NICKEL
o
UJ
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Agency for Toxic Substances and Disease Registry
U.S. Public Health Service
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ATSDR/TP-88/19
TOXICOLOCICAL PROFILE FOR
NICKEL
Date Published — December 1988
Prepared by
Syracuse Research Corporation
under Contract No. 68-C8-0004
for
Agency for Toxic Substances and Disease Registry (ATSDR)
U.S. Public Health Service
in collaboration with
U.S. Environmental Protection Agency (EPA)
Technical editing/document preparation by:
Oak Ridge National Laboratory
under
DOE Interagency Agreement No. I8S7-B026-A1
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DISCLAIMER
Mention of company name or product does not constitute endorsement by
the Agency for Toxic Substances and Disease Registry
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FOREWORD
The Superfund Amendments and Reauthorizacion Act of 1986 (Public
Law 99-499) extended and amended the Comprehensive Environmental
Response. Compensation, and Liability Act of 1980 (CERCLA or Superfund)
This public law (also known as SARA) directed the Agency for Toxic
Substances and Disease Registry (ATSDR) to prepare toxicological
profiles for hazardous substances which are most commonly found at
facilities on the CERCLA National Priorities List and which pose the
most significant potential threat to human health, as determined by
ATSDR and the Environmental Protection Agency (EPA) The list of the 100
most significant hazardous substances was published in the Federal
RegLscer on April 17, 1987.
Section 110 (3) of SARA directs the Administrator of ATSDR to
prepare a toxicological profile for each substance on the list. Each
profile must include the following content:
"(A) An examination, summary, and interpretation of available
toxicological information and epidemiologic evaluations on a
hazardous substance in order to ascertain the levels of significant
human exposure for the substance and the associated acute,
subacute, and chronic health effects.
(B) A determination of whether adequate information on the health
effects of each substance is available or in the process of
development to determine levels of exposure which present a
significant risk to human health of acute, subacute, and chronic
health effects.
(C) Where appropriate, an identification of toxicological testing
needed to identify the types or levels of exposure that may present
significant risk of adverse health effects in humans."
This toxicological profile is prepared in accordance with
guidelines developed by ATSDR and EPA. The guidelines were published in
the Federal Register on April 17, 1987. Each profile will be revised and
republished as necessary, but no less often than every three years, as
required by SARA.
The ATSDR toxicological profile is intended to characterize
succinctly the toxicological and health effects information for Che
hazardous substance being described. Each profile identifies and reviews
the key literature that describes a hazardous substance's toxicological
properties. Other literature is presented but described in less detail
than the key studies. The profile is not intended to be an exhaustive
document; however, more comprehensive sources of specialty information
are referenced.
I I I
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Foreword
Each toxicological profile begins with a public health statement,
which describes in nontechnical language a substance's relevant
toxicological properties. Following the statement is material that
presents levels of significant human exposure and, where known,
significant health effects. The adequacy of information to determine a
substance's health effects is described in a health effects summary
Research gaps in toxicologic and health effects information are
described in the profile Research gaps that are of significance to
protection of public health will be identified by ATSDR, the National
Toxicology Program of the Public Health Service, and EPA. The focus of
the profiles is on health and toxicological information; therefore, we
have included this information in the front of the document.
The principal audiences for the toxicological profiles are health
professionals at the federal, state, and local levels, interested
private sector organizations and groups, and members of the public. We
plan to revise these documents in response to public comments and as
additional data become available; therefore, we encourage comment that
will make the toxicological profile series of the greatest use.
This profile reflects our assessment of all relevant toxicological
testing and information that has been peer reviewed. It has been
reviewed by scientists from ATSDR, EPA, the Centers for Disease Control,
and the National Toxicology Program. It has also been reviewed by a
panel of nongovernment peer reviewers and was made available for public
review. Final responsibility for the contents and views expressed in
this toxicological profile resides with ATSDR.
James 0. Mason, M.D., Dr. P H.
Assistant Surgeon General
Administrator, ATSDR
iv
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CONTENTS
FOREWORD iii
LIST OF FIGURES ix
LIST OF TABLES xi
1. PUBLIC HEALTH STATEMENT 1
1.1 WHAT IS NICKEL' 1
1.2 HOW MIGHT I BE EXPOSED TO NICKEL AND ITS COMPOUNDS? ... 1
1.3 HOW DO NICKEL AND ITS COMPOUNDS GET INTO MY BODY? .... 2
1.4 HOW CAN NICKEL AND ITS COMPOUNDS AFFECT MY HEALTH? . . 3
1.5 IS THERE A MEDICAL TEST TO DETERMINE IF I HAVE BEEN
EXPOSED TO NICKEL OR ITS COMPOUNDS? 4
1.6 WHAT LEVELS OF EXPOSURE HAVE RESULTED IN HARMFUL
HEALTH EFFECTS? 4
1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT
MADE TO PROTECT HUMAN HEALTH? 7
2. HEALTH EFFECTS SUMMARY 9
2.1 INTRODUCTION 9
2.2 LEVELS OF SIGNIFICANT EXPOSURE 10
2.2.1 Key Studies and Graphical Presentations 10
2.2.1.1 Inhalation . .. 10
2.2.1.2 Oral 17
2.2.1.3 Dermal .. 19
2.2.2 Biological Monitoring as a Measure of
Exposure and Effect 20
2.2.3 Environmental Levels as Indicators of
Exposure and Effects . . 23
2.2.3.1 Levels found in the environment 23
2.2.3.2 Human exposure potential 23
2. 3 ADEQUACY OF DATABASE 25
2.3.1 Introduction . 25
2.3.2 Health Effect End Points 26
2.3.2.1 Introduction and graphic summary . . . 26
2.3.2.2 Descriptions of highlights of graphs . . 29
2.3.2.3 Summary of relevant ongoing research 30
2.3.3 Other Information Needed for Human
Health Assessment . 30
2.3.3 1 Pharmacokinetics and mechanisms
of action 30
2.3.3.2 Monitoring of human biological samples 31
2.3.3.3 Environmental considerations 32
3. CHEMICAL AND PHYSICAL INFORMATION 33
3.1 CHEMICAL IDENTITY 33
3.2 PHYSICAL AND CHEMICAL PROPERTIES 33
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Concents
4. TOXICOLOGICAL DATA 37
4 1 OVERVIEW ... . 37
4.2 TOXICOKINETICS 38
4.2.1 Absorption . ... 38
4 2.1.1 Inhalation 38
4.2 1.2 Oral . .39
4.2.1.3 Dermal . 39
4.2 2 Distribution 40
4 2.2.1 Inhalation 40
4.2.2.2 Oral 40
4.2.2.3 Dermal 40
4.2.3 Metabolism . . . . 41
4.24 Excretion 41
4.2.4.1 Inhalation 41
4.2.4.2 Oral 41
4.2.4.3 Dermal 42
4.3 TOXICITY 42
4.3.1 Lethality and Decreased Longevity 42
4.3.1.1 Inhalation 42
4.3.1.2 Oral 43
4.3.2 Systemic/Target Organ Toxicity 43
4.3.2.1 Overview 43
4.3.2.2 Effects on the respiratory system 43
4.3.2.3 Nickel sensitivity 48
4.3.2.4 Other immunological effects 49
4.3.2.5 Renal effects 51
4.3.2.6 Hematological and hematopoietic effects 52
4.3.2.7 Endocrine and neurotoxic effects 53
4.3.2.8 Studies showing no effects 54
4.3.3 Developmental Toxicity 54
4.3.3.1 Inhalation 54
4.3.3.2 Oral 54
4.3.3.3 Dermal 55
4.3.3.4 General discussion 55
4.3.4 Reproductive Toxicity 56
4.3.4.1 Inhalation 56
4.3.4.2 Oral 56
4.3.4.3 Dermal 57
4.3.4.4 General discussion 57
4.3.5 Genotoxicity 58
4.3.5.1 Human 58
4.3.5.2 Nonhuman 58
4.3.5.3 General discussion 58
4.3.6 Carcinogenicity 60
4.3.6.1 Inhalation 60
4.3.6.2 Oral 61
4.3.6.3 Dermal 64
4.3.6.4 General discussion 64
4.4 INTERACTIONS WITH OTHER CHEMICALS 65
5 MANUFACTURE, IMPORT. USE. AND DISPOSAL 67
5 1 OVERVIEW 67
5.2 PRODUCTION 67
5 3 IMPORT 67
vi
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Concents
5.4 USES 67
5.5 DISPOSAL 68
6 ENVIRONMENTAL FATE 69
6.1 OVERVIEW ....,.- 69
6.2 RELEASE TO THE ENVIRONMENT . 69
6.3 ENVIRONMENTAL FATE 69
7 POTENTIAL FOR HUMAN EXPOSURE 75
7.1 OVERVIEW 75
7.2 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT .. 75
7.2.1 Air . 75
7.22 Water 76
7.2.3 Soil 76
7.2.4 Other 76
7.3 OCCUPATIONAL EXPOSURES 78
7.4 POPULATIONS AT HIGH RISK 78
8. ANALYTICAL METHODS . 79
8.1 ENVIRONMENTAL MEDIA 79
8.2 BIOMEDICAL SAMPLES 79
8.2.1 Fluids/Exudates 79
8.2.2 Tissues . 81
9. REGULATORY AND ADVISORY STATUS . . 83
9.1 INTERNATIONAL (WORLD HEALTH ORGANIZATION) 83
9.2 NATIONAL 83
9.2.1 Regulations 83
9.2.2 Advisory Guidance 83
9.2.2.1 Air 83
9.2.2.2 Water 84
9.2.2.3 Food 84
9.2.3 Data Analysis 84
9.2.3.1 Reference dose 84
9.2.3.2 Carcinogenic potency 85
9.3 STATE 85
10. REFERENCES 87
11. GLOSSARY 107
APPENDIX: PEER REVIEW Ill
vii
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LIST OF FIGURES
1.1 Health effects from breathing nickel 5
1.2 Health effects from ingesting nickel 6
2.1 Effects of nickel--inhalation exposure 11
2.2 Effects of nickel--oral exposure 12
2.3 Levels of significant exposure for nickel--inhalation 13
2.4 Levels of significant exposure for nickel--oral 14
2.5 Relationship between air nickel levels and serum or plasma
nickel levels during various occupational exposures 21
2.6 Relationship between air nickel levels and urinary nickel
levels during various occupational exposures 22
2.7 Availability of information on health effects of nickel
(human data) 27
2.8 Availability of information on health effects of nickel
(animal data) 28
IX
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LIST OF TABLES
2.1 Nickel concentration in human tissues 24
3.1 Chemical identity of nickel 34
3 2 Physical and chemical properties of nickel and compounds . . 35
4.1 Oral LD,Q values for nickel compounds in rats 44
4.2 Genotoxicity of nickel and compounds in vitro 59
4.3 Genotoxicity of nickel and compounds in vivo 59
4.4 Hyperplastic and neoplastic changes in lungs of rats
exposed to nickel subsulfide 62
4.5 Inhalation carcinogenicity studies of nickel and
compounds 63
6.1 Worldwide emissions of nickel into the atmosphere 70
7.1 Nickel concentrations in various foodstuffs 77
8 1 Methods for analysis of nickel 80
XI
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1. PUBLIC HEALTH STATEMENT
L.I WHAT IS NICKEL?
Nickel is a naturally occurring silvery metal that is found in the
earth's crust in the form of various nickel minerals. Nickel comprises
about 0.009% of the earth's crust Nickel and its compounds can be
detected in all parts of the environment, including plants and animals
used for human consumption, air, drinking water, rivers, lakes, oceans,
and soil. Nickel used by industries comes from mined ores or from
recycled scrap metal and has a wide range of industrial uses. It is used
primarily in making various steels and alloys and in electroplating.
Minor applications include use in ceramics, permanent magnet materials,
and nickel-cadmium batteries. In 1985, the U.S. contribution was 0.7% of
the total nickel mined in the world. A large resource of yet untapped
nickel is in the seabed.
1.2 HOV MIGHT I BE EXPOSED TO NICKEL AND ITS COMPOUNDS?
Exposure of the general population to nickel and its compounds
results from breathing air, ingesting drinking water and food that
contain nickel and compounds, and skin contact with a wide range of
consumer products. Segments of the population that may be exposed to
higher levels of nickel include people whose diets contain foods
naturally high in nickel, people who are occupationally exposed to
nickel, people living in the vicinity of a nickel processing facility,
and people who smoke tobacco.
The single largest nickel source found in the atmosphere is from
fuel oil combustion. Other sources include atmospheric emissions from
mining and refining operations, atmospheric emissions from municipal
waste incineration, and windblown dust. Minor sources of atmospheric
nickel are volcanoes, s-teel production, gasoline and diesel fuel
combustion, vegetation, nickel alloy production, and coal combustion.
Sources of nickel in water and soil include stormwater runoff, soil
amended with municipal sewage sludge, wastewater from municipal sewage
treatment plants, and groundwater near landfill sites.
A minor source of nickel exposure is contact with consumer products
which, under normal use conditions, will contribute very little toward
exposure. Some of these consumer products are:
• Kitchen utensils
• Pipes and faucets
• Jewelry
• Buttons and zippers
• Beverage containers
• Household appliances
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2 Seccion I
• Medical and dental devices
• Coins
Occupations in which nickel exposure may occur include
• Battery makers
• Ceramic makers
• Coal gasification workers
• Dyers
• Electroformers
• Electroplaters
• Enaraellers
• Glass workers
• Ink makers
• Jewelers
• Magnet makers
• Metal workers
• Nickel miners
• Nickel refiners
• Nickel smelters
• Oil dehydrogenators
• Paint makers
• Sand blasters
• Spark plug makers
• Spray painters
• Stainless steel makers
• Textile dyers
• Varnish makers
• Welders
1.3 HOV DO NICKEL AND ITS COMPOUNDS GET INTO MY BODY?
Because nickel occurs in most food items, the highest level of
exposure to nickel commonly comes from dietary intake. Nickel is found
in fruits, vegetables, grains, seafood, and mother's and cow's milk. The
level of nickel in the diet can be increased by the use of certain
fertilizers on food crops, by varying the diet to include food items
naturally high in nickel content, or by the use of nickel-containing
cooking vessels or utensils.
