United States
Environmental Protection
Agency
Office of Health and
Environmental Assessment
Washington, DC 20460
EPA-600/8-83-012
May 1983
External Review Draft
Research and Development
Health Assessment
Document for
Nickel
Review
Draft
(Do Not
Cite or Quote)
NOTICE
This document is a preliminary draft. It has not been formally
released by EPA and should not at this stage be construed to
represent Agency policy. It is being circulated for comment on its
technical accuracy and policy implications.
-------
REVIEW DRAFT EPA-600/8-83-012
DO NOT CITE OR QUOTE May 1983
HEALTH ASSESSMENT DOCUMENT FOR NICKEL
May, 1983
NOTICE
This document is a preliminary draft. It has not been formally released by EPA
and should not at this stage be construed to represent Agency policy. It is
being circulated for comment on its technical accuracy and policy implications.
U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
ENVIRONMENTAL CRITERIA AND ASSESSMENT OFFICE
RESEARCH TRIANGLE PARK, NORTH CAROLINA 27711
012NIZ/C 3-21-83
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The authors of this document are:
Dr. Paul Mushak
University of North Carolina
Chapel Hill, North Carolina
Dr. Annemarie Crocetti
New York Medical College
New York, New York
Donna J. Sivulka
Environmental Criteria and Assessment Office
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina
The cancer risk assessment was written by:
Dr. Steven Bayard
Carcinogen Assessment Group
U.S. Environmental Protection Agency
Washington, D.C.
U,S. Environn-cn^:' rrctccilon Agency
Project Manager:
Donna J. Sivulka
Environmental Criteria and Assessment Office
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina
n
012NIZ/C 3-21-83
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DISCLAIMER
This report is an external draft for review purposes only and does not
constitute Agency policy. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
m
012NIZ/C _, 3-21-83
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PREFACE
The Environmental Criteria and Assessment Office, 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 is qualitatively 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.
012NIZ/C 3-21-83
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TABLE OF CONTENTS
LIST OF TABLES viii
LIST OF FIGURES x
1. INTRODUCTION.
2. SUMMARY AND CONCLUSIONS 3
2.1 BIOLOGICAL SIGNIFICANCE AND ADVERSE HEALTH EFFECTS OF NICKEL 3
2.1.1 Nickel Metabolism 3
2.1.2 Subcellular and Cellular Aspects of Nickel Toxicity. 4
2.1.3 Systemic Toxicity of Nickel in Man and Animals 5
2.1.4 Nickel Carcinogenesis 6
2.1.5 Dermatological Aspects of Nickel 8
2.1.6 Nickel as an Essential Element 9
2.2 EPIDEMIOLOGICAL ASPECTS OF NICKEL1 S EFFECTS 10
2.2.1 Nickel in Blood 10
2.2.2 Nickel in Urine 11
2.2.3 Nickel in Human Hair 11
2.2.4 Nickel Exposure and Nickel Hypersensitivity 12
2.2.5 Human Carcinogenicity of Nickel 12
2. 3 HUMAN HEALTH RISK ASSESSMENT OF NICKEL 13
2.3.1 Exposure Aspects 13
2.3.2 Health Effects Summary 14
2.3.3 Dose-Effect and Dose-Response Relationships of
Nickel in Man 14
2.3.4 Populations at Risk 16
2.3.5 Numbers of the U. S. Population at Risk 16
3. NICKEL BACKGROUND INFORMATION 18
3.1 CHEMICAL/PHYSICOCHEMICAL ASPECTS 18
3. 2 ENVIRONMENTAL CYCLING OF NICKEL 19
3.3 LEVELS OF NICKEL IN VARIOUS MEDIA 21
3.3.1 Levels of Nickel in Ambient Air 21
3.3.2 Nickel in Drinking Water 25
3.3.3 Nickel in Food 26
3.3.4 Nickel in Soil 28
3.3.5 Nickel in Cigarettes 29
4. NICKEL METABOLISM IN MAN AND ANIMALS 30
4.1 ROUTES OF NICKEL ABSORPTION 30
4.1.1 Nickel Absorption by Inhalation 30
4.1.2 Gastrointestinal Absorption of Nickel 33
4.1.3 Percutaneous Absorption of Nickel 34
4.1.4 Transplacental Transfer of Nickel 35
4.2 TRANSPORT AND DEPOSITION OF NICKEL IN MAN AND EXPERIMENTAL
ANIMALS 36
4. 3 EXCRETION OF NICKEL IN MAN AND ANIMALS 40
4.4 FACTORS AFFECTING NICKEL METABOLISM 41
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TABLE OF CONTENTS (continued)
Page
5. NICKEL TOXICOLOGY 43
5.1 ACUTE EFFECTS OF NICKEL EXPOSURE IN MAN AND ANIMALS 43
5.1.1 Human Studies 43
5.1.2 Animal Studies 44
5.2 CHRONIC EFFECTS OF NICKEL EXPOSURE IN MAN AND ANIMALS 44
5.2.1 Nickel Carcinogenesis 44
5.2.1.1 Experimental Animal Studies 46
5.2.1.2 Clinical Studies 53
5.2.1.3 Epidemiological Studies 53
5.2.1.4 In Vitro/In Vivo Correlates of Nickel
Carcinogenesis 65
5.2.2 Nickel Mutagenicity 68
5.2.2.1 Nickel Mutagenesis in Experimental
Systems 68
5.2.3 Nickel Allergenicity 71
5.2.3.1 Clinical Aspects of Nickel Hyper-
sensitivity 72
5.2.3.2 Epidemiological Studies of Nickel
Dermatitis 76
5.2.3.2.1 Nickel sensitivity and
contact dermatitis 76
5.2.3.2.2 Sensitivity to nickel in
prostheses 80
5.2.3.3 Animal Studies of Nickel Sensitivity 82
5.2.4 Nickel Teratogenicity and Other Reproductive
Effects 83
5.2.4.1 Generalized Embryotoxicity of Nickel
Compounds 86
5.2.4.2 Gametotoxic Effects of Nickel 88
5.2.5 Other Toxic Effects of Nickel 89
5.2.5.1 Respiratory Effects of Nickel 89
5.2.5.2 Endocrine Effects of Nickel 90
5.2. 5. 3 Renal Effects of Nickel 92
5.2.5.4 Miscellaneous Toxic Effects of Nickel 92
5.3 INTERACTIVE RELATIONSHIPS OF NICKEL WITH OTHER FACTORS 92
6. NICKEL AS AN ESSENTIAL ELEMENT 95
7. HUMAN HEALTH RISK ASSESSMENT FOR NICKEL 97
7.1 AGGREGATE HUMAN INTAKE OF NICKEL 97
7.2 SIGNIFICANT HEALTH EFFECTS OF NICKEL FOR HUMAN
RISK ASSESSMENT 98
7.3 DOSE-EFFECT AND DOSE-RESPONSE RELATIONSHIP OF NICKEL 100
7.3.1 Indices of Exposure 101
7.3.2 Effect and Dose-Response Relationships 106
7.4 POPULATIONS AT RISK 108
7.4.1 Numbers of the U.S. Population in Special
Risk categories 109
vi
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TABLE OF CONTENTS (continued)
Page
7.5 CURRENT REGULATIONS AND STANDARDS 109
7.5.1 Occupational Exposure 109
7.5.2 Dermal Exposure to Nickel in the Environment 110
7.5.3 Exposure to Nickel in Ambient Water 110
7.5.4 Exposure to Nickel in Ambient Air 112
7.6 QUANTITATIVE ESTIMATION OF CANCER RISK FOR NICKEL 112
7.6.1 Introduction 112
7.6.2 Procedures for Determination of Unit Risk from
Animal Data 113
7.6.2.1 Description of the Low Dose Animal-to-
Human Extrapolation Model 114
7.6.2.2 Selection of Animal Data 116
7.6.2.3 Calculation of Human Equivalent Dosages
from Animal Data 117
7.6.2.3.1 Oral Exposure 117
7.6.2.3.2 Inhalation Exposure 119
7.6.2.3.3 Adjustment of Dose for less
than Lifespan Duration of
Experiment 121
7.6.2.4 Calculation of the Unit Risk 121
7.6.2.5 Interpretation of Quantitative Estimates... 122
7.6.2.6 Alternative Methodological Approaches 123
7.6.3 Cancer Risk Unit Estimates Based on Animal Studies.. 123
7.6.4 Model for Estimation of Unit Risk Based on
Human Data 129
7.6.5 Cancer Risk Estimates Based on Human Studies 130
7.6.6 Comparison of Results 135
7.6.7 Relative Potency 135
8. REFERENCES 142
012NIZ/C
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LIST OF TABLES
Table Page
3-1 Urban cumulative frequency distributions of quarterly composit
ambient air nickel levels 22
3-2 Nonurban cumulative frequency distributions of quarterly
composit ambient air nickel levels of quarterly composite
samples 23
3-3 Cumulative frequency distribution of individual 24-hour
ambient air nickel levels 24
3-4 Nickel levels in U.S. drinking water, 1969-1970 25
3-5 Nickel levels of drinking water of 10 largest U.S. cities 26
3-6 Nickel content of various classes of foods in U.S. diet 27
4-1 Serum nickel in healthy adults of several species 37
4-2 Tissue distribution of nickel (II) after parenteral
administration 39
5-1 Acute pulmonary effects of nickel carbonyl exposure in
animals 45
5-2 Experimental models of nickel carcinogenesis 47
5-3 Histopathological classification of cancer of the lung and
nasal cavities in nickel workers 54
5-4 Number of men first employed at Clydach nickel refinery,
Wales, at different periods and mortality observed and
expected from al 1 causes 56
5-5 Mortality by cause and year of first employment, Clydach
nickel refinery, Wales 57
5-6 Chronological changes in the feed material at Clydach nickel
refi nery, Wai es 58
5-7 Smoking and tumor incidence in workers at the Falconbridge
nickel refinery 60
5-8 Average and high histological scores by age groups and
worki ng categor i es 62
5-9 Nickel concentrations in nasal mucosa in nickel workers,
retired nickel workers and controls 63
5-10 In vitro / in vivo correlates of nickel carcinogenesis 66
5-11 foites of positive reactors in large patient and population
studies 78
5-12 North American Contact Dermatitis Group patch test results
for 2.5 percent nickel sulfate in ten cities 79
5-13 Hand eczema in persons sensitive to nickel 80
7-1 Normal blood nickel concentrations 103
7-2 Nickel concentrations in human urine 105
7-3 Nickel concentrations in urine specimens from workers
in twelve occupational groups 107
7-4 Inhalation experiments with nickel compounds 124
7-5 Hyperplastic and neoplastic changes in lungs of rats
exposed to nickel sulfide 128
vm
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LIST OF TABLES (cont.)
Table Page
7-6 Estimation of fraction of lifetime exposed to nickel in
the workplace, Clydach, Wales 133
7-7 Human cancer unit risk estimates from nickel exposure 137
7-8 Relative carcinogenic potencies among suspect carcinogens
evaluated by the Carcinogen Assessment Group 138
IX
012NIZ/C 3-21-83
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LIST OF FIGURES
Figure Page
5-1 The scatter of occurrence of lung tumors related to time of
first employment and time of diagnosis of tumor 61
5-2 The correlation between the nickel concentrations in the
mucosa of 15 retired workers and the number of years after
reti rement 64
7-1 Histogram representing the frequency distribution of the
potency indices of 53 suspect carcinogens evaluated by the
Carcinogen Assessment Group 141
012NI2/C 3-21-83
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ACKNOWLEDGMENTS
The following individuals attended a review workshop on an early draft
of this document and submitted valuable comments:
Dr. Thomas Clarkson
Department of Environmental Health Sciences
University of Rochester
Rochester, New York
Dr. Annemarie Crocetti
New York Medical College
New York, New York
Dr. Philip Enterline
Department of Biostatisties
Graduate School of Public Health
University of Pittsburgh
Pittsburgh, Pennsylvania
Dr. Paul Hammond
Kettering Laboratory
University of Cincinnati
Cincinnati, Ohio
Dr. Dinko Kello
Institute for Medical Research
Zagreb, Yugoslavia
Dr. Paul Mushak
Department of Pathology
University of North Carolina
Chapel Hill, North Carolina
Dr. Magnus Piscator
Karolinska Institute
Department of Environmental Hygiene
Stockholm, Sweden
Dr. Samuel Shibko
Division of Toxicology
U.S. Food and Drug Administration
Washington, D.C.
In addition, there are several scientists who contributed valuable
information and/or constructive criticism to interim drafts of this report.
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012NIZ/C 3-21-83
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Of specific note are the contributions of: Gerald Akland, Mike Berry,
Joseph Borzelleca, Christopher DeRosa, Lester Grant, Bernard Haberman,
Ernest Jackson, Donna Kuroda, Si Duk Lee, Debdas Mukerjee, Charles Nauman,
John Schaum, Steven Seilkop, Robert Shaw, William Sunderman, and Stuart Warner.
xn
012NIZ/C 3-21-83
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1. INTRODUCTION
This document is concerned with the current data base for nickel toxi-
cology most relevant for assessing associated human health risks and in-
cludes information on the metabolism of nickel as it relates to the expres-
sion of nickel toxicity or other aspects of potential regulatory concern.
This document is not meant to be an exhaustive review of all available
literature regarding the toxicity of nickel.
The second chapter of the document provides a concise summary of the
information contained within the text of the report.
The third chapter provides background information, including dis-
cussion of: physical and chemical properties of nickel; the environmental
cycling of nickel; and levels of nickel in various media, e.g. air, water,
food and soil.
The fourth chapter is concerned with metabolism and includes infor-
mation on absorption, distribution, excretion and conditions influencing
nickel movement i_n vivo.
The fifth chapter dealing with nickel toxicology, is divided first
into experimental and clinical data for a variety of adverse effects in-
cluding carcinogenicity. The latter part is concerned with epidemiological
studies reported mainly for nickel carcinogenicity and its role as a potent
allergen.
There is growing evidence that nickel is an essential element in a
number of animal species, and this may also be the case for man. Since
this property necessitates that there be some minimal systemic intake of
the element, data on nickel essentiality must be considered in any regula-
tory framework for exposure control and, therefore, this subject is dis-
cussed in the sixth chapter.
As indicated in the title, the report is selective in that the focus
is on information most germane to assessing human health risks arising from
nickel exposure. As such, the seventh chapter deals with the most pertinent
information necessary for determining human health risk. This section
addresses: (1) the aggregate human intake of nickel; (2) the dose-effect
and dose-response relationship of nickel; (3) populations at risk; (4)
current regulations and standards; and (5) a quantitative cancer risk
012NIX/A 1 3/21/83
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PRELIMINARY DRAFT
assessment for exposure to nickel in the ambient air. This section calls
upon information presented within the previous sections for its analyses of
the human health risk to nickel.
Structurally, this report is based on several documents primarily prepared
by the present authors for the U.S. Environmental Protection Agency including
the Ambient Water Quality Criteria report for nickel. Information has been
updated where appropriate.
012NIX/A 2 3/21/83
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PRELIMINARY DRAFT
2. SUMMARY AND CONCLUSIONS
2.1 BIOLOGICAL SIGNIFICANCE AND ADVERSE HEALTH EFFECTS OF NICKEL
2.1.1 Nickel Metabolism
Routes of nickel intake for man and animals are inhalation, ingestion
and percutaneous absorption. Parenteral exposure is mainly of importance
in experimental animal studies.
The relative amount of inhaled nickel which is absorbed from various
compartments of the pulmonary tract is a function of both chemical and
physical forms. Pulmonary absorption into the blood stream is probably
greatest for nickel carbonyl vapor, with animal studies suggesting that
about half of the inhaled amount is absorbed. Nickel in particulate matter
is absorbed from the pulmonary tract to a considerably lesser degree than
nickel carbonyl. Smaller particles are lodged deeper in the respiratory
tract and the relative absorption is greater than with larger particles.
Lung models and limited experimental data suggest several percent absorp-
tion. While insoluble nickel compounds may undergo limited absorption from
the respiratory tract, their relative insolubility may have implications
for the carcinogenic character of nickel, as will be noted below.
Absorption from the gastrointestinal tract of dietary nickel is on the
order of one to ten percent in man and animals from both foodstuffs and
beverages.
Percutaneous absorption of nickel occurs and is related to nickel-in-
duced hypersensitivity and skin disorders. The extent to which nickel
enters the bloodstream by way of the skin cannot be stated at the present
time.
Absorbed nickel is carried by the blood, although the extent of parti-
tioning between erythrocyte and plasma cannot be precisely stated. In any
event, plasma or serum levels reflect the blood burden. Normal serum
nickel values in man are 0.2 - 0.3 ug/dl. Albumin is the main macromole-
cular carrier of nickel in a number of species, including man, while in man
and rabbit there also appear to be nickel-specific proteins.
Tissue distribution of absorbed nickel appears to be dependent on the
route of intake. Inhaled nickel carbonyl leads to highest levels in lung,
brain, kidney, liver, and adrenals. Parenteral administration of nickel
012NIX/A 3 3/21/83
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PRELIMINARY DRAFT
salts usually results in highest levels in the kidney, with significant
uptake shown by endocrine glands, liver, and lung.
Based on animal studies, nickel appears to have a very short half-time
in the body, several days, with little evidence for tissue accumulation.
The main excretory route of absorbed nickel in man and animals appears
to be through the urine, with biliary excretion also occurring in experi-
mental animals. 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.
A number of disease states or other physiological stresses can influ-
ence nickel metabolism in man. In particular, heart and renal disease,
burn trauma, and heat exposure can either raise or lower serum nickel
levels.
2.1.2 Subcellular and Cellular Aspects of Nickel Toxicity
Nickel, as the divalent ion, is known to bind to a variety of bio-
molecular 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 j_n vivo and _in
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 carbohy-
drate metabolism and enzymes that mediate transmembrane transport, such as
ATPase.
A number of ultrastructural alterations are seen in cellular organ-
elles 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 infections.
Nickel-induced human lymphocyte transformation has been studied as a
sensitive jn vitro screening technique for nickel hypersensitivity and this
procedure appears to be a reliable alternative to classical patch testing.
012NIX/A 4 3/21/83
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PRELIMINARY DRAFT
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.
2.1.3 Systemic Toxicity of Nickel in Man and Animals
The toxicity of nickel to man and animals is a function of the
chemical form of the element and the route of exposure.
For oral intake, nickel metal is relatively nontoxic, while nickel
carbonate, nickel soaps, or nickel catalyst show effects only when dietary
composition is at or exceeds 1000 ppm.
Exposure to nickel by inhalation, parenteral administration, or cutan-
eous contact is of considerably more significance to the picture of nickel
toxicology.
In terms of human health effects, probably the most acutely toxic
nickel compound is nickel carbonyl Ni(CO),. Exposure is usually through
accidental release and inhalation by nickel workers. Acute nickel carbonyl
poisoning is clinically manifested by both immediate and delayed symptomo-
logy. With the onset of the delayed, insidious symptomology there is
constrictive chest pain, dry coughing, hyperpnea, cyanosis, occasional
gastrointestinal symptoms, sweating, visual disturbances, and severe weak-
ness. 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 surviving an acute episode of exposure are frequently left with
pulmonary fibroses.
From the literature, little is known about the effect of chronic
nickel carbonyl exposure. In one reported case, such exposure was associ-
ated with asthma and Loffler's syndrome.
Adverse pulmonary effects for other nickel forms in occupational
settings have been reported. Chronic rhinitis and sinusitis have been
observed in workers engaged in nickel electroplating operations where the
nickel species is nickel salt aerosol.
There is surprisingly little information in the literature about the
effects of nickel on reproduction and development. Studies with both
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PRELIMINARY DRAFT
animals and humans indicate that nickel crosses the transplacental barrier
and is taken up by the conceptus.
While gametotoxic effects of nickel have been demonstrated in animals,
i.e., spermatogenesis impairment, there is no information on such exposures
in man, particularly nickel workers.
There appear to be reproductive effects in animals after exposure to
nickel given orally or parenterally, in the form of reduced litter size and
decreased viability of newborn.
Teratogenic effects of nickel compounds have been noted in experimental
animals, but have not been conclusively reported in man.
A number of effects of nickel on endocrine-mediated physiological
processes have been observed. In carbohydrate metabolism, nickel induces a
rapid transitory hyperglycemia in rats, rabbits, and domestic fowl after
parenteral 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.
Nickel-induced nephropathy in man or animals has not been widely docu-
mented. Pathologic alterations of renal tubules and glomeruli have been
seen in rats exposed to nickel carbonyl, while ingestion of nickel chloride
by rats produces ami no aciduria and proteinuria. Renal effects in man have
mainly been clinically detected in acute exposures to nickel carbonyl.
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 hyper-
pi asi a in bone marrow.
2.1.4 Nickel Carcinogenesis
A large number of experimental, clinical, and epidemiological studies
have been carried out over the years directed to the role of nickel com-
pounds in occupational and experimental carcinogenesis. Most of these
studies have centered on a limited number of specific nickel compounds.
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PRELIMINARY DRAFT
One can state generally that, of the compounds tested, most soluble
nickel salts are noncarcinogenic while insoluble forms--such as metallic
nickel, nickel subsulfide, and nickel oxide dusts--are variably carcinogenic.
Among the insoluble compounds of nickel, the most carcinogenic form appears
to be nickel subsulfide. However, there are exceptions to this generali-
zation and it is possible that several mechanisms may exist for the mani-
festation of nickel carcinogenesis.
Various experimental models of nickel carcinogenesis have been des-
cribed in the literature in the form of sarcomas, carcinomas, and mesothe-
liomas. In most of these animal models, sarcomas are elicited at the
injection site of insoluble nickel dust, while injected nickel acetate
induces lung adenocarcinomas and injected nickel carbonyl produces liver
and kidney sarcomas.
Experimental data exist that demonstrate that nickel has a synergistic
effect on the carcinogenicities of polycyclic aromatic hydrocarbons in
laboratory animals and that it synergizes the activity of at least one
virus, i.e. Newcastle Disease Virus.
Statistically excessive respiratory tract cancers in workmen at nickel
refineries have been widely and conclusively documented. There is wide
agreement that these are principally the effect of inhalation of respirable
particles of metallic nickel, nickel subsulfide, nickel oxide, and nickel
carbonyl. According to the International Agency for Research in Cancer:
"Epidemiological studies conclusively demonstrate an excessive risk of
cancer of the nasal cavity and lung in workers at nickel refineries. It is
likely that nickel in some form(s) is carcinogenic to man."
Since respiratory tract cancers have occurred in industrial facilities
that are diverse metallurgically in their operations, human carcinogenicity
probably resides in several compounds of nickel. This would certainly be
consistent with experimental models.
Other excess cancer risk categories involving nickel workers include
laryngeal, gastric, soft tissue, and renal carcinomas, but these types are
not as consistently seen as are the respiratory cancers.
As noted, nickel in the workplace has caused nasal cavity cancers, but
the greater proportion of relatively smaller-sized particles in the general
ambient environment compared to the workplace would likely lead to a greater
particle deposition in the lungs versus the nasal cavities. Thus, while
012NIX/A 7 3/21/83
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PRELIMINARY DRAFT
estimates of nasal cancer have been calculated, they have been presented
primarily for comparative purposes. An estimate of the relative carcinogenic
potency of nickel to other compounds has been calculated solely on lung and
larynx cancer.
Two unit risk estimates are made for the lung cancer risk associated
3
with lifetime exposure to 1 ug/m of nickel in the ambient air. The validity
of these estimates depends on several factors -- the accuracy of exposure
estimates in the workplace, the similarity of nickel compounds in the
workplace with those in the ambient air, the similarity of the physical
forms of nickel in the two environments, and the validity of the extra-
polation models used. All of these are very significant factors affecting
the accuracy of a quantitative risk estimate or a range of estimates as has
been attempted. The fact that most daily nickel exposure is not via inhal-
ation but by the oral route suggests that some special, yet unknown,
mechanism exists associating the physical form of the nickel with cancer of
the respiratory tract.
Given these caveats, two unit risk extrapolations are made for nickel
exposure in the ambient air. One is an animal-to-man extrapolation and the
other is based on human occupational studies. Based on human occupational
studies the estimates of respiratory cancer associated with a lifetime
3 -5 ~4
exposure to 1 |jg/m of nickel ranges from 7.5x10 to 5.8x10 . The upper
-3
limit unit risk estimate based on animal-to-man extrapolation is 4.8x10
3
for a lifetime exposure to 1 ug/m of nickel sulfide.
The relative potency index for nickel compounds based on lung cancer
in occupational studies by Pedersen and by Doll is 7xlO+ . This ranks in
about the middle of the third quartile among the 53 substances which the
EPA's Carcinogen Assessment Group has evaluated as suspect carcinogens.
No quantitative assessment has been attempted for nickel compounds
taken orally because there is no direct evidence that nickel compounds are
carcinogenic when ingested. On the other hand, no significant nickel
feeding studies have been done; yet, dietary nickel remains the largest
source of nickel exposure. This area remains a very significant unknown.
2.1.5 Dermatological Aspects of Nickel
Nickel dermatitis and other dermatological effects of nickel have been
extensively documented in both nickel worker populations and populations at
large.
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PRELIMINARY DRAFT
Although the frequency of nickel dermatitis has abated considerably
among nickel workers with advances in control technology and industrial
medicine, it may still be a problem in electroplating shops.
Nonoccupational exposure to nickel leading to dermatitis includes
nickel-containing jewelry, coins, tools, cooking utensils, stainless-steel
kitchens, prostheses, and clothing fasteners.
Clinically, nickel dermatitis is usually manifested as a papular or
papulovesicular dermatitis with a tendency toward lichenification, having
the characteristics of atopic rather than eczematous dermatitis.
Conflicting data in the literature have muddied any clear relationship
between atopic dermatitis and that elicited by nickel.
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 the 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 appears to be called for.
Nickel-containing implanted prostheses may provoke flare-ups of nickel
dermatitis in nickel-sensitive individuals. The extent to which this is a
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
diffusion of nickel through the skin and subsequent binding of nickel ion.
Useful animal experimental models of nickel sensitivity are few and
when conducted, have only been under very specialized conditions.
2.1.6 Nickel as an Essential Element
There is a growing body of literature which establishes an essential
role for nickel, at least in experimental animals.
One key criteria for element essentiality-existence of specific
nickel-deficiency syndromes—is reasonably satisfied for nickel. Various
researchers have shown different systemic lesions in various animals deprived
012NIX/A 9 3/21/83
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PRELIMINARY DRAFT
of dietary nickel. Nickel deprivation has an effect on body weight, repro-
ductive capability, and viability of offspring and induces an anemia through
reduced absorption of iron.
Jack bean urease (and possibly rumen microbial urease) has been shown
to be a nickel-requiring enzyme.
Further information in support of nickel as an essential element in
animals is the apparent existence of a homeostatic mechanism for regulating
nickel metabolism and the existence of nickel proteins in man and rabbit.
2.2 EPIDEMIOLOGICAL ASPECTS OF NICKEL'S EFFECTS
Studies on the impact of nickel on human populations are limited both
as to number and the quality of experimental design. Much of the informa-
tion of an epidemiological nature has been gathered in occupational settings,
and it appears that only more recent data are sufficiently complete in
terms of air nickel levels or indices of internal exposure. A major problem
has been the quality of analytical methodology in earlier reports and only
recently have acceptable methods evolved for measurements of nickel.
Studies of nonoccupational groups with reference to nickel exposure
have been especially sparse. Some reports involve other pollutants, and
the experimental designs reflect stratification of groups on the basis of
exposure to other agents.
2.2.1 Nickel in Blood
Normal blood nickel levels, as measured in plasma or serum, in unex-
posed populations in the United States and elsewhere appear to be 0.2 to
0.3 pg/dl.
Exposed populations, mainly occupational study groups, have blood
nickel values that are considerably above the normal figure, up to 3- to
4-fold. In a study comparing a control U.S. population and a Canadian
group living in the vicinity of a nickel-processing complex, the mean value
for the latter was about twice that of the reference mean level.
Complicating the evaluation of the levels of blood nickel in exposure
categories are questions about smoking status, the nature of the nickel
compounds in various workplace settings and the relative health status of
subjects.
It does appear that blood nickel levels reflect intensity of exposure,
rising rapidly with increase in exposure and falling correspondingly when
such exposure is reduced. Thus, blood nickel levels are mainly of value in
assessing the intensity of relatively recent or ongoing exposure.
012NIX/A 10 3/21/83
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2.2.2 Nickel in Urine
Problems with the assessment of urinary nickel in human subject groups
overlap those for human blood nickel values, with an added problem of the
feasible utility of total urinary output or urinary concentration from spot
sampling.
Most studies of nonexposed subjects indicate urinary excretion of 2 to
3 ug nickel/day.
As with blood nickel, one can say generally that occupational exposure
to nickel results in highly variable increases in urinary nickel output.
In particular, nickel refinery workers can show urinary values of several
hundred micrograms per liter.
It should be pointed out that, while average urine or blood nickel
values for an exposure group relfect a given external exposure level, there
is considerable individual variation.
