the 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 pyrometallurgical sulfide nickel matte refineries where the lung and nasal
cancer risks were high. Yet in other occupational settings, such as nickel
alloy manufacturing 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 measurements were taken and because of presumed differences in sampling
techniques.
8-227
-------
In animals, while nickel oxide was carcinogenic in five intramuscular
injection studies and one intrapleural injection study, it produced only injec-
tion site tumors. The response by the intrapleural route, however, was strong
and approached the response produced by nickel subsulfide. 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 nickel oxide is most likely less carcinogenic than nickel subsul-
fide. 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 nickel subsulfide.
8-4-1-5 Nickelic Oxide (NUO.,). Nickel (III) oxide (Ni203) 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 injec-
tion, but intramuscular injections of the same animals produced no injection-
site sarcomas. It produced no tumors in a second intramuscular injection study.
However, nickelic oxide is more active in the induction of morphological trans-
formations of mammalian cells in culture than is nickel oxide. The transforming
activity in BHK-21 cells approximates that of nickel subsulfide but in SHE cells
it shows only about one tenth the activity of nickel subsulfide.
8-4-1-6 Soluble Nickel Compounds rN1S04.N1CU JjifCH,f^-T. The evidence for
three soluble nickel compounds, nickel sulfate (NiS04), nickel chloride (NiClp),
and nickel acetate [Ni(CH3COO)2], is summarized here as a class both because of
hypothesized similar modes of action of the soluble compounds and because of
limited testing of the different compounds. The results from four intramuscular
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 in culture, sister chromatid exchange, chromosomal aberrations
in vitro, gene mutations in yeast, and mammalian cells in culture, and decrease
fidelity of DNA synthesis. The observation of pulmonary tumors in strain A mice
8-228
-------
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, but there is also a report of heavy exposure
to the less soluble forms. 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 possible that there
were qualitative and quantitative differences in 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.
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
8-229
-------
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 car-
cinogen by the intramuscular and intrarenal injection routes of exposure. Its
carcinogenic activity equals that of nickel subsulfide by the intramuscular
route and is more active than nickel subsulfied by the intrarenal route. It
also induces morphological transformations of mammalian cells in culture with
an activity equal to that of nickel subsulfide. In the same sets of experi-
ments, however, amorphous nickel sulfide was inactive both as an animal carcino-
gen 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 Ni3$2-injected mice indicated that a conversion of Ni3$2 to Ni?S6 and
NiS had occurred. The conversion of nickel subsulfide to nickel sulfide and
other nickel sulfide forms heightens the concern for the carcinogenicity of
nickel sulfide.
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 (Mi). 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
concurrent exposure to other known or suspected lung carcinogens which confound
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
8-230
-------
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 refinery
As a best estimate,
dust in workers of 1.1 x 10~5 to 4.6 x 10" (ug Ni./m )
-" O ~1
we take the midpoint of the range, 2.4 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 i_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 nickel subsulfide in
the refinery dust is appropriate. For nickel oxide and nickel sulfate, two
other important nickel compounds in the refinery dust, their possible carcino-
genic potencies relative to the subsulfide have not been established and the
above unit risk estimate cannot be used for either the oxide or the sulfate
form.
Upper-limit incremental unit risks for nickel subsulfide exposure have also
been estimated from a rat inhalation study. They range from qj =2.7 x 10 to
6.1 x 103 (ug/m3)'1, with maximum likelihood estimates ranging from 1.8 x 10
to 4.1 x 10~3 (ug/m3)'1. The estimate based on subsulfide exposure to human
refinery workers is about one-seventh of these estimates. 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
quantitative estimate. The animal data base of relative carcinogenic activities
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 the Environmental
8-231
-------
Protection Agency's classification scheme for evaluating carcinogens (U.S. Envi-
ronmental Protection Agency, 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 inade-
quate evidence from epidemiologic studies with regard to evaluating the carcino-
genicity of nickel carbonyl, there is sufficient evidence from animal studies
to classify it as Group B2. The carcinogenic potential of other nickel
compounds remains an important area for further investigation. Some biochemi-
cal and in vitro toxicological studies seem to indicate the nickel ion as a
potential carcinogenic form of nickel and nickel compounds. If this is true,
all nickel compounds might be potentially carcinogenic, with potency differ-
ences related to their ability to enter and make the carcinogenic form of
nickel available to a susceptible cell. However, at the present time neither
the bioavailability nor the carcinogenesis mechanism of nickel compounds is
well understood.