The intake of nickel or its compounds by the ingestion of drinking
water is typically less than through the diet; however, ingestion of
nickel in drinking water can be increased significantly by the
consumption of drinking water from plumbing or faucets that contain
nickel.
Nickel can enter the body when a person breathes nickel dust or
particles of nickel compounds Compared to oral intake, the typical
amount of inhaled nickel is small. The amount of nickel that enters the
blood from the lungs, or that remains in the lungs, depends on the
location in the lungs in which the nickel has been deposited and on the
properties of the nickel compound (e g , particle size and solubility in
body fluids). Breathing tobacco smoke can significantly increase the
amount of nickel inhaled.
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Public Health Scacemenc 3
Some nickel compounds (e.g., nickel chloride) can penetrate skin,
especially if the skin has been damaged. Skin exposures to the general
public are predominantly to nickel metal found in jewelry, coins,
buttons, zippers, and cooking utensils. Nickel metal does not readily
penetrate the skin; therefore, only those persons with skin allergies to
nickel should be concerned with skin exposures to nickel metal.
1.4 HOW CAN NICKEL AND ITS COMPOUNDS AFFECT MY HEALTH?
Very small amounts of nickel have been shown to be essential for
normal growth and reproduction in some species of animals; therefore,
small amounts of nickel may also be essential to humans.
The most common adverse effects of nickel exposure noted in the
general population are skin allergies. Surveys indicate that 2.5 to 5.0%
of the general population may be sensitive to nickel. Individuals may be
sensitized by frequent or prolonged contact with nickel-containing or
nickel-plated consumer products. In persons not sensitive to nickel,
normal, long-term oral, inhalation, and skin exposure to low levels of
this element has not been associated with adverse health effects.
Accidental or suicidal ingestion of very high amounts of some
nickel compounds may result in death, as illustrated by a single case of
a 2 1/2-year-old girl who died following the ingestion of a very large
amount of nickel sulfate. Ingestion af nickel metal is unlikely to
result in death.
Adverse effects have been noted in humans exposed by inhalation to
nickel compounds at work. Asthma has been reported in nickel platers
exposed to nickel sulfate, and in welders exposed to nickel oxides.
Inhalation exposure of workers to nickel refinery dust, which contains
nickel subsulfide, has resulted in increased numbers of deaths from lung
and nasal cavity cancers, and possibly cancer of the voice box. Because
there are no nickel refineries in the United States, there is very
little exposure to nickel refinery dust and nickel subsulfide.
Occupational exposure to nickel metal has not been associated with
cancer.
An inhalation study in rats has shown that nickel subsulfide is an
animal carcinogen, providing further support that nickel subsulfide is a
carcinogen in humans. A number of injection studies of nickel metal and
other nickel compounds in animals have revealed cancer growths. Because
of this carcinogenic response in animals, the potential of other nickel
compounds, or more broadly nickel in any form, to cause cancer in humans
is uncertain. By analogy, ingested nickel could be thought to have a
carcinogenic potential, yet limited animal testing of a few nickel
compounds has not shown carcinogenicity.
Animal studies have found that inhalation exposure to nickel
compounds can increase susceptibility to respiratory infection,
indicating that this effect may also be an area of possible concern for
humans. Studies in animals indicate that exposure to high levels of some
nickel compounds during pregnancy can cause miscarriages, pregnancy
complications, and low birth weight in newborns. There are no data
regarding birth defects from exposure to nickel or its compounds in
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4 Section 1
humans. Additional effects that have been observed in animals exposed Co
nickel compounds include those on the kidneys, blood, and growth,
1.5 IS THERE A MEDICAL TEST TO DETERMINE IF I
HAVE BEEN EXPOSED TO NICKEL OR ITS COMPOUNDS?
The amount of nickel in the urine and blood can be measured
Because humans are usually exposed to low levels of nickel or its
compounds in the diet, urine, and blood normally contain small amounts
of nickel. Although increases of nickel levels in urine and blood have
been noted in persons exposed to nickel compounds at work, the levels in
urine and blood cannot be predicted from exposure levels (or vice
versa). No reports of high blood and urine nickel levels following
environmental exposure to nickel compounds were located.
1.6 WHAT LEVELS OF EXPOSURE HAVE RESULTED
IN HARMFUL HEALTH EFFECTS?
The graphs on the following pages show the relationship between
exposure to nickel and known health effects. In the first set of graphs
labeled "Health effects from breathing nickel," exposure is measured in
milligrams of nickel per cubic meter (mg/m^). In the second set of
graphs, the same relationship is represented for the known "Health
effects from ingesting nickel." Exposures are measured in milligrams of
nickel per kilogram of body weight per day (mg/kg/day). In all graphs,
effects in animals are shown on the left side, effects in humans on the
right. Data are insufficient to determine the levels at which nickel
causes health effects following skin contact.
The wide range at which death occurred in animals breathing nickel
for a long time may be because of the different sensitivities of the
animals used in the experiments (rats and hamsters), the different
nickel compounds, and the different exposure durations. The levels
marked on the graphs as anticipated to be associated with minimal risk
for humans are based on currently available information from animal
studies; therefore, some uncertainty still exists. From available data
in humans, the Environmental Protection Agency (EPA) has estimated that
lifetime exposure to 1 microgram of nickel refinery dust per cubic meter
of air would result in 2.4 or 2400 additional cases of cancer in a
population of 10,000 or 10,000,000 people, respectively. Lifetime
exposure to 1 microgram of nickel subsulfide per cubic meter of air
would result in 4.8 or 4800 additional cases of cancer in a population
of 10,000 or 10,000,000 people, respectively. It should be noted that
these risk values are plausible upper-limit estimates. Actual risk
levels are unlikely to be higher and may be lower. The major sources of
nickel refinery dust and nickel subsulfide are nickel refineries.
Because there are no operating nickel refineries in the United States,
actual exposure of the general population to nickel refinery dust and
nickel subsulfide is expected to be very low.
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Public Healch Statement
SHORT-TERM EXPOSURE
(LESS THAN OR EQUAL TO 14 DAYS)
LONG-TERM EXPOSURE
(GREATER THAN 14 DAYS)
EFFECTS
IN
ANIMALS
EFFECTS ON
CONG IN EFFECTS EFFECTS CONG IN EFFECTS
AIR IN IN AIR IN
(mg/m3) HUMANS ANIMALS (mg/m3) HUMANS
1C
1
1
IMMUNE SYSTEM
LUNG EFFECTS
0
)0 QUANTITATIVE
DATA WERE
NOT AVAILABLE
}
0
LUNG
EFFECTS ^
IMMUNE
1C
s-
1
1
0
V*.
EFFECTS
)0 QUANTITATIVE
DATA WERE
NOT AVAILABLE
J
0
1
001
0001
00001
001
0001
00001
MINIMAL RISK FOR
•EFFECTS OTHER THAN
CANCER
Fig. 1.1. Health effects from breathing nickel.
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Section 1
SHORT-TERM EXPOSURE
(LESS THAN OR EQUAL TO 14 DAYS)
LONG-TERM EXPOSURE
(GREATER THAN 14 DAYS)
EFFECTS
IN
ANIMALS
EFFECTS ON
UNBORN OR -<
NEWBORN
EFFECTS EFFECTS EFFECTS
DOSE IN IN DOSE IN
(mg/kg/day) HUMANS ANIMALS (mg/kg/day) HUMANS
1000 1000 QUANTITATIVE
(
/
\
r I
DEATH
REPRODUCTIVE
DATA WE RE
NOT AVAILABLE
^ 100 EFFECTS AND 100
1
REDUCED
, LUNG AND
BLOOD EFFECTS -<
^
1
v^
o
1 0
1 0
01
MINIMAL
RISK FOR
-EFFECTS
OTHER THAN
CANCER
01
001
001
MINIMAL RISK FOR
-EFFECTS OTHER
THAN CANCER
Fig. 1.2. Health effects from ingesting nickel.
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Public Health Statement 7
1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT
MADE TO PROTECT HUMAN HEALTH?
To protect workers from occupational exposure to nickel, the
Occupational Safety and Health Administration (OSHA) has set a limit of
1 milligram of nickel per cubic meter of workroom air. The OSHA standard
refers only to nickel metal and soluble nickel compounds. The
carcinogenic potential of these compounds following inhalation exposure
is not known, although occupational exposure to nickel metal has not
been associated with an increased risk of cancer. NIOSH has recommended
that no employee be exposed to nickel at a concentration greater than 15
micrograms per cubic meter of air.
For exposure via drinking water, EPA advises that the following
concentrations are levels at which adverse effects would not be
anticipated to occur: 1 milligram of nickel per liter of water for 10
days of exposure of children, 3.5 milligrams of nickel per liter of
water for 10 days of exposure of adults, and 0.35 milligram of nickel
per liter of water for lifetime exposure of adults.
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2. HEALTH EFFECTS SUMMARY
2.1 INTRODUCTION
This section summarizes and graphs data on the health effects
concerning exposure to nickel. The purpose of this section is to present
levels of significant exposure for nickel based on key toxicological
studies, epidemiological investigations, and environmental exposure
data. The information presented in this section is critically evaluated
and discussed in Sect. 4, Toxicological Data, and Sect. 7, Potential for
Human Exposure.
This Health Effects Summary section comprises two major parts.
Levels of Significant Exposure (Sect. 2.2) presents brief narratives and
graphics for key studies in a manner that provides public health
officials, physicians, and other interested individuals and groups with
(1) an overall perspective of the toxicology of nickel and (2) a
summarized depiction of significant exposure levels associated with
various adverse health effects. This section also includes information
on the levels of nickel that have been monitored in human fluids and
tissues and information about levels of nickel found in environmental
media and their association with human exposures.
The significance of the exposure levels shown on the graphs may
differ depending on the user's perspective. For example, physicians
concerned with the interpretation of overt clinical findings in exposed
persons or with the identification of persons with the potential to
develop such disease may be interested in levels of exposure associated
with frank effects (Frank Effect Level, FEL). Public health officials
and project managers concerned with response actions at Superfund sites
may want information on levels of exposure associated with more subtle
effects in humans or animals (Lowest-Observed-Adverse-Effect Level,
LOAEL) or exposure levels below which no adverse effects (No-Observed-
Adverse-Effect Level, NOAEL) have been observed. Estimates of levels
posing minimal risk to humans (Minimal Risk Levels) are of interest to
health professionals and citizens alike.
Adequacy of Database (Sect. 2.3) highlights the availability of key
studies on exposure to nickel in the scientific literature and displays
these data in three-dimensional graphs consistent with the format in
Sect. 2.2. The purpose of this section is to suggest where there might
be insufficient information to establish levels of significant human
exposure. These areas will be considered by the Agency for Toxic
Substances and Disease Registry (ATSDR), EPA, and the National
Toxicology Program (NTP) of the U S. Public Health Service in order to
develop a research agenda for nickel.
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10 Section 2
2.2 LEVELS OF SIGNIFICANT EXPOSURE
To help public health professionals address Che needs of persons
living or working near hazardous waste sites, the toxicology data
summarized in this section are organized first by route of exposure--
inhalation, ingestion, and dermal--and then by toxicological end points
categorized into six general areas--lethality, systemic/target organ
toxicity, developmental toxicity, reproductive toxicity, genetic
toxicity, and carcinogenicity. The data are discussed in terms of three
exposure periods --acute, intermediate, and chronic.
Two kinds of graphs are used to depict the data. The first type is
a "thermometer" graph. It provides a summary of the human and animal
toxicological end points (and levels of exposure) for each exposure
route for which data are available. The ordering of effects does not
reflect the exposure duration or species of animal tested. The second
type of graph shows Levels of Significant Exposure (LSE) for each route
and exposure duration. The points on the graph showing NOAELs and LOAELs
reflect the actual doses (levels of exposure) used in the key studies.
No adjustments for exposure duration or intermittent exposure protocol
were made.
Adjustments reflecting the uncertainty of extrapolating animal data
to man, intraspecies variations, and differences between experimental vs
actual human exposure conditions were considered when estimates of
levels posing minimal risk to human health were made for noncancer end
points. These minimal risk levels were derived for the most sensitive
noncancer end point for each exposure duration by applying uncertainty
factors. These levels are shown on the graphs as a broken line starting
from the actual dose (level of exposure) and ending with a concave-
curved line at its terminus Although methods have been established to
derive these minimal risk levels (Barnes et al. 1987), shortcomings
exist in the techniques that reduce the confidence in the projected
estimates. Also shown on the graphs under the cancer end point are low-
level risks (iO'u to 10'7) reported by EPA. In addition, the actual dose
(level of exposure) associated with the tumor incidence is plotted.
2.2.1 Key Studies and Graphical Presentations
Dose-response duration data for the toxicity and carcinogenicity of
nickel are displayed in two kinds of graphs. These data are derived from
key studies of nickel and its compounds described in the following
sections. Inhalation and oral NOAELs and LOAELs are presented on
thermometer graphs in Figs. 2 1 and 2.2, respectively. NOAELs and LOAELs
for lethality, developmental toxicity, cancer, and the most sensitive
target organ end points for acute, intermediate, and chronic durations
for inhalation and oral exposures are presented graphically in Figs. 2.3
and 2.4, respectively. Data were insufficient for graphical display of
dermal data.