2.2.3 Nickel in Human Hair
Attempts to relate nickel exposure to nickel levels in hair in various
human study groups is complicated by the inherent difficulty of employing
hair as a biological matrix for element assessment. Different laboratories
use different techniques for both sample cleaning and sample collection.
Several studies have reported the relationship of nickel levels in
hair in terms of urban versus rural settings. The data are inconclusive in
demonstrating that hair levels reflect the amount of environmental exposure.
Nickel determinations in hair have not usually been carried out with
industrial populations. In one study where this was done, there is no
question that the levels of nickel in hair were markedly elevated over that
of a reference group.
There are very few data concerning nickel tissue levels and total body
burden in the literature. One estimate is that the total nickel burden in
man is about 10 ug.
One can generally state that in nonoccupational groups, tissue levels
of nickel are very low, in many cases below the detection capability of the
method being used. Lung, liver, and kidney do appear to be somewhat higher
in nickel than other tissues. In most of these studies, smoking status was
not taken into account nor was the existence of disease states which might
alter the levels of nickel in tissues.
012NIX/A 11 3/21/83
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PRELIMINARY DRAFT
Information on tissue nickel levels for occupational categories are
also limited. In cases of fatal nickel carbonyl poisoning, highest levels
are seen in the lung, with lesser amounts in the kidney, liver, and brain.
2.2.4 Nickel Exposure and Nickel Hypersensitivity
There are essentially no studies of general populations which relate
nickel exposure to the prevalence of nickel-related skin disorders, such as
contact dermatitis. Much of the existing information evolves from either
clinical or occupational groups having clinically demonstrable nickel
hypersensitivity.
In a 1972 survey of a clinical population representing mainly the
United States, the North American Contact Dermatitis Group reported that
the prevalence for positive nickel reactions was higher for females than
males, and the overall reaction rate was 11.2 percent. On a relative scale
with other allergens, nine other agents had higher positive reaction rates.
The above survey and other limited data suggest that nickel sensitivity
in the general population is more prevalent among women.
2.2.5 Human Carcinogem'city of Nickel
Epidemiologic data on the cardnogenicity of nickel has been reported
for occupationally exposed nickel refinery workers in a number of countries.
These studies have been reviewed and critiqued in other documents and there
appears to be no doubt that increased cancer risk for the respiratory tract
and nasal cavities exists in various operation categories for nickel re-
finery workers exposed to nickel subsulfide and nickel oxide dust, vapors
of nickel carbonyl, and aerosols of soluble nickel salts.
Retrospectively, the relative cancer risk of respiratory tract cancers
for nickel refinery workers was greatest prior to early changes in process
and exposure abatement technology. Nevertheless, even with improved condi-
tions some increased risk has continued, at least into the recent past.
Few of the occupational carcinogenesis studies of nickel workers have
controlled for other factors which may influence the degree of cancer risk.
One recent study has demonstrated that cigarette smoking among workers at a
Norwegian nickel operation probably enhances the overall respiratory cancer
risk, suggesting a synergistic effect between nickel and the polycyclic
hydrocarbons.
012NIX/A 12 3/21/83
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The cancer risk status in workers exposed to nickel in work sites
other than nickel refineries is not established at this time. A recent
study of workers in an aircraft engine factory failed to demonstrate an
increased relative cancer risk for workers exposed to nickel compounds. In
o
this case, the atmospheric nickel levels were below 1 |jg/m .
With regard to the general population, there are no data that suggest
whether low-level nickel exposure does or does not lead to increased cancer
risk. Such increased relative risk could be seen for rare tumor sites such
as nasal cancers, but for the common respiratory cancers would never be
statistically significant at ambient levels. Parenthetically, the lack of
nasal cavity cancer deaths in the cigarette smoking population (with relatively
high nickel intake) indicates that different forms of nickel exist in
nickel refineries and cigarette smoke.
2.3 HUMAN HEALTH RISK ASSESSMENT OF NICKEL
2.3.1 Exposure Aspects
In terms of routes of nickel exposure of relevance to the general U.S.
population, dietary sources are the main factor for nickel intake in man,
daily ingestion being on the order of 300 to 600 )jg nickel.
Percutaneous absorption of nickel from external contact with a wide
variety of nickel-containing commodities is of further significance for
those individuals with hypersensitivity to nickel.
In nonsmokers, the amounts of ambient air nickel entering the respi-
ratory tract are quite small, an average of 0.2-0.4 yg/day (assuming a
3
daily ventilation rate of 20 m ). By contrast, cigarette smoking can contri-
bute the major fraction of inhaled nickel, with estimates that smoking two
packs of cigarettes will result in the inhalation of 3 to 15 |jg nickel daily,
approximately 10 to 40 times normal ambient air exposure. The possible amount
of nickel inhaled through exposure to passive smoke is presently unknown and
needs further consideration.
Levels of nickel in drinking water are also very low. A national
survey for 1969-70 that involved 969 water supplies in the United States
yielded a mean content of 4.8 ug nickel/£ water.
Nickel levels in soil of relevance to this section in terms of impact
on man's terrestrial food chain vary considerably. Of less importance than
the nickel content are soil type, soil pH, and classes of plants grown on
the soil. Soil contamination occurs by virtue of man's activities and
012NIX/A 13 3/21/83
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increased nickel-soil values have been obtained near roadways and nickel-
emitting industrial operations. A potential source of increase in soil-
nickel burden has to do with increased land spreading of municipal sewage
sludges on agricultural lands.
2.3.2 Health Effects Summary
A variety of TJQ vitro and jm vivo effects of nickel compounds have
been documented in experimental animals.
Occupational exposure to various nickel compounds has been associated
with respiratory cancer and noncarcinogenic effects.
With reference to the various nickel-related health effects on the
general population of the United States, nickel hypersensitivity in the
form of contact dermatitis and associated skin disorders is the health
effect of broad concern in this document due to the wide exposure to
numerous nickel-containing commodities.
Some forms of nickel hypersensitivity, such as severe dermatitis, must
be taken as a significant adverse response in terms of limiting activity
and livelihood and predisposing individuals to further complications such
as skin infections.
Nickel hypersensitivity as an underlying condition appears to be irre-
versible, although the frequency of flare-ups of such hypersensitivity may
be ameliorated by limiting any obvious external contact.
2.3.3 Dose-Effect and Dose-Response Relationships of Nickel in Man
Assessment of dose-effect and dose-response relationships for nickel
in man can be framed in the form of several questions:
(1) How do external exposure levels of nickel relate to internal
indices of exposure?
(2) How do these internal indices of exposure relate to the eliciting
and grade severity of critical effect(s) in critical tissue(s)?
(3) Is the information in answer to questions (1) and (2) sufficient
to permit either modeling or statistical refinement of the data, to estimate
what fraction of a study population is apt to develop a particular health
effect at a given level of external exposure?
In general, literature dealing with the magnitude of nickel's effects
on man is meager. This is due, in part, to the perception of nickel as an
agent of lower toxicological potential than elements such as lead-, cadmium
012NIX/A 14 3/21/83
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PRELIMINARY DRAFT
or mercury in terms of chronic general population exposure. Such a percep-
tion is abetted by the fact that much of the literature over the years
dealing with human health effects has appeared in the area of occupational
hygiene.
With regard to dose aspects, the general population of the United
States receives its major external exposure to nickel via ingestion or skin
contact. Nickel inhalation is a comparatively minor source, although the
extent of respiratory intake can be markedly increased in the case of
cigarette smokers.
Of the daily dietary intake of 300 to 600 ug nickel, one to ten per-
cent is absorbed. Thus, 3 to 60 pg can enter the bloodstream from the
gastrointestinal tract. At present, it is not possible to state that
factors such as age or nutritional status affect the extent of absorption.
Urban residents would inhale less than 1 ug nickel daily, of which
some small fraction would be absorbed. Cigarette smoking could increase
this amount considerably, with estimates that smoking two packs of ciga-
rettes leads to inhaling 3 to 15 pg nickel daily, possibly in a form which
would be extensively absorbed into the bloodstream.
Average drinking water levels are about 5 ug/£. A typical consumption
of two liters daily would yield an additional 10 pg of nickel, of which 1
ug could be absorbed.
As summarized earlier, urinary and serum/plasma nickel levels both
appear to be indicators of nickel exposure. Taken collectively, occupa-
tional and limited nonoccupational group studies indicate that both urine
and nickel levels will rise in response to increased nickel exposure and
fall with exposure decrease, reflecting the intensity of relatively recent
or ongoing exposure.
Several factors complicate exposure-physiological level relationships.
In low-to-moderate nickel exposures, apparent homeostatic mechanisms con-
trol internal nickel movement in experimental animals. This may also be
the case in man. Furthermore, nickel levels in media such as serum and
urine change with a number of disease states.
In various experimental animal studies, there generally are demon-
strable gradients in severity of different effects as controllable exposure
levels are increased.
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The corresponding case for man, mainly involving occupational exposure,
permits one to also state generally that the extent of risk for carcinogenic
and noncarcinogenic effects in nickel workers is increased with both the
level of workplace exposure, e.g., respirable nickel, as well as the nature
of the nickel compounds.
For both occupational and nonoccupational population groups it is
difficult, but possible, to calculate the probable frequency of a given
adverse effect at a given external nickel exposure level, i.e., dose-response
curves. In nickel worker studies, there exists incomplete data or uncertain-
ties about the specific chemical composition of nickel compounds in certain
work sites. For nonoccupational groups such as individuals with nickel
hypersensitivity who have skin contact with nickel-containing objects, the
exposure parameter is difficult both to define and to estimate quantita-
tively. Nevertheless, at least for inhalation exposures, ambient air risk
estimates based upon occupational exposure to nickel can be derived.
2.3.4 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 hypersensi-
tivity 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 hypersensitive individuals, women who are housewives seem to
be at particular risk.
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. The possibility of nickel, alone, or in synergism
with other compounds, producing these various respiratory disorders places
cigarette smokers in a potential risk category.
Nickel crosses the placenta! barrier in animals and apparently in man;
thus, exposing the conceptus to nickel. There is no information at present
that nickel exposure i_n utero under conditions of nickel exposure encoun-
tered by pregnant women in the U.S. population leads to adverse effects.
2.3.5 Numbers of the U.S. Population at Risk
No data base exists by which to determine the prevalence of nickel
hypersensitivity in the general U.S. population.
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Cigarette smokers, who may be at potential risk for any nickel-related
respiratory disorders, number 54 million according to the American Cancer
Society's 1982 figures.
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3. NICKEL BACKGROUND INFORMATION
3.1 CHEMICAL/PHYSICOCHEMICAL ASPECTS
Nickel is a silvery metal with an atomic weight of 58.71 (derived from
a composite of five stable isotopes), a melting point of 1455°C and a
boiling point of 2900°C. Nickel is found in nature (along with such ele-
ments as arsenic, antimony, and sulfur) as the ores millerite (sulfide) and
garnierite (silicate), the latter being the most commercially important
form. Nickel is liberated via conversion to the sub-sulfide, Ni~S?, air-
roasted to give nickel oxide, NiO, followed by carbon reduction to the
metal.
In the Mond or carbonyl process (Mond, 1890), impure nickel is reacted
with carbon monoxide at 50°C and ordinary pressures, or nickel-copper matte
is reacted under pressure to give the volatile and highly toxic nickel
carbonyl, Ni(CO)4> which is thermally decomposed at 200°C to yield the
metal in high purity.
The metal itself has good electrical and thermal conductivity pro-
perties and is easily drawn, rolled, forged, and polished. Its inertness
to chemical attack accounts for its commercial value in electroplating.
The chemically most significant form of nickel is the divalent ion,
which occurs in a myriad of simple compounds and coordination complexes.
Of the inorganic derivatives, the insoluble oxides and sulfides and the
soluble salts used in electroplating and other solution processes account
for much of the toxicology associated with nickel.
In the atmosphere, nickel appears as particulate matter of variable
chemical composition with the oxide being a major form from high-temperature
emission sources. Nickel carbonyl is quite labile to decomposition and is
oxidatively decarbonylated in open air (National Academy of Sciences,
1975).
Particulate size is of importance in terms of atmospheric movement,
fallout processes and deposition in the human respiratory tract. In one
report (Natusch et al. , 1974), it was noted that nickel enrichment occurs
in the smaller particulate fraction (< 1 pm) from coal-fired power plants,
smaller particles being not only the most difficult to control but pene-
trating deepest into the lung. A study directed to the particulate size
distribution in dust fall in Seattle, Washington, and San Jose, California,
012NIX/A 18 3/21/83
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PRELIMINARY DRAFT
revealed that the percent of total nickel as a function of size range was:
<43 urn, 27.5 percent; <840 urn, 75 percent, and 840-2,000 urn, 25 percent
(National Academy of Sciences, 1975). More recent data show that ambient
nickel is about equally divided between fine and course cuts approximately
50 percent of the time. The other 50 percent of the time, about twice as
much particulate matter containing nickel is found in the fine fractions.
(Akland, 1981).
In biological systems, the divalent nickel ion readily complexes with
binding groups on various types of biotnolecular species-proteins, peptides,
DNA, amino acids, ATP (through interaction with nitrogen), sulfur and oxy
groups, and such binding plays a role in its pharmacokinetics and toxicity.
These complexes may be six-or four-coordinate.
3.2 ENVIRONMENTAL CYCLING OF NICKEL
Consumption of nickel in the United States for 1979 totalled about
196,000 tons (Predicasts, 1980) of which 70,000 tons were used in stainless
steel production, 41,000 tons were used in nickel alloys (other than steel),
29,000 tons were used in electroplating, 20,000 tons were used in alloy
steel production, and 18,000 tons were used in superalloys.
Of this annual consumption figure, some fraction is dissipated into
various compartments of the environment, although the actual values cannot
be determined from available information. Municipal incineration of general
refuse containing nickel in diverse forms and soluble nickel salts in
effluents dispersed to waters and municipal treatment facilities are two of
the routes of entry. Augmenting such input are atmospheric emissions from
fossil-fueled power plants and residential heating units, the former being
a source of input which may increase in the future due to increased use of
coal to fuel power plants. In addition, it is presently unclear whether
burning wood for home heating purposes significantly contributes to atmos-
pheric nickel emissions. Further research on this topic would be valuable
in light of the increased home use of wood burning as a supplement to
residential heating units.
In wastewaters, industrial sources account for over 50 percent of the
observed nickel while residential sources supply up to 25 percent (Snodgrass,
1980). Industrial hazardous wastes containing nickel include spent plating
baths/sludges from electroplating operations, spent pickle liquors/sludges
from steel finishing operations and nickel carbonyl and nickel cyanide
012NIX/A 19 3/21/83
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PRELIMINARY DRAFT
wastes from smelting and refining operations, powder metallurgy and chemical
plant operations. Over 80 percent of nickel in influents of many waste-
water treatment plants is soluble and removals vary from 10 to 40 percent
(Snodgrass, 1980). The removal mechanism appears to be some uptake by
biological solids of the soluble forms and subsequent removal by sedimenta-
tion.
The atmosphere is a major conduit for nickel, as particulate matter;
contributions to atmospheric loading come from both natural sources and
anthropogenic activity, with input from both stationary and mobile sources.
Various dry and wet precipitation processes remove particulate matter
as washout or fallout from the atmosphere with transfer to soils and waters.
Soil-borne nickel may enter waters by surface runoff or by percolation
into ground water. Once nickel is in surface and groundwater systems,
physical-chemical interactions (complexation, precipitation/dissolution,
adsorption/desorption, and oxidation/reduction) occur that will determine
its fate and that of other chemical constituents (Richter and Theis, 1980).
Nickel may also undergo uptake by plants. Movement of airborne nickel
into rainfall, soils, and vegetation has been well documented in the case
of smelter operations (Hutchinson and Whitby, 1977; Regaini, et al., 1977;
Beavington, 1975; Burkitt et al., 1972; Little and Martin, 1972; Goodman
and Roberts, 1971). In addition, several reports have implicated auto
traffic as a second factor in air emission of nickel resulting in subse-
quent fallout and movement of nickel into soils and vegetation (Burton and
John, 1977; Lagerwerff and Specht, 1970).
The above studies also indicate that there is a relationship of soil
and vegetation nickel to distance from the source as well as to existing
wind patterns, decreasing with increasing distance except for transects
lying in the wind path where the extension of contaminate range is rela-
tively greater. Furthermore, there is a vertical gradient in soil nickel
content, the greatest levels being measured in the top 5 cm.
Lability of nickel in soil is a function of pH, soil type and chemical
exchange capacity. It is quite possible that in a given pollution setting
other pollutants may affect such mobility. Hutchinson and Whitby (1977)
found that soil pH around a nickel smelting complex was lowered enough to
permit extensive aqueous extraction of soil-borne nickel.
012NIX/A 20 3/21/83
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3.3 LEVELS OF NICKEL IN VARIOUS MEDIA
Although it is not possible to furnish figures on the total input of
nickel into the general environment of the United States, the extent of
population exposure can be determined from levels of the element in various
media encountered by the United States population.
3.3.1 Levels of Nickel in Ambient Air
The most comprehensive assessment of ambient air levels of nickel in
the U.S. is that of the National Air Surveillance Network (NASN). Tabula-
tion of air nickel levels for the period 1964 through 1969 are contained in
the NAS Nickel Report (Nickel. National Academy of Sciences, 1975). More
recent figures are available for the period 1970-1976 (Environmental Protection
Agency, 1979).
Table 3-1 tabulates the air nickel averages for urban stations for the
period 1970-1976. Table 3-2 presents the corresponding values for all
nonurban stations for the same period. Table 3-3 presents the cumulative
frequency distribution of individual 24-hour ambient air nickel levels for
the years 1977-1980. This table also shows measurements obtained by two
different networks—the hereto mentioned NASN network and the Inhalable
Particulate Network (IP), which was initiated in 1979.
It may be seen from these tables that prior to 1975 ambient levels of
nickel were generally below the limit of detection in both urban and nonurban
areas. After 1976, detectable concentrations of nickel in ambient air samples
were found in more than 50 percent of the samples. The observation that more
samples were above the detection limit may be due in part to changes in ana-
lytical procedures, since newer analytical instrumentation was introduced in 1977.
It may also be seen from Table 3-3 that differences exist between the
two monitoring networks. The differences in the arithmetic means in
3 3
1979--21 ng/m versus 9 ng/m --are difficult to explain, especially when
this difference is not apparent in 1980; nevertheless, it is still possible
to generalize that the observed ambient air nickel concentrations have de-
clined over the past several years.
Nearly all of the measurements of nickel in atmospheric aerosols have
been made using optical emission spectroscopy (OES) of Hi-vol filter ex-
tracts and X-ray fluorescence spectroscopy (XRF) of dichotomous sampler
filters. No suitable states exist in the nuclei of nickel isotopes for
012NIX/A 21 3/21/83
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PRELIMINARY DRAFT
TABLE 3-1. URBAN CUMULATIVE FREQUENCY DISTRIBUTIONS OF
QUARTERLY COMPOSIT AMBIENT AIR NICKEL LEVELS
Year
1970
1971
1972
1973
1974
1975
1976
No. of
Sites
92
101
96
83
93
171
165
No. of
Samples
797
717
708
559
594
695
670
30
LDb
LD
LD
LD
LD
LD
LD
Percenti
50
LD
LD
LD
LD
LD
0.012
0.014
lea
70
019
018
013
013
012
019
022
99
0.127
0.126
0.100
0.133
0.057
0.062
0.079
An'
Mean
NCC
NC
NC
NC
NC
0.014
0.017
thmetic
(SO)
NC
NC
NC
NC
NC
0.014
0.017
Values under given percentile indicate the percentage of stations below the
given air level. Values in pg/m3.
Below the lower limit of discrimination, approximately 0.001 ug/m^ (for
years 1970-1974).
Statistics not calculated if more than 50 percent of the values are below the LD.
Source: Adapted from Environmental Protection Agency (1979). More recent data
provided by Environmental Monitoring Systems Laboratory, Research Triangle Park,
Environmental Protection Agency (Akland, 1981).
routine neutron activation analysis. The detection limits for both OES and
3
XRF are of the order of 10 ng/m for samples collected under normal condi-
tions (typical sampler flow rates and 24 hour periods). In instances where
nickel has been detected, it has been more often reported in urban aerosols.
(Shaw and Stevens, 1980).
As previously stated, nickel is one of the metals associated with
fossil-fuel combustion and residential heating units. This association is
based on documented season-dependent gradients in air levels with highest
levels in the winter quarter when space heating is at a maximum. Sulfur
regulations which have been in effect over the period 1965-1974 appear to
be the major factor in lower air nickel levels, particularly in the north-
012NIX/A 22 3/21/83
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TABLE 3-2. NONURBAN CUMULATIVE FREQUENCY DISTRIBUTIONS OF
QUARTERLY COMPOSIT AMBIENT AIR NICKEL LEVELS
OF QUARTERLY COMPOSITE SAMPLES
Year
1970
1971
1972
1973
1974
1975
1976
No. of
Sites
7
3
10
11
5
20
15
No. of
Samples
124
94
137
100
79
98
98
30
LDb
LD
LD
LD
LD
LD
LD
Percenti
50
LD
LD
LD
LD
LD
LD
LD
lea
/O
LD
LD
LD
LD
LD
LD
LD
99
0.076
0.046
0.076
0.188
0.020
0.036
0.038
An'
Mean
NCC
NC
NC
NC
NC
NC
NC
thmetic
(SD)
NC
NC
NC
NC
NC
NC
NC
a Values under given percentile indicate the percentage of stations below the
given air level. Values in ug/rn^.
Below the lower limit of discrimination, approximately 0.001 (jg/m^.
c Statistics not calculated if more than 50 percent of the values are below the
LD (for years 1970-74).
Source: Adapted from Environmental Protection Agency (1979). More recent data
provided by Environmental Monitoring Systems Laboratory, Research Triangle Park,
Environmental Protection Agency (Akland, 1981).
012NIX/A 23 3/21/83
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TABLE 3-3. CUMULATIVE FREQUENCY DISTRIBUTION OF INDIVIDUAL
24-HOUR AMBIENT AIR NICKEL LEVELS
Year
1977
1978
1979
1980
Network
NASN
NASN
NASN
IP
IP
IP
IP
IP
NASN
IP
IP
IP
IP
IP
Sampler
9 TypeB
HiVol
HiVol
HiVol
HiVol
SSI
Dicot
Dicot
Dicot
HiVol
HiVol
SSI
Dicot
Dicot
Dicot
T
C
F
T
C
F
Number
of
Sites
238
195
160
65
15
49
49
49
142
132
105
72
72
72
Number
of Obse
vations
5400
4147
2931
602
211
364
364
364
2881
1731
1302
759
759
759
r-
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
Percenti lec
50
0.006
0.006
0.005
0.015
0.017
0.612
0.005
0.006
0.003
0.004
0.003
0.010
0.005
0.005
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
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
Arithmetic
Mean
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
(SD)
(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)
Network: NASN is the National Air Surveillance Network which in 1980 was changed
to the National Air Monitoring Filter Sites.
IP is the Inhalable Particulate Network.
Sampler Type:
HiVol is the high volume air sampler which collects particles
less than 50 urn diameter.
SSI is the size selective (<15pm) version of the HiVol.
Dicot (T,C,F) is the dichotomous sampler where T is < 15um,
F is <2.5 pm, and C is the difference, i.e. greater than
2.5 pm and less than 15 |jm.
Values under given percentile indicate the percentage of stations below
the given air level. Values in pg/m .
Source: Akland (1981).
012NIX/A
24
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PRELIMINARY DRAFT
eastern United States. Sulfur removal from residual oil necessitated by
these regulations indirectly removes nickel as well (Faoro and McMullen,
1977). How long a trend to lower air nickel values in ambient air con-
tinues, in view of the above, will depend primarily on the future status of
sulfur regulations as well as the level of fuel oil consumption.
3.3.2 Nickel in Drinking Water
Table 3-4 presents the values for nickel levels in 969 U. S. public
water supplies for 1969-1970. The survey includes eight metropolitan areas
(Nickel. National Academy of Sciences, 1975). The average value, taken at
the consumer tap, was 4.8 p:g/£, with only 11 systems of this total exceed-
ing 25 ug/£. The highest level in one supply was 75 pg/£.
Since the data in Table 3-4 do not furnish any measure of the number
of people consuming drinking water of variable nickel content, the nickel
levels for water supplies of the ten largest U.S. cities are listed in
Table 3-5, based on the data of Durfor and Becker (1964).
The values for New York City, Chicago, and Los Angeles do not appear
to be markedly at variance with the average concentration of 4.8 |jg/£
nickel in water samples taken at the consumer's tap (Table 3-4).
TABLE 3-4.
NICKEL LEVELS IN U.<
WATER, 1969-1970'
DRINKING
Ni cone. ,
mg/£
0.000
0.001-0.005
0.006-0.010
0.011-0.015
0.016-0.020
0.021-0.025
0.026-0.030
0.031-0.035
0.036-0.040
0.041-0.045
0.046-0.050
0.051-0.055
0.075
Total
No. of
samples
543
1,082
640
167
46
14
4
2
1
1
1
1
I
2,503
Ni frequency
(percent of samples)
21.69
43.22
25.57
6.68
1.84
0.56
0.16
0.08
0.04
0.04
0.04
0.04
0.04
100.00
012NIX/A
Samples from 969 water systems.
Source: National Academy of Sciences (1975).
25
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PRELIMINARY DRAFT
TABLE 3-5. NICKEL LEVELS OF DRINKING WATER
OF 10 LARGEST U.S. CITIES
City
Nickel level,
New York City
Chicago
Los Angeles
Philadelphia
Detroit
Houston
Baltimore
Dallas
San Diego
San Antonio
2-3h
7.4b
4-8,
13. Oa
_ -.3
4-5K
4.7b
5.2b
<7.8
Not detected
.In storage.
Post-treatment.
Source: Adapted from National Academy of Sciences
(1975); values for 1962 survey of Durfor
and Becker (1964).
3.3.3 Nickel in Food
The route by which most people in the general population receive the
largest portion of daily nickel intake is through foods.
The assessment of average daily nickel intake in food can be done
either by considering the aggregate nickel content of average diets in the
population or by fecal nickel determinations. Although fecal nickel levels
would be more meaningful than diet analysis, given the very small gastro-
intestinal absorption of nickel in man, such data have been sparse in the
literature in terms of representative groups of individuals.
Some representative nickel values for various foodstuffs, adapted from
data in the NAS Nickel Report (Nickel. National Academy of Sciences,
1975), are given in Table 3-6. These values have been obtained by differ-
ent laboratories using different methods and may be dated in some cases.
Schroeder et al. (1962) calculated an average oral nickel intake by
American adults of 300-600 (jg/day, while Louria and co-workers (1972)
arrived at a value of 500 jjg/day. Murthy et al. (1973) calculated the
daily food nickel intake in institutionalized children, 9-12 years old,
012NIX/A
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PRELIMINARY DRAFT
TABLE 3-6. NICKEL CONTENT OF VARIOUS CLASSES
OF FOODS IN U.S. DIET
Food class and examples
Nickel content,
ppm, wet weight
Grains/grain products
Wheat flour, all-purpose
Bread, whole-wheat
Corn, fresh frozen
Rice, polished American
Rye flour
Rye bread
Fruits and vegetables
Potatoes, raw
Peas, fresh frozen
Peas, canned
Beans, frozen
Beans, canned
Lettuce
Cabbage, white
Tomatoes, fresh
Tomato juice
Spinach, fresh
0.54
1.33
0.70
0.47
0.23
0.21
0.56
0.30
0.46
0.65
0.17
0.14
0.32
0.02
0.05
0.35
Celery, fresh
Apples
Bananas
Pears
Seafood
Oysters, fresh
Clams, fresh
Shrimp
Scallops
Crabmeat, canned
Sardines, canned
Haddock, frozen
Swordfish, frozen
Salmon
Meats
Pork (chops)
Lamb (chops)
Beef (chuck)
Beef (round)
0.37
0.08
0.34
0.20
1.50
0.58
0.03
0.04
0.03
0.21
0.05
0.02
1.70
0.02
Not detected
Not detected
Not detected
Source: Adapted from National Academy of Sciences (1975).
012NIX/A
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PRELIMINARY DRAFT
from 28 U.S. cities at an average value of 451 |jg/day. In a related study,
Myron et al. (1978) determined the nickel content of nine institutional
diets in the U.S. and calculated an average intake of 165 ug/day.
Food processing methods apparently add to the nickel levels already
present in foodstuffs via (1) leaching from nickel-containing alloys in
food-processing equipment made from stainless steel, (2) the milling of
flour, and (3) catalytic hydrogenation of fats and oils by use of nickel
catalysts.
Several studies have reported daily fecal excretions of nickel.
Nodiya (1972) reported a fecal excretion average of 258 ug in Russian
students. Horak and Sunderman (1973) determined fecal excretions of nickel
in 10 healthy subjects and arrived at a value of 258 ug/day, identical to
the Russian study.
3.3.4 Nickel in Soil
Soil nickel levels are considered in this section chiefly from the
aspect of the influence of soil nickel on man's food chain, e.g., plants -*
animals -> man.
Soils normally contain nickel in a wide range of levels, 5-500 ppm,
and soils from serpentine rock may contain as much as 5000 ppm (Nickel.