Estimates of carcinogenic risk to humans from exposure via inhalation of
nickel refinery dust and nickel subsulfide have been calculated from cancer
epidemiologic studies. The quantitative incremental unit risk for nickel
refinery dust is 2.4 x Iff4 (pg/m3)'1; the quantitative unit risk estimate for
nickel subsulfide is twice that for nickel refinery dust. Comparing the potency
of nickel subsulfide to 55 other compounds that the Environmental Protection
Agency has evaluated as suspect or known human carcinogens, nickel subsulfide
would rank between the second and third quartiles.
8-232
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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;
National Academy of Sciences, 1975), owing in part to the technical difficul-
ties of controlling nickel intake because of its ubiquity. Later studies
demonstrated adverse effects of nickel deprivation in various animal models,
including chicks, cows, goats, minipigs, rats, and sheep.
Nielsen and Higgs (1971) showed a nickel-deficiency syndrome in chicks fed
nickel at levels of 40 to 80 ppb (control diet: 3 to 5 ppm) characterized by
swollen hock joints, scaly dermatitis of the legs, and fat-depleted livers.
Sunderman et al. (1972) observed ultrastructural lesions such as perimitochon-
drial 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 (Spears, 1984; Spears et al., 1984; Anke et al., 1974). Rats main-
tained on nickel-deficient diets through three successive generations showed a
16 percent and 26 percent weight loss in the first and second generations,
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
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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 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, 1984; Spears and
Hatfield, 1977). Spears and Hatfield (1977) demonstrated disturbances in
metabolic parameters in lambs maintained on a low-nickel diet (65 ppb), includ-
ing 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) found that a mutant strain of
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Aspergillis nidulans, which is urease-deficient, requires nickel II for resto-
ration 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) studied the activation of the
calmodulin-dependent phosphoprotein phosphatase, calcineurin, by various
divalent cations. Activation of calcineurin by nickel II was observed in the
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 bacte-
ria that mediate the Knall gas reaction (2H2 + 02< + 2H20) (Albrecht et al.,
1982), (2) the sulfate-reducing bacterium Desulfovibrio gigas (Legal! et al.,
1982), and (3) the enzyme carbon monoxide dehydrogehase in acetogenic bacteria
(Drake, 1982). Furthermore, a number of studies have established that nickel
is the core metal in the tetrapyrrole, Factor F43Q (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 )jg 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
11 i/iln. hydr°9enase from methanobacterium thermo-autotrophicum. FEBS
J.4U: oJ.l~.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
^^rig1""! Pasteurianum and Clostridium thermoaceticum. J. Bacteriol
149: 561-566. " -
Fishbein, W.
natural
35: 1680.
N.; Smith, M. J.; Nagarajan, K.; Scurzi, W. (1976) The first
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King, M.; Lynn, K. K.; Huang, C. (1985) Activation of the calmodulin-dependent
pnosphoprotein phosphatase by nickel ions. In: Brown, S. S.; Sunderman F
W., Jr., eds. Progress in nickel toxicology: proceedings of the third
™;;!rna,?lonal conference on nickel metabolism and toxicology: September
1984; Paris, France. Oxford, United Kingdom: Blackwell Scientific
Publications; 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 qiqas. 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.
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(1975) Nickel. Washington, DC: National Academy
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vanadium and their possible nutritional significance. In: Draper, H. H.
ed. Advances in nutrition research, v. 3. New York, NY: Plenum-
pp. 157-172.
Nielsen, F.
21-41.
H. (1984) Ultratrace elements in nutrition. Ann. Rev. Nutr. 4:
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conference on trace substances in environmental health]; June; Columbia,
MO. Columbia, MO: University of Missouri-Columbia; pp. 241-246.
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Nielsen, F. H.; Ollerich, D. A. (1974) Nickel: A new essential trace element.
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Nielsen, F. H.; Myron, D. R.; Givand, S. H.; Zimmerman,.!. 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.
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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) Veraenderungen 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
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levels. J. Nutr. 104: 239-243.
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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,
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Thomson, A. J. (1982) Proteins containing nickel. Nature (London) 298: 602-603.
U.S. GOVERNMENT PRINTING OFFICE : 1986-646-116/40653
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