2.2.1.1 Inhalation
Lethality and decreased longevity. Reports of deaths in humans
resulting from acute inhalation exposures to inorganic nickel compounds
were not found. In a series of studies, rats and mice were exposed by
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Health Effects Summary 11
ANIMALS
(mg/m*)
100 r
HUMANS
HAMSTER DECREASED LONGEVITY LIFETIME INTERMITTENT
10
RAT REDUCED SURVIVAL 12 DAYS INTERMITTENT
RAT MOUSE REPRODUCTIVE TOXICITY 12 DAYS INTERMITTENT
MOUSE REDUCED SURVIVAL 12 DAYS INTERMITTENT
RAT. DEVELOPMENTAL TOXICITY. 21 DAYS INTERMITTENT
RAT RABBIT. LUNG TOXICITY 3-6 MONTHS. RAT LUNG CANCER. 1 5 YEARS
INTERMITTENT
RAT MOUSE REPRODUCTIVE TOXICITY 12 DAYS INTERMITTENT
MOUSE REDUCED SURVIVAL 12 DAYS INTERMITTENT
RAT DEVELOPMENTAL TOXICITY. 21 DAYS. CONTINUOUS
MOUSE. IMMUNOTOXICITY 2 h. CONTINUOUS
0 1
• RAT IMMUNOTOXICITY 4 MONTHS CONTINUOUS
O RABBIT. LUNG TOXICITY 44 MONTHS INTERMITTENT
• RAT LUNG TOXICITY 2 WEEKS INTERMITTENT
• RAT. DECREASED LONGEVITY LUNG TOXICITY 31 MONTHS CONTINUOUS
O RAT IMMUNOTOXICITY 4 MONTHS CONTINUOUS
001 L-
INHALAT1ON EXPOSURE OF
HUMANS HAS SEEN
ASSOCIATED WITH LUNG
TOXICITY CANCER
ASTHMA IMMUNOTOXICITV
AND NASAL EFFECTS BUT
DOSE RESPONSE DATA
WERE NOT AVAILABLE
• LOAEL
O NOAEL
Fig. 2.1. Effects of nickel—inhalation exposure.
-------
12 Section 2
ANIMALS
(mg/Xg/day)
1000 r
100
10
1 L
HUMANS
(mg/Xg/day)
1000 r
• MOUSE. DEVELOPMENTAL TOXICITY. 15 DAYS
- O MOUSE. DEVELOPMENTAL TOXICITY. 15 DAYS
• RAT. LDM
• DOG. HEMATOPOIETIC TOXICITY 2 YEARS
• RAT. DEVELOPMENTAL TOXICITY 2 GENERATIONS
• RAT. DECREASED BODY WEIGHT. 2 YEARS
JO RAT. DEVELOPMENTAL TOXICITY. 2 GENERATIONS
[• RAT, INCREASED MORTALITY. HEMATOTOXICITY. 91 DAYS
O DOG. HEMATOPOIETIC TOXICITY. 2 YEARS
O RAT. INCREASED MORTALITY. HEMATOTOXICITY. 91 DAYS RAT.
DECREASED BODY WEIGHT. 2 YEARS
100
10
A DEATH.ACUTE
• LOAEL FOR ANIMALS
O NOAEL FOR ANIMALS
LOAEL FOR HUMANS
Fig. 2.2. Effects of nickel—oral exposure.
-------
Health Effects Summary 13
ACUTE
(<14DAYS)
INTERMEDIATE
(15-364 DAYS)
CHRONIC
(>365 DAYS)
DEVELOP- TARGET REPRO- TARGET
LETHALITY MENTAL ORGAN DUCTION ORGAN
DECREASED TARGET
LONGEVITY ORGAN CANCER
tmg/m3)
I00r
10
0 1
001
0 001
00001
000001
0 000001 •
0 00000011-
• s
I r J,
i r. m
i r (LUNG)
• r
• m (IMMUNE SYSTEM) r(|MMUNE SYSTEM)
• r(LUNG) t on (LUNG)
• r
• r (LUNG)
r RAT
m MOUSE
S HAMSTER
h RABBIT
• LOAEL
O NOAEL
LOAEL AND NOAEL
IN THE SAME
SPECIES
, MINIMAL RISK LEVEL
I FOR EFFECTS OTHER
O. THAN CANCER
10-*-i
10-5-
10" -1
ESTIMATED
UPPER-BOUND
HUMAN
CANCER
RISK LEVELS
Fig. 2.3. Levels of significant exposure for nickel—inhalation.
-------
Secc-ion 2
ACUTE INTERMEDIATE
(<14DAYS) (15-364 DAYS)
LETHALITY
DEVELOP-
MENTAL LETHALITY
TARGET
ORGAN
CHRONIC
(>365 DAYS)
TARGET ORGAN
1000 r
100
• r
10
01
r
• r
r (BLOOD
AND
DECREASED
BODY
WEIGHT GAIN)
d (BONE MARROW)
r(DECREASED
BODY
WEIGHT
GAIN)
001 L-
r RAT
m MOUSE
0 DOG
• LOAEL FOR ANIMALS
O NOAEL FOR ANIMALS
A LOAEL FOR HUMANS
I MINIMAL RISK FOR EFFECTS
OTHER THAN CANCER
1
LOAEL AND NOAEL IN THE
SAME SPECIES
Fig. 2.4. Levels of significant exposure for nickel—oral.
-------
Health Effects Summary 15
inhalation to nickel sulfate. nickel subsulfide, or nickel oxide
6 h/day, 5 days/week for up to 12 days (Dunnick et al. 1985, 1987;
Benson et al. 1988). When exposure concentrations of individual
compounds are expre.ss.ed in terms of nickel content, nickel sulfate was
found to be the most toxic. In the animals exposed to nickel sulfate,
the lowest concentrations of nickel that resulted in reduced survival
were 1.7 mg/tn3 for mice and 3 3 mg/m3 for rats. The animals died
following the development of pulmonary inflammation. Nickel sulfate at
nickel concentrations of 0 8 and 1.7 mg/m3 did not result in reduced
survival in mice and rats, respectively. The levels of nickel as nickel
sulfate that resulted in death and the levels that did not result in
death in these species are plotted in Figs 2.1 and 2.3 as LOAELs and
NOAELs, respectively, for acute lethality.
In studies of chronic exposure, reduced survival was observed in
hamsters exposed to nickel oxide ("Bakers analyzed" reagent) at 41.7
mg/m3 nickel, 7 h/day, 5 days/week (Wehner et al. 1975), and in rats
exposed to nickel oxide produced by the pyrolysis of nickel acetate at
60 or 200 pg/m3 nickel (0.06 or 0.2 mg/m5) 23 h/day (Takenaka et al.
1985). These doses are plotted in Figs 2.1 and 2.3 for reduced survival
due to chronic inhalation exposure. Even the lowest exposure levels in
the Takenaka et al. (1985) study resulted in significantly reduced
survival.
Systemic/target organ toxicity, respiratory system. The lung is the
target organ of nickel toxicity in humans, but dose-response data for
respiratory effects in humans are not provided in either studies or case
reports. Nickel-plating workers and welders exposed to water-soluble
nickel compounds have developed asthma as an allergic response or as a
response to primary irritation. Nickel-plating workers chronically
exposed to high levels of nickel sulfate (as well as acid mists) have
also developed anosmia (the loss of the sense of smell) and severe nasal
injury such as septal perforation, chronic rhinitis, and sinusitis (EPA
1986a). Increased susceptibility to pulmonary infections, probably due
secondarily to the effect of nickel on the immune system, has been
observed in animals following exposure to nickel compounds, indicating
that this effect may also be a concern for humans. After comparing
ambient air nickel levels with nickel levels in occupational
environments that were associated with adverse effects, the EPA (1986d)
concluded "that human health effects other than cancer appear to be
limited to the occupational environment."
Effects on the lungs have been observed in inhalation studies of
short-, intermediate-, and long-term durations using various inorganic
nickel compounds in rats, mice, and rabbits. Only the intermediate-
duration study in rabbits defined a NOAEL for lung effects. A LOAEL in
rats for short-term exposure was provided in a study by Bingham et al.
(1972) in which exposure to nickel chloride at 109 A»g/ra3 nickel (0.109
mg/m3) for 12 h/day, 6 days/week for 2 weeks, resulted in hyperplasia of
the bronchial epithelium and mucus secretion. Short-term exposure to
nickel sulfate at 0.7 mg/m3 nickel 6 h/day, 5 days/week for 12 days.
resulted in pulmonary inflammation and degenerative bronchiolar lesions
in rats and mice (Benson et al. 1988) The LOAEL of 0.109 mg/m3 is
plotted in Figs. 2.1 and 2.3 for target organ toxicity for acute
exposure. A minimal risk level cannot be determined from the acute data
-------
16 Section 2
because a threshold for lung effects is not clearly defined. For
intermediate exposure, a LOAEL of 1 mg/m3 nickel (see Figs. 2.1 and 2 3)
given as nickel chloride 5 days/week for 3 to 6 months to rats produced
increased lung weight, fibrosis in the alveolar ducts, increased numbers
of foamy macrophages*, and signs of irritation (Clary 1977). An
intermediate FEL of 1 mg/m3 nickel (nickel dust) (see Fig. 2 1), which
resulted in alveolar nodules and hemorrhagic foci in rabbits exposed for
3 to 6 months, was found in a study by Curstedt et al. (1984) A NOAEL
for intermediate exposure in rabbits (see Figs. 2.1 and 2.3) was
provided in a study by Curstedt et al. (1983) in which exposure to
nickel dust at 0.13 rag/m3, 6 h/day, 5 days/week for 4 or 8 months,
resulted in a significant increase in the concentration of
phospholipids, with significantly increased levels of
phosphatidylcholines, indicating an effect on type II cells without an
interference on cellular mechanisms for alveolar clearance. For chronic
exposure, a study by Takenaka et al. (1985) provided an FEL for rats of
60 Mg/™3 nickel (0.06 mg/m3) administered as nickel oxide produced by
the pyrolysis of nickel acetate (see Figs. 2.1 and 2.3). The rats,
exposed to nickel oxide 23 h/day, 7 days/week for up to 31 months,
developed increased lung weight, alveolar proteinosis, accumulation of
foamy macrophages, and focal septal fibrosis. Survival of rats exposed
to nickel oxide at 0.06 mg/m3 was also reduced. Because the FEL is the
lowest exposure level used in long-term studies, a minimal risk level
for chronic inhalation exposure cannot be derived.
Systemic/target organ toxicity, immune system. Effects on the
immune system have also been observed in animals. Exposure of mice to
nickel chloride for 2 h increased the susceptibility to bacterial
infection resulting in death at 500 /ig/m3 nickel (0.5 mg/m3) (FEL) and
caused imraunosuppression at 250 ^g/m3 nickel (0.25 mg/m3) (LOAEL for
target organ toxicity in mice for acute exposure in Figs. 2.1 and 2.3)
(Adkins et al. 1979, Graham et al. 1978). Exposure of rats to nickel
oxide produced by the pyrolysis of nickel acetate for 4 months at >150
^g/m3 nickel (0.15 mg/m3) (LOAEL for intermediate exposure; Figs. 2.1
and 2.3) caused reduced humoral immune response (Spiegelberg et al.
1984). At higher exposures, decreased alveolar macrophage activity and
macrophage death were observed. At 50 pg/m3 nickel, macrophage activity
was increased, probably representing a normal physiological response to
the presence of NiO in the lung. Therefore, 50 A»g/n>3 nickel (0.05 mg/m3
nickel) is a NOAEL (see Figs. 2.1 and 2.3) and serves as the basis for
the minimal risk level for intermediate inhalation exposure.
Developmental toxicity. There are no studies regarding
developmental effects of nickel in humans. A reduction in fetal body
weight was observed in rats exposed to nickel oxide by inhalation
throughout gestation at 2.5 and 1.3 mg/m3 nickel (LOAEL) but not at 0 6
mg/m3 (NOAEL) (Weischer et al., 1980). These levels are indicated in
Figs. 2.1 and 2.3. This NOAEL is higher than the LOAELs for target organ
effects; therefore, a minimal risk level for acute inhalation exposure
cannot be derived from this NOAEL.
Reproductive toxicity. Testicular effects were observed in rats
and mice in the 12-day inhalation studies of Benson et al. (1987, 1988).
Degeneration of the germinal epithelium of rat testes occurred at a
nickel concentration of >1.6 mg/m3 (>7 mg/m3 nickel sulfate), but not at
-------
Healch Effaces Summary 17
0.7 mg/ra3 nickel (3.5 mg/m3 nickel sulfate). Rats and mice exposed co
nickel subsulfide had testicular degeneration at >1.8 mg/m3 nickel, but
not at 0.9 mg/m3 nickel. Therefore, the range of 1.6 to 1.8 mg/m3 nickel
is a LOAEL, and the range of 0.7 to 0.9 mg/m3 nickel is a NOAEL for
short-term inhalation exposure for reproductive effects in rats and
mice. These levels are indicated in Figs. 2.1 and 2.3 for intermediate
exposure because reproductive effects are end points of concern for
intermediate-duration exposures.
Genotoxicity. Tests of nickel compounds such as nickel chloride
sulfate, nitrate, sulfide, acetate, oxide, and subsulfide for
genotoxicity indicate that nickel may induce gene mutations and
chromosome aberrations in bacteria and mammalian cells and cell
transformation in mammalian cells in vitro. In vivo induction of
chromosomal aberrations in humans and animals has not been demonstrated.
Waksvik and Boysen (1982) failed to find increased frequencies of
chromosomal aberrations and SCE in the lymphocytes of nickel refinery
workers, but this single study does not rule out the possibility that
nickel is clastogenic to humans.
Carcinogenicity. Occupational exposure to nickel refinery dust,
which contains nickel subsulfide, has been associated with increased
risks of lung and nasal cancers, and possibly cancer of the larynx.
Based on several epidemiological studies, EPA (1986a) derived
incremental unit-risk slopes for carcinogenic potency of 2.4 x 10"4
(/jg/m3)'1 for nickel refinery dust and 4.8 x 10*4 (Mg/m3)"1 for nickel
subsulfide. The exposure levels associated with individual lifetime
upper-bound risks of cancer in 1/10,000 to 1/10,000.000 persons are 4 x
10'1 to 4 x 10'4 A»g/m3 (4 x 10"4 to 4 x 10"7 mg/m3) for nickel refinery
dust and 2 x 10'1 to 2 x 10'4 (2 x 10'4 to 2 x 10'' mg/m3) for nickel
subsulfide. The levels for nickel refinery dust are indicated in
Fig. 2.3. Several epidemiology studies have not found increased risks of
cancer following occupational exposure to nickel metal.
Nickel subsulfide was carcinogenic in a long-term inhalation study
in rats (Ottolenghi et al. 1974). Rats exposed to nickel subsulfide at
0.97 mg/m3 nickel, 6 h/day, 5 days/week for 78 to 84 weeks developed
increased incidences of lung tumors compared with controls (see Figs.