National Academy of Sciences, 1975). While these levels may appear high in
some instances, nickel content of soils, as such, is less important for
plant uptake than such factors as soil composition, soil pH, organic matter
in soil, and the classes of plants grown therein.
Natural levels of soil nickel may be added to by contamination from
human activity such as atmospheric fallout in the areas of nickel-emitting
industrial activities or auto traffic, as well as treatment of agricultural
lands with nickel-containing superphosphate fertilizers or municipal sewage
sludge.
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) ob-
served: (1) at first-year harvest, nickel levels in the above food crops
were increased 2- to 3-fold compared to control soil crops, the corre-
sponding 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.
012NIX/A 28 3/21/83
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John and Van Laerhoven (1976) determined the effect of applying sludge
at various loading rates on trace metal uptake by romaine lettuce and beets
grown on amended soil with and without liming. Sludge used with unlimed
soil significantly increased nickel levels in lettuce, did not affect the
element level in beet tops, and reduced the nickel content of beet tubers.
On the other hand, liming led to increases of nickel in all plant tissues
at a 25 g/kg loading rate for one type of sludge (Milorgam'te) but not with
a second type produced at a local treatment plant.
Frank et al. (1982) reported that aerial fallout from a nickel smelter at
Port Colborne, Ontario, Canada, resulted in accumulation of nickel ranging from
600 to 6455 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 from the smelter and
in direct line with the prevailing winds. In order to evaluate the possible
impact of nickel contamination on the soil, nickel content of the edible parts
of crops grown on this soil was determined. Nickel (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.
3.3.5 Nickel in Cigarettes
Cigarette smoking can contribute significantly to man's daily nickel
intake by inhalation and nickel from this source probably exceeds the
amount absorbed by breathing ambient air. An individual smoking two packs
of cigarettes a day would inhale 1-5 mg of nickel per year or about 3-15 ug
nickel daily (National Academy of Sciences, 1975). It is presently unknown
what amount of nickel is inhaled by individuals subjected to passive smoke
in indoor environments. Information on this topic is needed as such ex-
posure may prove to be of importance for some individuals in certain working
and home environments.
012NIX/A 29 3/21/83
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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 nickel's
systemic effects but important in the allergenic responses to nickel.
Parenteral administration of nickel is mainly of interest to experimental
studies and particularly helpful in assessing the kinetics of nickel trans-
port, distribution, and excretion as well as maximizing the physiological
parameters for nickel's effects. 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. Other factors, such as host organism nutritional and
physiological status, also play a role, but they have been little studied
outside of investigations directed at an essential role for nickel.
4.1.1 Nickel Absorption by Inhalation
Respiratory absorption of various forms of nickel is probably the
major route of nickel entry into man under conditions of occupational
exposure, and considerable attention has been given to nickel inhaled as
either the highly toxic nickel carbonyl or nickel participate 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. More recently, the threshold limit value (TLV) for a work day
exposure has been set at 0.05 ppm (.35 mg/m ), which may be compared to the
corresponding value for hydrogen cyanide of 10 parts per million (ppm), or
200-fold greater (American Conference of Governmental Industrial Hygienists,
1981). Its presence and toxicological history as a workplace hazard followed
closely upon the development of the Mond process of nickel purification in
its processing (Mond et al., 1890). A detailed discussion of the toxico-
logical aspects of nickel carbonyl poisoning is included in the NAS report
on nickel (Nickel. National Academy of Sciences, 1975) as well as a recent
review by Sunderman (1977).
012NIX/A 30 3/21/83
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Studies of nickel carbonyl metabolism by Sunderman and co-workers
(Sunderman and Selin, 1968; Sunderman, Roszel, and Clark, 1968) indicate
that pulmonary absorption is both rapid and extensive, the agent passing
the alveolar wall intact. Sunderman and Selin (1968) observed that rats
exposed to nickel carbonyl at 100 mg Ni/£ air for 15 minutes excreted 26
percent of the inhaled amount in the urine by 4 days post-exposure. On
taking into account the exhaled quantity, as much as half of the inhaled
amount could have been initially absorbed.
Few data exist on the pulmonary absorption of nickel from particulate
matter deposited in the lung. The International Radiological Protection
Commission (IRPC) Task Group on Lung Dynamics (1966) has advanced detailed
deposition and clearance models for inhaled dusts of whatever chemical
origin as a function of particle size, chemical properties, and compart-
ments! ization within the pulmonary tract. Nickel oxide and nickel halides
i are classified as Class W compounds, i.e., compounds having moderate re-
tention in the lungs and a clearance rate from the lungs of weeks in dura-
tion.
While the model described above has limitations, it can be of 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 1-2 pm mass median aerodynamic
diameter (MMAD), this being a size that penetrates deepest into the pulmon-
ary tract. According to the approaches of the IRPC model, particles of 1
pm undergo a total deposition percentage of 63 percent, with 30 percent in
the nasopharyngeal tract, 8 percent in the tracheobronchial part, and 25
percent in the pulmonary compartment. The clearance rate of deposited
particulate matter in the IRPC model is based on chemical homogeneity of
the particulates, 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 par-
ticle surface. If one approximates the clearance rate by assuming that
particles enriched in nickel in the outer portions of the particle are
handled by the model lung in a fashion similar to a homogeneous particle,
then one obtains a total absorption (clearance) of approximately 6 percent,
012NIX/A 31 3/21/83
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PRELIMINARY DRAFT
with major clearance, 5 percent, calculated as taking place from the pul-
monary compartment.
Wehner and Craig (1972), in their studies of the effect of nickel
oxide aerosols on the golden hamster, observed that inhalation by these
animals of nickel oxide particles in a concentration of 2-160 ug/£ (2-160
mg/m ) and particle size of 1.0-2.5 (jm MMAD led to a deposition of 20
percent of the total amount inhaled. After 6 days post-exposure, 70 per-
cent 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 ap-
peared that absorption in this interval was negligible. In a later, related
study (Wehner et al., 1975), co-inhalation of cigarette smoke showed no
effect on either deposition or clearance.
Wehner et al. (1979) exposed Syrian hamsters to nickel-enriched fly
ash aerosol (respirable concentration, approximately 185-200 ug fly ash/
liter) for either 6 hours or 60 days and found that, in the short exposure,
about 90 percent of 80 ug deposited in the deep tract remained 30 days
after exposure, indicating very slow clearance. In the two-month study,
the deep tract deposition was approximately 5.7 mg enriched fly ash, or 510
ug Ni. Thus, nickel leaching from the nickel-enriched fly ash in the
hamster's lung does not occur to any extent and, while little systemic
toxicity was seen in these animals over the experimental time frame, such
forms of nickel in lung may be of importance in respiratory carcinogenesis.
In this connection, Hayes et al. (1978) found from scanning electron
microscope studies that trace elements such as nickel are not uniformly
distributed among particles of similar size; some particles carry much of
the element for a given concentration determined by ordinary chemical
analysis. Thus, in the Wehner et al. (1979) study, it is likely that the
deep tract burden of relatively inert nickel contains some particles very
high in nickel which would also suggest another risk factor for nickel
respiratory carcinogenesis.
The implication of these two reports for human health risk are accen-
tuated when considering the Natusch et al. (1974) report cited above that
shows that respirable nickel-enriched fly ash is emitted from coal-fired
power plants.
012NIX/A 32 3/21/83
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Leslie and co-workers (1976) have described their results from ex-
posing rats to nickel and other elements contained in welding fumes. In
this case, the particle size vs. nickel content was known precisely, high-
est nickel levels being determined in particles 0.5-1.0 urn in diameter at
o
an air level of 8.4 ug Ni/m . While the authors did not determine the
total nickel deposition in the lungs of these animals, they observed that
essentially no clearance of the element from the lung had occurred within
24 hours, nor were there elevations in blood nickel, suggesting negligible
absorption. In contrast, Graham et al. (1978), using mice and nickel
o
chloride aerosol (< 3 urn diameter, 110 mg Ni/m ) found about 75 percent
clearance by day 4 post-exposure. The rapid clearance of the nickel halide
was probably due to its solubility relative to the oxide.
In addition to nickel exposure in man due to inhalation of ambient and
workplace air, cigarette smoking constitutes a possible significant source
among heavy smokers. Studies by Stahly (1973), Szadkowski and co-workers
(1970), and Sunderman and Sunderman (1961a) indicate that 10-20 percent of
cigarette nickel is carried in mainstream smoke, with better than 80 per-
cent of this amount being in gaseous, rather than particulate, form. Since
it is quite possible that nickel carbonyl constitutes the gaseous fraction
(Sunderman and Sunderman, 1961a), one must assume that the relative absorp-
tion of nickel from cigarette smoke is proportionately greater than from
airborne nickel particulates and with heavy smokers may be the main source
of inhalatory nickel absorbed. Individuals smoking two packs of cigarettes
daily can inhale up to 5 mg nickel annually (Nickel. National Academy of
Sciences, 1975). By contrast, an individual in an urban U.S. area having
3
an air level of Ni of 0.025 ug/m (Nickel. National Academy of Sciences,
o
1975) and breathing 20 m daily would inhale somewhat less than 0.2 mg.
The relative significance for absorption would be even greater (vide supra).
As stated previously, the effect of exposure to passive smoke remains an
unknown in that nickel-specific studies addressing this problem have not
been conducted.
4.1.2 Gastrointestinal Absorption of Nickel
Gastrointestinal intake of nickel by man is surprisingly high, rela-
tive 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.
012NIX/A 33 3/21/83
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PRELIMINARY DRAFT
Total daily dietary intake values may range up to 900 \\q nickel,
depending on the nature of the diet, with average values of 300-500 pg
daily (Nickel. National Academy of Sciences, 1975).
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 1-10 percent of dietary nickel is absorbed.
One question that arises in considering the dietary intake and absorp-
tion of toxic elements has to do with the bioavailability of the agent in,
solid foodstuffs versus water and beverages. Ho and Furst (1973) observed
CO
that intubation of Ni in dilute acid solution leads to 3-6 percent absorptioi
of the radio-labeled nickel regardless of the dosing level. It does not
appear, then, that nickel in simple aqueous solution is absorbed to any
greater extent than that incorporated into the matrix of foodstuffs.
Fecal analysis more accurately reflects dietary intake where the rate
of absorption is known and the existence and extent of biliary excretion is
known. Diet profiles tend to be different than fecal analysis data owing
to the obvious inherent difficulty of arriving at "true" diets for human
subjects. In the case of nickel, where absorption is assumed to be small,
the fecal analysis data approximate the low end of dietary profile esti-
mates, and one can say that daily GI intake is probably 250-300 ug Ni/day.
4.1.3 Percutaneous Absorption of Nickel
Percutaneous absorption of nickel is mainly viewed as important in the
dermatopathologic effects of this agent, such as contact dermatitis, and
absorption viewed this way is restricted to the passage of nickel past the
outermost layers of skin deep enough to bind with apoantigenie factors.
Wells (1956) demonstrated that divalent nickel penetrates the skin at
sweat-duct and hair-follicle ostia and binds to keratin. Using cadaver
skin, Kolpokov (1963) found that nickel (II) accumulated in the Malpighian
layer, sweat glands and walls of blood vessels. Spruitt et al. (1965) have
shown that nickel penetrates to the dermis.
Values for the amounts of nickel passing through outer layers of skin
relative to amounts applied have not been determined. Samitz and Pomerantz
(1958) have reported that the relative extent of nickel penetration is
enhanced by sweat and detergents.
Mathur and co-workers (1977) have reported the systemic absorption of
nickel from the skin using nickel sulfate at very high application rates.
012NIX/A 34 3/21/83
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PRELIMINARY DRAFT
After 30 days of exposure to nickel at doses of 60 and 100 mg Ni/kg, a
number of testicular lesions were observed in rats, while hepatic effects
were seen by 15 days at these exposure levels. It is not possible to
calculate any absorption data from this study.
4.1.4 Transplacental Transfer of Nickel
Evidence for the transplacental transfer of nickel to the fetus dates
to the study of Phatak and Patwardhan (1950) who found that newborn of rats
fed nickel in various chemical forms had whole-body levels up to 22-30 ppm
when mothers received 1000 ppm Ni in the diet.
Pregnant mice given nickel chloride intraperitoneally as one dose (3.5
mg/kg) at 16 days of gestation showed transfer to placental tissue with
peak accumulation having occurred by eight hours post-exposure (Lu and
co-workers, 1976).
ro
Jacobsen et al. (1978), using Ni-labeled nickel chloride and single
intraperitoneal injections into pregnant mice at day 18 of gestation,
showed rapid passage from mother to fetus, with fetal tissues generally
showing higher concentrations than that of the mothers. Kidney levels were
highest in the fetus with lowest levels being seen in brain. Furthermore,
CO
01 sen and Jonsen (1979) used Ni whole body radiography in mice to deter-
mine that placental transfer occurs throughout gestation.
A similar study is that of Sunderman et al. (1978a), who administered
CO
Ni-labeled solution to pregnant rats intramuscularly. Embryo and embry-
onic membrane showed measurable label by day eight of gestation, while
autoradiograms demonstrated label in yolk sacs of placentae one day post-
injection (day 18 of gestation).
Several reports indicate transplacental passage of nickel also occurs
in man. Stack et al. (1976) showed levels of 11-19 ppm in dentition from
four fetuses as well as a mean element concentration of 23 ppm in teeth
from 25 cases of stillbirth and neonatal death.
Casey and Robinson (1978) found detectable levels of nickel in tissue
samples from 40 fetuses of 22-43 weeks gestation, with levels in liver,
heart and muscle being comparable to those seen in adult humans. Values
ranged from 0.04-2.8 ppm (ug Ni/g dry weight). This study suggests ready
movement of nickel into fetal tissues, given the similarity in fetal versus
adult human levels.
012NIX/A 35 3/21/83
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Creason et al. (1976) studied the maternal-fetal tissue levels of 16
trace elements in eight selected U.S. communities. The authors reported
geometric mean nickel levels of 3.8 ug/100 m£ in maternal blood, 4.5 ug/100
m£ in cord blood and 2.2 ug/100 g in placenta. In order to examine the
relative levels of maternal and cord blood trace elements, ratios of these
values were computed and a standard t-test was applied to the logs of these
ratios. The geometric mean of the ratio for nickel was 1.15 based upon 166
observations. This ratio was not significantly different from 1 at the .05
level. While statistical significance was not shown, this study, neverthe-
less, 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.
Blood is the main vehicle for transport of absorbed nickel. While it
is difficult to determine from the literature the exact partitioning of
nickel between erythrocytes and plasma or serum for unexposed individuals,
serum levels are rather good reflections of blood burden and exposure
status (Nickel. National Academy of Sciences, 1975). In unexposed indi-
viduals, serum nickel values are approximately 0.2-0.3 ug/dl.
Distribution of serum-borne nickel among the various biomolecular
components has been discussed in some detail in a recent review (Nickel.
National Academy of Sciences, 1975), and it will mainly be noted here that
serum albumin is the main carrier protein in sera of man, rabbit, rat, and
bovine. Furthermore, there exists in sera of man and rabbits a nickel-rich
metal!oprotein identified as an a-,-macroglobulin (nickeloplasmin) in rabbits
and in man as a 9.5 S a,-glycoprotein. Sunderman (1977) has suggested that
nickeloplasmin may be a complex of the or,-glycoprotein with serum a-^-macro-
globulin.
In vitro study of nickel (II) binding in human serum (Lucassen and
Sarkar, 1979) shows histidine to be a major micromolecular binding species
and an equilibrium between albumin and histidine may be the factor in blood
to tissue transfer of nickel.
While the relative amounts of protein-bound nickel in sera of various
species have a considerable range (Hendel and Sunderman, 1972) which reflect
012NIX/A 36 3/21/83
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PRELIMINARY DRAFT
relative binding strengths of albumins, the total nickel levels are markedly
similar, as may be seen in Table 4-1.
A number of studies of the distribution of nickel in experimental
animals exposed to nickel carbonyl have been described (Nickel. 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 have observed elevated, rapidly cleared
levels of nickel in lungs, brain, kidney, and liver of various animal
species (Mikheyev, 1971; Sunderman and Selin, 1968; Ghiringhelli and Agamennone,
1957; Sunderman et al., 1957; Barnes and Denz, 1951).
Sunderman and Selin (1968) have shown that one day after exposure to
inhaled Ni-labeled nickel carbonyl, viscera contained about half of the
total absorbed label with one-third in muscle and fat. Bone and connective
tissue accounted for about one-sixth of the total. Spleen and pancreas
also appear to take up an appreciable amount of nickel. Presumably, nickel
TABLE 4-1. SERUM NICKEL IN HEALTHY ADULTS OF SEVERAL SPECIES
Species (N)
Nickel concentration,
Mean (and range)
Source: Sunderman et al. (1972a).
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)
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)
012NIX/A
37
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PRELIMINARY DRAFT
carbonyl crosses the alveolar membrane intact from either route, inhalation
or injection, suggesting that its stability is greater than has usually
been assumed (Kasprzak and Sunderman, 1969; Sunderman et al., 1968; Sunderman
and Selin, 1968). Retained nickel carbonyl undergoes decomposition to
carbon monoxide and zero-valent nickel in the erythrocyte and tissues,
followed by intracellular oxidation of the element to the divalent form and
subsequent release into serum.
In human subjects acutely exposed to nickel carbonyl vapor, highest
nickel levels were found in the lung, followed by kidney, liver, and brain
(Nickel. 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. Rela-
tively little nickel is lodged in neural tissue, consistent with the ob-
served 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.
CO
Onkelinx et al. (1973) studied the kinetics of injected Ni meta-
bolism in rats and rabbits. In both species, a two-compartment model of
clearance could be discerned, consisting of fast and slow components. In
the rabbit, better than 75 percent of the dose was excreted within 24
hours, while comparable clearance in the rat required 3 days. In a later
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study, Onkelinx (1977) reported whole body kinetics of Ni in rats. The
time course of plasma nickel levels entailed first-order kinetics analyz-
able in terms of a two-compartment model. The major portion of nickel
clearance is accounted for by renal excretion.
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Chausmer (1976) has measured exchangeable nickel in the rat using Ni
given intravenously. Tissue exchangeable pools were directly estimated
and compartmental analysis performed by computer evaluation of the relative
isotope retention versus time. Kidney had the largest labile pool within
16 hours with two intracellular compartments. Liver, lung, and spleen
012NIX/A 38 3/21/83
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PRELIMINARY DRAFT
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PRELIMINARY DRAFT
pools could also be characterized by two compartments, while bone fit a
one-compartment model. Corresponding half-times for the fast and slow
components were several hours and several days, respectively.
Oral exposure of experimental animals to nickel with regard to ab-
sorption and tissue distribution appears to be dependent upon the relative
amounts of the agent employed. Schroeder et al. (1974) could find no
uptake of nickel in rats chronically exposed to nickel in drinking water (5
ppm) over the lifetime of the animals. Phatak and Patwardhan (1950) re-
ported the effects of different nickel compounds given orally to rats in
terms of tissue accumulation. Among the three chemical forms of nickel
used, i.e., carbonate, nickel soaps, and metallic nickel catalyst, tissue
levels were greatest in the groups fed the carbonate. O'Dell and co-workers
(1971) fed calves supplemental nickel in the diet at levels of 62.5, 250,
and 1000 ppm. While levels of nickel were somewhat elevated in pancreas,
testis, and bone at 250 ppm, pronounced increases in these tissues were
seen at 1000 ppm. Whanger (1973) exposed weanling rats to nickel (acetate)
in the diet at levels up to 1000 ppm. As nickel exposure was increased,
nickel content of kidney, liver, heart, and testis was also elevated, with
greatest accumulation in the kidneys. Spears et al. (1978) observed that
CO
lambs given tracer levels of Ni orally with or without supplemental
nickel in diet had the highest levels of the label in kidney; the relative
levels in kidney, lung and liver being less for the low-nickel group.
Comparison of the above studies suggests that a homeostatic mechanism
exists to regulate low levels of nickel intake, e.g., 5 ppm, but such
regulation is overwhelmed in the face of large levels of nickel challenge.
4.3 EXCRETION OF NICKEL IN MAN AND ANIMALS
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 gastrointestinal absorption (vide supra), fecal
levels of nickel roughly approximate daily dietary intake, 300-500 M9/day
in man.
Urinary excretion in man and animals is usually the major clearance
route for absorbed nickel. Reported normal levels in urine vary consider-
ably in the literature,-and earlier value variance probably reflects metho-
dological limitations. More recent studies suggest values of 2-4 ug/£
(Andersen et al., 1978; McNeely et al., 1972).
012NIX/A 40 3/21/83
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PRELIMINARY DRAFT
While biliary excretion 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), what role it plays in nickel metabolism in man is unknown.
Sweat can constitute a major route of nickel excretion. Hohnadel and
co-workers (1973) determined nickel levels in the sweat of healthy subjects
sauna bathing for brief periods at 93°C to be 52 ± 36 ug/£ for men and 131
± 65 ug/£ 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 assess-
ing overall nickel body burdens as well as exposure chronology 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 ug/g, S.E.M. = ± 1.06) about fourfold those of men
(0.97 ug/g, S.E.M. = ± 0.15). Such a difference, however, was not en-
countered by Nechay and Sunderman (1973) nor were their average sample
values as high. The differences in these two studies serve to point out
some of the difficulties in establishing quantitative relationships for the
role of hair levels in nickel metabolism.
In experimental animals, urinary excretion is the main clearance route
for nickel compounds introduced parenterally.
Animals exposed to nickel carbonyl via inhalation exhale a part of the
respiratory burden of this agent within 2-4 hours, while the balance is
slowly degraded i_n vivo to divalent nickel and carbon monoxide, with nickel
eventually undergoing urinary excretion (Mikheyev, 1971; Sunderman and
Selin, 1968).
The pattern of labeled-nickel urinary excretion in rats given a single
CO
injection (4 mg/kg, 12.5 u 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 ligating moieties having a molecu-
lar weight of 200-250.
4.4 FACTORS AFFECTING NICKEL METABOLISM
A number of disease states and other physiological stresses are re-
ported to alter the movement and tissue distribution of nickel in man as
well as experimental animals. Furthermore, J_n 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.
012NIX/A 41 3/21/83
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PRELIMINARY DRAFT
In man, increased levels of serum nickel are seen in cases of acute
myocardial infarction (Sunderman et al., 1972a; McNeely et al., 1971;
D'Alonzo and Pell, 1963), such alterations presently being considered as
secondary to leukocytosis and leukocytolysis (Sunderman, 1977).
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.
Palo and Savolainen (1973) report that hepatic nickel was increased
tenfold over normal values in a deceased patient with aspartylglycosami-
nuria, a metabolic disorder characterized by reduced activity of aspartyl-p-
glucosaminidase.
Other stresses appear to have an effect on nickel metabolism. Signi-
ficant reduction in serum nickel has been seen in mill workers exposed to
extremes of heat (Szadkowski et al., 1970), probably due to excessive
nickel loss through sweating, as was noted earlier. While tissue nickel
levels are reported to be elevated in rats during pregnancy (Spoerl and
Kirchgessner, 1977), no comparable data are available for man.
The use of various classes of chelating agents to expedite the removal
of nickel from man and animals has been reported with the goal of develop-
ing efficient chemotherapeutic agents for use in nickel poisoning. The
data have been reviewed (Sunderman, 1977; Nickel. National Academy of
Sciences, 1975) and will only be summarized in this section.
On the basis of reported clinical experience, sodium diethyldithiocar-
bamate (dithiocarb) is presently the drug of choice in the management of
nickel carbonyl poisoning, being preferable overall to EDTA salts, 2,
3-dimercaptopropanol (BAL), and penicillamine. In all cases, the agents
work to accelerate the urinary excretion of absorbed amounts of nickel
before extensive tissue injury can result.
012NIX/A 42 3/21/83
-------
PRELIMINARY DRAFT
5. NICKEL TOXICOLOGY
Both acute and chronic effects of exposure to various nickel compounds
have been extensively documented over the years, with those effects which
are chronic in nature comprising both the bulk of available information and
being most relevant to general population exposure.
5.1 ACUTE EFFECTS OF NICKEL EXPOSURE IN MAN AND ANIMALS
5.1.1 Human Studies
In terms of human health effects, probably the most acutely toxic
nickel compound is nickel carbonyl, Ni(CO),, a volatile, colorless liquid
formed when finely divided nickel comes into contact with carbon monoxide,
as in the Mond process for purification of nickel (Mond et al., 1890). Its
threshold limit value (TLV) for a work day is 0.05 parts per million (ppm)
as compared to the corresponding value of 10 ppm for hydrogen cyanide
(American Conference of Governmental Industrial Hygienists, 1981).
A sizable body of literature has developed over the years dealing with
the acute inhalation exposure of nickel-processing workers to nickel carbonyl
(Sunder/nan, 1977; National Institute for Occupational Safety and Health,
1977b; Nickel. National Academy of Sciences, 1975). Since much of this
information is relevant mainly to industrial accidents and occupational
medicine rather than general environmental health, it is not appropriate to
accord it detailed discussion in this document.
According to Sunderman (1970) and Vuopala et al. (1970), who have
studied the clinical course of acute nickel carbonyl poisoning in workmen,
clinical manifestations include both immediate and delayed symptomatology.
In the former, frontal headache, vertigo, nausea, vomiting, insomnia, and
irritability are commonly seen, followed by an asymptomatic interval before
the onset of insidious, more persistent symptoms. These include constric-
tive chest pains, dry coughing, hyperpnea, cyanosis, occasional gastro-
intestinal symptoms, sweating, visual disturbances, and severe weakness.
Aside from the weakness and hyperpnea, the symptomatology strongly re-
sembles that of viral pneumonia.
The lung is the target organ in nickel carbonyl poisoning in man and
animals. Pathological pulmonary lesions observed in acute human exposure
include pulmonary hemorrhage and edema accompanied by derangement of alveolar
012NIX/A 43 3/21/83
-------
PRELIMINARY DRAFT
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 man, nephrotoxic effects of nickel have been clinically detected in
some cases of accidental industrial exposure to nickel carbonyl (Carmichael,
1953; Brandes, 1934). This takes the form of renal edema with hyperemia
and parenchymatous degeneration.
5.1.2 Animal Studies
The pronounced pulmonary tract lesion formation seen in animals acutely
exposed to nickel carbonyl vapor strongly overlaps that reported for cases
of acute industrial poisoning, and these have been tabulated in Table 5-1.
As in man, the lung is the target organ for effects of nickel carbonyl
in animals regardless of the route of administration. The response of
pulmonary tissue is very rapid, interstitial edema developing within 1 hour
of exposure. There is subsequent proliferation and hyperplasia of bronchial
epithelium and alveolar lining cells. By several days post-exposure,
severe intra-alveolar edema with focal hemorrhage and pneumocyte cyel de-
rangement has occurred. Death usually occurs by the fifth day. Animals
surviving the acute responses show regression of cytological changes with
fibroblastic proliferation within alveolar interstitium.
Acute renal injury with proteinuria and hyaline casts were observed by
Azary (1879) in cats and dogs given nickel nitrate. Pathological lesions
of renal tubules and glomeruli have been seen in rats exposed to nickel
carbonyl (Hackett and Sunderman, 1967; Sunderman et al., 1961; Kincaid et
al., 1953). Gitlitz et al. (1975) observed aminoaciduria and proteinuria
in rats after single intraperitoneal injection of nickel chloride, the
extent of the renal dysfunction being dose-dependent. Proteinuria was
observed at a dose of 2 mg/kg, while higher dosing occasioned aminoaci-
duria. Ultrastructurally, the site of the effect within the kidney appears
to be glomerular epithelium. These renal effects were seen to be transi-
tory, abating by the fifth day.
5.2 CHRONIC EFFECTS OF NICKEL EXPOSURE IN MAN AND ANIMALS
5.2.1 Nickel Carcinogenesis
The present status of nickel's role in occupational and experimental
Carcinogenesis has been the subject of a number of recent reviews (Sunderman,
1981, 1979, 1977, 1976, 1973; National Institute for Occupational Safety
012NIX/A 44 3/21/83
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PRELIMINARY DRAFT
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PRELIMINARY DRAFT
and Health, 1977a, 1977b; International Agency for Research on Cancer,
1976; National Academy of Sciences, 1975).
5.2.1.1 Experimental Animal Studies—The qualitative and quantitative
character of the carcinogenic effects of nickel as seen in experimental
animal models has been shown to vary with the chemical form of the nickel,
the routes of exposure, the animal model employed (including strain differ-
ences within animal models), and the amounts of the substance employed.
Some of the experimental models of nickel carcinogenesis which have
evolved out of various laboratories are given in Table 5-2, along with the
various carcinogenic nickel compounds employed, the levels of material
used, and the routes of administration. Responses are usually at the site
of injection, although in the case of nickel acetate injection, pulmonary
carcinomas were detected in mice given repeated intraperitoneal injections
(Stoner et al., 1976). There have been no reports of experimental carcino-
genesis induced by oral or cutaneous exposure.
Nickel metal, in the form of dust or pellets, leads to 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 in-
halation study of nickel dust carcinogenesis, Hueper (1958) reported that
an alveolar anaplastic carcinoma was found in one guinea pig lung, and a
"metastic lesion" (lymph node) was found in a second animal. However, this
study has been criticized as being inconclusive in that the lymph node
tumor could not be associated with a primary lung tumor, nor were control
animals used in the guinea pig experiment.
In a study of the carcinogenicities of various metal compounds, Gilman
(1962) noted that nickel subsulfide (Ni^S^) was a potent inducer of rhabdo-
myosarcomas when given intramuscularly. Later studies of the carcino-
genicity of nickel subsulfide demonstrated adenocarcinomas in rats given
the substance intrarenally (Jasmin and Riopelle, 1976); rhabdomyosarcomas,
fibrosarcomas, and fibrous histocytomas in rat testicular tissue after
intratesticular dosing (Damjanov et al., 1978); and, epidermoid and adeno-
carcinomas in the lung in rats inhaling nickel subsulfide (Ottolenghi et al.,
012NIX/A 46 3/21/83
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PRELIMINARY DRAFT
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PRELIMINARY DRAFT
1974). Hamster fetal cells transformed by Ni^S^ 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 Ni^S^ implantation by as early as 6 months.
Sunderman et al. (1980a) have extended the site tumorigenicity of Ni'3S? to
the eye, where injection of 0.5 mg into the vitreous cavity in rats led to
a high incidence of ocular tumors by 8 months.
Exposure to nickel carbonyl either via inhalation (Sunderman and
Donnelly, 1965; Sunderman et al., 1959) or intravenously (Lau et al., 1972;
has been observed to induce pulmonary carcinomas or carcinomas and sarcomas
in organs such as liver and kidney, respectively. As noted above, repeated
dosing intraperitoneally yields lung carcinomas in mice when nickel acetate
is used (Stoner et al., 1976), while nickelocene, an organom'ckel "sandwich"
structure, induces sarcomas in rats and hamsters when given intramuscularly
(Furst and Schlauder, 1971; Haro et al., 1968).
Comparative carcinogenicity for various nickel compounds has been
studied and demonstrated in various laboratories (Sunderman and Maenza,
1976; Jasmin and Riopelle, 1976; Payne, 1964; Gil man, 1962).
Sunderman and Maenza (1976) studied the incidence of sarcomas in
Fischer rats within two years after single intramuscular injections of four
insoluble nickel-containing powders: metallic nickel, nickel sulfide,
ornickel subsulfide and nickel-iron sulfide matte. Amorphous nickel sul-
fide had no tumorigenic potential, while nickel subsulfide was most active.
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 corre-
sponding arsenides, selenides, and tellurides.
In a later, related study, Sunderman et al. (1979b) studied the rela-
tive potential for carcinogenesis of alpha-Ni^, beta-NiS, Ni"3Se2, Ni
dust, the cyclopentadiene derivative of nickel carbonyl, amorphous NiS and
NiSe. Using a single injection of 14 mg (as Ni) per animal and a 100 week
interval, the percent incidence of site sarcomas were: alpha-Ni^ and
beta-NiS, 100; Ni'3Se2, 91; Ni dust, 65; NiSe, 50; cyclopentadiene-carbonyl
complex, 19; and, amorphous NiS, 0 percent, respectively. Notable in this
study was the marked effect of the crystalline form of NiS on reactivity;
012NIX/A 50 3/21/83
-------
PRELIMINARY DRAFT
amorphous sulfide had no tumorigenicity, while the beta-crystalline form
was as potent as the subsulfide.
The above discussion has focused on nickel compounds used alone to
induce carcinogenic responses. An equally important aspect of these effects
is the synergizing action of nickel in the carcinogenicity of other agents,
since environmental situations entail simultaneous exposure to a number of
such substances.
Experimental data exist to demonstrate that nickel has a synergistic
effect on the carcinogenicities of polycyclic aromatic hydrocarbons. Toda
(1962) has found that 17 percent of rats receiving intratracheal doses of
nickel oxide along with 20-methylcholanthrene developed squamous cell
carcinomas; Maenza et al. (1971) demonstrated a synergistic, rather than
additive, effect in the latency period reduction (30 percent) of sarcomas
when simultaneous exposure to benzopyrene and nickel subsulfide was carried
out. Kasprzak et al. (1973) observed pathological reactions in lungs of
rats given both nickel subsulfide and benzopyrene that were greater than
was the case for either agent alone.
Nickel and other elements are known to be present in asbestos and may
possibly be a factor in asbestos carcinogenicity. The pertinent literature
has been reviewed (Nickel. National Academy of Sciences, 1975; Morgan et
al., 1973). Little in the way of experimental studies exists to shed light
on any etiological role of nickel in asbestos carcinogenicity. Cralley
(1971) has speculated that asbestos fibers may serve as a transport mech-
anism for metals into tissue and that the presence of chromium and manga-
nese may enhance the carcinogenicity of nickel.
This possible synergizing effect between nickel and other elements or
compounds also has implications in regard to the carcinogenicity of ciga-
rettes, the nature and magnitude of this effect presently being unknown.
Virus-nickel synergism is suggested by the observation of Treagan and
Furst (1970) that jm vitro suppression of mouse L-cell interferon synthesis
occurs in response to Newcastle Disease virus in the presence of nickel.
Looking at the literature in aggregate, there appears to be a general
inverse relationship between solubility and carcinogenic potential in the
nickel compounds that have been studied—insoluble nickel metal, nickel
oxide, and nickel subsulfide generally being carcinogenic, while most
nickel salts generally being non-carcinogenic. It has been suggested that
012NIX/A 51 3/21/83
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PRELIMINARY DRAFT
the prolonged contact of the 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 postu-
lates regarding the solubility or insolubility of nickel compounds.
Examination of some of the inhalation studies suggests that particle
size may interact significantly with solubility in determining the carcino-
genic outcome. The smaller the particle, the deeper it goes in the respi-
ratory tract (Task Group on Lung Dynamics, 1966) which provides a rationale
for using small particles in studying carcinogenic responses in the lung
itself. However, in retrospect, the smaller the nickel particle, the more
efficiently it can be "neutralized" by the lung's defense mechanisms and
removed by solubilization. To the extent that this shortens the contact
time of the particle with tissue, it may minimize the likelihood of a
carcinogenic response. This may have been the case in the negative report
of Wehner et al. (1975) in which the investigators used nickel oxide, but
at particle sizes of 0.3 urn mean diameter. Conversely, this was not the
case for Ottolenghi et al. (1974) who used nickel subsulfide, also at small
particle sizes (70 percent under 1.0 pm), but reported significant lung
tumor incidence. The different results of these two studies further demon-
strates the complexity of the issue.
In addition, in an experimentally well-designed study of Stoner et al.
(1976), mice given repeated i.p. injections of nickel (II) acetate showed
statistically significant incidence of pulmonary tumors at a level of 360
mg/kg, demonstrating that soluble compounds can be carcinogenic. It has
been suggested that either movement of divalent nickel into the nucleus of
cells in this particular animal model is greater or that cell division is
more sensitive to nickel ion; thus, causing a carcinogenic response (Sunderman,
1981).
In regard to the mechanism for nickel carbonyl carcinogenicity, only a
hypothesis can be presented at this time. It is known that nickel carbonyl
passes the alveolar wall intact and subsequently is decarbonylated and
oxidized from the zero-valent to the divalent state (Sunderman and Selen,
1968). Such oxidation requires a 2-electron transfer from nickel at the
site(s) of oxidation and it may be that reactive intermediates, free radicals
012NIX/A 52 3/21/83
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PRELIMINARY DRAFT
necessary in such transformation, have been responsible for provoking a
neoplastic response roughly analogous to what happens in ionizing radiation.
From the above information, it therefore becomes apparent that there
are likely several mechanisms for nickel carcinogenesis.
5.2.1.2 Clinical Studies—Statistically excessive respiratory tract cancers
in workmen at nickel refineries have been widely and conclusively demon-
strated, and there exists wide agreement that these are principally the
effect of inhalation of respirable particles of metallic nickel, nickel
subsulfide, nickel oxide, and nickel carbonyl (National Institute for
Occupational Safety and Health, 1977a, 1977b; International Agency for
Research on Cancer, 1976; Nickel. National Academy of Sciences, 1975).
According to the International Agency for Research on Cancer (1976):
"Epidemiological studies conclusively demonstrate an excessive risk of
cancer of the nasal cavity and lung in workers at nickel refineries. It is
likely that nickel in some form(s) is carcinogenic to man."
Inasmuch as respiratory tract cancers have occurred in industrial
facilities that are metallurgically diverse in their operations, carci-
nogenicity probably resides in several compounds of nickel (Nickel. National
Academy of Sciences, 1975). This is certainly consistent with the animal
models of carcinogenicity described in the previous section. Furnace
workers appear to have the highest risk in this regard, and freshly formed
hot nickel dusts from some roasting procedures may be especially carcino-
genic.
In Table 5-3 is an earlier tabulation (Nickel. National Academy of
Sciences, 1975) of the numbers of different types of cancers of the lung
and nasal cavities seen in nickel workers. As of March 1977, Sunderman
(1977) had tabulated 477 cases of lung cancer and 143 cases of cancers of
the nose and paranasal sinuses. Other excess cancer risk categories re-
ported are laryngeal cancers in Norwegian nickel refinery workers (Pedersen
et al. , 1973), gastric and soft tissue carcinomas in Russian nickel re-
finery employees (Saknyn and Shabynina, 1973), and the relatively rare
renal cancer in Canadian nickel electrolytic refinery workers (Sunderman,
1977).
5.2.1.3 Epidemiological Studies—Most of the epidemiological data on the
carcinogenicity of nickel is contained in studies of occupationally exposed
workers. Among these, nickel refinery workers have been studied most
012NIX/A 53 3/21/83
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PRELIMINARY DRAFT
TABLE 5-3. HISTOPATHOLOGICAL CLASSIFICATION OF CANCER OF THE LUNG
AND NASAL CAVITIES IN NICKEL WORKERS
Tumor Classification
Lung Cancer Nasal-Cavity Cancer
No. % No. %
Epidermoid carcinoma
(squamous cell)
Anaplastic
34
69
22
45
(undifferentiated) carcinoma
Alveolar cell carcinoma
Adenocarcinoma
Columnar cell carcinoma
Spheroidal cell carcinoma
Spindle cell carcinoma
Scirrhus carcinoma
Pleomorphic carcinoma
Reticulum cell carcinoma
TOTALS
13
1
1
0
0
0
0
0
0
49
27
2
2
0
0
0
0
0
0
100
6
0
0
2
1
1
1
15
1
49
12
0
0
4
2
2
2
31
2
100
Source: National Academy of Sciences (1975).
extensively. Other occupations involving exposure to various nickel com-
pounds have not been studied extensively and, consequently, the data avail-
able bears the limitations of initial exploration. The study populations
at risk and the periods of exposure are fragmentary as are the potentials
for the experience of mortality and development of detectable cancers in
view of the latency periods of cancers. The following presentation will,
therefore, be limited to data for nickel refinery workers.
The reports concern experience with cancer of the respiratory tract,
specifically the lung and nasal cavities, among nickel refinery workers.
The variety of processes for different raw nickel materials results in the
production of different nickel compounds and, consequently, workers at
012NIX/A
54
3/21/83
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PRELIMINARY DRAFT
specific refineries at different work stations are exposed in significantly
different ways.
The data have been summarized and reviewed by numerous authors and,
since the evidence is incontrovertible, there has been universal agreement
that nickel refinery workers were, at least in the past, at significantly
higher risk for cancer of the lungs and nasal cavity (Sunderman, 1977;
National Institute for Occupational Safety and Health, 1977a, 1977b; Inter-
national Agency for Research on Cancer, 1976; Nickel. National Academy of
Sciences, 1975). Since these reviews, Lessard et al., (1978) have provided
evidence that nickel refinery workers in New Caledonia also experience
increased risk to lung cancers. Sunderman (1979), in a review, points out
that in addition to the significantly higher risk for cancer of the lungs
and nasal cavities, increased risk has been found for cancer of the larynx
in Norwegian refinery workers and for gastric cancer and soft tissue sarcoma
in Russian refinery workers.
The nickel compounds which are implicated are insoluble dusts of
nickel subsulfide (Ni,Sp) and nickel oxides (NiO and Ni?0\); the vapor of
nickel carbonyl [Ni(CO)4]; and soluble areosols of nickel sulfate, nitrate,
or chloride (NiS04, NiN03, N1C12), (Sunderman, 1977).
The earliest epidemiological investigation of the increased risk of
cancer is that of the nickel refinery workers at Clydach, Wales, where the
Mond refining process had been used since the opening of the refinery in
1900. The mortality experience of these workers has been monitored con-
tinuously. The systematic retrospective investigations showed that there
were significant changes in risk for workers beginning employment after
1925, the year when the refinery had undergone basic changes in the re-
finery processes which resulted in control of pollutants and decrease of
exposure.
Doll et al. (1977) reported an update of the Clydach workers' studies.
Due to the passage of time, the number of workers and the years at risk had
increased, as had the period of observation of mortality. Table 5-4 shows
the population and man-years for Clydach. Table 5-5 shows the findings for
employment date cohorts and deaths from nasal sinus cancer, lung cancer,
all other malignant neoplasms, and all other causes.
The effects of changes in production processes and pollution control
likely contributed to the significant change of risk by 1930. In addition,
012NIX/A 55 3/21/83
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PRELIMINARY DRAFT
TABLE 5-4. NUMBER OF MEN FIRST EMPLOYED AT CLYDACH NICKEL REFINERY, WALES
AT DIFFERENT PERIODS AND MORTALITY OBSERVED AND EXPECTED FROM ALL CAUSES
Year of first
employment
Before 1910
1910-14
1915-19
1920-24
1925-29
1930-44
All periods
No. of
men
119
150
105
285
103
205
967
Man-years
of risk
1,980.0
2,666.5
2,204.0
7,126.5
2,678.0
4,538.5
21,193.5
Number
Observed
117
137
89
209
60
77
689
of deaths
Expected
102.01
92.84
55.44
146.25
51.91
60.42
508.87
Ratio of observed
and expected
deaths 0/E
1.15
1.48
1.61
1.43
1.16
1.27
1.35
Source: Doll et al. (1977).
it has been suggested that changes in the chemical composition of the raw
material (Table 5-6) also affected the change in risk. The hypothesis that
arsenic in the acid was responsible for the high lung cancer incidence in
workers first exposed prior to 1925 has been put forth by some investigators.
However, several lines of evidence, both from the study of other groups
occupationally exposed to nickel compounds and experimental animals, indi-
cate that this hypothesis is unlikely and that the nickel compounds them-
selves were the carcinogenic materials. For example, high cancer rates
occured in Ontario nickel refineries where the sulfuric acid has always
been arsenic-free (Sutherland, 1959). Also there is evidence that nickel
sulfide and nickel oxide, both of which were present, are carcinogenic.
Whatever the exact reasons for the change in risk around 1930, the
Clydach workers' studies establish the unquestionable existence of an
increased risk for nasal and lung cancers in nickel refinery workers. The
012NIX/A
56
3/21/83
-------
TABLE 5-5. MORTALITY BY CAUSE AND YEAR OF FIRST EMPLOYMENT, CLYDACH NICKEL REFINERY, WALES
on
No. deaths from
nasal sinus cancer
Year of first
employment
Before 1910
1910-14
1915-19
1920-24
1925-29
All periods
before 1930
1930-44
Observed
14
24
11
7 (1)
0 (1)
56 (2)
0
Expected
0.036
0.137
0.025
0.071
0.026
0.195
0.034
Ratio
0/E
389
649
440
99
0
287
0
No. deaths from
lung cancer
Observed
24
34
20
50
9
137
8
Expected
2.389
3.267
3.070
9.642
3.615
21.983
5.463
0/E
10.0
10.4
6.5
5.2
2.5
6.2
1.5
No. deaths from other
malignant neoplasms
Observed
10
10
10
27
7
64
11
Expected
14.637
13.549
8.064
20.902
7.247
64.399
8.786
Ratio
0/E
0.68
0.74
1.24
1.29
0.97
0.99
1.25
No. deaths from
other diseases
Observed
69
69
48
125
44
355
58
Expected
84.95
75.99
44.28
115.63
41.02
361.87
46.14
Ratio
0/E
0.81
0.91
1.08
1.08
1.07
0.98
1.25
Number of cases of nasal sinus cancer referred to as an associated cause of death shown in parentheses.
Source: Doll et al. (1977).
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PRELIMINARY DRAFT
studies also represent the findings of a "natural experiment" in that they
show significant decreases in these risks with significant removal of the
pollutants.
Pedersen et al. (1973) studied Norwegian nickel refinery workers in a
historical prospective study involving 1,916 men whose first employment at
the Falconbridge refinery near Kristiansand had started prior to 1961 and
who had been employed there for at least 3 years. Analysis was limited to
those alive in 1953 and follow-up continued to 1971. The results were
consistent with the results on Clydach workers first employed prior to 1930.
These workers had a 3.75-fold increased risk of lung cancer as well as a
27-fold increased risk of nasal cavity cancer. However, in Norway the
excess cancer deaths persisted at least up to the early 1950's. In addi-
tion, the excess risk from cancer of the larynx (International Classifica-
tion of Disease-ICD 161) was also significant. Two updates of the study
(Andersen et al. 1980; Pedersen and Andersen, 1978) had similar results.
The 1978 update used 2,241 men followed through the end of 1976; this
showed 62 lung cancers and 19 cancers of the nasal cavities. The 1980
update used 2,247 persons followed from 1953 to the end of 1979. In this
latest update there were 21 cancers of the nasal cavities versus .88 expected
for an observed to expected ratio of 23.9. For lung cancer the ratio was
3.7 (82 observed versus 22 expected). These ratios are only slightly
smaller than those of the initial study.
Further analysis of the Norwegian lung cancer data was done by Kreyberg
(1978), who was able to identify the histological character of the lung
cancers, the cigarette smoking status, and the employment history of the
lung cancer cases. The ability to control for these variables resulted in
establishing that Group I cancers, epidermal and small cell anaplastic,
were predominant and associated with cigarette smoking, Table 5-7. The
latency period of these Group I cancers also explained the apparent anomalies
in the development times for lung tumors when age at beginning of employ-
ment and age of beginning cigarette smoking had not been considered.
Figure 5-1 shows the effect of the differences in age at first employment
on the apparent decrease in latency period when defined as interval between
beginning of employment and diagnosis.
The exposed workers still show an increased risk of lung cancer,
though much of the risk appears to be attributable to cigarette smoking.
012NIX/A 59 3/21/83
-------
PRELIMINARY DRAFT
TABLE 5-7. SMOKING AND TUMOR INCIDENCE IN WORKERS
AT THE FALCONBRIDGE NICKEL REFINERY
Type of tumor
Series I
Epidermoid carcinoma
Small cell anaplastic carcinoma
Group II tumor
Series II
Epidermoid carcinoma
Small cell anaplastic carcinoma
Adenocarcinoma
Smokers
10
2
0
13
4
3
Nonsmokers
3 (?)a
0
2
0
0
2
Smoking history not ascertainable. Allocation as nonsmokers is the assumption
against the hypothetical relationship.
Source: Kreyberg (1978).
Torjussen et al. (1979) reported on histopathological changes of the
nasal mucosa in active and retired nickel workers from Falconbridge as well
as controls. Biopsy materials were scored from 0 to 7, with 6 representing
epithelial dysplasia and 7 carcinoma or carcinoma J_n situ. Table 5-8
reports the findings. There were two previously undetected cancers among
the exposed active workers.
Quantitative analysis for nickel concentrations of nasal mucosa samples
for the same individuals was also performed and reported by Torjussen and
Andersen (1979). The nickel concentrations are shown in Table 5-9, and
indicate that the nickel workers, whether active or retired, have much
larger concentrations in these tissues than the controls. The elevated
level in retired workers points to the body retention of nickel with moder-
ate clearance.
012NIX/A 60 3/21/83
-------
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PRELIMINARY DRAFT
TABLE 5-9. NICKEL CONCENTRATIONS IN NASAL MUCOSA IN NICKEL WORKERS,
RETIRED NICKEL WORKERS AND CONTROLS
Category of
subjects/work
Roasti ng/smel ti ng
Electrolysis
Non-process
All nickel workers
Retired nickel workers
Controls
Number of
subjects
97
144
77
318
15
57
Concentrati
on
(ug/100 g, wet weight)
Mean
467.2
178.1
211.1
273.9
114.4
12.9
SD±
594.6
234.7
300.7
412.1
178.2
20.3
Source: Torjussen and Andersen- (1979).
Correlation between nickel concentrations in the mucosa and years of retirement
was examined and the correlation coefficient was reported as r = -0.434
(which was statistically significant in a one-sided test). Figure 5-2
shows these data.
The work from Falconbridge indicates that sophisticated screening and
diagnostic procedures can and do locate unknown cancers and cancers J_n situ
among nickel refinery workers and bring dysplasias under surveillance, so
that mortality may be prevented or reduced. Nelems et al. (1979), in a
study of Canadian nickel refinery workers, reported identification of 12
workers among 268 screened who had cancerous lesions or sputum changes.
Mortality in 10 has been prevented at the time of reporting. The cancers
had been unknown and were located in the respiratory tract, ranging from
the maxillary sinus or larynx to the lung itself.
Another historical prospective study was conducted in 1959 by Sutherland
among Canadian nickel refinery workers in Port Colborne, Ontario. Sutherland
gathered data on all employees at the refinery with five years or more of
service who were on the payroll in January 1930. Age specific male death
rates from Ontario were used to calculate the expected number of deaths in
012NIX/A 63 3/21/83
-------
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CONCENTRATION,
Ni/IOOg NASAL MUCOSA (WET WT.)
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PRELIMINARY DRAFT
the refinery cohort. Sutherland found that these workers had 2.2 times the
expected number of deaths from lung cancer and 37 times the expected deaths
from nasal cavity cancer. An updating of this study to include deaths
until 1974 shows similar relative risks (International Nickel Company,
1976). Environmental studies reported on the plant indicated high exposure
to nickel dust (Sutherland, 1959) and nickel oxide (National Institute of
Occupational Safety and Health, 1977a), as well as other nickel compounds.
As mentioned above, this study provides evidence against the hypothesis
that arsenic was the carcinogenic agent to which Clydach workers were exposed
prior to 1925, since sulfuric acid used in Ontario refineries has always
been arsenic-free.
Although epidemiological occupational studies provide substantial
evidence that exposure to airborne nickel in dust, mist, or fumes increases
the risk of respiratory cancer, it is difficult to determine which nickel
compounds are carcinogenic in the occupational setting. In nickel re-
fineries, exposure to several nickel compounds occurs simultaneously.
Attention has been focused on the respirable particles of nickel, nickel
sulfide, nickel oxide, and carbonyl vapor as the possible causes of cancer.
5.2.1.4 In-Vitro/In-Vlvo Correlates of Nickel Carcinogenesis—A number of
studies employing nickel compounds in various tests systems and i_n vivo
data have been reported which shed light on some of the mechanisms by which
carcinogenic metals in general, and nickel in particular, may express such
effects in intact organisms. A recent review by Sunderman (1979) has
summarized much of the pertinent literature. These test systems are tabu-
lated in Table 5-10.
Several authors have noted that the nucleus is enriched in nickel when
different nickel compounds are employed in various experimental systems to
assess subcellular distribution of the element. Webb and coworkers (1972)
found that 70-90 percent of nickel in nickel-induced rhabdomyosarcomas is
sequestered in the nucleus, of which half is in the nucleolus and half in
nuclear sap and chromatin. Furthermore, nickel binding to RNA/DNA has been
shown by both Beach and Sunderman (1970), using Ni(CO.) and rat hepatocytes,
and Heath and Webb (1967), in nuclei from Ni^S^-induced rat rhabdomyosarcomas.
IB vivo inhibition of RNA synthesis by nickel compounds has also been
demonstrated (Witschi, 1972; Beach and Sunderman, 1970).
012NIY/A 65 3/21/83
-------
PRELIMINARY DRAFT
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PRELIMINARY DRAFT
Several reports, those of Si rover and Loeb (1977) and Miyaki et al.
(1977), document the effect of nickel ion (nickel sulfate) in increasing
the error rate (decreasing the fidelity) of DNA polymerase in E. coli and
avian myeloblastosis virus.
A number of studies (Table 5-10) using test systems of varying com-
plexity have documented both the direct cellular neoplastic transformation
potency of soluble nickel (nickel sulfate) and insoluble Ni3S2, Ni'3Se2 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, 1979b; 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 into 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 synthetics (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 com-
pounds with carcinogenic activities can induce damage to DNA and form DNA-
protein crosslinks.
5.2.2 Nickel Mutagenicity
5.2.2.1 Nickel Mutagenesis in Experimental Systems—The mutagenic activity
of nickel compounds has been reviewed by Flessel (1979) and Sunderman
(1981).
Some recent reports involving eukaryotic cell culture systems treated
with various nickel compounds indicate some mutagenic potential (Wulf,
1980; Amacher and Pail let, 1980; Nishimura and Umeda, 1979; Umeda and
Nishimura, 1979; Miyaki et al., 1979).
Miyaki et al. (1979) examined the mutations at the hypoxanthine-guanine
phosphoribosyl transferase locus in Chinese hamster V79 cells induced by
nickel chloride, using development of resistance to 8-azoguanine as the
endpoint. "Weak" mutagenicity, in the words of the authors, was noted at
nickel concentrations up to 0.8 millimolar but, as the authors pointed out,
the cytotoxicity of the nickel ion was such as to preclude study of higher
012NIY/A 68 4/1/83
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concentrations. It is possible that a dose-response relationship would
exist at increasing levels, if cytotoxicity did not intervene. However, in
the actual case, cell toxicity becomes the endpoint for concern, not muta-
genicity, with elevated levels.
It should be noted that this cell culture study cannot be compared
directly to the microbial assay systems, in part because of cell membrane
permeability differences in mammalian versus microbial cells (vide infra).
Amacher and Paillet (1980) tested seven inorganic metal salts, includ-
ing nickel chloride, for their potential to induce trifluorothymidine-resistant
(TFT ) mutants in L5178Y/TK mouse lymphoma cell by directly exposing
cells to varied doses of each compound for three hours. Nickel chloride
consistently produced dose-related increases in the absolute number of
TFT es mutants as well as increases in mutation frequencies at compound
concentrations permitting greater than 20 percent survival (cytotoxicity
precluding the study of mutants at higher concentrations). Cell survival
_4
as percent of control ranged from 5 percent at 7.12 x 10 M to 49 percent
at 2.25 x 10 M. Corresponding mutation frequencies (per 10 survivors)
ranged from 1.52 to 0.33, respectively. Cultures treated with 1 percent
saline for three hours served as controls. At 100 percent cell survival,
controls had a mutation frequency of 0.20. The authors did not report any
statistical analysis distinguishing controls from treated cultures.
Wulf (1980) investigated sister chromatid exchange (SCE) in human
_3
lymphocytes exposed to nickel ion as sulfate at levels of 2.33 x 10 to
2.33 x 10"6 mol/je. In the SCE test system, the relative increase in SCE
produced compared to controls is taken as a measure of mutagenic potential.
At all concentrations, the number of SCE was significantly higher (one-sided
Student's t-test) than in the control series, with the exception of the
highest level where the cytotoxicity to the cells was too severe to assess
SCE. Each time the nickel concentration was increased 10 times, the SCE
count increased approximately 20 percent indicating a dose-response rela-
tionship: at 10 mol/£ the increase was 56 percent versus controls (p <
.0005); at 10 the increase was 36 percent (p < .0025); and at 10 the
increase was 16 percent (p < .5).
The induction of chromosomal aberrations in FM3A mammary carcinoma
cells (from C3H mice) in culture, using nickel chloride, nickel acetate,
potassium cyanonicklate (KNKCN).) and nickel sulfide, was studied by
012NIY/A 69 3/21/83
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Umeda and Nishimura (1979). Nickel chloride and nickel acetate induced few
aberrations when tested at levels of 1.0 x 10 , 6.4 x 10 , 3.2 x 10 and
~4
2.0 x 10 M for up to 48 hours. Potassium cyanonicklate, at the same
levels, induced definite increases in aberrant metaphase cells which con-
sisted mainly of gaps. The aberrant frequency for this compound at 48
hours was 37, 28, 8 and 12 percent for the above mentioned levels. Nickel
sulfide also showed a definite increase in the frequency of aberrant meta-
phases at 48 hours—29 percent at 1.0 x 10"3; 12 percent at 6.4 x 10~4, and
~4
2 percent at 3.2 x 10 . Although all four compounds demonstrated toxicity
_2
at a concentration of 10 M, their respective abilities to induce chromo-
somal aberrations were quite variable and no clear dose-response trends
emerged for any of the compounds. In addition, the authors reported
(Nishimura and Umeda, 1979) that the chromosomal aberration data for the
_2
Ni(CN)» anion was possibly complicated by the mutagenic behavior of the
cyanide groups. The authors did not report any statistical treatment of
the data.