2.1 and 2.3). Other inhalation studies of nickel or nickel compounds
(Hueper 1958, Hueper and Payne 1962, Wehner et al. 1975, Horie et al.
1985) gave negative or equivocal results.
2.2.1.2 Oral
Lethality and decreased longevity. The only fatal case of nickel
poisoning by the oral route was that of a 24-year-old girl who ingested
15 g of nickel sulfate crystals (3.3 g Ni) (Daldrup et al. 1983).
Assuming a body weight (bw) of 15 kg, 3.3 g of nickel is equivalent to
220 mg/kg bw. This FEL is plotted on Figs. 2.2 and 2.4 for acute oral
lethality in humans.
Oral LD5QS in rats that have been reported for various nickel
compounds are as follows: 355 mg/kg for nickel acetate (118 mg/kg
nickel) (Haro et al. 1968); 1600 mg/kg for nickel hydroxide (1021 mg/kg
nickel); 300 mg/kg for nickel sulfate hexahydrate (67 rag/kg nickel);
>9000 mg/kg for nickel powder; and >5000 mg/kg for nickel oxide (green
-------
18 Section 2
and black) (>3292 mg/kg nickel), nickel sulfide (>3233 rag/kg nickel),
and nickel subsulfide (>3666 mg/kg nickel) (Mastromatteo 1986). Causes
of death were not stated. It appears that the soluble nickel compounds
are more toxic than the insoluble compounds by the oral route. In terms
of nickel, the lowest U>50 is 67 mg/kg nickel for nickel sulfate
hexahydrate, an FEL for acute exposure (see Figs. 2 2 and 2.4).
In a two-generation drinking water study of nickel chloride in rats
(RTI 1987), the 1000-ppm nickel (mg/L) level was dropped after 2 weeks
due to excessive mortality. Dose-related but not significant mortality
associated with pregnancy complications occurred in parental females at
>50 ppm (mg/L). American Biogenics (1986) dosed groups of 30 rats/sex by
gavage with nickel chloride at 0, 5, 35, or 100 mg/kg bw nickel per day
for 91 days. High rates of mortality occurred at the 35- and 100-mg/kg
doses (FELs) but not at 5 mg/kg (NOAEL). Some of the deaths were due to
gavage errors. The 35- and 5-mg/kg/day doses are plotted in Figs. 2.2
and 2.4 as the LOAEL and NOAEL, respectively, for lethality due to
intermediate oral exposure
Systemic/target organ toxicity. The hematological system is a
target for oral exposure to nickel. In the American Biogenics (1986)
study, white blood cell counts were significantly increased in rats
treated with nickel chloride at doses of 35 mg/kg/day nickel and
slightly increased at 5 mg/kg/day nickel (NOAEL). Platelet counts were
also significantly increased at 35 mg/kg/day nickel. The 35-mg/kg/day
nickel dose was also associated with decreased body weight gain, while
the 5-mg/kg/day nickel dose was not. These levels are plotted in Figs.
2.2 and 2.4 as the LOAEL and NOAEL for target organ toxicity for
intermediate oral exposure. The. NOAEL is the basis for the minimal risk
level for intermediate oral exposure. In a study by Ambrose et al.
(1976), dogs fed nickel sulfate in the diet for 2 years had histological
lesions in the bone marrow at 2500 ppm nickel (62.5 mg/kg/day) (LOAEL)
but not at <1000 ppm (25 mg/kg/day) (see Figs. 2.2 and 2.4). The only
effect in rats fed nickel sulfate in the diet for 2 years was decreased
body weight gain at 2500 and 1000 ppm nickel but not at 100 ppm (Ambrose
et al. 1976). Assuming that a rat consumes a daily amount of food equal
to 5% of its body weight, the 1000-ppm level is equivalent to 50
mg/kg/day (LOAEL) and the 100-ppm level is equivalent to 5 mg/kg/day,
which is the chronic NOAEL for systemic toxicity in rats (see Figs. 2.2
and 2.4). The NOAEL serves as the basis of the minimal risk level for
chronic oral exposure as derived by EPA (1987a) (see Fig. 2.4).
Developmental and reproductive toxicity. Data regarding
developmental and reproductive effects in humans were not available In
a drinking water teratogenicity study of nickel chloride in mice, no
effects were observed at 500 ppm nickel (mg/L) (NOAEL), but at 1000 ppm
nickel (mg/L) (FEL). a loss of maternal weight, a reduction in mean
birth weights of pups, and an increased incidence of spontaneous
abortions were observed (Berman and Rehnberg 1983). Assuming that a
0 03-kg mouse consumes 0.006 L water per day (EPA 1986b), 1000 ppm is
equivalent to 200 mg/kg/day and 500 ppm is equivalent to 100 mg/kg/day.
These levels are indicated in Figs 2.2 and 2.4. RTI (1987) maintained
rats on drinking water containing nickel chloride at 0, 50, 250, or 500
ppm nickel (mg/L) for cwo generations There appeared to be increased
pup mortality and decreased live litter size in the Fl generation at all
-------
Health Effaces Summary L9
exposure concentrations.. As determined by an independent statistical
analysis by the EPA, these effects were statistically significant in the
500-ppm group, but in the SO- and 250-ppm groups, increased pup
mortality was not statistically significant compared with controls and
the decreased live litter size was not statistically significant
compared with historic litter sizes. In the F2 generation, there was
increased postnatal mortality at 500 ppm. Increased incidences of shore
ribs per fetus (but not per litter) were found at 50 ppm, but not ac 250
or 500 ppm. The absence of a dose-related trend suggests that the effect
in the 50-ppm group is spurious and not compound-related. Since the
independent statistical evaluation indicated no compelling evidence of
nickel-related effects in any but the high-dose group, the 50- and 250-
ppm levels are NOAELs for developmental toxicity. The FEL of 500 ppm,
expressed as the dose of 51.6 mg/kg nickel per day, and the higher NOAEL
of 250 ppm, expressed as the dose of 30.8 mg/kg nickel per day, are
indicated on Figs. 2.2 and 2.4 for developmental toxicity for acute
exposure, since developmental toxicity is an end point of concern for
short-term exposure. This NOAEL is the basis for the minimal risk level
for acute oral exposure.
Genotoxicity. See Sect. 2.2.1.1, Inhalation Exposure.
Carcinogenicity. Nickel and inorganic nickel compounds do not
appear to be carcinogenic to animals by the oral route, but the data are
inadequate because not all inorganic nickel compounds have been studied
and the available studies are limited. In chronic oral studies
(Schroeder et al. 1964, Schroeder and Mitchener 1975), the
administration of nickel acetate in the drinking water of mice at 5 ppm
(mg/L) throughout their lifetime did not result in increased tumor
incidences. This was the only exposure level examined. No treatment -
related tumors were observed in rats given nickel sulfate hexahydrate in
their diets at 0, 100, 1000, or 2500 ppm nickel for 2 years (Ambrose et
al. 1976), but a single adequate negative study does not rule out the
possibility of carcinogenicity. Although no treatment-related tumors
were found in dogs in this study, a 2-year study in dogs is usually not
sufficiently long to determine a carcinogenic effect. There are no data
for humans. NAS (1975) concluded that human exposure (oral and dermal)
to "natural concentrations of nickel in waters, soils, and foods does
not constitute a biologic threat."
2.2.1.3 Dermal
Lethality and decreased longevity. No data were available.
Systemic/target organ toxicity. liver. Effects on the liver were
observed in rats treated dermally with nickel sulfate hexahydrate at 60
mg/kg nickel per day for 15 or 30 days (Mathur et al. 1977). The effects
included swollen hepatocytes and feathery degeneration after 15 days and
focal necrosis and vacuolization after 30 days. No liver effects were
observed at 40 mg/kg nickel per day. In this study, there was no
indication that the rats were prevented from licking the nickel sulface
hexahydrate from the skin; therefore, these effects could have resulted
from oral exposure. The study was considered inadequate for graphical
display for this reason.
-------
20 Section 2
Systemic/target organ toxlcity, skin. Contact dermatitis is the
most prevalent effect of nickel in the general human population. Dose-
response relationships, however, cannot be estimated from the available
data. Once an individual is sensitized, even minimal contact with nickel
will result in a reaction.
In an attempt to sensitize mice to nickel, Holler (1984) produced
only moderate dermatitis by repeated dermal application of a 20%
solution of nickel salt solution for 2 weeks. This point is not plotted
because the nickel salt is not known, precluding quantitation of a dose
of nickel.
Developmental toxicity. No studies were available.
Reproductive toxicity. In the study by Mathur et al. (1977), rats
treated dermally with nickel sulfate hexahydrate at 100 or 60 mg/kg
nickel per day for 30 days had testicular effects including tubular
damage and lumen filled with degenerated sperm. No testicular effects
were observed at 40 mg/kg nickel per day (NOAEL). Since there was no
indication in the study that the rats were prevented from licking the
nickel sulfate from their skin, the effects could have resulted from
oral exposure. The study, therefore, was considered to be inadequate for
graphical display.
Genotoxicity. See Sect. 2.2.1.1, Inhalation Exposure.
Carcinogenicity. No studies were available.
2.2.2 Biological Monitoring as a Measure of Exposure and Effect
The only biological monitoring data available are from occupational
settings. Determination of nickel in the urine (Sunderman and Sunderman
1958, McNeely et al. 1972), serum (McNeely et al. 1972), hair (Nechay
and Sunderman 1973), and nasal mucosa (Torjussen et al. 1978, Torjussen
and Andersen 1979) have all been used to demonstrate human exposure to
nickel compounds. In relating body burden to occupational exposure
levels, serum and urine levels are the most studied. Grandjean (1986)
plotted data from a number of epidemiology studies shown in Figs. 2.5
and 2.6. Figure 2.5 shows a general positive relation between air levels
of nickel and serum nickel levels after occupational exposure to various
forms of nickel (insoluble, mixed, or soluble). According to Grandjean
(1986), "the somewhat scattered observations cannot be used for any
accurate predictions of air levels from serum/plasma concentrations or
vice versa." Figure 2.6 also shows a general positive relationship
between air nickel levels and urinary levels. Because of the scatter,
the data are not useful for prediction of exposure levels.
Serum and urine nickel levels are dependent on the form of nickel
to which a person was exposed and do not clearly relate to body burden.
Nickel levels in the body fluids reflect recent exposures to relatively
soluble nickel compounds, which have urinary half-lives of 17 to 39 h
(Grandjean 1986) . Nickel levels in body fluids can also be elevated as a
result of the slow release of nickel from sparingly soluble compounds
deposited in the lungs.
Biological monitoring in the occupational setting does not reflect
exact exposure levels but may indicate whether absorbed doses are at an
-------
Health Effects Stun/nary 21
12
5
? 10
~
< 8
_i
OL
OC
0 6
OC
LU
w 4
z
_,
HI
* 2
0
Z
A
I I
• EXPOSURE TO INSOLUBLE
_ NICKEL COMPOUNDS
9 MIXED EXPOSURES ..
O EXPOSURE TO SOLUBLE
NICKEL COMPOUNDS 9
—
0 0
«•
•
—
0
Q 0
— >^
^
i i i
1 10 100 1000 10, (
NICKEL IN AIR
Fig. 2.5. Relationship between air nickel levels and serum or plasma nickel levels during various
occupational exposures. Source: Grandjean 1986.
-------
22
Section 2
uj 330
z
uj 100
tr
o
O
O
tt 33
O
1
mm
d
•3. 10
UJ
z
E
? 3.3
_j
UJ
0
5 1
i i i i I -
• O 9 MQ NI/L OF URINE O
• O O Mg Nl/g OF CREATININE Q
—
O A
O
O
w *
•
ff
a
a
•
• t-
a
a a •
a
1 1 1 1 l I
3.3
10 33 100
NICKEL IN AIR
330
1000
3300
Fig. 2.6. Relationship between air nickel levels and urinary nickel levels during various
occupational exposures. • • Insoluble nickel compounds; O D soluble nickel compounds; 9 B mixed
exposures. Source: Grandjean 1986.
-------
Health Effaces Summary 23
acceptable level. Grandjean (1986) suggests that a reasonable limit for
plasma nickel was 5 pg/L. This value is based on unstated considerations
and a study by Rubanyi et al. (1981) that found a significant increase
in coronary resistance in dog hearts exposed to perfusion fluid
containing nickel at 6 /Jg/L. All biological monitoring data must be
considered in the context of exposure levels, the compound involved, and
the individual medical conditions that may affect nickel levels. Because
of the lack of data to clearly relate exposure levels to blood/urine
nickel levels, and a lack of data to relate blood/urine nickel levels to
systemic or other effects, routine biological monitoring may not be very
useful. Grandjean (1986) suggests that when nickel exposures and
identities of nickel compounds are known, biological monitoring should
be made available on a voluntary basis.
Normal levels of nickel have been reported at <0.1 mg/kg wet weight
in tissues, 3 to 7 Mg/L in whole blood, 1 to 5 pg/L in blood serum, and
1.5 jig/L in urine (National Research Council of Canada 1981). More
recent reference values of 0.28 ± 0.24 /jg/L nickel in the serum (Linden
et al. 1985) and 2.0 ± 1.5 Aig/g creatinine in the urine (Sunderman et
al. 1986) were reported by Grandjean (1986). The values have decreased
in recent years due to improved sampling, reduced contamination, and
improved analytical technology. Rezuke et al. (1987) determined nickel
concentrations in human tissues and bile from 10 autopsies of adult
persons not occupationally exposed to nickel compounds. These data are
shown in Table 2.1.
2.2.3 Environmental Levels as Indicators of Exposure and Effects
2.2.3.1. Levels found in the environment
This subsection is intended to provide data that will show if any
correlation can be found between the level of nickel in any body fluid
or tissue (blood, urine, adipose tissue, etc.) and the intake of nickel
from soil, drinking water, and food. Diet typically contributes 83 to
94% of the total body burden of nickel in the general population. Food
with nickel concentrations >1 mg/kg are oatmeal, wheat bran, fried
beans, soya products, hazelnuts, peanuts, sunflower seeds, licorice,
cocoa, and dark chocolate. Consumption of such foods in large amounts
could raise the nickel intake to 900 pg/day (Sunderman and Oskarsson
1987). Similarly, levels as high as 24,000 /ig/g nickel soil have been
found in soils near metal refineries (EPA 1986a). No studies that
attempt to correlate the level of nickel in body fluids or tissues with
environmental levels of nickel were found in the available literature.