In a continuation of their experimental model, Nishimura and Umeda
(1979) reported that the difference in chromosomal aberrations induced by
the four nickel compounds could not be elucidated by differences in cell
incorporation or by uptake differences of labeled precursors of DNA, RNA or
protein. The authors were able to state that the differences seemed related
to the cumulative toxicity of the compounds; only slight compound differences
were observed for treated cells to regain their ability to divide during
periods of recovery. The authors speculated that the slight differences in
regained ability to divide may have been related to the solubility of the
compounds, but suggested that further data collection was necessary to
confirm this relationship. Again, no statistical treatment of the data
was reported.
Mathur et al. (1978) conducted chromosomal studies on male albino rats
treated for a period of 7 and 14 days at doses of 3 and 6 mg Ni/kg. (The
nickel was administered intraperitoneally as NiSO^ dissolved in 1 ml of 0.9
percent NaCl. The controls received equal volumes of normal saline.)
Nickel treatment did not induce marked chromosomal changes in bone marrow.
Although rats administered 6 mg Ni/kg for 14 days showed a few chromatid
breaks, according to the authors, these did not differ significantly from
012NIY/A 70 3/21/83
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PRELIMINARY DRAFT
controls. (The authors used a Student's t-test; levels of significance for
this portion of the study were not reported.) Spermatogonial cells did not
show any chromosomal aberrations at either concentrations and durations of
nickel exposure.
Unlike other carcinogenic metals, nickel has given consistently nega-
tive results for mutagenicity in microbial test systems (Flessel, 1978)
such as E. coli (Green et al., 1976) and the rec-assay in B. subtil is
(Kanematsu et al. , 1980; Nishioka, 1975).
In Nishioka's study, 0.05 ml aliquots of 0.05 M solution of nickel
(II) chloride was used in the rec-assay protocol with B. subtil is. No
effect was seen on difference in inhibition for the Rec /Rec strain.
Using an improved rec-assay with B. subtil is, Kanematsu et al. (1980)
tested for mutagenic activity using 0.05 ml aliquots of 0.005 - 0.5 M
solution of nickel chloride (NiCl^) and nickel oxide (NiO, Ni^O.,). The
improved procedures consisted of the insertion of a cold incubation before
incubation of plates at 37°C, the cold incubation considerably increasing
the assay sensitivity by prolonging the contact period of the compound with
non-growing cells. Even with the improved technique, the authors reported
negative results for all nickel compounds tested.
Green et al. (1976) used the E. coli reversion fluctuation test to
assess nickel (II) chloride mutagenicity over a 5-25 ppm range and found no
mutagenic activity for the nickel salt.
In a mutagenicity screening survey using the rec-assay in B. subtil is,
Shirasu et al. (1976) reported negative results when testing two nickel-containing
pesticides--Baykel, nickel propylenebis (dithiocarbamate) and Sankel,
nickel dimethyldithiocarbamate. In subsequent tests, the authors also
reported negative results for these two compounds (using one percent solutions)
when carrying out reversion-assays on plates using E. coli WP2 and Salmonella
TA series of strains; thus, supporting the findings in the above studies
that nickel gives negative results in microbial test systems.
5.2.3 Nickel Allergenicity
Nickel dermatitis and other dermatological effects of nickel have been
extensively documented in both nickel worker populations and populations at
large (Nickel. 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
012NIY/A 71 3/21/83
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PRELIMINARY DRAFT
a widespread problem in individuals not having occupational exposure to
nickel but encountering an increasing number of nickel-containing commodi-
ties in their everyday environment.
5.2.3.1 Clinical Aspects of Nickel Hypersensitivity--Qccupational sources
of nickel that have been associated with nickel sensitivity include mining,
extraction, and refining of the element as well as such operations as
plating, casting, grinding, polishing, and preparation of nickel alloys
(Nickel. 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 (Nickel. National Academy of Sciences, 1975).
Nonoccupational exposure to nickel leading to dermatitis includes
nickel-containing jewelry, coinage, tools, cooking utensils, stainless
steel kitchens, prostheses, and clothing fasteners. Women appear to be
particularly at risk for dermatitis of the hands, which has been attributed
to their continuous contact with many of the nickel-containing commodities
noted above (Maiten and Spruit, 1969).
Nickel dermatitis in nickel miners, smelters, and refiners usually
begins as itching or burning papular erythema in the web of the fingers and
spreads to the fingers, wrists, and forearms. Clinically, the condition is
usually manifested as a papular or papulovesicular dermatitis with a ten-
dency 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: spread-
ing of the dermatitis in a symmetrical fashion; and (3) associated: af-
flicted areas having no relation to contact areas. Furthermore, the affliction
may persist some time after removal of obvious sources of exposure.
A clear relationship between atopic dermatitis and that elicited by
nickel has been muddied by conflicting reports in the literature. Watt and
Baumann (1968) showed that atopy was present in 15 of 17 young patients
with earlobe nickel dermatitis, but other workers (Caron, 1964; Marcussen,
1957; Calnan, 1956; Wilson, 1956) have failed to demonstrate any connection
between the two disorders. Juhlin et al. (1969) demonstrated elevated
immunoglobulin (IgE) levels in atopy patients, while Wahlberg and Skog
(1971) saw no significant increases of IgE in patients having nickel and
atopic dermatitis histories.
012NIY/A 72 3/21/83
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The occurrence of pustular patch test reactions to nickel sulfate has
been considered significant in connecting nickel and atopic dermatitis
(Becker and O'Brien, 1959). Uehara et al. (1975) have reported that pus-
tular patch test reactions to 5 percent nickel sulfate were regularly
produced in patients with atopic dermatitis, but only when applied to areas
of papulae, erythema, lichenification, and minimal trauma; such response
seldom occurred on normal-appearing skin surface. Furthermore, trauma-
tizing the test areas in control, as well as dermatitic subjects, furnished
positive responses. These workers suggest that pustular patch testing is
primarily a primary irritant reaction.
Christensen and Moller (1975a) found that of 66 female patients with
hand eczema and nickel allergy, 51 had an eczema of the pompholyx type;
i.e., a recurring itching eruption with deeply seated fresh vesicles and
little 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 influenced 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, claimed by the authors to be at the high end of dietary
intake in Scandinavian populations.
The role of oral nickel in dermatitic responses has also been demon-
strated by Kaaber et al. (1978), who investigated the effect of a low
nickel diet in patients with chronic nickel dermatitis presenting as hand
eczemas of dyshidrotic morphology. Of 17 subjects in the clinical trial,
nine showed significant improvement during a period of 6 weeks on a low
nickel diet. Of these nine showing improvement, seven had a flare-up in
their condition when placed on a normal diet. Furthermore, there was no
correlation apparent between the level of urinary nickel and the degree of
improvement following the diet. These authors recommend 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.
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While Kaaber et al. (1978) found little correlation between nickel
excretion and the status of dermatitis in their patients, Menne and Thorboe
(1976) have reported elevated urinary nickel levels during dermatitis
flare-ups. deJongh et al. (1978) found limited correlation between plasma
nickel level, urinary excretion of nickel, and the clinical activity of the
condition in a patient followed during two periods of 5 and 6 weeks each.
Internal exposures to nickel associated with nickel sensitivity and
arising from prosthesis alloys have been reviewed (Fisher, 1977; Nickel.
National Academy of Sciences, 1975; Samitz and Katz, 1975), and much 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 10-14 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 (Nickel. National Academy of
Sciences, 1975; Samitz and Katz, 1975). Apparently, sufficient solubiliza-
tion of nickel from the surface of the material appears to trigger an
increase in dermatitis activity. In support of this, Samitz and Katz
(1975) have shown the release of nickel from stainless steel prosthesis by
the action of blood, sweat, and saline.
Fisher (1977), in his review, has counseled caution in interpreting
the reports and has recommended specific criteria for proof of nickel
dermatitis from a foreign body to include evidence of surface corrosion and
sufficient corrosion to give a positive nickel spot test.
Determination of nickel dermatitis classically involves the use of the
patch test and site response to a nickel salt solution or contact with a
nickel-containing object. The optimal nickel concentration in patch test
solution is set at 2.5 percent (nickel sulfate). Patch test reactions may
be ambiguous in that they can reflect a primary irritation rather than a
pre-existing sensitivity (Uehara et al. , 1975). Intradermal testing as
described by Epstein (1956) has also been employed, but the procedure
appears to offer no overall advantage to the conventional method (Nickel.
National Academy of Sciences, 1975).
The effect of nickel on lymphocyte transformation and the utility of
this phenomenon as an u» vitro alternative to conventional patch testing
with its attendant ambiguity and dermatological hazards merit discussion.
012NIY/A 74 3/21/83
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PRELIMINARY DRAFT
Transformation of cultured human peripheral lymphocytes as a sensitive
jj} vitro screening technique for nickel hypersensitivity versus the classi-
cal patch testing has been studied in a number of laboratories, and the
earlier conflicting studies have been reviewed (Nickel. 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.
The comparable value of the leukocyte migration inhibition test as an
alternative technique remains to be demonstrated conclusively (Macleod et
al., 1976; Jordan and Dvorak, 1976; Thulin, 1976).
The induction of nickel sensitivity in human subjects has been claimed
by Haxthausen (1936) and Burckhardt (1935). In their subjects, prior
sensitivity was not ruled out. Furthermore, the concentration of the
sensitizing solution, 25 percent, may easily have induced an irritation
response. More recently, Vandenberg and Epstein (1963) successfully sensi-
tized 9 percent (16 of 172) of their clinical subjects.
One area of controversy with regard to nickel dermatitis involves the
question of hypersensitivity to groups of metals, i.e., cross sensitivity,
and various sides of the issue have been reviewed (Nickel. National Academy
of Sciences, 1975). Of particular concern is the existence of hypersensi-
tivity to both nickel and cobalt, as the elements occur together in most of
the commodities with which susceptible individuals may come in contact.
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 (Nickel. 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-alaline) was a better sensi-
tizer than nickel alone, while Thulin (1976) observed that inhibition of
leukocyte migration in 10 patients with nickel contact dermatitis could be
elicited with nickel bound to bovine and human serum albumin or human
epidermal protein, but not with nickel ion alone. Hutchinson et al. (1975)
noted nickel binding to lymphocyte surfaces from both sensitive and control
subjects; thus, nickel binding, per se, is not the key part of the immuno-
logical response (lymphocyte transformation).
012NIY/A 75 3/21/83
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5.2.3.2 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
previously cited do not cover properly designed and executed samples of
either total populations or selected population segments which would permit
projection of findings to the total population from which subjects were
selected. Only some industrially-exposed worker populations have been
surveyed or monitored in any statistically adequate manner, and these
studies will be reported later in connection with nickel carcinogenesis.
The literature on adverse health effects in relation to nickel exposure for
the general population is limited to the investigation of nickel dermatitis
and nickel sensitivity, with only occasional reports related to other
diseases or conditions. These latter are so fragmentary that they will not
be considered.
5.2.3.2.1 Nickel sensitivity and contact dermatitis. Nickel dermatitis
and other dermatological effects of nickel have been extensively documented
in both nickel worker populations and populations at large (Nickel. 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 widespread problem
among individuals not having occupational exposure to nickel but encounter-
ing an increasing number of nickel-containing commodities in their every-day
environment.
There has not been a single population survey using a probability
sample to determine the incidence or prevalence of this allergic condition
and its clinical manifestation, contact dermatitis. The literature is
mostly limited to studies of patient populations, and this provides an
unreliable basis for projection to the general population. Clinic popula-
tions in specialty clinics are either self-selected and represent indi-
viduals 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 charac-
teristics. 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.
012NIY/A 76 3/21/83
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Large scale surveys 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).
Peltonen (1979) and Prystowsky et al. (1979) departed from the practice of
surveying patient samples to surveying subjects more representative of the
general population, Table 5-11.
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. Women
always show a higher positive reaction rate than do men, and elicitation of
contact history reveals universal exposure to the ubiquitous metal and its
compounds.
The North American study permits examination of race as a factor in
positive reaction rates. As Table 5-12 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 5-11 shows a summary of findings from large scale studies. The find-
ing 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 popula-
tion, and women in particular, are at risk for this condition.
Table 5-13 shows, for a range of studies, the proportion of nickel
sensitives 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 negli-
gible 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
ladies' hairdressers; they showed a positive reaction rate of 40 percent to
nickel sulfate (5 percent) solution. Wahlberg1s finding for atopy are in
accord with the earlier work by Caron (1964).
012NIY/A 77 3/21/83
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PRELIMINARY DRAFT
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TABLE 5-12. NORTH AMERICAN CONTACT DERMATITIS GROUP PATCH TEST RESULTS FOR
2.5 PERCENT NICKEL SULFATE IN 10 CITIES
Positive Reactions
Subjects
Black
White
All
Total
Females
Males
Total
Females
Males
Total
Females
Males
Total No.
79
64
143
612
445
1057
691
509
1200
No.
14
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20
89
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111
103
28
131
Percent
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12.7
4.4
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14.9
5.5
11.2
Source: North American Contact Dermatitis Group (1973).
Spruit and Bongaarts (1977b) and Wahlberg (1975) reported that posi-
tive reaction to nickel sulfate occurs at very low dilution levels in some
individuals. Wahlberg found 5 of 14 positive reactors sensitive to <0.039
percent nickel sulfate solution. Spruit and Bongaarts (1977b) found one
female patient with a positive reaction when the solution was 10 ug Ni /&.
The avoidance of contact with nickel suggests itself as an obvious
preventive measure. Kaaber et al. (1978) reported encouraging results in
attempts to manage chronic dermatitis by reduction of nickel intake via the
diet. However, total avoidance of contact with nickel would be extremely
difficult, as it is commonly found in articles and substances found in the
home and in metals used for jewelry, metal fasteners of clothing, coinage,
etc. Some preparations used in hairdressing contain nickel, and conse-
quently hairdressers exhibit nickel dermatitis. The consequences of nickel
contact dermatitis seems to vary with the surrounding social factors. Male
factory workers appear not to be handicapped by it (Spruit and Bongaarts,
1977b) and continue in their work; hairdressers leave their occupation when
they develop dermatitis (Wahlberg, 1975).
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TABLE 5-13. HAND ECZEMA IN PERSONS SENSITIVE TO NICKEL
Author
Bonnevie (1939)
Wilson (1956)
Cat nan (1956)
Fisher and
Shapiro (1956)
Wagmann (1959)
Marcussen (1960)
Wahlberg and
Nickel
sensi-
tive
63
85
400
40
62
621
53
Hand
eczema
No.
32
14
81
16
22
272
41
Percent
50.2
16.5
20.0
40.0
35.0
43.2
77.3
Skog (1971)
Cronin (1972)
Christensen and
84
50
60.0
Moller (1975a,b)
Peltonen (1979)
185
44
96
9
52.0
20.5
Source: Adapted from Peltonen (1979).
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
severity, the consequences, and the costs of the condition.
5.2.3.2.2 Sensitivity to nickel in prostheses. Stainless steel, chrome,
and other metal alloys used in prostheses and other surgical devices fre-
quently contain proportions of nickel that have proved to cause reactions
in patients ranging from itching to dermatitis to tissue breakdown requir-
ing replacement of the device. The National Academy of Sciences report
(1975) lists the following devices and prostheses reported in the litera-
ture as associated with adverse reactions to their nickel contents: wire
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suture materials; metallic mesh for nasal prostheses; heart valves; intra-
uterine contraceptive devices; batteries for implanted pacemakers; alloys
for dental castings and fillings; and orthopedic implants.
The alloys, contrary to general assumption, appear not to be biologi-
cally inert and produce adverse reactions in some of the individuals sensi-
tive to nickel. Two cases of cancer in humans at the site of steel plate
implantation were reported. These cancers developed 30 years after implan-
tation in both cases. In both cases the alloys of the plates and screws
differed and possibly electrolysis and metallic corrosion may have occurred.
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 replacement and followed up these patients to ascertain if sensi-
tivity 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 experi-
ence 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
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nickel and one to cobalt. This included one woman with a negative preoperative
patch test but who had a history of eczema from garters and who was positive
on the postoperative patch test. None of the 66, regardless of sensitivity
status, had shown pain, loosening of the prosthesis, infection, or skin
symptoms during the postoperative period of the study which was approximately
two years. This represents a postoperative conversion rate of 6 percent
within approximately two years. A sensitivity rate of 4.6 percent to
nickel by patch test was found in the 173 patients without previous bone
surgery.
Since the publication of the National Academy of Sciences report,
additional reports have appeared augmenting the list of items which have
created sensitization and symptoms.
This special area of exposure 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. The problem does not constitute a risk for the general population
and is not related to exposure to nickel in environmental media.
5.2.3.3 Animal Studies of Nickel Sensitivity—Useful experimental animal
models of nickel sensitivity have only slowly been forthcoming and only
under very specialized conditions.
Nilzen and Wikstrom (1955) reported the sensitization of guinea pigs
to nickel via repeated topical application of nickel sulfate in detergent
solution. Samitz and Pomerantz (1958), however, have attributed this to
local irritation rather than true allergenic response. Samitz et al.
(1975) were unable to induce sensitization in guinea pigs using any nickel
compound from complexation of nickel ion with amino acids or guinea pig
skin extracts.
Wahlberg (1976) employed intradermal injection of nickel sulfate in
highly sensitive guinea pigs. The reactions to the challenge were statis-
tically greater than with control animals. Turk and Parker (1977) reported
sensitization to nickel manifested as allergic-type granuloma formation.
This required the use of Freund's complete adjuvant followed by weekly
intradermal injections of 25 ug of the salt after 2 weeks. Delayed hyper-
sensitivity reactions developed in two of five animals at 5 weeks by use of
a split-adjuvant method. Interestingly, these workers also observed sup-
pression of the delayed hypersensitivity when intratracheal intubation of
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nickel sulfate was also carried out on these animals (Parker and Turk,
1978).
5.2.4 Nickel Teratogenicity and Other Reproductive Effects
While it is not a necessary condition of J_n utero toxicity that a
toxic element actually enter the fetus, the observation of such entry of an
agent helps strengthen a case for overt and subtle teratogenesis. As noted
earlier in the discussion on metabolic routes of absorption (Section 4.1.4),
nickel crosses the placental barrier in animals and limited data suggests
transplacental movement in man.
Teratogenic data for various animal species have been reported for
inhalation of nickel carbonyl (Sunderman et al., 1979a, 1980b), and injec-
tion of nickel chloride (Gilani and Marano, 1980; Lu et al., 1979; Perm,
1972). No evidence of teratogenicity was seen in two studies using rats
injected with nickel chloride or nickel subsulfide (Sunderman et al.,
1978a, 1978b) or rats fed nickel chloride (Nadeenko et al., 1979).
In the Sunderman et al. (1979a) report, two separate studies were
described. In the first, pregnant Fischer 344 rats were allowed to breathe
either ambient air (controls) or nickel carbonyl on day 7 of gestation for
a single 15-minute exposure at a level of 0.3 mg Ni(CO)./liter in an inha-
lation chamber. Progeny were studied at birth and for up to 16 weeks.
Control animals had no malformed pups in any of the litters (0/8 litters)
whereas exposed animals had malformed pups in the majority of litters (6/9
litters) (p < 0.01). The live pups/litter were statistically significantly
lower in the carbonyl-exposed group (p < 0.001, 10.9 in controls versus 8.7
in exposed). Total number of pups with malformations, 22 out of 78 in the
exposed group, included 4 with bilateral anophthalmia, 7 with unilateral
anophthalmia, 5 with bilateral microphthalmia, 4 with unilateral micro-
phthalmia, and 2 with anophthalmia and microphthalmia. These ophthalmic
malformations—lack of eyes or abnormally small eyes—were the only overt
teratogenic signs. Furthermore, the rat pups in the exposure group showed
significant body weight deficits over controls at both 4 and 16 weeks for
males: 41 ± 6 g versus 50 ± 8 g at 4 weeks; 232 ± 15 g versus 267 ± 24 g
at 16 weeks, p < 0.001.
In the second study, pregnant dams were exposed to ambient air (con-
trols), carbon monoxide (positive controls), or nickel carbonyl at levels
of 0.08, 0.16, and 0.30 mg/liter, for 15 minutes at day 7 or 8 of gestation.
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In this latter study, where fetuses were examined at day 20 via caesarian
section, ophthalmic malformations were seen to have a dose-response relation-
ship. At an exposure of 0.08 mg/liter nickel carbonyl, the number of
fetuses with malformations was not statistically different from controls,
while levels of 0.16 and 0.30 showed 15 (of 113 total live fetuses) and 29
(of 91 total live fetuses), respectively, with malformations (p < 0.001
versus controls). Again, the types of malformations centered on the
ophthalmic tract. It appeared that the timing of exposure to nickel
carbonyl was crucial in this study. Exposure at day 9 of gestation gave
results not different from controls. Since the carbon monoxide control
group showed 0 response teratogenically, and CO was employed at levels well
above (15X greater) any amounts calculated to arise from Ni(CO)4 decom-
position, it could be concluded that nickel carbonyl itself was the teratogen
and that this type of teratogenicity appears to be peculiar to nickel
carbonyl.
In this same report, the authors drew implications of their results
for pregnant women working in areas where nickel carbonyl release may
occur. This prompted a response from Warner (1979), who indicated that the
Inco refinery at Clydach, Wales, where women were employed intermittently
in the early and mid-1900s, has no clinical data suggesting teratogenic
behavior. Warner (1979) also pointed out that in the Sunderman et al.
(1979a) study, air levels were 3-18 times greater than those measured in
the refinery in the late 1950s. No data were given for earlier levels.
In a more recent report, Sunderman et al. (1980b) reported on the
teratogenicity and embryotoxicity of nickel carbonyl in Syrian hamsters.
Groups of pregnant hamsters inhaled Ni(CO). (0.06 mg carbonyl/liter/15
minutes) on days 4, 5, 6, 7 or 8 of gestation. Animals were sacrificed on
day 15 of gestation and the fetuses were examined for evidence of malforma-
tions. For exposure on days 4 or 5 of gestation, the proportion of litters
with malformed fetuses was 33 percent and 24 percent respectively, versus 0
percent in control litters (p < 0.05). The malformations in affected
litters included 7 fetuses with exencephaly, 9 with cystic lung, one with
exencephaly plus fused rib, and one with anophthalmia plus cleft palate.
Exposure at day 6 or 7 of gestation yielded a much lower incidence of
malformations: one fetus with fused ribs and 2 fetuses with hydronephrosis.
Of interest in this study is the fact that the micro- and anophthalmia seen
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in rats exposed i_n utero was not seen in hamsters, the latter showing
exencephaly and cystic dysplasia of pulmonary parenchyma.
Perm (1972), in a comprehensive study of the mammalian teratology of
metals, reported that nickel (II) acetate at a level of 30 mg/kg injected
intravenously into pregnant golden hamsters at day 8 of gestation induced
"a few general malformations" in surviving embryos. No further details
were reported as to the nature of the malformations or the statistical
significance of their occurrence. Embryotoxicity data, however, was pro-
vided for a nickelous acetate given via the above protocol, using dosing
levels of 2, 5, 10, 20, 25 and 30 mg/kg. The corresponding number of
resorbed embryos at these levels were 0, 1, 22, 10, 59 and 33, respectively,
for corresponding total embryo counts of 24, 22, 56, 55, 68 and 33, respec-
tively. The number of surviving abnormal embryos at these dosing levels
were 2, 1, 2, 1, 4 and 0, the last figure arising from the fact that there
were no survivors at the 30 mg/kg dose. The rate of embryo resorption
appeared to be dose-dependent in a more consistent manner than were the
numbers showing malformations.
Lu et al. (1979) have described the teratogenic effects of nickel (II)
chloride in mice. Pregnant mice of the ICR strain were given a single i.p.
injection of nickel chloride at a level of 1.2, 2.3, 3.5, 4.6, 5.7, or 6.9
mg Ni/kg at days 7-11 gestation. Abnormalities observed in fetuses, ranked
according to decreasing frequency of type of anomaly across the treatment
groups, were: rib and/or vertebral fusion; cleft palate; open eyelid; club
foot; ankylosis of extremity, cerebral hernia; exencephaly; micromelia and
acephaly. The five control groups for days 7, 8, 9, 10 and 11 of gestation
showed 0 percent abnormalities, except for day 9 where the control fre-
quency was 1.7 percent. The percent frequency of abnormalities was gener-
ally seen to increase with increasing dosage at a given period of gestation
and to be greatest at day 8 or 9 for a given dosing.
This study clearly showed a dose-response relationship for terato-
genesis and level of nickel (II) administration. At day 9, for example,
the frequency for abnormalities in the 1.2, 2.3, 3.5, 4.6, 5.7 mg/kg treat-
ment groups was 4.9, 13.0, 21.4, 50.8 and 69.4 percent, respectively, with
an observed 100 percent mortality in the 6.9 mg/kg exposure group. A
similar dose-response relationship between percentage of fetal deaths and
nickel dosing levels was recorded. It should be noted that the dosing
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levels represented approximately one-tenth of the LD-50 dose for the mothers.
Gilani and Marano (1980) demonstrated teratogenic effects of nickel
chloride in developing chick embryos receiving levels of 0.02 to 0.7 mg/egg
via injection into the air sacs at days 0-4 of incubation. Control eggs
received the same volume (0.1 ml) of saline vehicle. All embryos were
studied at day 8. Malformations observed included exencephaly, everted
viscera, short and twisted neck, deformed limbs, microphthalmia and hemor-
rhage.
Of the embryos that survived the injection on day 0 (at all dose
levels of nickel (II) ion), 48 percent had gross malformations, while from
injections at days 1, 2, 3 and 4 the respective percentages of gross mal-
formations were 50, 66, 16 and 22, indicating that embryogenesis at day 2
was most vulnerable to nickel ion's teratogenic potential. Saline-injected
controls showed a malformation incidence of 2 percent.
By contrast, Sunderman et al. (1978a) studied the teratogenic potential
of nickel (II) chloride and nickel subsulfide when injected into pregnant
rats on day 8 of gestation, using single i.m. dosing of 16 mg/kg nickel
chloride and 80 mg/kg nickel subsulfide and found no evidence for malforma-
tions among the fetuses.
5.2.4.1 Generalized EmbryotoxjcHy of Nickel Compounds--In all of the
studies cited above which showed teratogenic effects, generalized i_n utero
toxicity ranging from reduced fetus weights to fetal mortality was also
reported.
In the Sunderman et al. (1979a) study demonstrating the teratogenicity
of nickel carbonyl for rat fetuses when pregnant rats were exposed to a
15-minute inhalation interval, 0.30 mg/liter, the mean number of live
pups/litter in the exposed groups was 8.7 versus 10.9 in control animals,
statistically signficant at p < 0.001. Weights of live fetuses were signi-
ficantly reduced relative to control weights, p < 0.01 at exposure levels
of 0.08, 0.16 and 0.30 mg/liter, 15-minute interval, in a second study
(Sunderman, 1979a).
Perm (1972) found that nickelous acetate, when given as i.v. single
doses to pregnant hamsters, resulted in decreases in the numbers of surviv-
ing embryos and increases in embryo resorption with a dose-response rela-
tionship over the range 2-30 mg/kg, as noted above (Section 5.2.4).
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In the study of Lu et al. (1979), not only were the dose-response
relationships for malformations, but also for the number of resorbed fetuses
and fetal mortality when nickel was given as a single i.p. injection of the
chloride to pregnant mice over the dosing range 1.2-6.9 mg/kg and from the
7th to llth day of gestation. For example, exposure at day 9 of gestation
gave the following fetal death percentages for various exposures: 1.2 - 4.1;
2.3 - 11.1; 3.5 - 35.9; 4.6 - 77.7; 5.7 - 71.1; and 6.9 mg/kg - 100 percent.
Live fetus weights were signficantly reduced at an exposure level as low as
3.5 mg/kg on day 8 of gestation (p < 0.05, versus controls) and at higher
doses the level of significance was even greater (p < 0.01 versus controls).
In the study of Sunderman et al. (1980b), where pregnant Syrian hamsters
were exposed to nickel carbonyl by inhalation (0.06 mg/liter, 15 minutes)
on day 5 of gestation, the neonatal mortality was increased by day 4 post-
partum. Live pup numbers averaged 7.6 in exposed litters, versus 9.6 in
control litters (p < 0.01).
In the chick embryo study of Gilani and Marano (1980), a dose-response
relationship was seen for embryo mortality at day 0, 1, 2 and 3 when nickel
chloride was injected into eggs at levels from 0.02-0.7 mg/egg. For example,
on day 1 of incubation the percentages of viable embryos relative to injected
nickel levels were: 0.02 - 46; 0.05 - 46; 0.08 - 17; 0.1 - 17; 0.4 - 8;
0.7 mg - 4 percent. On the same day the control value was 92 percent
demonstrating a statistically significant difference between treated and
control eggs (p < 0.01).
Several studies have explored the effect on progeny of feeding nickel
compounds to pregnant animals.
Phatak and Patwardhan (1950) placed breeding pairs of albino rats on
diets containing 250, 500 or 1,000 ppm nickel and in the form of dispersed
metallic nickel catalyst, nickel carbonate or nickel soap at eight weeks
prior to breeding and continued through gestation, delivery and lactation.
No statistically significant effect was seen on litter size or newborn body
weights.