2.2.3.2 Human exposure potential
Host nickel compounds are relatively soluble at pH <6.5. Nickel
exists predominantly as insoluble hydroxides at pH >6.7. In unpolluted
waters, nickel may exist primarily as hexahydrate ion, which is poorly
absorbed by most living organisms. Water-insoluble inorganic nickel
compounds present in soil or water are generally not bioavailable.
Bioavailability of these nickel compounds for most plants and animals
requires environmental conditions that promote solubilization of nickel
-------
24 Section 2
Table 2.1. Nickel concentration in human tissues
Tissue
Lung
Thyroid
Adrenal
Kidney
Heart
Liver
Brain
Spleen
Pancreas
No. of
subjects
9"
8
10
10
9*
10
7
10
10
Wet weight Ug/kg)
Mean ± SO
18 ± 12
20 ± 10
26 ± 15
9 ± 6
8 ± 5
10 ± 7
8 ± 2
7 ± 5
8 ± 6
Median (range)
12(7-46)
24(7-32)
24(13-56)
7(3-25)
6(1-14)
8(2-21)
8(5-11)
4(1-15)
6(9-19)
Dry weight (jig/kg)
Mean ± SD
173 ± 94
141 ± 83
132 ± 84
62 ± 43
54 ± 40
50 ± 31
44 ± 16
37 ± 31
34 ± 25
Median (range)
130(71-371)
126(41-240)
126(53-341)
54(19-171)
51 (10-110)
38 (11-102)
51 (20-65)
21 (9-95)
37(?-7l)
"Excluding an outlier result (241 Mg/kg wet weight, 2060 Mg/kg dry weight) m lung tissue
or Patient No 4. a former machinist, based upon Dixon's outlier test.
*Excludmg an outlier result (78 jig/kg wet weight. 758 Mg/kg dry weight) m heart tissue
of Patient No. 2 with acute myocardial infarction, based upon Dixon's outlier test
Source Rezuke et al. 1987
-------
Health Effects Summary 25
(e.g., acid rain) or complexation with organic ligands (e.g., huraic
acid). Acid rain has a pronounced tendency to mobilize nickel from soil
and increase the concentrations of soluble nickel in surface water and
groundwater (Sunderman a*id Oskarsson 1987). This could lead to increased
uptake in microorganisms, plants, and animals (Sunderman and Oskarsson
1987). Nickel exists in river waters approximately half in ionic form
and half as stable organic complexes (e.g., with humic acids). The
organic nickel complexes become adsorbed on silica particles present in
bottom sediments of rivers, leading to a decrease in bioavailability
(Sunderman and Oskarsson 1987).
Nickel is reasonably mobile in low PH and CEC (cation exchange
capacity) mineral soils, but less mobile in basic mineral soils and
soils with high organic content. Nickel present in dump sites will have
higher mobility under acid rain conditions and will be more likely to
contaminate the aquifer. The extractable nickel content of soil affects
its uptake by plant roots (Sunderman and Oskarsson 1987). This
extractability is influenced by physical factors (e.g., soil texture,
temperature, and water content), chemical factors (e.g., pH, organic'
content, and redox potential), and biological factors (e.g., plant
species variability and microbial activity). In soil derived from
serpentine rocks (which contain higher concentrations of nickel), the
extractable nickel concentration can reach 70 mg/kg, which is toxic to
most plants. Alkalization of such soils decreases the nickel uptake by
plants and reduces the likelihood of their exhibiting nickel toxicity
(Sunderman and Oskarsson 1987, Tyler and McBride 1982).
Nickel is an essential constituent in such urease-rich plants as
Jack beans and soybeans, the concentration of nickel in these plants is
very high. Numerous species of nickel-accumulating plants have been
identified. One such plant, Sebercia acuminaca. native to nickel-rich
New Caledonia, attains an exceptionally high concentration of nickel
(10 g/kg dry weight in leaves and 250 g/kg in latex). Such plants
usually contain elevated concentrations of citric acid and malic acids.
The solubilization of nickel due to complexation may be involved in the
transport and storage of nickel in these plants (Sunderman and Oskarsson
1987).
In a dermal absorption study, Fullerton et al. (1986) found that
nickel ions from a chloride solution passed through excised human skin
-50 times faster than nickel ions from a sulfate solution. These data
suggest that dermal penetration of nickel from nickel chloride in water
would be much greater than from nickel sulfate in water.
2.3 ADEQUACY OF DATABASE
2.3.1 Introduction
Section 110 (3) of SARA directs the Administrator of ATSDR to
prepare a toxicological profile for each of the 100 most significant
hazardous substances found at facilities on the CERCLA National
Priorities List. Each profile must include the following content:
"(A) An examination, summary, and interpretation of available
toxicological information and epidemiologic evaluations on a
hazardous substance in order to ascertain the levels of
-------
26 Section 2
significant human exposure for the substance and the
associated acute, subacute, and chronic health effects.
(B) A determinati9n of whether adequate information on the health
effects of each substance is available or in the process of
development to determine levels of exposure which present a
significant risk to human health of acute, subacute, and
chronic health effects.
(C) Where appropriate, an identification of toxicological testing
needed to identify the types or levels of exposure that may
present significant risk of adverse health effects in humans "
This section identifies gaps in current knowledge relevant to
developing levels of significant exposure for nickel. Such gaps are
identified for certain health effects end points (lethality,
systemic/target organ toxicity, developmental toxicity, reproductive
toxicity, and carcinogenicity) reviewed in Sect. 2.2 in developing
levels of significant exposure for nickel, and for other areas such as
human biological monitoring and mechanisms of toxicity. The present
section briefly summarizes the availability of existing human and animal
data, identifies data gaps, and summarizes research in progress that may
fill such gaps.
Specific research programs for obtaining data needed to develop
levels of significant exposure for nickel will be developed by ATSDR,
NTP, and EPA in the future.
2.3.2 Health Effect End Points
2.3.2.1 Introduction and graphic summary
The availability of data for health effects in humans and animals
is depicted on bar graphs in Figs 2.7 and 2.8, respectively. The bars
of full height indicate that there are data to meet at least one of the
following criteria:
1. For noncancer health end points, one or more studies are available
that meet current scientific standards and are sufficient to define
a range of toxicity from no effect levels (NOAELs) to levels that
cause effects (LOAELs or FELs).
2. For human carcinogenicity, a substance is classified as either a
"known human carcinogen" or "probable human carcinogen" by both EPA
and the International Agency for Research on Cancer (IARC)
(qualitative), and the data are sufficient to derive a cancer
potency factor (quantitative).
3. For animal carcinogenicity, a substance causes a statistically
significant number of tumors in at least one species, and the data
are sufficient to derive a cancer potency factor.
4. There are studies which show that the chemical does not cause this
health effect via this exposure route.
-------
HUMAN DATA
V SUFFICIENT
'INFORMATION*
J
SOME
INFORMATION
NO
INFORMATION
ORAL
INHALATION
n
rt>
o
DERMAL
LETHALITY
ACUTE INTERMEDIATE CHRONIC DEVELOPMENTAL REPRODUCTIVE CARCINOGENICITV
/ TOXICITY TOXICITY
SYSTEMIC TOXICITY
'Sufficient Information exists to meet at least one of the criteria tor cancer or noncancer end points.
Fig. 2.7. Availability of information on health effects of nickel (human data).
-------
ANIMAL DATA
ro
co
(si
n
r»
t-.
§
Na
v SUFFICIENT
/^INFORMATION*
J
SOME
INFORMATION
NO
INFORMATION
ORAL
INHALATION
DERMAL
LETHALITY ACUTE INTERMEDIATE CHRONIC DEVELOPMENTAL REPRODUCTIVE CARCINOOENICITY
/ __/ TOXICITY TOXICITV
SYSTEMIC TOXICITY
'Sufficient information exists to meet at least one of the criteria for cancer or noncancer end points.
Kig. 2.8. Availability of information ' Sralth effects of nickel (animal data).
-------
Healch Effects Summary 29
Bars of half height indicate chat "some" information for the end
point exists but does not meet any of these criteria
The absence of a column indicates that no information exists for
that end point and route
2.3.2.2 Descriptions of highlights of graphs
Human. Figure 2.7 indicates that there are many areas for which
there are no data regarding the effects of short-term or long-term
exposure by inhalation, oral, and dermal routes of exposure. The only
data regarding lethality was that a 2 1/2-year-old-girl died as a result
of ingesting 15 g of nickel sulfate (Daldrup et al. 1983) For systemic
toxicity, qualitative data exist to show that occupational exposure of
welders and nickel platers to nickel sulfate or nickel oxide can result
in asthma as a result of sensitization or irritation. In sensitive
individuals, dermal nickel exposure can result in contact dermatitis
which can be aggravated by oral exposure to nickel. Data for the
systemic effects of nickel in humans are insufficient for determining
dose-response relationships. Low-level oral exposure to nickel may be of
little concern, because nickel in small quantities may be essential to
human health The normal daily dietary intake of nickel has been
reported to be as high as 900 jig (NAS 1975) , with average values of
120-520 A*g/day (Bennett 1984), only 1 to 10% of the amount is absorbed.
Epidemiology data in nickel refinery workers are sufficient to indicate
that nickel refinery dust and nickel subsulfide are human carcinogens
following inhalation exposure Epidemiology studies of workers exposed
to nickel metal have not shown increased risks of cancer.
Data on developmental and reproductive effects of nickel exposure
in humans are not available, but animal studies indicate that high doses
of nickel compounds can result in reproductive and developmental
effects. Data also indicate that nickel crosses the placenta in humans
and animals.
Animal. As seen in Fig. 2 8, data for dermal exposure of animals to
nickel are limited. Such studies may be important for studying nickel
sensitivity. Data for oral exposure are adequate to determine levels of
significant exposure for systemic effects due to intermediate and
chronic exposure and developmental effects due to short-term exposure,
but are not adequate to indicate that ingested nickel is carcinogenic.
Data are adequate for developmental effects and acute lethality
following inhalation exposure. Although a LOAEL and a NOAEL were
available for testicular histopathology due to inhalation exposure, only
some data are indicated in Fig. 2.8, because it is not known if
inhalation exposure to inorganic nickel compounds results in impaired
reproductive capacity. Some data exist for acute systemic toxicity and
for lethality and systemic toxicity following chronic inhalation
exposure, but none of the studies defined NOAELs. Data are adequate to
determine a minimal risk level for intermediate inhalation exposure.
Data are sufficient to indicate that nickel subsulfide is carcinogenic
by the inhalation route.
-------
30 Section 2
2.3.2.3 Summary of relevant ongoing research
The NTP is sponsoring inhalation carcinogenicity and subchronic and
chronic toxicity studies of nickel oxide, nickel sulfate, and nickel
subsulfide in rats and mice (Dunnick et al. 1985, NTP 1987). These
studies will include comprehensive gross and histological examinations
of all organ systems. Under the sponsorship of the Nickel Producers
Environmental Research Association (NiPERA), Kodama and associates in
Japan are conducting an inhalation study of green nickel oxide in rats,
and Muhle and associates of the Frauhofer Institute in West Germany are
conducting intratracheal studies of nickel powder, nickel subsulfide,
pentlandite, and stainless steel grinding in hamsters (NiPERA 1988).
NiPERA (1988) has also sponsored a study of renal effects in workers
exposed to soluble forms of nickel. The EPA, along with the Ontario
Ministry of Labour; National Health and Welfare, Canada; Energy, Mines
and Resources, Canada; NiPERA; and the Commission of European
Communities, is sponsoring a reanalysis of epidemiologic studies (EPA
1986a). The project, headed by Sir Richard Doll of Oxford University,
hopes to clarify exposure of individual workers to specific nickel
compounds, and results should be available by mid-1988. The studies of
inorganic nickel compounds currently in progress should greatly increase
the knowledge of nickel-induced health effects.
2.3.3 Other Information Needed for Human Health Assessment
2.3.3.1 Pharmacokinetics and mechanisms of action
Target organs/pharmacokinetic profiles are substantially
characterized for human and animal exposure to nickel and nickel
compounds. Pharmacokinetics appear to be similar for humans and animals,
although studies identifying similar effects in animals and humans
(e.g., contact dermatitis, liver, and reproductive effects) are limited.
The mechanism of nickel-induced lung toxicity is not well
understood but may be due to irritancy, binding of nickel to
macromolecules, or direct toxicity of nickel to pulmonary epithelial
cells. The mechanisms of nickel-induced sensitivity and immunotoxicity
have been partially characterized, but more research is needed. These
effects are the most sensitive systemic/target organ end points.
Studies of biochemical genotoxicity indicate that nickel compounds
induce such genotoxic effects as binding to DNA, DNA strand breaks, and
misincorporation of nucleotide bases in DNA, but how these biochemical
effects translate into actual mutations is not clearly understood.
The mechanism of carcinogenicity may be related to the mutagenic
and clastogenic process. Costa and Heck (1984) suggested that the
carcinogenic potency of nickel is dependent on the selective
phagocytosis of the various nickel compounds, although Sunderman (1984a)
did not observe a significant correlation between in vitro phagocytosis
of various inorganic nickel compounds and carcinogenicity in rats
following an intramuscular injection.