Ambrose et al. (1976) reported data for a three-generation study of
albino rats fed nickel sulfate in rat chow at levels of 250, 500 and 1,000
ppm of nickel. After 11 weeks of nickel-in-diet exposure, the females were
bred to males having the same dietary regimen. The first generation con-
sisted of two groups of offspring, Fla and Fib, derived from the remating
of the parent generation. For the second generation study, breeding pairs
from dams and sires exposed to nickel in Fib were then placed on the same
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diet. Progeny from this generation were carried through the same protocol;
subsequently, all generations were comprised of two groups of offspring.
The authors noted increased fetal mortality in the first generation at
all dietary levels of nickel; however, no statistical analysis was per-
formed on the stillbirth data. Decreased body weights of weanlings on the
1,000 ppm nickel diet were noted in all generations. In addition, nickel
exposure to this highest level significantly reduced the life span of rats
followed over a 2-year interval (p = 0.05). This study poses some inter-
pretive problems, however. Stillborn effects were only noted in the first
generation; however, it is possible that the absence of stillbirths in the
second and third generations represented a selection process that occurred
in the first generation. That is, all of the vulnerable members of the
litter died in the first generation, and the survivors selected for further
breeding represented a selection for resistance to j_n utero effects of
nickel. It should also be noted that no clear dose-response relationship
between exposure level and number of stillbirths were consistently seen for
both Fla and Fib offspring, this relationship only being apparent in Fib.
Schroeder and Mitchener (1971) reported that nickel ion (sulfate) in
drinking water at a level of 5 ppm over lifetime resulted in increased
numbers of runts and increased neonatal mortality in all 3 generations of a
3-generation study. However, a number of design problems exist with this
particular study. Diets were deficient in a number of trace elements,
animals were not randomly assigned to experimental groups, nor were effects
assessed on a litter versus individual animal basis. Furthermore, these
workers could not duplicate the results in a repeat study according to
their final progress report (Schroeder and Nason, unpublished).
5.2.4.2 Gametotoxic Effects of Nickel—Several studies have reported the
gametotoxic effects of injected nickel (II) salts in animals, specifically
with respect to spermatogenesis and testicular injury (Von Weltschewa et
al., 1972; Hoey, 1966; Kamboj and Kar, 1964).
Kamboj and Kar (1964) gave nickel nitrate either as a single intra-
testicular injection, 0.08 mMoles/kg (~ 5.0 mg/kg) into albino rats or as
30 s.c. injections over 30 days for a total of 5.0 mg/kg in Swiss mice.
Significant reduction in testicular weights was observed by day 7 in rats
and by day 2 in mice. In rats, damage to the seminiferous epithelium with
exfoliation and cell lipes was seen, such injury being transitory with
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interstitial regeneration occurring with time. Spermatozoa were not affected.
In the mice given repeated s.c. injections, there was shrinkage of semini-
ferous tubules and arrest of spermatogenesis at the primary spermatocyte or
spermatogonal stages, with no effect on testicular interstitium. Thus,
there was a species difference in the site of effect of nickel in testes.
Repeated s.c. administration of nickel ion (Hoey, 1966) as the sulfate
(2.4 mg Ni/kg, single or multiple injections) in male rats produced such
testicular effects as shrinkage of central tubules, hyperemia of inter-
tubular capillaries, and disintegration of spermatozoa in testicular tissue
as early as 18 hours after a single dose. Multiple dosing produced disin-
tegration of spermatocytes and spermatids with destruction of Sertoli
cells. Such effects were noted to be reversible.
Von Weltschewa et al. (1972) noted inhibition of spermatogenesis in
rats fed nickel sulfate in their diets, 25 mg/kg, for a total of 120 days.
In addition, a reduction was seen in the number of tubule basal cells and
in the number of spermatozoa-containing tubules. By the end of the 120-day
oral exposure period, these animals showed total obliteration of fertility.
No gametotoxic effects have been reported in man.
5.2.5 Other Toxic Effects of Nickel
5.2.5.1 Respiratory Effects of Nickel—The acute effects of Ni(CO)4 on the
lung in man and experimental animals were summarized earlier (Section 4.1).
Little data are available on the chronic respiratory effects of this agent,
except for one case described by Sunderman and Sunderman (1961b) in which a
subject exposed to low levels of the carbonyl developed asthma and Lo'ffler's
syndrome, a condition characterized by fever, cough, breathlessness, anorexia,
weight loss and associated with eosinophilia and granulomatous tissue.
Russian workers (Sushenko and Rafikova, 1972; Kucharin, 1970; Tatarskaya,
1960) have observed chronic rhinitis and nasal sinusitis in workers engaged
in nickel electroplating operations where chronic inhalation of nickel
aerosols, such as nickel sulfate, had occurred. Associated findings com-
monly encountered were anosmia and nasal mucosal injury including nasal
septum perforation. Asthmatic lung disease in nickel plating workers has
been documented by McConnell et al. (1973) and Tolat et al. (1956).
Adverse effects in animals by inhalation of several 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
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the region of those acceptable for human industrial exposure. Hyperplasia
of bronchiolar and bronchial epithelium with peri bronchial lymphocytic
infiltrates was seen. Port et al. (1975) noted that intratracheal injec-
tion of a suspension of nickel oxide (5 mg, < 5 (jm) into Syrian hamsters
first treated with influenza A/PR/8 virus 48 hours previously, signifi-
cantly increased mortality versus controls. Surviving animals at this
dosing and lesser doses showed mild to severe acute interstitial infiltrate
of polymorphonuclear cells and macrophages several weeks later. Additional
pathological changes included bronchial epithelial hyperplasia, focal
proliferative pleuritis and adenomatosis.
A number of studies have involved the cellular toxicity of nickel
compounds as they relate to the incidence of infections in the respiratory
tract, particularly the impairment of alveolar macrophage activity (Castronov<
et al., 1980; Johansson et al., 1980; Aranyi et al., 1979; Adkins et al,
1979; Graham et al, 1975; Waters et al., 1975).
At 1.1 mM nickel ion, rabbit alveolar macrophages show no morpho-
logical evidence of injury but apparently lose the ability for phagocytosis
(Graham et al., 1975). At 4.0 mM, cell viability is reduced to approxi-
mately 50 percent of controls (Waters et al., 1975).
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 |jm to 8 |jm. The effect increased with increased particle loading of NiO
and decreased particle size.
5.2.5.2 Endocrine Effects of Nickel — In different experimental animal
species, nickel (II) ion has been shown to affect carbohydrate metabolism.
Bertrand and Macheboeuf (1926) reported that the parenteral administration
of nickel salts antagonized the hypoglycemic action of insulin. Later
workers (Horak and Sunderman, 1975a and 1975b; Freeman and Langslow, 1973;
Clary and Vignati, 1973; Kadota and Kurita, 1955) observed a rapid, transi-
tory 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) pro-
duced prompt elevations in plasma glucose and glucagon levels with a return
to normal 2-4 hours afterwards, suggesting that hyperglucagonemia may be
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responsible for the acute hyperglycemic response to divalent nickel (Horak
and Sunderman, 1975a). Nickel had the most pronounced hyperglycemic effect
when this element was studied versus effects of other ions given in equimolar
amounts, while concurrent administration of insulin antagonized the hyper-
glycemic effect (Horak and Sunderman, 1975b). Kadota and Kurita (1955)
observed marked damage to alpha cells and some degranulation and vacuoliza-
tion 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 decreas-
ing 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 depression of serum prolactin without any affect on growth
hormone or thyroid-stimulating hormone. The iji vitro release of pituitary
hormones other than PIF have been demonstrated for bovine and rat pituitary
(La Bella et al., 1973b).
Dormer and coworkers (1973; 1974) have studied the i_n 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 mem-
brane fusion and microvillus formation.
Effects of nickel on thyroid function have been noted by Lestrovoi et
al. (1974). Nickel chloride given orally to rats (0.5-5.0 mg/kg/day, 2-4
weeks) or by inhalation (0.05-0.5 mg/m ) significantly decreased iodine
uptake by the thyroid, such an effect being more pronounced for inhaled
nickel.
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5.2.5.3 Renal Effects of Nickel—Nlckel-induced nephropathy in man or
animals has not been widely documented. Acute renal injury with protein-
uria 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.
In man, nephrotoxic effects of nickel have been clinically detected in
some cases of accidental industrial exposure to nickel carbonyl (Carmichael,
1953; Brandes, 1934). This takes the form of renal edema with hyperemia
and parenchymatous degeneration.
5.2.5.4 Miscellaneous 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, 1977b;
Nickel. National Academy of Sciences, 1975). Neural tissue lesion forma-
tion 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), the erythrogenic effect being appar-
ently unrelated to the carcinogenicity of the compound (Jasmin and Riopelle,
1976). Morse et al. (1977) showed that the erythrocytosis 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.
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. (Carcino-
genic interactions have been previously discussed in Section 5.2.1.)
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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 dehydro-
genase and liver glutamic-oxaloacetic transaminase (Chatterjee et a!.,
1980).
According to Hill (1979), dietary protein antagonizes the effect of
dietary nickel (as the chloride, 400 or 800 ppm) on retarding growth in
chicks over the range of 10-30 percent protein.
Ling and Leach (1979) studied element interaction in diets containing
300 mg/kg of nickel and 100 mg/kg of iron, copper, zinc, and cobalt.
Indices of toxicity were growth rate, mortality, and anemia. The lack of
interaction among these elements and nickel is in contrast to a protective
effect of nickel for the adverse effects of copper deficiency (Spears and
Hatfield, 1977). Presumably, the existence of any interactive mechanism is
overwhelmed at large levels of agents employed in the former study.
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
hematocrit values in iron-deprived rats when the ferric ion was employed,
but less so when divalent-trivalent iron mixtures were used. This author
postulates that the enhanced absorption of the trivalent iron was directly
related to nickel.
Divalent nickel appears to antagonize the digoxin-induced arrythmias
in the rat, rabbit, and guinea pig in both intact, as well as, isolated
hearts, 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).
Nickel ion combined with benzo(a)pyrene enhanced the morphological
transformation 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 vg/m] nickel salt
and 0.78 (jg/ml benzo(a)pyrene. Futhermore, in a mutagenesis system using
hamster embryo cells, as described by Barrett et al. (1978), a co-mutagenic
effect between nickel sulfate and benzo(a)pyrene has also been observed
(Rivedal and Sanner, 1980; 1981). These observations, supported by co-car-
cinogenic effects between nickel compounds and certain organic carcinogens
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(Toda, 1962; Maenza et al., 1971; Kasprzak et al., 1973), are of considerable
importance in evaluating the enhancing effect of cigarette smoke on the inci-
dence of lung cancer in nickel refinery workers (Kreyberg, 1978).
012NIY/A 94 3/21/83
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6. NICKEL AS AN ESSENTIAL ELEMENT
There is a growing body of literature that establishes an essential
role for nickel, at least in experimental animals (Sunderman, 1977; Spears
and Hatfield, 1977; Nielsen, 1976; Nickel. National Academy of Sciences,
1975; Nielsen and Sandstead, 1974).
Mertz (1970) has spelled out criteria for essentiality of trace ele-
ments 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 workers in trace-element nutritional research could not demon-
strate any consistent effects of nickel deficiency (Spears and Hatfield,
1977; Nickel. National Academy of Sciences, 1975) owing in part to the
technical difficulties of controlling nickel intake because of its ubiquity.
Later workers have demonstrated adverse effects of nickel deprivation in
various animal models.
Nielsen and Higgs (1971) have shown a nickel-deficiency syndrome in
chicks fed nickel at levels of 40-80 ppb (control diet: 3-5 ppm) charac-
terized by swollen hock joints, scaly dermatitis of the legs, and fat-depleted
livers. Sunderman et al. (1972b) observed ultrastructural lesions such as
perimitochondrial dilation of rough endoplasmic reticulum in hepatocytes of
chicks fed a diet having 44 ppb nickel. Nielsen and Ollerich (1974) also
noted hepatic abnormalities similar to those reported by Sunderman et al.
(1972b). Nickel is also essential in swine nutrition. Pigs fed a diet
having 100 ppb nickel showed signs of decreased growth rate, impaired
reproduction, and rough hair coats (Anke et al., 1974).
Growth responses to nickel supplementation have also been reported for
rats (Nielsen et al., 1975; Schnegg and Kirchgessner, 1975a; Schroeder
et al., 1974). Rats maintained 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).
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).
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Nickel appears to be essential also for ruminant nutrition (Spears and
Hatfield, 1977). Spears and Hatfield (1977) demonstrated disturbances in
metabolic parameters in lambs maintained on a low-nickel diet (65 ppb),
including reduced oxygen consumption in liver homogenate preparations,
increased activity of alanine transaminase, decreased levels of serum
proteins, and enhanced urinary nitrogen excretion. In a follow-up study,
Spears et al. (1978) found that these animals had significantly lower
microbial urease activity.
Schnegg and Kirchgessner (1976; 1975b) demonstrated that nickel de-
ficiency leads to reduced iron content in organs and iron deficiency anemia,
resulting from markedly impaired iron absorption.
Nickel also appears to adhere to other criteria for essentiality
(Mertz, 1970) e.g., apparent homeostatic control, and partial transport by
specific nickel-carrier proteins (see Metabolism section). Furthermore,
Fishbein et al. (1976) have reported that jackbean urease is a natural
nickel metalloenzyme. It is possible that rumen bacterial urease may also
have a specific nickel requirement (Spears et al., 1977). In this connection,
Mackay and Pateman (1980) have found that a mutant strain of Aspergillis
nidulans, which is urease-deficient, requires nickel (II) for restoration
of urease-activity. In particular, the strain carrying a mutation in the
ure-D locus was responsive to nickel.
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7. HUMAN HEALTH RISK ASSESSMENT FOR NICKEL
Assessment of the risk posed by nickel to public health in the United
States entails consideration of two general facets of the issue: sources
of exposure relevant to U.S. populations at large and population response.
Two obvious questions about the exposure aspects of nickel are: (1)
What are the environmental sources of nickel in the United States? (2)
What are the various routes by which nickel enters the body?
Nickel, in common with other metallic elements, is a multimedia con-
taminant. Thus, one needs to have some idea of the comparative contribu-
tions to human exposure by all the various routes before one can assess the
relative significance of any given avenue of intake. A second complicating
factor is the impact of a primary route of environmental entry on other
compartments of the environment. For example, to what degree does airborne
nickel contribute to contamination of water and soil via fallout?
Some aspects of the problem of human population response to nickel
include: (1) the relevant human biological and pathophysiological responses
to nickel; (2) subgroups of the U.S. population that can be identified as
being at particular risk to effects of nickel by virtue of either exposure
setting or some physiological status imparting heightened vulnerability;
and (3) the magnitude of the risk to these subgroups in terms of the numbers
exposed as can best be determined by available population data.
7.1 AGGREGATE HUMAN INTAKE OF NICKEL
The general population of the United States receives its major ex-
ternal exposure to nickel via ingestion, inhalation, and skin contact.
While estimates of the daily dietary intake of nickel vary, a range of
300-600 ug nickel/day on the basis of composite diet analysis appears to
exist in the United States. Fecal nickel analysis, a more accurate measure
of dietary nickel intake, suggests about 300 |jg nickel/day. Assuming an
absorption of 1-10 percent, up to 60 ug nickel/day may be taken up from the
gastrointestinal tract.
For the inhalation route, a nonsmoking urban resident exposed to a
3
mean air level of nickel of about 10 ng/m would take in 0.2 ug nickel,
assuming a daily ventilation rate of 20 m . Of this amount, some fraction
would be absorbed, depending on the size of the nickel-containing particu-
012NIY/A 97 3/21/83
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PRELIMINARY DRAFT
late. Even with the assumption of 100 percent absorption, the relative
amount of inhaled nickel absorbed into the blood stream would be minor
compared to dietary nickel.
Cigarette smokers probably have a markedly increased nickel intake
from the respiratory tract. As noted in Chapters 3 and 4, individuals
smoking two packs of cigarettes a day would inhale 1-5 mg of nickel per
year or about 3-15 (jg nickel daily (National Academy of Sciences, 1975).
Considering that (1) better than 80 percent of cigarette nickel in main-
stream smoke is in gaseous, rather than particulate form (Stahly, 1973;
Szadkowski et al., 1970; Sunderman and Sunderman, 1961a) and (2) inhalation
of gaseous nickel compounds is likely to result in greater nickel deposi-
tion in the pulmonary parenchyma (National Academy of Sciences, 1975), it
would not be unreasonable to assume the strong likelihood of absorption of
a major portion of the daily cigarette amount (1.5-7.5 pg for 50 percent
absorption).
It would also not be unreasonable to assume for a certain portion of
the general populace, that inhalation of passive smoke may constitute a
possible exposure route, the magnitude of which is presently unknown and,
therefore, cannot be quantifiably figured into aggregate nickel intake.
Average drinking water nickel values are about 5 pg/£. Assuming a
typical daily consumption of 2.0 liters, about 10 pg of nickel may be
ingested. Assuming 1-10 percent absorption, 0.1-1.0 pg is absorbed.
It is not possible to make any quantitative statements about the
amounts of systemic or percutaneous absorption of nickel via external
contact with nickel-containing commodities by the general population.
The aggregate daily absorption from all sources is approximately 3-60
ug nickel, with most of this amount coming from the diet.
7.2 SIGNIFICANT HEALTH EFFECTS OF NICKEL FOR HUMAN RISK ASSESSMENT
A variety of uj vivo adverse effects of nickel have been documented in
experimental animals and man and are described in Chapter 5. It should be
kept in mind that these studies involved rather high levels of exposure,
employed parenteral administration of the nickel agent in a number of
cases, and in some cases employed nickel in forms which may not be relevant
to general population exposure and are of more concern in occupational
settings.
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Acute exposure of man to nickel is mainly of concern in workplaces
where nickel carbonyl or nickel dusts are present at high levels. Here,
inhalation is the main route of entry into the body and the lung is the
critical organ, although in cases of accidental exposure to high levels of
nickel carbonyl, other systems such as the central nervous system may also
be involved. Most of what is known about acute exposure effects is based
upon nickel carbonyl inhalation. Aside from accompanying weakness and
hyperpnea, symptomatology from such exposure strongly resembles that of
viral pneumonia.
Chronic exposure to nickel compounds is of more concern in both occu-
pational and general population groups. In nickel workers, an extensive
literature points to a significantly increased nasal and lung cancer risk,
as well as noncarcinogenic effects, such as skin disorders, inflammation of
the upper respiratory tract, and possible renal dysfunction. In workers
chronically exposed to nickel, the route of intake is mainly by inhalation,
although percutaneous absorption figures in skin disorders.
The major problem posed by nickel for the U.S. population at large, as
can best be determined at present, is nickel hypersensitivity. Nickel
reactions, originally equated with occupational diseases, appear today with
much greater frequency, especially among women. Environmental exposure,
mainly via contact with many nickel-containing commodities, is responsible
for a preponderance of such reactions. Data cited in Chapter 5 also suggest
that nickel could play a role in altering defense mechanisms against xenobio-
tic agents in the respiratory tract, leading to heightened risk for respiratory
tract infections.
The possible role of certain nickel compounds as co-carcinogens in
respiratory cancer is suggested by animal studies but remains to be con-
clusively demonstrated.
Any discussion of health risk assessment of nickel must consider two
key points regarding the effects relevant for human populations: (1) the
reversibility or irreversibility of a given health effect if the subject is
removed from exposure to nickel and (2) the relative significance of a
given effect in impairing the individual's systemic well-being or ability
to fully function.
If one takes clinically manifested nickel sensitivity in the form of
contact dermatitis or other skin disorders as the effect of nickel most
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PRELIMINARY DRAFT
germane to chronic exposure of populations at large, it would appear that
reversibility exists in one sense, i.e., avoiding obvious exposure to
nickel-containing material may ameliorate the immediate symptoms. To the
extent that a nickel-hypersensitized individual will suffer a flare-up of
symptoms when exposed again, one can argue that the symptomatology may be
reversible but that the underlying condition is irreversible.
The extent to which nickel hypersensitivity as manifested in skin
disorders is an adverse health effect depends on both the severity of the
condition and other factors, for example, occupational status. While a
condition such as nickel contact dermatitis may not be life-threatening,
severe cases of nickel-induced skin disorders can have a significant impact
in limiting the daily activities of individuals and can predispose those
afflicted to further complications such as skin infections. Also, for such
occupational groups as hairdressers, chronic skin disorders induced by
nickel can have a marked impact on continued livelihood, particularly in
situations involving public contact.
Evidence was presented in Chapter 6 pointing to nickel as an essential
element, at least in animals. Nickel deficiency has been associated with
reduced growth, impaired reproduction and the induction of anemia by inter-
fering with iron absorption. Further data in support of essentiality
includes apparent homeostatic control of nickel in a number of animal
species and the existence of nickel carrier proteins in man and rabbit.
7.3 DOSE-EFFECT AND DOSE-RESPONSE RELATIONSHIPS OF NICKEL
Attempts to quantify the health impact of nickel on man with reference
to potential effects on the U.S. population as a whole are discussed in
this section, with emphasis on data for chronic exposure. Unlike the
relevant literature available for elements such as cadmium, lead, and
mercury on dose-response relationships, the corresponding information for
nickel is sparse. In large measure, this is due to the perception of
nickel both as mainly a problem in occupational medicine and as having
overall lower toxicity with regard to chronic exposure of non-occupational
populations.
An approach to assessing dose-effect, dose-response relationships for
nickel or any agent in man can be framed in the form of several questions:
(1) How do the various levels of external exposure—nickel in air,
food, water—quantitatively translate to reliable internal indices of
012NIY/A 100 3/21/83
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PRELIMINARY DRAFT
exposure such as blood nickel, urinary nickel, nickel in hair, autopsy
tissue?
(2) How do the levels of nickel in these internal indices of exposure
relate to the eliciting and the graded severity of critical effect in the
critical tissue?
(3) Is the information in answer to questions (1) and (2) sufficient
to permit either modeling or statistical refinement of the data, to estimate
what fraction of a study population is apt to develop a particular health
effect at a given level of external exposure?
7.3.1 Indices of Exposure
Taken collectively, occupational and limited nonoccupational group
studies indicate that both urinary and serum nickel levels generally re-
flect the intensity of recent or ongoing exposures. Nickel in these media
rise rapidly with increases in external exposure and rapidly decrease in
levels with reduced external exposure. Nickel workers usually show higher
serum and urine levels than control groups. While hair nickel levels may
be of value in elucidating a history of chronic or episodic acute nickel
exposure, various technical problems associated with this medium have
limited its wide acceptance as an index in assessing dose-effect, dose-
response relationships.
Norseth (1975) attempted to calculate the degree of correlation between
nickel levels in physiological media (urine in this case) and workplace
exposure. For welders, he found that the exposure/excretion ratios were
well correlated as a group (correlation coefficient of 0.85), but that
urinary nickel was poorly correlated with any individual's exposure.
Norseth (1975) also observed that welders had exposure/excretion ratios
which were similar to those of nickel roasters and smelters, suggesting
exposure to similar forms of nickel.
The data for nickel levels in blood, urine, hair, and other tissue in
"normal" populations must be viewed with great caution for several reasons.
The definition of "normal" population varies enormously from study to
study. In many cases, it is defined as "not occupationally exposed" with-
out provision of criteria for such definitions. Studies using patients or
other subjects as controls do so on the basis of freedom from a particular
disease or condition, rather than on general health status. Since nickel
levels are affected by a number of stresses, this is an important, yet
012NIY/A 101 3/21/83
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PRELIMINARY DRAFT
overlooked consideration. In some studies, population selection may also
have been done to primarily assess exposure to other pollutants, and group
stratification based on gradients for other pollutants may not necessarily
reflect nickel exposure differences since sources of nickel may not always
be the same as those of other selected contaminants. In addition, it
should be noted that smoking status of tested individuals has not been
systematically considered in many of these studies. Finally, the quality
of analytical methodology varies significantly for nickel, both with tech-
niques and with time, so that earlier studies may not have yielded levels
which are as reliable as more recent findings (Adams and co-workers, 1978;
National Academy of Sciences, 1975; Lewis and Ott, 1970).
"Normal" levels of nickel in blood of various population groups in the
United States and elsewhere are presented in Table 7-1. The table is a
compilation of more recent data which were obtained with the relatively
more reliable method of atomic absorption spectrometry. Generally, serum
or plasma values are less than 1.0 pg/dl, or 10 pg/liter.
Age and sex do not appear to be associated with nickel blood levels,
as authors frequently report mean values for total groups only because they
have found no significant differences by age or sex. Other variables such
as race, residence, and geographic location similarly cannot be evaluated,
and further, there are no data for "unacculturated" populations who are not
exposed to industrial pollution.
The only study addressing the question of differences in mean blood
nickel levels for normal populations living in environments with different
degrees of pollution due to the absence or presence of nickel refineries is
that of McNeely et al. (1972). They examined normal adults who were not
occupationally exposed to nickel in Sudbury, Ontario, the location of North
America's largest nickel refinery, and compared them to adults from Hartford,
Connecticut. The Sudbury mean serum nickel level for 25 adults was 0.46 ±
0.14 with a range of 0.20 - .73 (jg/dl, while respective values for Hartford
were 0.26 ± 0.09 (range 0.08 - 0.52 pg/dl).
Data from two studies reporting values of nickel in blood for occupa-
tional ly exposed persons and nonexposed controls show significant differ-
ences between these groups. Hdgetveit and Barton (1976) reported on the
results of monitoring blood plasma Ni levels in workers in the Falconbridge
nickel refinery. They found Ni plasma values of 0.74 pg/dl for 701 samples
012NIY/A 102 3/21/83
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TABLE 7-1. "NORMAL" BLOOD NICKEL CONCENTRATIONS
o
GO
Author
Schaller et al . (1968)
Nomoto and Sunderman (1970)
McNeely et al. (1972)
Pekarek and Hauer (1972)
Hrfgetveit and Barton (1976)
Spruit and Bongaarts (1977a)
Method
Atomic absorption
Atomic absorption
Atomic absorption
Atomic absorption
Atomic absorption
Atomic absorption
Area
Germany
Connecticut
Connecticut
Washington, D.C.
Norway
Holland
No. of
Subjects
26
40
26
20
3
10
Serum(S)
or Plasma Nickel concentration in ug/dl
(P)
P
S
S
S
P
P
Mean (± SD)
2.1
0.26
0.26
1.5 (± 0.5)
0.42
0.16
Range
0.6-3.7
0.11-0.46
0.08-0.52
-
0.2-0.6
-
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from 305 workers while controls showed an average value of 0.42 ug/dl in 86
samples. Atomic absorption spectrometry was used in the analyses. The
plasma levels for workers at different work stations showed that 179 elec-
trolysis department workers had a mean blood nickel concentration of 0.74
ug/dl, while 126 roasting-smelting workers averaged 0.60 ug/dl. Workers
engaged in electrolysis operations were found to be exposed to soluble
nickel salts in aerosol form, while the workers in roasting-smelting opera-
tions were exposed to largely insoluble compounds in dust (H^getveit and
Barton, 1977).
Spruit and Bongaarts (1977a, 1977b) tested for blood plasma nickel
levels in eight occupationally exposed volunteers and found average levels
of 1.02 and 1.11 pg/dl at different periods during the work year, but 0.53
ug/dl after the annual two-week holiday. The controls, patients from the
dermatology service without occupational exposure, showed plasma levels of
0.16 and 0.20 ug/dl for 10 males and 14 females, respectively. These data
support the Htfgetveit and Barton (1976) finding that plasma concentrations
reflect current exposure and, further, provide evidence that there is very
quick response to exposure.
The specific effects on blood levels of nickel from faulty hygiene and
failure to observe safety regulations among exposed workers have either not
been evaluated or, if evaluated, have not been reported.
Presented in Table 7-2 are urinary nickel levels measured in non-occupa-
tional groups in the United States and elsewhere. Mean levels in the
various reports range from less than 1.0 to approximately 20 ug/liter, with
more recent United States data conforming to the low end of the range.
In occupational settings, urinary levels are seen to be markedly
elevated. Hrfgetveit and Barton (1976) found an average urine nickel con-
centration of 8.9 ug/dl for 729 samples from 305 workers, while the value
for controls was 2.1 ug/dl. The data for average urine concentrations for
different work sites and exposure to different nickel compounds were not
given.
Spruit and Bongaarts (1977a, 1977b) found a mean nickel urine concen-
tration of 1.8 ug/dl for seven occupationally exposed individuals and 0.06
ug/dl for 10 unexposed males. After a two-week vacation period, the mean
value for the exposed workers had gone down to 0.18 ug/dl.
012NIY/A 104 3/21/83
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PRELIMINARY DRAFT
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Bernacki et al. (1978) determined urine concentrations by volume and
creatinine ratio for workers with different environmental exposures. Table
7-3 shows the findings for exposed, nonexposed, and control subjects, as
well as air concentrations for seven work environments. There is only
partial concordance between atmospheric concentrations and urine values.