NiPERA (1988) is sponsoring a number of studies at the Lovelace
Inhalation Toxicology Research Institute to explore the toxicity of a
-------
Healch Effects Summary 31
wide range of nickel compounds and to help determine the mechanism of
action of nickel toxicity. The studies being sponsored include:
• An in vitro study of the relative cytotoxicity of selected nickel
compounds (including Ni3S2; NiS04; nickel oxides calcined at <635,
850, and 1045°C, and mixed nickel/copper oxides containing 48 and
47% nickel) to rat type II epithelial cells and rat nasal
epithelial cells;
• An evaluation of the effect of Ni3$2 and nickel oxides calcined at
different temperatures on the cell cycle of nasal epithelial cells
in culture;
• A study of the cellular uptake and the functional and biochemical
response of pulmonary macrophages from various species (F344/N rat,
B6C3F1 mouse, beagle dog, cynomolgus monkey, and human volunteers)
to selected nickel compounds;
• Determination of (1) the sites of deposition and retention of
nickel compounds within the respiratory system, (2) the
intracellular macromolecular localization of nickel within cells
following a single nose-only exposure of F344/N rats to labeled
NiS04 and Ni3S2 to evaluate the relative retention of nickel in the
respiratory tract following exposure to a soluble or moderately
soluble compound, and (3) whether sites of retention correlate with
the sites of lesion development following repeated inhalation
exposures;
• A study of the time course of lesion development in the respiratory
tract of F344/N rats exposed from 1 to 22 days; the extent of DNA
damage and repair and changes in protein kinase activity will be
quantitated;
• A study to begin the characterization of the nickel-binding
protein(s) within the lung to determine if the binding reduces the
availability of nickel or if it results in a biological effect.
NiPERA (1988) is also sponsoring a study of the role of phagocytic-
induced reactive oxygen metabolites in the pathogenesis of nickel
carcinogenesis using the PMN chemiluminescent technique. The principal
investigator is E. Yano of the Tokyo University School of Medicine,
Japan.
2.3.3.2 Monitoring of human biological samples
Nickel levels have been determined in the urine, serum, hair, and
nasal mucosa of occupationally exposed individuals. The results
generally indicate a positive correlation of exposure concentration to
body levels, but the data are not adequate for use in predicting body
levels from serum concentrations. No relationship between serum/urine
nickel levels and effects has been noted; therefore, routine biological
monitoring of nickel-exposed workers is not generally recommended. There
are no data available to relate body burden to effect or to relate
environmental levels to exposure or effects.
-------
32 Section 2
NiPERA (1988) is sponsoring a study of the renal clearance of
nickel in nickel-exposed workers compared with nonexposed workers. The
primary investigator is E. Nieboer at McMaster University, Canada.
Under the sponsorship of NiPERA (1988), H. Aitio of the Institute of
Occupational Health, Finland, is determining the nickel content of
tissues in autopsy specimens of individuals not occupationally exposed
to nickel.
2.3.3.3 Environmental considerations
Bioavailability from environmental media. Methods for measuring
nickel in its elemental state are available; however, measurement of
specific nickel compounds is very difficult, and inorganic compounds
tend to break down into their ionic or atomic forms during analysis. As
a result, studies providing data on the bioavailability of specific
nickel compounds are not available.
Environmental transport and fate. Although significant data on the
physical fate processes of nickel in different environmental media
leading to its transport from one media to another are available, data
on its chemical fate are limited. Even the nature of chemical species
present in a medium is not known with certainty. Therefore, significant
uncertainties regarding its fate and transport exist.
Interactions with other co-contaminants. Limited information is
available on the interactions between nickel and other environmental
pollutants. For example, nickel is speculated to form insoluble sulfide
in the presence of sulfides both in water and in air (Callahan et al.
1979, Pacyna and Ottar 1985).
Ongoing research. There are no known ongoing experimental studies
pertaining to the environmental fate of nickel.
-------
33
3. CHEMICAL AND PHYSICAL INFORMATION
3.1 CHEMICAL IDENTITY
Data pertaining to the chemical identity of nickel are listed in
Table 3.1.
3.2 PHYSICAL AND CHEMICAL PROPERTIES
The physical and chemical properties of metallic nickel and a few
representative soluble and insoluble inorganic nickel compounds are
presented in Table 3.2. Soluble compounds include nickel acetate, nickel
sulfate hexahydrate, nickel nitrate hexahydrate, and nickel chloride.
These compounds dissolve fairly readily in water, whereas insoluble
compounds remain in the solid phase in solution. Consequently, soluble
nickel compounds as a class have greater bioavailability and are
excreted more readily than are insoluble nickel compounds.
There are several forms of nickel oxide that have commercial and/or
environmental significance. The various nickel oxide species have
markedly different physicochemical characteristics and biological
effects; as a result, it is important to distinguish between the various
nickel oxide species, particularly nickel oxide black, which is
chemically reactive, and nickel oxide green, which is inert and
refractory (Sunderman et al. 1987). The chemical and physical properties
of nickel oxide green are presented in Table 3.2.
Physical and chemical properties of nickel carbonyl vary markedly
from those of metallic nickel and inorganic nickel compounds; therefore,
data for nickel carbonyl were not included in Table 3.2 or elsewhere in
this profile since nickel carbonyl has little, if any, environmental
significance (half-life, 100 s) (Schmidt and Andren 1980, EPA 1986a).
Nickel refinery dust, as discussed in this document, refers to dust
from pyrometallurgical sulfide nickel matte refineries.
-------
34 Section 3
Table 3.1. Chemical identity of nickel
Chemical name
Synonyms
Trade name
Chemical formula
Wiswesser line notation
Chemical structure
Identification numbers
CAS registry No.
NIOSH RTECS No.
EPA Hazardous Waste No.
OHM-TADS No.
DOT/UN/NA/IMCO Shipping No.
STCC No.
Hazardous Substance Data Bank No.
National Cancer Institute No.
Nickel
CI 77775. nickel powder;
Raney nickel
Raney catalyst 28
Ni
Ni
Ni
7440-02-0
QR 5950000
Unknown
7216810
UN2881; nickel
catalyst, dry
UN 1378; nickel
catalyst, wet
4916225; nickel
catalyst, not spent
4916226; nickel
catalyst, spent
1096
Not available
SANSS 1987
Bennett 1983
NLM 1987
NLM 1987
NLM 1987
NLM 1987
NLM 1987
NLM 1987
NLM 1987
NLM 1987
NLM 1987
NLM 1987
-------
Tabk 3.2. Physical and chemical propertiei of ilckd aad compouds
Property Nickel
Molecular 58 7
weight
Color Silvery
Physical Solid
slate
Odor Unknown
Melting 1455
point. "C
Boiling 2920
point. °C
Autoignition NAa
temperature
Solubility
Water Insoluble
Organic Insoluble
solvents
Density 8 90
(g/cm')
Partition Unknown
coefficients
Vapor Unknown
pressure
Nickel oxide.
green
74.7
Green-black.
yellow when hot
Cubic crystals
Unknown
1984
Unknown
NA
Insoluble
Soluble in
acid, alcohol
667
Unknown
Unknown
Nickel oxide.
black
1654
Gray-black
Powder
Unknown
Decomposes,
600
NA
NA
Insoluble
Unknown
Unknown
Unknown
Unknown
Nickel chloride
hexahydrate
2377
Green
Monoclmic
deliquescent
crystals or
powder
Unknown
Unknown
Unknown
NA
111% (w/v)
at 20°C
Very soluble in
alcohol
Unknown
Unknown
Unknown
Nickel
subsulfide
2402
Pale yellowish
bronze metallic
Solid
Unknown
790
Unknown
NA
Insoluble
Soluble in
nitric acid
582
Unknown
Unknown
Nickel sulfalc
hexahydrate
2628
a blue-green
0 green
a telrahedral
crystals
0 monoclmic
crystals
Unknown
a transition to 0,
533
ft -6 H,O. 103
NA
NA
a 401% (w/v)
at 20°C
0 44 1% (w/v) at 20°C
Very soluble in
alcohol
a 207
Unknown
Unknown
Nickel nitrate
hexahydrate
2908
Green
Monoclmic,
deliquescent
crystals
Unknown
567
1367
NA
150% (w/v)
at 20°C
Very soluble in
alcohol
205
Unknown
Unknown
References
Dean 1985,
Sax 1984.
Wmdholz 1983
Weast 1986
Dean 1985.
lARC 1976,
Weast 1986
Dean 1985.
Weast 1986
Dean 1985.
Weast 1986
Dean 1985.
Weast 1986
Dean 1985,
IARC 1976,
Weast 1986
Dean 1985.
Weast 1986
o»
3-
n
n>
K,
Dl
(^
Ti
V
a-
^
n
hi
t—
H
pJi
0
g
n
O
-------
Table 3.2 (Coalinucd)
Properly Nickel
Henry's law NA
constant
Refractive Unknown
index
Nickel oxide.
green
NA
2 1818
Nickel oxide,
black
NA
Unknown
Nickel chloride
hcxahydrale
NA
1 57
Nickel
subsulfide
NA
Unknown
Nickel sulfate
hexahydrate
NA
Unknown
Nickel nitrate
hexahydrate
NA
Unknown
References
Weasl 1986
Dean' 1985
O
3
u»
Flashpoint NA NA NA NA NA NA NA
Flammability Unknown Unknown Unknown Unknown Unknown Unknown Unknown
limits
Conversion factors
ppm to mg/m'
in air at 20'C b b b b c c c
"Not available
*Smce these compounds do not exist in the atmosphere in the vapor phase, their concentrations are always expressed in weight by volume unit (e g, Mg/m1)
rFinely divided nickel dust has the potential lo ignite when exposed to air (Hawley 1981) If this happens in a closed container, a I..MII iuplure could result
-------
37
4. TOXICOLOGICAL DATA
4.1 OVERVIEW
The absorption of nickel from the pulmonary trace is dependent on
the chemical and physical properties of the particles deposited in the
lungs. Absorption of dietary nickel is -1 to 10% in man and laboratory
animals. Absorption of nickel through the skin is important in relation
to nickel-induced sensitivity.
Animal studies indicate that soluble inorganic nickel compounds
have a short half-life in the body (several days) with little evidence
for tissue accumulation. Inhalation exposure to nonsoluble nickel can
result in the accumulation of nickel in the lungs.
Absorbed nickel is excreted predominantly in the urine. Nickel is
also excreted in perspiration, and it is deposited in the hair Dietary
nickel that is not absorbed is excreted in the feces.
Effects in the lungs are the major effects of inhalation exposure
to inorganic nickel compounds. Lung effects are the result of nickel
deposited in the lungs so that the effects are observed following
exposure to both soluble and insoluble nickel compounds. Other effects
observed in laboratory animals following exposure to soluble and
insoluble inorganic nickel compounds include effects on the immune
system, the kidney, and hematological and hematopoietic systems.
The administration of soluble inorganic nickel compounds to
laboratory animals has resulted in reproductive effects. Because
insoluble compounds are not well absorbed, these compounds are not
likely to result in reproductive effects following oral exposure.
Occupational exposure to nickel refinery dust, which contains
nickel subsulfide, has been associated with lung cancer. 'No association
between cancer and occupational exposure to nickel metal has been
observed. Nickel subsulfide has been shown to be carcinogenic in rats
exposed by inhalation, thus providing support for the conclusion that
nickel subsulfide is a human carcinogen. Limited oral animal studies of
a few nickel compounds have not resulted in a carcinogenic effect.
Nickel metal and other nickel compounds produced local tumors in animals
following injection. Because nickel compounds have resulted in
carcinogenic effects, all nickel-containing compounds are considered
potentially carcinogenic.
-------
38 Section 4
4.2 TOXICOKINETICS
4.2.1 Absorption .
4.2.1.1 Inhalation
Human. Quantitative data concerning the uptake of nickel by the
respiratory tract are not available. Kalliomaki et al. (1981) observed
that urinary nickel in stainless steel welders increased very little
even when the nickel content of inhaled fumes reached up to 30 jig/m3,
indicating that very little nickel may be absorbed from the respiratory
tract.
Torjussen and Andersen (1979) found that the nickel content of
nasal mucosa in workers exposed to nickel subsulfide and oxide were
higher than levels in workers exposed to nickel chloride/sulfate
aerosols. As nickel chloride and sulfate are soluble, while nickel
subsulfide and oxide are not, this probably reflects greater absorption
of the soluble nickel compounds. By examining retired workers, the
investigators estimated the half-life of nickel clearance from the nasal
mucosa as 3.5 years.
Animal. Absorption of nickel compounds following inhalation
exposure is dependent on the deposition of particles in the lungs.
Deposition is dependent on size, shape, density, hygroscopicity, and
electric charge of the particles, and, in general, smaller particles are
deposited deeper in the lung so that more nickel can be absorbed. A more
complete discussion of the deposition of particles in the lungs is
available in EPA (1986a).
Studies by Wehner and Craig (1972), Kodama et al. (1985), Wehner et
al. (1979), and Tanaka et al. (1985) indicate that nickel oxide is
slowly cleared from the lungs of rats and hamsters following inhalation
exposure. Wehner and Craig (1972) found that 45 days after exposure,
about half of the deposited nickel oxide was still present in the lungs
of hamsters exposed to nickel oxide of particle size [mass median
aerodynamic diameter (MMAD)) 1.0-2.5 pm. Valentine and Fisher (1984)
reported two phases of the exponential clearance of nickel subsulfide in
rats treated by intratracheal instillation (MMAD < 5 pm) ;v during the
first phase, 38% of the dose was cleared from the lungs with a half-time
of 1.2 days, whereas during the second phase, 42% of the dose was
cleared with a half-time of 12.4 days. The faster clearance was
attributed to retrociliary removal to the gastrointestinal tract. After
35 days, about 10% of the nickel subsulfide dose was still in the lungs
of rats, indicating that nickel subsulfide is more readily cleared from
the lungs than nickel oxide. In a study of the lung clearance of nickel
chloride, Carvalho and Ziemer (1982) found that in rats given an
intratracheal instillation, 71% of the dose was removed from the lungs
by 24 h, with only 0.1% of the dose in the lungs by day 21.