Crucial to the assessment of the effects of nickel on human popula-
tions is the necessity of determining key tissue levels of the element and,
where possible, total body burden. It is generally not feasible to assess
these levels in humans other than through autopsy studies, and several
investigators have carried out such surveys of nickel levels in selected
organs. These studies can be roughly classed into case studies concerned
with specific diseases or population studies, as discussed below. No J_n
vivo studies for nickel have been reported.
There are very few data in the literature concerning nickel tissue
levels and total body burden. The National Academy of Sciences (1975)
report summarized the available findings and concluded that the total
nickel content in a normal man is approximately 10 mg.
Bernstein et al. (1974) reported results for 25 autopsies of subjects
aged 20 to 40 years from New York City, with a diagnosis of sudden death
and no indication of illness. Tissues were taken from the right lung and
paratracheal, peribronchial, and hilar lymph nodes. Mean values were 0.23
± 0.06 ug/Ni/g wet weight for lung tissue and 0.81 ± 0.41 for lymph nodes.
Sumino et al. (1975) reported various organ nickel levels taken from
30 Japanese subjects who died of varying causes. Mean values, expressed as
ug/g wet weight, (and range) for lung, liver, and kidney were: 0.16 (0.04-
0.44); 0.078 (0.028-0.22); and 0.098 (0.012-0.30), respectively.
Sunderman et al. (1971) found, in 4 subjects, the following mean (ppm,
wet weight) levels of nickel for lung, liver and heart: 1.59, 0.87, and
0.61, respectively.
There is little in the literature reporting autopsy tissue studies of
nickel refinery workers except from cases of fatal nickel carbonyl poison-
ing (Nickel. National Academy of Sciences, 1975), where highest levels of
nickel are seen in lung, with lesser amounts in kidney, liver, and brain.
7.3.2 Effect and Dose-Response Relationships
The severity of a given marker effect is dependent upon the form and
level of nickel exposure. In a number of experimental models of nickel
012NIY/A 106 3/21/83
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TABLE 7-3. NICKEL CONCENTRATIONS IN URINE SPECIMENS FROM WORKERS IN TWELVE OCCUPATIONAL GROUPS
Group
A
B
C
0
E
F
G
H
I
J
K
L
Occupation
Hospital workers
Nonexposed industrial
workers
Coal gasification
workers
Buffers/polishers
External grinders
Arc welders
Bench mechanics
Nickel battery workers
Metal sprayers
Electroplaters
Nickel platers
Nickel refinery
workers
No. of
Subjects
and sex
19 (15M.4F)
23 (20M.3F)
9M
7 (6M.1F)
9 (7M.2F)
10 (7M.3F)
8 (4M.4F)
6 (5M.1F)
5 (4M.1F)
11M
21M
15M
Description
Physicians, technologists, and
clerks
Managers, office workers and
storekeepers
Ni-catalyzed hydrogenation
process workers
Abrasive buffing, polishing and
deburring aircraft parts made
of Ni alloys
Abrasive wheel grinding of exteriors
of parts made of Ni alloys
DC arc welding of aircraft parts
made of Ni alloys
Assembling, fitting, and finishing
parts made of Ni alloys
Fabricating Ni-Cd or Ni-Zn
electrical storage batteries
Flame spraying Ni-contaim'ng
powders in plasma phase onto
aircraft parts
Intermittent exposure to Ni in
combined electrodeposition oper-
ations involving Ag, Cd, Cr, or
Cr plating as well as Ni
Full-time work in Ni plating
operations
Workers in a nickel refinery that
employs the electrolytic process
Atmospheric Ni
cone, ug/m
Not measured
Not measured
Not measured
26+48
(0.05-129)
1.613.0
(2.1-8.8)
6.0+14.3
(0.2-46)
52+94
(0.01+252)
Not measured
2.4+2.6
(0.04-6.5)
0.8+0.9
(0.04-2.1)
Not measured
4891560
(20-2,200)
Urine ug/£.
2.711.6
(0.4-5.1)
3.2+2.6
(0.3-8.5)
4.212.4
(0.4-7.9)
4.113.2
(0.5-9.5)
5.412.4
2.1-8.8)
6.3+4.1b
(1.6-14)
12. 2113. 6b
(1.4-41)
11.7+7.75C
(3.4-25)
17.2+9.8C
(1.4-26)
10.5l8.1c
(1.3-30)
27. 5+21. 2d
(3.6-65)
222±226d
(8.6-8.3)
Concna ug/g
creatinine
2.5+1.3
(0.7-5.7)
2.7+1.7
(0.6-6.1)
3.2+1.6
(0.1-5.8)
2.4+1.4
(0.5-4.7)
3.5+1.6
1.7-6.1)
5.6+6.2
(1.1-17)
7.2l6.8b
(0.7-20)
10. 2+6. 4C
(7.2-23)
16.0±21.9
(1.4-54)
5.9+5.0b
(1.0-20)
19. 0+14. 7d
(2.4-47)
124+109d
(6.1-287)
-<
o
TO
>
.Mean 1 SO with range in parentheses.
p < 0.05 vs control subjects in Group A, computed by t test.
Source: Bernacki (1978).
< 0.01 vs control subjects in Group A, computed by t test.
< 0.001 vs control subjects in Group A, computed by t test.
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PRELIMINARY DRAFT
toxicity, a proportionality between the level of nickel and the severity of
effect has been reported. In most cases, the levels of nickel administered
were quite high and were administered parenterally to obtain maximum toxi-
cological effect.
Similarly, the extensive literature dealing with the occupational
carcinogenesis of nickel points to increased nasal and lung cancer risk
with increasing levels of exposure to nickel in work place air.
Studies of accidental acute exposure of workmen to nickel carbonyl
indicate that there is a gradient of serious injury depending on the amount
of nickel carbonyl inhaled. According to Sunderman et al. (1971), an
initial 8-hr, urine specimen having a nickel level less than 10 ug/dl is
associated with mild exposure, and minimal symptomatology is apparent.
Moderate exposure is associated with corresponding nickel levels of greater
than 10 ug/dl but less than 50 ug/dl, while levels in excess of 50 ug/dl
are associated with severe exposure resulting in serious illness and hos-
pital ization.
With regard to the general population, the increased or persistent
prevalence of nickel-related skin disorders generally reflects the wide-
spread use of a variety of nickel-containing commodities. Given the clini-
cal nature of nickel hypersensitivity and the route of exposure (external
contact), it is difficult to place dose-response relationships in any kind
of quantitative framework. Several studies suggest that there may exist a
relationship between the flare-up of nickel dermatitis and the level of
nickel in the diet. Well-designed epidemiological studies would be re-
quired to establish conclusive relationships between diet nickel and fre-
quency of dermatitis occurrence.
In summary, then, it appears that the frequency or extent of various
effects of nickel are generally related to the level or frequency of nickel
exposure in man. A quantitative dose-response risk assessment is presented
for cancer due to exposure to nickel in ambient air (Section 7.5.5).
7.4 POPULATIONS AT RISK
Populations at risk may be defined as those segments of the population
who are placed at increased risk to the effects of nickel either by virtue
of a special exposure status or by some physiological status that renders
them more susceptible to nickel's effects. Thus, there are external and
physiological aspects to the relationship of risk to nickel.
012NIY/A 108 3/21/83
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In terms of exposure, occupational groups, such as nickel workers and
other workers engaged in handling nickel, obviously comprise the individuals
at highest risk. With regard to the population at large, it appears that
women, particularly housewives, are at special risk to nickel-induced skin
disorders. In large part, this is due to the extended exposure to a number
of nickel-containing commodities such as stainless-steel kitchens, jewelry
and household chemicals. The dietary nickel-hypersensitivity relationship
requires much further study.
With reference to heightened susceptibility to nickel effects by
virtue of physiological status, the issue is far from clear. In Chapter 5
it was noted that a familial history of atopic dermatitis may predispose an
individual to nickel hypersensitivity, but the difficulty in making clear
distinctions between, or defining clear relationships of, nickel dermatitis
and atopic dermatitis do not permit any firm conclusions to be drawn.
Although it remains to be clearly established, the role of nickel as a
possible carcinogen or potentiator in the epidemiological association of
cigarette smoking and respiratory cancer is suggestive; thus, cigarette
smokers constitute a potential population at greater risk.
In Chapter 4 it was noted that nickel can cross the placenta! barrier
in man and animals. Thus, one can classify women of child-bearing age as a
potential risk population by virtue of risk to the conceptus in pregnancy.
The paucity of data regarding jhn utero effects of low or moderate exposure
to nickel in man limits any definition of the nature of fetal effects of
nickel at the present time.
7.4.1 Numbers of the U.S. Population in Special Risk Categories
The epidemiological data on the prevalence of nickel hypersensitivity
in the U.S. and elsewhere and as put forth in Chapter 5 do not permit the
assessment of its true prevalence in the general population. Thus, one
cannot determine numbers of individuals in the U.S. who fall into this
category.
7.5 CURRENT REGULATIONS AND STANDARDS
7.5.1 Occupational Exposure
The threshold limit value (TLV) for nickel as a soluble inorganic salt
3
is set at 0.1 mg/m to prevent irritation (ACGIH, 1981). However, earlier TLV
documentation states that this TLV is probably not sufficiently low to pre-
vent dermatitis or sensitization from soluble salts and mists (ACGIH, 1976).
3
The TLV for nickel carbonyl is set at .35 mg/m (0.05 ppm) to prevent acute
systemic effects (ACGIH, 1976; 1981).
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The National Institute for Occupational Safety and Health (1977b) has
recommended a standard of .007 mg/m (0.001 ppm) for nickel carbonyl and
that the compound be regulated as a carcinogen.
7.5.2 Dermal Exposure to Nickel in the Environment
The major problem posed by nickel for the United States population at
large is nickel hypersensitivity, mainly via contact with many nickel-con-
taining commodities. However, there are essentially no studies of general
populations which quantitatively relate nickel exposure to the prevalence
of nickel-related skin disorders such as contact dermatitis. Although an
occupational TLV for nickel as a soluble inorganic salt has been set at 0.1
o
mg/m to prevent irritation, no corresponding threshold value has been
determined for nickel-sensitive individuals exposed to nickel in everyday
contact with household commodities. At present, there is insufficient
information to provide any quantitative guidelines for protecting sensitive
individuals; avoidance of contact with nickel is the best obvious preven-
tive measure.
7.5.3 Exposure to Nickel in Ambient Water
The U.S. Environmental Protection Agency (EPA, 1980) has recently set
forth its criterion value for nickel in ambient water. Since ambient water
levels are of more significance for the general United States population
than TLV values directed to occupational settings, the former will be
discussed.
In arriving at an oral criterion for nickel, several factors were
taken into account. There is little evidence for accumulation of nickel in
various tissues. Absorption through the gastrointestinal tract is low.
Acute exposure of man to nickel, particularly nickel carbonyl, is primarily
of concern in workplaces. In many of these situations, inhalation is the
main route of entry and the lung is the critical organ. Although certain
nickel compounds have been shown to be carcinogenic in humans and experi-
mental animals, there is no evidence for carcinogenicity due to the pre-
sence of nickel in the diet. The role of nickel as an essential element is
a confounding factor in any risk estimate.
In order to develop an oral risk assessment based on toxicological
effects other than carcinogenicity, dose-response data would have been most
012NIY/A 110 3/21/83
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helpful. However, while the frequency or extent of various effects of
nickel are related to the level or frequency of nickel exposure in man, the
relevant data do not permit any quantitative estimation for oral dose-
response relationships. Studies published in the available literature have
not demonstrated a no-observable-effect level (NOEL); therefore, the study
demonstrating the lowest-observable-adverse-effect level (LOAEL) was used
in establishing a criterion level for nickel in drinking water.
The study originally used as a basis for a risk estimate was that of
Schroeder and Mi tenner (1971) in which adverse effects in rats were demon-
strated at a level of 5 mg/£ (5 ppm) in drinking water. However, since the
publication of the ambient water quality criterion (Environmental Protection
Agency, 1980), several limitations regarding the Schroeder and Mitchner
(1971) study have surfaced which preclude its use as a basis for a risk
estimate. These include: (1) suggestive inappropriate randomization of
experimental animals in their cages, (2) lack of historical data for con-
trol animals, and (3) failure of subsequent studies to support the effects
noted at 5 ppm.
Examination of other studies for possible use in calculating an oral
risk estimate reveals that effects in test animals due to nickel challenge
have been reported within a range of 250-1000 ppm nickel administered via
diet (Ling and Leach, 1979; Ambrose et al., 1976; O'Dell et al., 1970;
Weber and Reid, 1968; Phatak and Patwardhan, 1950). The reported effects
have primarily been those of depressed body weight and growth in the test
animals. A number of problems beset these studies in regard to their
usefulness for calculating a risk estimate: i.e., use of non-mammalian
test animals (Ling and Leach, 1979; Weber and Reid, 1968); use of semi-
purified diets (Weber and Reid, 1968); lack of paired feeding controls
(Ling and Leach, 1979; Ambrose et al., 1976; O'Dell et al. , 1970); never-
theless, collectively, the studies suggest that nickel may induce adverse
effects within the range of 250-1000 ppm. In the Phatak and Patwardhan
study (1950), statistical analysis (statistical tests not reported) showed
no effect differences between control and treated rats; however, this same
study did show transplacental passage of nickel up to 22-30 ppm when dams
received 1000 ppm Ni in their diet.
Of particular interest is the study of Ambrose et al. (1976) where, in
a multigeneration study in rats, the authors reported a higher incidence of
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stillbirths in the first generation of rats fed dietary concentrations of
nickel of 0, 250, 500, and 1,000 ppm. Although the authors did not report
performing any statistical tests on these data, the effect of higher still-
birth incidence, coupled with teratogem'c effects reported in several
animal species (albeit routes of exposure other than oral) (Gilani and
Marano, 1980; Sunderman et al., 1980b, 1979a; Lu et a!., 1979; Perm, 1972)
are such that the data have been deemed worth further analysis. However,
as noted previously, this study imposes not only interpretive problems, but
statistical problems as well relating to the independence of stillbirths
within a litter. These problems, as well as other issues relevant to
determining an oral criterion, are discussed in greater detail elsewhere
(Seilkop, 1982; Sivulka, 1982). A human health water quality criterion of
632 ug/£ based upon the Ambrose et al. study has been derived.
7.5.4 Exposure to Nickel in Ambient Air
There are presently no standards set based upon exposure to nickel in
ambient air. This is due, in part, to the fact that inhalation, as a route
of exposure, has been historically considered as less relevant, in terms of
magnitude, to the general U.S. population than have other routes of exposure.
The amounts of ambient air nickel entering the respiratory tract are quite
small, an average of less than 1 ug in nonsmokers to 3-15 ug/day for a 2
pack/day cigarette smoker, as compared to an average daily ingestion of
nickel on the order of 300 to 600 ug. This absence of a standard is also
due, in part, to the perception of nickel as an agent of lower toxicological
potential than other elements such as lead, cadmium and mercury. This
perception may be warranted in terms of the noncarcinogenic, low-level
effects of nickel, but is questionable in terms of nickel's carcinogenic
potential.
7.6 QUANTITATIVE ESTIMATION OF CANCER RISK FOR NICKEL
7.6.1 Introduction
There is no question, based upon studies of workers in nickel re-
fineries, that nickel in some form(s) is carcinogenic to man by the inhala-
tion route. Therefore, a case can be made for deriving an air quality
criterion based upon carcinogenic effects. Such a derivation is presented
below, albeit recognizing that some of the forms of nickel in the ambient
air may not be carcinogenic.
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This quantitative section deals with the unit risk for nickel in air
and the potency of nickel relative to other carcinogens that the U.S.
Environmental Protection Agency Carcinogen Assessment Group (CAG) has
evaluated. The unit risk estimate for an air pollutant is defined as the
lifetime cancer risk occurring in a hypothetical population in which all
individuals are exposed continuously from birth throughout their lifetimes
to a concentration of 1 ug/m3 of the agent in the air which 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 which might be
associated with air or water exposure to these agents, if the actual ex-
posures are known.
7.6.2 Procedures for Determination of Unit Risk from Animal Data
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. 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, then
responses will also occur at all lower doses with an incidence determined
by the extrapolation model.
There is no solid scientific basis for any mathematical extrapolation
model that relates carcinogen exposure to cancer risks at the extremely low
concentrations that must be dealt with in evaluating environmental hazards.
For practical reasons, such low levels of risk cannot be measured directly
either by animal experiments or by epidemiologic studies. We must, there-
fore, depend on our current understanding of the mechanisms of carcinogens
for guidance as to which risk model to use. At the present time the dominant
view of the carcinogenic process involves the concept that most agents that
cause cancer also cause irreversible damage to DNA. This position is
reflected by the fact that a very large proportion of agents that cause
cancer are also mutagenic. There is reason to expect the quantal type of
biological response that is characteristic of mutagenesis is associated
with a linear non-threshold dose-response relationship. Indeed, there is
substantial evidence from mutagenicity studies with both ionizing radiation
and a wide variety of chemicals that this type of dose-response model is
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the appropriate one to use. This is particularly true at the lower end of
the dose-response curve; at higher doses, there can be an upward curvature
probably reflecting the effects of multistage processes on the mutagenic
response. The linear non-threshold dose-response relationship is also
consistent with the relatively few epidemiologic studies of cancer responses
to specific agents that contain enough information to make the evaluation
possible (e.g., radiation-induced leukemia, breast and thyroid cancer, skin
cancer induced by arsenic in drinking water, liver cancer induced by afla-
toxin in the diet). There is also some evidence from animal experiments
that is consistent with the linear non-threshold model (e.g., liver tumors
induced in mice by 2-acetylaminofluorene in the large scale EDQ1 study at
the National Center for Toxicological Research and the initiation stage of
the two-stage carcinogenesis model in rat liver and mouse skin).
Because it has the best, albeit limited, scientific basis of any of
the current mathematical extrapolation models, the linear non-threshold
model has been adopted as the primary basis for animal-to-human risk extra-
polation to low levels of the dose-response relationship. The risk estimates
made with this model should be regarded as conservative, representing the
most plausible upper-limit for the risk, i.e., the true risk is not likely
to be higher than the estimate, but it could be lower.
The mathematical formulation chosen to describe the linear non-threshold
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 and it incorporates a procedure
for estimating the largest possible linear slope (in the 95% confidence
limit sense) at low extrapolated doses that is consistent with the data at
all dose levels of the experiment.
7.6.2.1 Description of the Low Dose Animal -to-Human Extrapolation Model—
Let P(d) represent the lifetime risk (probability) of cancer at dose d.
The multistage model has the form
P(d) = 1 - exp [-(q0 + qjd + q£d2 + ... + qkdk)]
where
QJ * 0, 1 = 0, 1, 2, .... k
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Equivalently,
P.(d) = I - exp [(q-,d + q^d + ... + c
where
P(d) - P(o)
Pt(d) =
1 - P(o)
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
consequently the extra risk function P.(d) at any given dose d, is calculated
by maximizing the likelihood function of the data.
The point estimate and the 95% upper confidence limit of the extra
risk Pt(d) are calculated by using the computer program GLOBAL 79 developed
by Crump and Watson (1979). At low doses, upper 95% confidence limits on
the extra risk and lower 95% confidence limits on the dose producing a
given risk are determined from a 95% upper confidence limit, q?, on parameter
q,. Whenever q, >0, at low doses the extra risk A(d) has approximately the
form A(d) = q-, x d. Therefore, q-, x d is a 95% upper confidence limit on
the extra risk and R/q? is a 95% lower confidence limit on the dose producing
an extra risk of R. Let LQ be the maximum value of the low-likelihood
function. The upper limit q-, is calculated by increasing q-, to a value q?
such that when the log-likelihood is remaximized subject to this fixed
value q? for the linear coefficient, the resulting maximum value of the
log-likelihood L-, satisfies the equation
2 (LQ - L1) = 2.70554
where 2.70554 is the cumulative 90% point of the chi-square distribution
with one degree of freedom, which corresponds to a 95% upper-limit (one-sided).
This approach of computing the upper confidence limit for the extra risk
A(d) is an improvement on the Crump et al. (1977) model. The upper confidence
limit for the extra risk calculated at low doses is always linear. This is
conceptually consistent with the linear non-threshold concept discussed
earlier. The slope, q?, is taken as an upper bound of the potency of the
chemical in inducing cancer at low doses. (In the section calculating the
risk estimates, P*(d) will be abbreviated as P).
In fitting the dose-response model, the number of terms in the poly-
nomial is chosen equal to (h-1), where h is the number of dose groups in
the experiment including the control group.
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Whenever the multistage model does not fit the data sufficiently well,
data at the highest dose is deleted and the model is refitted to the rest
of the data. This is continued until an acceptable fit to the data is
obtained. To determine whether or not a fit is acceptable, the chi-square
statistic
X2 =
i = 1
is calculated where N. is the number of animals in the i dose group, X.
th "*
is the number of animals in the i dose group with a tumor response, P. is
the probability of a response in the i dose group estimated by fitting
the multistage model to the data, and h is the number of remaining groups.
P
The fit is determined to be unacceptable whenever X is larger than the
cumulative 99% point of the chi-square distribution with f degrees of
freedom, where f equals the number of dose groups minus the number of
non-zero multistage coefficients.
7.6.2.2 Selection of Animal Data—For some chemicals, several studies in
different animal species, strains, and sexes, each run at several doses and
different routes of exposure are available. A choice must be made as to
which of the data sets from several studies to use in the model. It may
also be appropriate to correct for metabolism differences between species
and absorption factors via different routes of administration. The pro-
cedures used in evaluating these data are consistent with the approach of
making a maximum-likely risk estimate. They are listed below.
1. The tumor incidence data are separated according to organ sites or
tumor types. The set of data (i.e., dose and tumor incidence) used in the
model is the set where the incidence is statistically significantly higher
than the control for at least one test dose level and/or where the tumor
incidence rate shows a statistically significant trend with respect to dose
level. The data set which gives the highest estimate of the lifetime
carcinogenic risk, q?, is selected in most cases. However, efforts are
made to exclude data sets which produce spuriously high risk estimates
because of a small number of animals. That is, if two sets of data show a
similar dose-response relationship, and one has a very small sample size,
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the set of data which has larger sample size is selected for calculating
the carcinogenic potency.
2. If there are two or more data sets of comparable size which are
identical with respect to species, strain, sex, and tumor sites, the geo-
metric mean of q?, estimated from each of these data sets, is used for risk
assessment. The geometric mean of numbers A-,, A~, ..., A is defined as
(A x A x x A }l/m
V /IT A f*r\ A ... A n I
12 m
3. If two or more significant tumor sites are observed in the same
study, and if the data are available, the number of animals with at least
one of the specific tumor sites under consideration is used as incidence
data in the model.
7.6.2.3 Calculation of Human Equivalent Dosages from Animal Data—Foil owing
the suggestion of Mantel and Schneiderman (1977), we assume that mg/surface
area/day is an equivalent dose between species. Since, to a close approxi-
mation, the surface area is proportional to the 2/3rds power of the weight
as would be the case for a perfect sphere, the exposure in mg/day per
2/3rds 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
1 = duration of exposure
me = average dose per day in mg during administration of the agent
(i.e., during 1 ), and
W = average weight of the experimental animal
Then, the lifetime average exposure is
1 x m
d = -f—
7.6.2.3.1 Oral exposure. Often exposures are not given in units of mg/day and
it becomes necessary to convert the given exposures into mg/day. For example,
in most feeding studies exposure is in terms of ppm in the diet. Similarly,
in drinking water studies, exposure is in ppm in the water. In these cases the
exposure in mg/day is
m = ppm x F x r
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where ppm is parts per million of the carcinogenic agent in the diet or water,
F is the weight of the food or water consumed per day in kg, and r is the absorp-
tion fraction. In the absence of any data to the contrary, r is assumed to be
equal to one. For a uniform diet, the weight of the food consumed is proportions
to the calories required, which in turn is proportional to the surface area or
2/3rds power of the weight. Water demands are also assumed proportional to the
surface area, so that
m a ppm x W x r
or
As a result, ppm in the diet or water is often assumed to be an equivalent
exposure between species. However, we feel that this is not justified
since the calories/kg of food is very different in the diet of man compared
to laboratory animals primarily due to moisture content differences. Conse-
quently, the amount of drinking water required by each species also differs
because of the amount of moisture in the food. Therefore, we use an
empirically-derived factor, f = F/W, which is the fraction of a species body
weight that is consumed per day as food or water. We use the following rates:
Species
Man
Rats
Mice
W
70
0.35
0.03
f
food
0.028
0.05
0.13
f
water
0.029
0.078
0.17
Thus, when the exposure is given as a certain dietary or water concentration in
2/3
ppm, the exposure in mg/W is
m ppm x F ppm x f x W , ,,
= ppm x f x w
W' W
When exposure is given in terms of mg/kg/day = m/Wr = s, the conversion is
simply
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7.6.2.3.2 Inhalation exposure. When exposure is via inhalation, the calculation
of dose can be considered for two cases where 1) the carcinogenic agent is either
a completely water-soluble gas or an aerosol, and is absorbed proportionally to
the amount of air breathed in, and 2) where the carcinogen is a poorly water-
soluble gas which reaches an equilibrium between the air breathed and the body
compartments. After equilibrium is reached, the rate of absorption of these
agents is expected to be proportional to the metabolic rate, which in turn is
proportional to the rate of oxygen consumption, which in turn is a function
of surface area.
Case 1"
Agents that are in the form of parti cul ate matter or virtually com-
pletely absorbed gases, such as SO,,, can reasonably be expected to be
absorbed proportional to the breathing rate. In this case the exposure in
mg/day may be expressed as
m = I x v x r
3 3
where I = inhalation rate per day in m , v = mg/m of the agent in air, and
r = the absorption fraction.
The inhalation rates, I, for various species can be calculated from
the observations (Federation of American Societies for Experiemental Biology,
1974) that 25 g mice breathe 34.5 liters/day and 113 g rats breathe 105
liters/day. For mice and rats of other weights, W (in kilograms), the
3
surface area proportionality can be used to find breathing rates in m /day
as follows:
For mice, I = 0.0345 (W/0.
For rats, I = 0.105 (W/0.113) nT/day
3
For humans, the value of 20 m /day* is adopted as a standard breathing
rate (ICRP 1977).
2/3
The equivalent exposure in mg/W for these agents can be derived
from the air intake data in a way analogous to the food intake data. The
empirical factors for the air intake per kg per day, i = I/W, based upon
the previous stated relationships are tabulated as follows:
*From "Recommendation of the International Commission on Radiological
Protection", page 9. The average breathing rate is 107 cm3 per 8-hour work-
day and 2 x 107 cm3 in 24 hours.
012NIY/A 119 3/21/83
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PRELIMINARY DRAFT
Species
Man
Rats
Mice
W
70
0.35
0.03
i = I/W
0.29
0.64
1.3
Therefore, for participates or completely absorbed gases, the equivalent
2/3
exosure in mW
2/3
exposure in mg/W is
m Ivr iWvr
,,„
d = = ~~ = = iW vr
In the absence of experimental information or a sound theoretical argument
to the contrary, the fraction absorbed, r, is assumed to be the same for
all species.
Case 2—
The dose in mg/day of partially soluble vapors is proportional to the
p /O
Q£ consumption, which in turn is proportional to W and is also proportional
to the solubility of the gas in body fluids, which can be expressed as an absorp
tion coefficient, r, for the gas. Therefore, expressing the 00 consumption as
2/3
02 = k W , where k is a constant independent of species, it follows that
2/3
m = k W xvxr
or
m .
, = kvr
d = -
As with Case 1, in the absence of experimental information or a sound theore-
tical argument to the contrary, the absorption fraction, r, is assumed to be
the same for all species. Therefore, for these substances a certain concentra-
tion in ppm or ug/m in experimental animals is equivalent to the same concen-
tration in humans. This is supported by the observation that the minimum
alveolar concentration necessary to produce a given "stage" of anesthesia is
similar in man and animals (Dripps et al., 1977). When the animals are exposed
via the oral route and human exposure is via inhalation or vice-versa, the
assumption is made, unless there is pharmacokinetic evidence to the contrary,
that absorption is equal by either exposure route.
012NIY/A 120 3/21/83
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PRELIMINARY DRAFT
7.6.2.3.3 Adjustment of dose for less than lifespan duration of experiment. If
the duration of experiment (L ) is less than the natural life-span of the test
animal (L), the slope q?, or more generally the exponent g(d), is increased by
1 o
multiplying a factor (L/L ) . We assume that if the average dose d, is continued,
the age-specific rate of cancer will continue to increase as a constant function
of the background rate. The age-specific rates for humans increase at least by
the 2nd power of the age and often by a considerably higher power as demonstrated
by Doll (1971). Thus, we would expect the cumulative tumor rate to increase by
at least the 3rd power of age. Using this fact, we assume that the slope q?, or
more generally the exponent g(d), would also increase by at least the 3rd power
of age. As a result, if the slope q^ [or g(d)] is calculated at age Lg> we
would expect that if the experiment had been continued for the full lifespan,
L, at the given average exposure, the slope q? [or g(d)] would have been
3
increased by at least (L/L ) .