Benson et al (1987, 1988) found that the lung burdens of nickel
were -10 times greater in rats exposed to 7 mg/m3 nickel as insoluble
Ni3$2 Chan as soluble NLSO& 6H20 These investigators found that lung
burdens of nickel in Ni3S2-exposed rats were proportional to
concentration while lung burdens were not proportional to concentration
in NiSO^ 6H20-exposed racs
-------
Toxicological Data 39
4.2.1.2 Oral
in. SCudies reviewed by EPA (1986a) indicate that 1 to
10% of dietary nickel is absorbed. Christensen and Lagesson (1981) found
that gastrointestinal absorption was 3% in eight adult volunteers who
ingested 5.6 mg nickel as determined by serum and urine nickel levels
over 2 days In a study by Solomons et al. (1982), nickel sulfate was
ingested by fasting humans (5 mg nickel) with water, and other beverages
and with two test meals. Serum nickel levels were elevated when 5 mg in
water was consumed by fasting subjects. When nickel was ingested with
meals plasma nickel levels did not rise above fasting levels. A rise in
nickel serum levels was observed when nickel was administered in a soft
drink, but absorption was suppressed when nickel was administered in
whole milk, coffee, tea. and orange juice. EDTA added to the diet
suppressed nickel in serum to below fasting baseline levels.
in» . Scudies in racs- dogs, and mice indicate that only 1 to
10% of administered nickel is absorbed by the gastrointestinal tract
following exposure to nickel, nickel sulfate hexahydrate. or nickel
?o-},°rid.Vn u6 dietl in drinkin8 wacer- °r by gavage (Schroeder et al
IOQ!' *edeschi and Sunderman 1957, Ambrose et al. 1976, Nielsen et al'
1986, Ho and Furst 1973). Unabsorbed nickel is excreted in the feces.'
4.2.1.3 Dermal
Human. Several studies indicate that nickel can penetrate human
skin. Using aqueous solutions of nickel sulfate, Norgaard (1955) found
that 55 to 77% of the nickel applied to occluded skin was absorbed with
most absorbed during the first 24 h. Nickel uptake did not differ in
nickel-sensitive individuals. In a study using excised human skin,
Fullerton et al. (1986) showed that when skin was not occluded only
f ?5,a? applied dose of aqueous nickel chloride permeated the skin
after 144 h, while approximately 3 5% permeated the skin in 144 h when
occluded. The investigators also found that nickel ions from a chloride
solution pass through the skin about 50 times faster than nickel ions
from a sulfate solution.
Animal. Studies of dermal absorption of nickel in laboratory
animals also indicate that it can penetrate the skin. Using radioactive
nickel sulfate, Norgaard (1957) observed that nickel was absorbed
through the depilated skin of guinea pigs and rabbits and distributed to
various tissues. Lloyd (1980) found that 1 h after Ni2+ was applied to
shaved guinea pig skin, nickel had accumulated in keratinaceous areas
and in hair sacs. In 4 h. nickel was in the stratum corneum and stratum
spinosum. As summarized by the National Institute for Occupational
Safety and Health (NIOSH) (1977). however. Kolpakov (1964) did not find
nickel in the liver and kidneys of rabbits given skin applications of
nickel sulfate. In contrast, nickel was detected and toxic effects
(convulsions, salivation followed by death) were observed in rabbits
treated with nickel sulfate whose skin had been abraded or pretreated
with an unspecified organic solvent.
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40 Section 4
4.2.2 Distribution
4.2.2.1 Inhalation
Human. Studies have examined human nickel levels at autopsy in
average individuals and workers occupattonally exposed to nickel. EPA
(1986a) concluded that age-dependent accumulation of nickel in soft
tissue appears to occur only in the lungs.
Animal. Seven days after rats received an intratracheal injection
of radioactive nickel chloride, measurable concentrations were present
in the spleen and bone (Carvalho and Ziemer 1982). Twenty-one days after
the injection, only the lungs and kidneys showed detectable levels of
nickel.
Nickel concentrations in the lungs of rats exposed to nickel oxide
aerosols for up to 3 months increased compared with controls (Kodama et
al. 1985). No significant differences in nickel concentrations in other
organs were noted. Benson et al. (1988) found that the quantity of
nickel in the kidneys of rats exposed to aerosols of NiS04 increased in
proportion to exposure concentration. Exposure to Ni2S3 resulted in
small increases in kidney nickel level only in rats exposed at the
highest concentration (10 mg/ra3 Ni3S2) (Benson et al. 1987).
4.2.2.2 Oral
Human. In human and rabbit blood, nickel is present in serum as
ultrafilterable nickel, albumin-bound nickel, and in a metalloprotein
(nickeloplasmin) (Sunderman et al. 1972). Nickel levels in serum and
whole blood (baseline 1.6 pg/L serum, 3.0 >ig/L whole blood) increased
when volunteers ate 5.6 mg nickel as nickel sulfate (Christensen and
Lagesson 1981). The half-life of nickel in the serum was 11 h. Labeled
nickel in human serum was bound to two proteins: albumin and an alpha-
2-protein (Scott and Bradwell 1984).
Animal. Following oral dosing with radioactive nickel chloride,
radioactive nickel localized in the kidneys, lungs, and central nervous
system of mice (Oskarsson and Tjalve 1979). Whanger (1973) found that as
the amount of nickel in the diet of rats increased, the nickel content
of the kidney, liver, heart, and testis was elevated. Highest levels
were found in the kidneys. Tissue accumulation was reported by Phatak
and Patwardhan (1950), who fed rats nickel carbonate, nickel soaps, or
metallic nickel catalyst. Levels were greatest in rats fed nickel
carbonate.
4.2.2.3 Dermal
Human. No studies were available.
Animals. Using radioactive nickel sulfate, Norgaard (1957)
observed that nickel was absorbed through the depilated skin of guinea
pigs and rabbits and distributed to various tissues. Lloyd (1980) found
that 1 h after Ni2* was applied to shaved guinea pig skin, nickel had
accumulated in keratinaceous areas and in hair sacs. In 4 h, nickel was
in the stratum corneum and stratum spinosum.
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Toxicological Daca 41
4.2.3 Metabolism
Once absorbed, nickel binds to a number of serum biomolecular
components. In human serum, nickel binds to albumin, L-histidine, and
Q2-macroglobulin (Sarkar 1984). Binding in animals is similar. A
transport model that has been proposed involves the removal of nickel
from albumin to histidine via a ternary complex composed of albumin,
nickel, and L-histidine (Sarkar 1984). The low-molecular-weight
L-histidine nickel complex can then cross biological membranes.
A number of disease states and physiological stresses have been
reported to alter the metabolism of nickel in man and animals. Increased
levels of serum nickel have been reported in cases of acute myocardial
infarction (EPA 1986a). Leach et al. (1985) found hypernickelemia in 65%
of patients with acute myocardial infarction and in 54% of those with
unstable angina pectoris. Serum nickel levels were not found to be
related to age, sex, medication, or cigarette smoking. Serum nickel
levels in 30 healthy controls averaged 0.28 ± 0.24 pg/L. Peak nickel
concentrations in acute myocardial infarction patients averaged 4.5 ±
10.2 Mg/L. The authors concluded that elevated serum nickel levels may
be associated with the pathogenesis of ischemic myocardial injury. The
sources and mechanisms of nickel release in patients with myocardial
infarction are unknown.
Serum nickel levels are also elevated in acute stroke and extensive
burn injury, with reductions observed in hepatic cirrhosis or uremia
(McNeely et al. 1971).
4.2.4 Excretion
4.2.4.1 Inhalation
Humans. Nickel that is absorbed following inhalation exposure is
excreted in the urine. A general discussion of nickel excretion is found
in Sect. 4.2.4.2 (excretion in humans after oral exposure).
Animals. Three days following intratracheal administration of
nickel chloride to rats, -80% of the initial body burden was excreted
via the urine (Carvalho and Zieraer 1982). After intratracheal
instillation of radioactive nickel subsulfide in mice, clearance was
observed in two phases with biological half-lives of 1.2 and 12.4 days
(Valentine and Fisher 1984). The faster clearance was attributed to
retrociliary removal to the gastrointestinal tract, consistent with
label appearing in the feces during the first 12-h period. About 60% of
the label excreted was lost in the urine, indicating a significant
degree of solubilization.
4.2.4.2 Oral
Humans. Regardless of the route of exposure, absorbed nickel is
excreted in the urine. Unabsorbed nickel following oral exposure is
excreted in feces. Fecal excretion of nickel by 10 healthy humans
averaged 258 Mg/day (Horak and Sunderman 1973). This value was -100
times greater than urinary excretion noted in 50 healthy subjects
(Nomoto and Sunderman 1970, McNeely et al. 1972). The subjects were noc
exposed experimentally to nickel
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42 Section 6
Nickel is excreted in the hair (Nechay and Sunderman 1973,
Schroeder and Nason 1969), and excretion of nickel in the sweat may be a
major route of nickel elimination (Hohnadel et al. 1973).
Animals. As nickel and its compounds are poorly absorbed following
oral exposure of animals, the majority of the nickel is excreted in the
feces. Rats excreted 3 to 6% of a gavage dose of nickel as nickel
chloride in the urine and the remainder in the feces within 48 h. Dogs
excreted 90% of ingested nickel in the feces and 10% in the urine
(Tedeschi and Sunderman 1957). Oogs fed nickel sulfate for 2 years
excreted -1 to 3% of the metal in the urine (Ambrose et al. 1976).
4.2.4.3 Dermal
Humans. See Sect. 4.2.4.2 on excretion after inhalation exposure
in humans for a general discussion of nickel excretion in humans.
Animals. Pertinent data regarding the excretion of nickel
following dermal exposure of animals were not available.
4.3 TOXICITY
4.3.1 Lethality and Decreased Longevity
4.3.1.1 Inhalation
Human. Exposure to nickel refinery dust that contains nickel
subsulfide has been associated with increased risk of death due to lung
and nasal cancers (see Sect. 4.3.6.1 on carcinogenicity after inhalation
exposure).
Animal. Inhalation LCSQs for the nickel compounds were not located
in the literature. In mice and rats exposed to NiS04 at 0.8, 1.7, 3.3,
6.7, or 13 mg/m3 nickel 6 h/day, 5 days/week for up to 12 days, deaths
occurred at >3.3 and >1.7 mg/ra3 nickel for rats and mice, respectively
(Dunnick et al. 1987). Pulmonary inflammation was observed in animals
that died (Benson et al. 1988). No deaths were noted in mice at 0.8
mg/ra3 nickel or in rats at 1.7 mg/ra3 nickel. In mice and rats exposed to
Ni3S2 at 0.4, 0.9, 1.8, 3.6, or 7.3 mg/m3 nickel, no deaths were
observed in rats, while all mice exposed at 7.3 mg/m3 nickel died due to
necrotizing pneumonia (Benson et al. 1987). No deaths were observed in
mice or rats exposed to NiO (green) at 0.9 to 23.6 mg/m3 nickel 6 h/day,
5 days/week for 12 days (Dunnick et al. 1985).
Reduced survival due to emphysema was observed in a study in which
approximately 50 hamsters were exposed to nickel oxide (Baker's analyzed
reagent, not further characterized) at 41.7 mg/m3 nickel, 7 h/day, 5
days/week throughout their life span compared with 50 controls (Wehner
et al. 1975).
In an inhalation study by Takenaka et al. (1985), 40 and 20 male
Wistar rats were exposed to nickel oxide produced by the pyrolysis of
nickel acetate at 60 or 200 /ig/m3 nickel, respectively, 23 h/day, 7
days/week for up to 31 months. As a result of the method of exposure,
rats may also have been exposed Co additional compounds (carbon
monoxide, acetic acid, and acetanhydride) produced by the decomposition
-------
Toxicological Data 43
of nickel acetate. A group of 40 rats served as controls Because of
pulmonary effects, survival of both dosed groups was greatly reduced
compared to controls.
4.3.1.2 Oral
Human. The only fatal case of nickel poisoning by the oral route
was that of a 2 1/2-year-old girl who ingested 15 g of nickel sulfate
crystals (Daldrup et al. 1983). She had pulmonary rales on auscultation
and died of cardiac arrest.
Animal. Oral LDSQs in rats that have been reported for various
nickel compounds are presented in Table 4.1. It appears that the soluble
compounds are more toxic. Causes of death were not stated. The racs chac
died from nickel acetate in the study by Haro et al. (1968) had
respiratory difficulty, lethargy, and diarrhea.
In a two-generation study, groups of -30 rats were given drinking
water containing nickel chloride at 0, 50, 250, 500, or 1000 ppra (mg/L)
nickel (RTI 1987). After 2 weeks, the 1000-ppm level was discontinued
because of excessive mortality in this group. Dose-related mortality
associated with pregnancy complications occurred in parental females at
>50 ppm.
American Biogenics (1986) dosed groups of 30 rats per sex by gavage
with nickel chloride at 0, 5, 35, or. 100 mg/kg/day nickel for 91 days.
High rates of mortality occurred at the 35- and 100-mg/kg doses (FELs)
but not at 5 mg/kg. Histopathological examination revealed that 3/6 dead
males and 5/8 dead females in the 35 mg/kg/day group died as a result of
gavage error.
Dermal. No studies are available.
4.3.2 Systemic/Target Organ Tozicity
4.3.2.1 Overview
The lung is the primary target of inhalation exposure to nickel and
its compounds in humans and animals. Dermal exposure to nickel is
associated with contact dermatitis. Oral and inhalation exposure to
nickel also has effects on the immune system, the kidney, and
hematological and hematopoietic systems. Administration of nickel to
animals by parenteral routes has been shown to have effects on the
endocrine system and the cardiovascular system, as reviewed by EPA
(1986a).
4.3.2.2 Effects on the respiratory system
Inhalation, human. The lung is the target organ of nickel toxic icy
in humans. Inhalation exposure to nickel refinery dust that contains
nickel subsulfide is associated with lung cancer (Sect. 4.3.6 on
carcinogenicity). Asthma, as an allergic response or a response to
primary irritation, has been observed in nickel-plating workers exposed
to nickel sulfate and in welders exposed to nickel oxides. Anosmia,
septal perforation, chronic rhinitis, and sinusitis have also been
reported in nickel-plating workers exposed at high concentrations (EPA
1986a). Exposure of nickel-plating workers to acid mists may contribute
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44 Section 4
Table 4.1. Oral LDM values for nickel compounds in rats
Compound
Nickel acetate
Nickel hydroxide
Nickel sulfate
hexahydrate
Nickel oxide
(green and black)
Nickel sulfide
Nickel subsulfide
Nickel powder
LD50
(mg compound/kg)
355
1600
300
>5000
>5000
>5000
>9000
LD50
(mg Ni/kg)
118
1021
67
>3929
>3233
>3666
>9000
Reference
Haro 1968
Mastromatteo 1986
Mastromatteo 1986
Mastromatteo 1986
Mastromatteo 1986
Mastromatteo 1986
Mastromatteo 1986
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lexicological Data 45
to these effects. Specific dose-response data for respiratory effects in
humans are not available. Animal studies, which have found increased
susceptibility to pulmonary infections probably due secondarily to the
effect of nickel on the immune system (see Sect. 4.3.2.3 on
systemic/target organ'to'xicity, nickel sensitivity), indicate that chis
effect may be a concern for humans.