This adjustment is conceptually consistent with the proportional
hazard model proposed by Cox (1972) and the time-to-tumor model considered
by Crump (1979) where the probability of cancer by age t and at dose d is
given by
P(d,t) = 1 - exp [-f(t) x g(d)]
7.6.2.4 Calculation of the Unit Risk—The 95% upper limit risk associated with
_ —
d mg/kg /day is obtained from GLOBAL 79 and, for most cases of interest to risk
assessment, can be adequately approximated by P(d) = 1 - exp (-q£d). A "unit
risk" in units X is simply the risk corresponding to an exposure of X = 1. To
2/3
estimate this value we simply find the number of mg/kg /day corresponding to
one unit of X and substitute this value into the above relationship. Thus,
3
for example, if X is in units of ug/m in the air, we have that for case
-i /q _ q y /q q
(1) d = 0.29 x 70 x 10 mg/kg ' /day and for case (2) d = 1, when ug/m
is the unit used to compute parameters in animal experiments.
If exposures are given in terms of ppm in air, we may simply use the
fact that
3
1 ppm = 1.2 x molecular weight (gas) mg/m
molecular weight (air)
012NIY/A 121 3/21/83
-------
PRELIMINARY DRAFT
Note, an equivalent method of calculating unit risk would be to use mg/kg
for the animal exposures and then increase the jth polynomial coefficient
by an amount
(Wh/Wa)j/3 j = l, 2, ..., k
and use mg/kg equivalents for the unit risk values.
7.6.2.5 Interpretation of Quantitative Estimates—For several reasons, the
unit risk estimate is only an approximate indication of the absolute risk in
populations exposed to known carcinogen concentrations. First, there are
important species differences in uptake,metabolism, and organ distribution of
carcinogens, as well as species differences in target site susceptibility,
immunological responses, hormone function, dietary factors, and disease.
Second, the concept of equivalent doses for humans compared to animals on a
mg/surface area basis is virtually without experimental verification regarding
carcinogenic response. Finally, human populations are variable with respect
to genetic constitution and diet, living environment, activity patterns, and
other cultural factors.
The unit risk estimate can give a rough indication of the relative
potency of a given agent compared with other carcinogens. The comparative
potency of different agents is more reliable when the comparison is based
on studies in the same test species, strain, and sex, and by the same route
of exposure, preferably by inhalation.
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, evaluating the adequacy of technology-
based controls, etc. 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 an accurate representation of the true cancer
risks even when the exposures are accurately defined. The estimates pre-
sented may be factored into regulatory decisions to the extent that the
concept of upper risk limits is found to be useful.
012NIY/A 122 3/21/83
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PRELIMINARY DRAFT
7.6.2.6 Alternative Methodological Approaches—The methods used by the CAG
for quantitative assessment are consistently conservative, i.e., tending toward
high estimates of risk. The most important part of the methodology contributing
to this conservatism in this respect is the linear non-threshold extrapolation
model. There are a variety of other extrapolation models that could be used,
most of which would give lower risk estimates. In other documents, other models
have been used for comparative purposes only. However, the animal data for
nickel have only two dosages; these limited data do not allow estimation of
the parameters necessary for fitting these other models.
The position is taken by the CAG that the risk estimates obtained by
use of the linear non-threshold model are upper-limits and the true risk
could be lower.
With respect to the choice of animal bioassay as the basis for extrapola-
tion, the present approach is to use the most sensitive responder. Alternatively,
the average responses of all the adequately tested bioassays could be used.
7.6.3 Cancer Risk Unit Estimates Based on Animal Studies
An extensive animal data base indicates that many nickel compounds
induce cancer either by injection or inhalation (National Institute of
Occupational Safety and Health 1977a; IARC 1976, 1973). Some studies have
suggested that the ability of nickel compounds to induce tumors following
parenteral administration is related to their aqueous solubility (Sunderman
and Maenza, 1976; Sunderman, 1973; Payne 1965, 1964), although one recent
study found essentially no correlation between solubility and injection
site tumors (Sunderman, 1981).
Table 7-4 summarizes the results of five chronic inhalation experiments
on nickel compounds, four of which showed that nickel was carcinogenic.
Only one of these four (Ottolenghi 1974) can be used for a quantitative
risk assessment.
A risk assessment cannot be made from the experiment of Sunderman and
co-workers (1959, 1957), because survival was too poor. Only 9 of 96 (9
percent) exposed animals survived for two years. The toxicity can be
attributed to the administration of nickel carbonyl in an alcohol-ether
mixture, evidenced by the fact that only 3/41 (7 percent) of the vehicle
control rats survived two years. In a subsequent experiment (Sunderman and
Donnelly 1965), only one of 64 rats chronically exposed to nickel carbonyl
developed a lung tumor. In rats acutely exposed, two lung tumors were
012NIY/A 123 3/21/83
-------
TABLE 7-4. INHALATION EXPERIMENTS WITH NICKEL COMPOUNDS
Author
and Year
Sunderman
et al.
1957,
1959
Ottolenghi
et al.
1974
Hueper
1958
Species
Male albino
Wistar rats
Pathogen-free
male and
female F344
rats
I. Guinea pigs
of inbred
strain 13
2. Wistar rats
3. Bethesda bl
rats
Form of
Nickel
Nickel
Carbonyl
Nickel
sulfide
(Ni- S?)
O C.
Nickel
powder
ack
Treatment Dose
1. 0.03 mg per liter
for 30 minutes
3 times weekly
2. 0.06 mg per liter
for 30 minutes
3 times weekly
3. Controls (received
only ether-alcohol
mixture)
1. 0.97 mg/m3
5 days/week
6 hours/day
2. Controls (re-
ceived clean
air)
3
15 mg/m
6 hours/day
4-5 days/week
4. C57 black mice
No
. of
Animals
1.
2.
3.
1.
2.
1.
2.
3.
4.
64
32
41
208
215
42
100
160
20
Duration
52 weeks
52 weeks
52 weeks
78 weeks
(observed
for addi-
tional 30
week period)
Maximal
period of
21 months
(until
death)
Significant Findings
4/9 rats surviving 2 yrs
developed neoplasms of
the lung.
0/3 surviving controls
developed neoplasms of
the lung.
Exposed: 29/208 had
lung tumors.
Controls: 2/215 had
lung tumors.
In guinea pigs and
rats, "abnormal multicen-
tric adenomatoid
formation" in lung.
In mice, 2 lympho-
sarcomas.
-o
TO
O
TO
-------
PRELIMINARY DRAFT
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-------
PRELIMINARY DRAFT
observed. Because the acute and chronically exposed groups cannot be
combined, the number of lung tumors observed was too small for a risk
assessment to be made from this data. A high incidence of malignant
lymphomas was also observed in this experiment. The authors concluded that
a relationship to nickel exposure appeared doubtful in view of a high
spontaneous incidence of lymphoma in rats reported in the literature and
found among control animals. A risk assessment cannot be made from Hueper's
(1958) data because no control groups were used. Wehner et al. (1975)
concluded that nickel oxide did not appear to cause lung tumors under his
experimental conditions.
In the Ottolenghi et al. study (1974), 110 male and 98 female Fischer
3
344 rats were exposed to 970 ug/m nickel sulfide inhalations for 78 weeks
(5 days/wk, 6 hrs/day). Compared with 108 male and 107 female controls,
the treated groups of both sexes showed statistically significant increases
in both adenomas and adenocarcinomas of the lung. These results are shown
in Table 7-5.
The results show significant increases in adenomas and in combined
adenomas/adenocarcinomas for both males and females and also an increased
incidence of squamous cell carcinoma of the lung in treated males and
females. Since the authors conclude that these "benign and malignant
neoplasms. .. .are but stages of development of a single proliferative lesion"
a unit risk assessment can be calculated which includes combined adenomas
and adenocarcinomas.
Based on combining adenomas and adenocarcinomas and adding in squamous
cell carcinomas, the treated males had a 14.5 percent incidence (16/110)
versus 1 percent (1/108) for the controls. The equivalent lifetime con-
tinuous exposure is:
c c
~
o c c 70 o
970 ug/m x - brs x day x ~ wks = 122.8 ug/m
Since nickel sulfide is a particulate, the equivalent human dosage is
estimated according to Case 1, Section 7.6.2.3.2, where
d = iW1/3vr
2/3
where d = equivalent exposure in mg/W , i for rats = .64, i for humans =
o
.29, v = mg/m of nickel sulfide in air, and r, the absorption fraction, is
assumed equal in)( both species. Setting d equal in both species gives
v = (i /i )(W /W ) v
humans v rats humans'v rats humans' rats
012NIY/A 127 3/21/83
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PRELIMINARY DRAFT
TABLE 7-5. HYPERPLASTIC AND NEOPLASTIC CHANGES IN LUNGS OF RATS EXPOSED
TO NICKEL SULFIDE
Controls
Males
Pathologic Changes
Typical hyperplasia
Atypical hyperplasia
Squamous metaplasia
Tumors: '
Adenoma
Adenocarcinoma
Squamous cell
carcinoma
Fibrosarcoma
(108a)
26b
17
6
0
1
0
0
(24)
(16)
(6)
(0)
(1)
(0)
(0)
Females
Nickel
Males
(107a) (110a)
20
11
4
1
0
0
0
(19)
(10)
(4)
(1)
(0)
(0)
(0)
68
58
20
8
6
2
1
(62)
(53)
(18)
(7)
(5)
(2)
(1)
Sulfide
Females P values
(98a) Males
65
48
18
7
4
1
0
(66)
(49)
(18)
(7) .005
(4) .06
(1)
(0)
Females
.02
.05
Number of animals.
Values represent the number of affected animals in each group. Percentage of
affected animals is given in parentheses. Subtreatment groups were combined,
since no significant differences were found among them.
Source: Ottolenghi et al. (1974).
Filling in the numbers gives
vh = (.64/.29)(.35/70)1/3 122.8 ug/m3 = 46.3 |jg/m3
Use of the multistage model with the above data results in an upper
* ~3 3 ~1
limit risk estimate of the linear component of q, = 4.8 x 10 (pg/m ) .
Thus, based on animal studies, the upper limit risk to humans breath-
3 -3
ing 1 ug nickel sulfide/m over a lifetime is 4.8 x 10 . If only the
nickel content of the compounds had been considered, adjusting for the 73
percent weight composition of nickel, the upper-limit estimate would have
been 6.6 x 10"3.
012NIY/A
128
3/21/83
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PRELIMINARY DRAFT
7.6.4 Model for estimation of Unit Risk Based on Human Data
If human epidemiologic studies and sufficiently valid exposure infor-
mation are available for the compound, they are always used in some way.
If they show a carcinogenic effect, the data are analyzed to give an estimate
of the linear dependence of cancer rates on lifetime average dose, which is
equivalent to the factor BM. If they show no carcinogenic effect when
positive animal evidence is available, then it is assumed that a risk does
exist, but it is smaller than could have been observed in the epidemiologic
study, and an upper-limit to the cancer incidence is calculated assuming
hypothetical ly that the true incidence is just below the level of detection
in the cohort studied, which is determined largely by the cohort size.
Whenever possible, human data are used in preference to animal bioassay
data.
Very little information exists that can be utilized to extrapolate
from high exposure occupational studies to low environmental levels.
However, if a number of simplifying assumptions are made, it is possible to
construct a crude dose-response model whose parameters can be estimated
using vital statistics, epidemiologic studies, and estimates of worker
exposures.
In human studies, the response is measured in terms of the relative
risk of the exposed cohort of individuals compared to the control group.
The mathematical model employed assumes that for low exposures the lifetime
probability of death from lung cancer (or any cancer), PQ, may be repre-
sented by the linear equation
P0 = A + BHX
where A is the lifetime probability in the absence of the agent, and x is
the average lifetime exposure to environmental levels in some units, say
ppm. The factor, BH, is the increased probability of cancer associated
with each unit increase of the agent in air.
If we make the assumption that R, the relative risk of lung cancer for
exposed workers, compared to the general population, is independent of the
length or age of exposure but depends only upon the average lifetime ex-
posure, it follows that
P A + BH (x1 + x2)
PQ A + BH (xx)
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PRELIMINARY DRAFT
or
RPQ = A + BH (Xl + x2)
where x-^ = lifetime average daily exposure to the agent for the general
population, x2 = lifetime average daily exposure to the agent in the occu-
pational setting, and PQ = lifetime probability of dying of cancer with no
or negligible agent exposure.
Substituting PQ = A + B,, x., and rearranging gives
BH = P0 (R - D/x2
To use this model, estimates of R and Xp must be obtained from the epidemic-
logic studies. The value PQ is derived from the age-cause-specific death
rates for combined males found in 1976 U.S. Vital Statistics tables using
the life table methodology. For lung cancer the estimate of PQ is 0.036.
This methodology is used in the section on unit risk based on human studies.
7.6.5 Cancer Risk Estimates Based on Human Studies
The epidemiological/occupational studies discussed in the cancer
epidemiology section show increases in both nasal and lung cancer. Exposures
at the various plants, however, and at various locations within the plant
were to several different compounds of nickel. Exposures at the Port
Colborne, Ontario plant, included exposures to nickel subsulfide and nickel
oxide in the high temperature, calcining and sinter furnace areas. Fifty-
five of the 90 workers who developed lung cancer had been employed in one
of these areas for at least one year. Furthermore, 21 of the 35 remaining
workers who developed lung cancers were exposed to nickel from electrolysis
operations associated with exposures to nickel sulfate, nickel chloride,
nickel metal and nickel carbonate (National Institute of Occupational
Safety and Health, 1977a). In the Clydach, Wales plant, high nickel dust
and fume concentrations were present in the calciner buildings prior to
1925; after 1925 more moderate exposures were predominant. In the
Kristiansand, Norway plant, concentrations of nickel chloride and nickel
sulfate were measured. In all three of these plants exposures to different
forms and concentrations of nickel varied by area.
Although a general weakness exists in attempting a unit risk analysis
based on the above exposure synopsis; nevertheless, public health concerns
dictate providing such an analysis.
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PRELIMINARY DRAFT
A unit risk to ambient nickel and nickel compounds based on nickel
exposure in the occupational environment can be estimated recognizing that
the combination of forms and particulate sizes in the two environments are
likely to be qualitatively different. Pedersen et al. (1973), for example,
specifically associates the nickel caused nasal sinus cancer with nickel
refinery exposure and not to those forms in the general environment.
Therefore, separate ambient unit risk estimates for lung cancer and nasal
cancer based upon occupational exposures are presented below. Both Doll's
and Pedersen1s epidemiological studies of nickel workers were used to make
quantitative risk assessments, although better estimates of exposure exist
for the Doll study.
PEDERSEN
The Pedersen et al. study showed increased but differential risks
among different occupational groups, specifically the roasting, smelting,
and electrolysis workers. Nickel compounds associated with these processes
include nickel sulfide, nickel oxide, nickel chloride, nickel sulfate, and
nickel dust. Measurements observed in the early 1970's showed levels
averaging from below 0.1 to 0.8 mg/m . In determining an exposure estimate
for the earlier periods it must be acknowledged that the earlier exposures
must have been considerably higher. Determination of an estimate can be
based on a modification of the International Nickel Company (INCO) estimates
o
from the Clydach, Wales plant which ranged from 20-50 mg Ni/m between
1902-1930, to 3-50 mg Ni/m3 in the mid to late 1940's, (INCO, 1976), the
higher exposures occurring in the calciner sheds. Because the calciners
represent a much higher exposure than what workers would have experienced
3
in Norway, choice of other estimates, ranging from 3-35 mg Ni/m , appears
to be more suitable. Estimates of unit risk will be based on this range.
The Pedersen study does not record the number of years worked so the
estimate is made that exposure lasted for about one quarter of a lifetime.
For the low exposure range, we can estimate an average lifetime exposure
for workers as:
exposure = 3 mg/m x ^4 hrs x ^55 days x j lifetime x 10 ug/mg
= 164 ug/m3
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For the high end of the range, average lifetime exposure is 1918 ug/m3.
The estimated unit lifetime probability, BH, of dying from cancer from
3
exposure to these airborne nickel compounds at 1 ug/m over 70 years of
continuous exposure is given by:
BH = Po
where PQ is the lifetime risk of dying from that particular type of cancer
for a person living in the United States, R is the relative risk in exposed
workers, X« is the exposure experienced by the nickel workers usually in
ug/m or ppm.
The relative risk estimated for the Norwegian workers in the 1980
update was 3.7 for lung cancer, and 23.9 for nasal sinus cancer. The life-
time probability of death from lung cancer in the general population in the
United States is .036 (ICD 161-163, includes larynx) and the probability of
death from nasal sinus cancer (ICD 160) is 2.8 x 10 .
The estimated lifetime probability of death from lung and larynx
2r from nickel at
years is estimated as:
cancer from nickel at the rate of 1 ug/m of continuous exposure for 70
BH = 0.036(2.7)7164 = 5.9 x 10"4 for the low exposure estimate and
B = 5.1 x 10 for the high exposure estimate.
Likewise, the estimated unit lifetime probability of death from nasal sinus
cancer fro
posure is:
cancer from nickel at the rate of 1 ug/m for 70 years of continuous ex-
BH = 0.00028(23.9)/164 = 4.1 x 10"5 for the low exposure estimate and
Bu = 3.5 x 10 for the high exposure estimate.
n
The range of total unit risk from combined lung, larynx and nasal cancer
can be estimated by adding the two risks above, as follows:
for the lower limit:
Bu = 5.1 x 10"5 + 3.5 x 10"6 = 5.4 x 10~5
n
and for the upper limit of risk:
Bu = 5.9 x 10"4 + 4.1 x 10"5 = 6.3 x 10"4
n
012NIY/A 132 3/21/83
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PRELIMINARY DRAFT
DOLL
A risk assessment can also be made from the epidemiologic data at
Clydach, Wales (Doll et al., 1977). The rates prior to 1930 will be used
to calculate the risk assessment, because 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 new procedure
used after 1925 led to the carcinogen being at least drastically reduced in
the environment. INCO estimates that prior to 1930, the concentration of
airborne nickel dust in areas of high exposure was 20-50 mg Ni/m . Because
not all workers were in high risk areas and those who were, probably were
exposed for less than 8 hrs/day, we estimate 10 mg Ni/m as the lower bound
to the range.
Because the exposure estimate used describes conditions between 1900-
1930 only, the fraction of lifetime exposed should reflect exposure before
1930 only. This can be estimated as shown in Table 7-6.
TABLE 7-6. 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
Man-years
= Exposed
2975
1875
787.5
2137.5
257.5
8032.5
Source: Adapted from Doll et al. (1977).
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PRELIMINARY DRAFT
Average number of years exposed 8032.5/762 = 10.5 years or 0.15 of 70
year lifetime.
The average lifetime exposure for the workers, Xp, was:
X2 = 10 mg/m x 24 nrs * ffg days x °-15 "lifetime x 103 ug/mg
= 329 ug/m3
for the low exposure estimate and X2 = 1644 ug/m3 for the high exposure
estimate.
The relative risk estimated by Doll was 6.2 for lung cancer (ICD
161-163) and 287 for nasal sinus cancer (ICD 160). The lifetime lung
cancer risk, PQ, to the general population is approximately 0.036.
The range of estimated lifetime probability of death from lung cancer
from nickel at the rate of 1 ug/m for 70 years of continuous exposure is:
(0.036) (5.2) (1 ug/m3) ..
B., = 5 = 5.7 x 10 4
" 329
for the low exposure limit and
-4
B,, = 1.1 x 10 for high exposure limit.
The lifetime nasal sinus cancer risk P in the general population is
-4
approximately 2.8 x 10
The range of estimated lifetime probability of death from nasal sinus
cancer from nickel at the rate of 1 ug/m for 70 years of continuous exposure
is:
(2.8 x 10"4) (286) (1 ug/m3)
B = = 2.4 x 10
329 ug/nT
-5
for the low exposure estimate and BH = 4.9 x 10 for the high exposure
estimate.
The range of total unit risk from lung, larynx, and nasal cancer
combined can be estimated as before by adding the range of risk as follows:
012NIY/A 134 3/21/83
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PRELIMINARY DRAFT
for the lower limit:
Bu = 1.1 x 10"4 + 4.9 x 10~5 = 1.6 x Iff4
M
and for the upper limit of risk:
Bu = 5.7 x 10"4 + 2.4 x 10"4 = 8.1 x 10"4
n
7.6.6 Comparison of Results
Calculation of risks from both animal and human studies show similar
results. Based on 1 ug Ni^S^/m over a lifetime, the projected upper limit
lifetime unit risk based on data from the Ottolenghi study on Fischer rats
_0
is 4.8 x 10 . This compared with an upper limit total unit risk to humans
-4
from the human data in the Pedersen study of 6.3 x 10 and from the human
-4
data in the Doll study of 8.1 x 10 . If these upper limit risks from the
Pedersen and Doll studies are averaged, the geometric mean is
-A -A 1/9 -4
[(6.3 x 10 ^) (8.1 x 10 *)r = 7.1 x 10 H
which is just slightly less than the upper limit risks estimated for the
animal studies. A comparison of these human cancer risk estimates with
those extrapolated from animal data is presented in Table 7-7.
'7.6.7 Relative Potency
One of the uses 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 weights and the resulting number
expressed in terms of (mMol/kg/day) . This is called the relative potency
index.
Figure 7-1 is a histogram representing the frequency distribution of
potency indices of 53 chemicals evaluated by the CAG as suspect carcinogens.
The actual data summarized by the histogram are presented in Table 7-8. When
human data are available for a compound, they have been used to calculate the
index. When 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 most of the chemicals have
animal oral studies; this allows potency comparisons by route.
The potency index for nickel compounds based on lung cancer in occu-
pational studies by Pedersen and by Doll is 7 x 10 . This is derived as
follows: the range of unit risk estimates based on the geometric mean of
012NIY/A 135 3/21/83
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PRELIMINARY DRAFT
both studies is 7.5 x 10~5 - 5.8 x 10"4 (pg/m3)'1 Table 7-7. We first take
the midpoint of the range 3.3 x 10 (ug/m3)"1. This is then converted to
units of (mg/kg/day) , assuming a breathing rate of 20 m3 of air per day
and 70 kg person.
3.3 x 10"4 ((jg/m3)"1 x 1 day x 1 |jg x 70 kg = 1.2 (mg/kg/day)'1
20 m3 10"3 mg
Multiplying by the molecular weight of 58.7 gives a potency index of 7 x
10 . Rounding off to the nearest order of magnitude gives a value of +2
which is the scale presented on the horizontal axis of Figure 7-1. The
index of 7 x 10+ lies in about the middle of the third quartile of the 53
substances which the CAG has evaluated as suspect carcinogens.
Ranking of the relative potency indices is subject to the uncertainty of
comparing estimates of potency of different chemicals based on different routes
of exposure to different species using studies of different quality. Further-
more, 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 is subject to the addi-
tional uncertainty of not being able to accurately identify the specific nickel
compounds in the workplace. Multiplying by the molecular weight of 58.7 based
on the nickel ion probably represents an underestimation of the potency.
012NIY/A 136 3/21/83
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PRELIMINARY DRAFT
LU
O
Q_
X
LU
_J
LU
O CO
i— i E
Z \
s cu
o -^
Q£
^) CU
ii
C£ •<-
LU — 1
O
Z
o
z
^£
s:
ni
•
7"
r*~
LU
_J
03
I—
T3
C
r— TO
«
4-> X S-
O C CU
^£>2
i|- TO TO
O — 1 O
!—
en co TO
c c in
TO 3 TO
Qi _i z
s_
CU
o
c
4- TO
O C_3
CU r-
en TO
c: 10
TO TO
Qi Z
en
g~
33
—1 X
c
O i-
TO S-
4J
o
. 137
-------
PRELIMINARY DRAFT
TABLE 7-8. RELATIVE CARCINOGENIC POTENCIES AMONG 53 CHEMICALS EVALUATED
BY THE CARCINOGEN ASSESSMENT GROUP AS SUSPECT HUMAN CARCINOGENS1'2'-3
Compounds
Acrylonitrile
Aflatoxin B,
Aldrin
Allyl Chloride
Arsenic
B[a]P
Benzene
Benzidine
Beryl lium
Cadmi urn
Carbon Tetrachloride
Chlordane
Chlorinated Ethanes
1,1,2-trichloroethane
1,1,2,2-tetrachloroethane
Hexachloroethane
Chloroform
Chromium
DDT
Dichlorobenzidine
1,1-dichloroethylene
Dieldrin
Slope ,
(mg/ kg/day)
0.24(W)
2924
11.4
1.19xlO"2
14(H)
11.5
5.2xlO"2
234(W)
4.86
6.65(1)
8.28xlO"2
1.61
5.73xlO"2
0.20 ?
1.42x10 ^
0.11
41
8.42
1.69
1.04
30.4
Molecular
Weight
53.1
312.3
369.4
76.5
149.8
252.3
78
184.2
9
112.4
153.8
409.8
133.4
167.9
236.7
119.4
104
354.5
253.1
97
380.9
Potency
Index
1.3xlO+1
9xlO+5
4xlO+3
9X10"1
2xlO+3
3xlO+3
4x10°
4xlO+4
4xlO+1
7xlO+2
lxlO+3
7xlO+2
8x10?
3x10 X
3xlOU
lxlO+1
4xlO+3
3xlO+3
4xlO+2
lxlO+2
1X10+4
Order of
Magnitude
Index;
+1
+6
+4
0
+3
+3
+1
+5
+2
+3
+3
+3
+1
+1
0
+1
+4
+3
+3
+2
+4
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PRELIMINARY DRAFT
TABLE 7.8 (continued)
Compounds
Dinitrotoluene
Diphenylhydrazine
Epichlorohydrin
Bis(2-chloroethyl )ether
Bis(chloromethyl )ether
Ehtylene Dibromide (EDB)
Ethylene Dichloride (EDC)
Ethylene Oxide
Formaldehyde
Heptachlor
Hexachlorobenzene
Hexachl orobutadiene
Hexachl orocycl ohexane
technical grade
alpha isomer
beta isomer
gamma isomer
Nickel
Nitrosamines
Dimethyl nitrosamine
Di ethyl ni trosami ne
Di butyl nitrosamine
N-nitrosopyrrol idine
N-nitroso-N-ethylurea
N-nitroso-N-methylurea
N-nitroso-diphenylamine
PCBs
Slope ,
(mg/kg/day)
0.31
0.77
2.4xlO"2
1.14
9300(1)
8.51
5.84xlO"2
0.63(1)
2.14xlO"2(I)
3.37
1.67
7./5X10"2
4.75
11.12
1.84
1.33
1.15(W)
25.9(not by q?)
43.5(not by q?)
5.43
2.13
32.9
302.6
4.92x10
4.34
Molecular
Weight
182
180
92.5
143
115
187.9
99.0
44.0
30
373.3
284.4
261
290.9
290.9
290.9
290.9
58.7
74.1
102.1
158.2
100.2
117.1
103.1
198
324
Potency
Index
6xlO+1
lxlO+2
2x10°
2xlO+2
lxlO+6
2xlO+3
6x10°
3xlO+1
exio"1
lxlO+3
5xlO+2
2xlO+1
So;3
4xlO+2
7xlO+1
2xl°+3
4xl°+2
9xl°+2
2xl°+3
4xl°+4
1x10°
lxlO+3
Order of
Magnitude
(log1Q
Inde*}
+2
+2
0
+2
+6
+3
+1
+1
0
+3
+3
-1
+3
+3
+3
+3
+2
+3
+4
+3
+2
+4
+4
0
+3
012NIY/A
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Remarks:
PRELIMINARY DRAFT
TABLE 7.8 (continued)
Compounds
Phenols
2,4,6-trichlorophenol
Tetrachl orodioxin
Tetrachl oroethyl ene
Toxaphene
Trichloroethyl ene
Vinyl Chloride
Vinylidene Chloride
Slope ,
(mg/kg/day)
1.99xlO~2
4.25xl05
5.31xlO"2
1.13
1.26xlO~2
1.75xlO~2(I)
0.13(1)
Molecular
Weight
197.4
322
165.8
414
131.4
62.5
97
Potency
Index
4x10°
lxlO+8
9x10°
5xlO+2
2x10°
1x10°
1X10+1
Order of
Magnitude
Index)
+1
+8
+1
+3
0
0
+1
1. Animal slopes are 95% upper-limit slopes based on the linear multistage
model. They are calculated based on animal oral studies, excpet for those
indicated by I (animal inhalation), W (human occupational exposure), and H
(human drinking water exposure). Human slopes are point estimate, based on
a linear non-threshold model.
2. The potency index is a rounded-off slope in (mMol/kg/day) 1 and is calculated by
multiplying the slopes in (mg/kg/day) 1 by the molecular weight of the compound.
3. Not all the carcinogenic potencies presented in this table represent the same
degree of certainty. All are subject to change as new evidence becomes available.
012NIY/A
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PRELIMINARY DRAFT
11
I
4TH 3RD 2ND 1ST
QUARTILE I QUARTILE i QUARTILE i QUARTILE
1X10
+ 1
4X10
+ 2
2X10
+ 3
18
246
LOG OF POTENCY INDEX
T
8
Figure 7-1. Histogram representing the frequency distribution of the
potency indices of 53 suspect carcinogens evaluated by the Carcinogen
Assessment Group
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PRELIMINARY DRAFT
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