Inhalation, animal. Effects on the lungs have been observed in
inhalation studies of short-, intermediate-, and long-terra durations
using various nickel compounds in rats, rabbits, and hamsters.
Benson et al. (1988) exposed groups of five male and five female
F344/N rats and similar groups of B6C3F1 mice to aerosols of nickel
sulfate hexahydrate (MMAD - 1.9 ± 0.2 A*m) at concentrations of 0, 35,
7, 13. 30, or 60 mg/m3 (0, 0.7, 1.6, 3.3, 6.7, or 13.5 mg/ra3 nickel) 6
h/day for 12 days. Respiratory effects occurred at all exposures. The
effects, which were more severe in rats than mice, included pulmonary
inflammation, degenerative changes in the bronchiolar mucosa, and
atrophy of the olfactory epithelium.
In a study of the inhalation toxicity of nickel subsulfide (Benson
et al. 1987), groups of five male and five female F344/N rats and B6C3F1
mice were exposed to aerosols of Ni3S2 (MMAD - 2.8 ± 0.2 \u&) at 0, 0.6,
1.2, 2.5, 3.7, 5.0, or 10 mg/ra3 (0. 0.4. 0.9, 1.8. 2.7. 3.7, or 7.3
mg/m3 nickel) 6 h/day for 12 days. At concentrations >5 mg/m3 Ni3S2,
necrotizing pneumonia, emphysema, or fibrosis was observed in exposed
rats and mice. Degeneration of the respiratory epithelium was observed
in rats and mice at concentrations >1.2 mg/m3 Ni3S2- At 0.6 mg/m3 Ni3S2.
mild lung inflammation was observed in rats, with no pulmonary effects
noted in mice.
Bingham et al. (1972) exposed an unspecified number of Wistar
derived rats to nickel chloride at 109 pg/m3 nickel (MMAD - 0.32 ^m) or
to nickel oxide at 112 jig/ra3 nickel (MMAD - 0.25 /*ra) for 12 h/day, 6
days/week for at least 2 weeks. Exposure to nickel oxide resulted in
marked accumulations of macrophages in alveolar spaces, which may be a
normal response to particulates in the lung, and a thickening of
alveolar walls. Bronchial epithelium of rats exposed to nickel chloride
for 2 weeks was hyperplastic with evidence of marked mucus secretion.
Macrophages were present in the alveolar spaces but were not as
prevalent as in nickel oxide exposed rats. The exposure levels used in
this study clearly were associated with adverse effects. This study can
be considered a key study for short-term exposure because the
concentrations are lower than those examined in other short-term
inhalation studies.
Intratracheal administration of nickel oxide, sulfate, chloride, or
subsulfide to rats, with a 7-day observation period, also resulted in
lung lesions (Benson et al. 1985).
NIOSH (1977) summarized an unpublished study by Clary (1977) in
which groups of 30 rats were exposed to airborne nickel chloride at 0 or
1 mg/m3 nickel (particle size not stated), 5 days/week for 3 or 6
months. No differences in serum biochemistry, body weights, or liver
glucose levels were noted between exposed and control rats. Necropsy
revealed increased lung weights and nickel accumulation in the lungs and
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46 Section 6
kidneys, fibrosis in the alveolar ducts, increased numbers of foamy
macrophages, and signs of irritation in the treated rats. The fibrosis
is a frank effect. Examinations of liver, kidneys, and pancreas revealed
no lesions.
In a study by Johansson et al. (1983), groups of eight rabbits were
exposed to nickel chloride (MMAD = 1 pm) at 0 or 0.3 rag/m3 nickel, 6
h/day, 5 days/week for approximately 1 month. Treated rabbits had
increases in cell number and volume of alveolar epithelial cells,
nodular accumulation of macrophages and laminated structures, and
increased phospholipids in the lower lobe.
Curstedt et al. (1983) exposed groups of six rabbits to nickel dust
at 0.13 mg/m3 (MMAD - 1 /ira) , 6 h/day, 5 days/week for 4 or 8 months.
Twelve rabbits were maintained as controls. At sacrifice, exposed
rabbits showed a significant (P < 0.05) increase in the concentration of
phospholipids, with significantly (P < 0.01) increased levels of
phosphatidylcholines, indicating an effect on type II cells without an
interference on cellular mechanisms for alveolar clearance. Thus, 0.13
mg/m3 can be considered a NOAEL. Because this is the only study of lung
effects that identified a NOAEL, it can be considered a key study even
though only six rabbits per group were studied.
In a second study, Curstedt et al. (1984) exposed groups of 6
rabbits to nickel dust at 1 mg/m3 (particle size <40 pra) for 3 or 6
months. Twelve rabbits were maintained as controls. At sacrifice, the
lungs of the exposed rabbits contained numerous yellow-gray nodules and
occasional hemorrhagic foci, a definite frank effect. Measuring
phospholipids in lung lavage fluid, the investigators found that
nonacidic phospholipids were increased by a factor of 5 or more. In
contrast, acidic phospholipids were decreased. These effects are
consistent with effects of nickel on alveolar type II cells.
In an inhalation study by Takenaka et al. (1985), 20 to 40 rats
were exposed to nickel oxide produced by the pyrolysis of nickel acetate
at 0, 60, or 200 /ig/m3 nickel (particle size not stated), 23 h/day, 7
days/week for up to 31 months. Because nickel oxide was produced by the
pyrolysis of nickel acetate, rats may also have been exposed to organic
compounds, including carbon monoxide, acetic acid, and acetanhydride. In
exposed rats, a sixfold increase in lung weight was noted.
Histopathologic examinations of the lungs showed that, in every exposed
rat, pulmonary alveolar lumina were filled with homogeneous,
acidophilic, and strongly PAS-positive material, findings characteristic
of alveolar proteinosis. An accumulation of foamy macrophages was noted
in some rats. Two rats (one from each exposure group) sacrificed at 31
months had also developed focal septal fibrosis. This study is a key
study because it examined lower exposure concentrations of nickel than
did other chronic studies.
In a study by Wehner et al. (1981), hamsters were exposed to an
aerosol of fly ash (about 0.3% nickel) at 70 mg/m3 (MMAD - 2.7 ± 0.6
urn), or to nickel-enriched fly ash (about 6% nickel) at 17 or 70 mg/m3
(MMAD - 2.8 ± 1.7 urn). Effects observed included increases in lung
weights and volumes at 70 mg/m3 fly ash and nickel-enriched fly ash and
a dose-related increased severity of anthracosis, interstitial reaction,
and bronchiolization The investigators concluded that the observed
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Toxicological Data 47
effects were due to the quantity of dust rather than the nickel content
of the dust. Emphysema and other proliferative and inflammatory changes
were observed in rats exposed to nickel oxide ("Baker analyzed" reagent,
median diameter - 0.3 ± 2.2 /*ra) at 42 mg/m3 nickel, 7 h/day 5 days/week
for life (Wehner et al. 1975).
Oral, human. No studies are available.
Oral, animal. American Biogenics (1986) dosed groups of 30 rats
per sex by gavage with nickel chloride hexahydrate at 0, 5, 35, or 100
mgAg/day nickel for 91 days. The examinations performed included
hematology and clinical chemistry, urinalysis, ophthalmological
examination, organ weights, and histopathologic examinations. Pulmonary
effects (intraalveolar accumulation of pulmonary macrophages and
rounding and degeneration of type II alveolar cells) were observed at 35
mg/kg/day. Rats treated at 5 or 100 mg/kg/day were not examined for lung
effects.
Ambrose et al. (1976) also found lung lesions in dogs fed nickel in
the diet. In this study, groups of three dogs per sex were fed nickel
sulfate hexahydrate in the diet at 0, 100, 1000, or 2500 ppm nickel for
2 years. Because dogs fed nickel at 2500 ppm vomited at the start of the
study, the diet level was adjusted to 1500 ppm and then gradually raised
back to 2500 ppm. The parameters examined included food intake, body
weight, hematological values, organ weights, and histopathologic
examinations of major organs and tissues. Lung changes were observed at
2500 ppm and included subpleural peripheral cholesterol granulomas,
bronchiolectasis, emphysema, and focal cholesterol pneumonia. Because
lung lesions are relatively common in dogs, the lesions observed may not
be a result of nickel treatment, although lung lesions were not observed
at lower dietary levels.
Dermal. No studies are available.
General discussion. As indicated by the studies cited above, the
lung is the primary target for nickel in humans and animals following
inhalation exposure. Pharmacokinetic data (see Sect. 4.2, toxicokinetics)
indicate that following inhalation, nickel oxide is cleared from the
lungs slowly, whereas clearance of nickel subsulfide and nickel chloride
is more rapid. Lung effects may be a result of irritancy or binding
macromolecules. For example, Kasprzak et al. (1986) examined the binding
of nickel to DNA and found that the high-affinity Ni(II)-binding sites
were phosphate groups. Nickel may also be directly toxic to cells.
Treatment of human pulmonary epithelial cells with nickel chloride at
0.1, 0.2, or 1.0 mrt resulted in dose-related decreases in cell growth
rate, ATP content, and viability (Dubreuil et al. 1984).
Pulmonary lesions following oral nickel dosing may not be
compound-related. The lung lesions observed in rats may be a result of
gavage errors since deaths due to gavage errors were also common in the
American Biogenics (1987) study. Although lung lesions were seen only at
the high dose in dogs in the Ambrose et al. (1976) study, lung lesions
are fairly common in dogs.
Lipid peroxidation may be the mechanism of acute nickel toxicity on
target organs including the lungs (Sunderman 1987). By measuring echene
and ethane exhalation. Knight et al. (1986) found that lipid
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48 Section 6
peroxidation in the lungs of rats is increased following a subcutaneous
injection of nickel chloride (0.5 or 0.75 mmol/kg). Rats treated by
subcutaneous injection with nickel chloride, sulfate, acetate, or
nitrate (500 /jmol/kg) showed an increase in the levels of thiobarbituric
acid chromogens in the liver, kidneys, and lungs (Sunderman 1987). The
specific reactions by which nickel stimulates lipid peroxidation are not
yet known.
4.3.2.3 Nickel sensitivity
Inhalation, human. EPA (1986a) summarized a number of reports of
asthmatic disease, as either a primary irritation or an allergenic
response, in nickel-plating workers and stainless steel welders.
Exposure levels in these reports were not quantified.
Inhalation, animal. No studies are available.
Oral, human. Eczema of the pompholyx type was observed in 51/66
women with eczema and nickel allergy (Christensen and Holler 1975a). The
condition was not influenced by steps to reduce external exposure. In a
second study, Christensen and Moller (1975b) found that oral
administration of 5 mg of nickel aggravated the condition in 9/12
subjects.
Kaaber et al. (1978) found that 9/17 patients with chronic nickel
dermatitis showed improvement when placed on a low nickel diet.
Additional studies reviewed by EPA (1986a) confirm that dietary nickel
is a factor in nickel dermatitis flare-up in a sizable fraction of the
nickel-sensitive population. A relationship between flare-ups of hand
eczema and nickel in the diet in certain individuals has been shown by
Jordan and King (1979) and Cronin et al. (1980).
Oral, animal. No studies are available.
Dermal, human. Contact dermatitis is the most prevalent effect of
nickel in the general population. Nickel was the cause of dermatitis in
198 patients seen over a 5-year period at the New York skin and cancer
unit--180 women and 18 men from 16 to 63 years old (Fisher and Shapiro
1956). Occupational exposure was once considered the primary cause of
nickel dermatitis (NAS 1975). Nonoccupational exposure to nickel via
contact with jewelry, coinage, tools, cooking utensils, stainless steel
kitchens, prostheses, and clothing fasteners can also result in nickel
dermatitis. Women appear to be at a greater risk for dermatitis of the
hands, attributed to continuous contact with the nickel-containing
commodities listed above. Dose-response relationships, however, cannot
be estimated.
Surveys of the prevalence of nickel dermatitis have been reviewed
by EPA (1986a). The value of these surveys is limited in that most
examine patient populations. In a patch test study, the North American
Contact Dermatitis Group (1973) found that 11% of 1200 patients were
sensitive to nickel sulfate applied as a 2.5% solution for 48 h via an
occluded patch. Study results indicate that blacks have a higher nickel
sensitivity than whites, and women in either racial group have higher
reaction rates. Other surveys of patient populations have been conducted
by Fregert et al. (1969) and Brun (1975), while Veien et al. (1982)
reported on pediatric patients in their clinic. Peltonen (1979) and
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Toxicological Data 49
Prystowsky et al. (1979) surveyed subjects more representative of the
general population and concluded that 2.5 to 5% of the population is
sensitive to nickel, with females at a greater risk. Using interviews,
Menne et al. (1982) examined the prevalence of nickel allergy and hand
eczema in a sample of Danish females from the general population. The
prevalence of nickel allergy was found to be 14.5% in the total sample,
with 57% of the allergic women experiencing hand eczema.
Dermal, animal. In an attempt to sensitize mice to nickel, Moller
(1984) produced only moderate dermatitis by repeated dermal application
of a 20% solution of nickel salt solution for three weeks. Nickel
sensitivity has also been reported in guinea pigs, but only by
intradermal injection (Wahlberg 1976, Turk and Parker 1977).
General discussion. Contact dermatitis is the most prevalent
effect of nickel in the general human population and, in sensitized
individuals, can result from long-term contact with nickel-containing
jewelry, cooking utensils, coins, etc. Relatively high levels of nickel
in the diet can aggravate the condition, while nickel-restricted diets
may improve the condition. Inhalation exposure of humans can result in
asthma as an allergenic response.
Examination of stainless steel welders and metal platers with
asthma revealed a role for IgE in nickel sensitivity (Keskinen et al.
1980, Novey et al. 1983). In one worker with allergic asthma, there was
an association with an antigenic determinant consisting of divalent
nickel bound to serum at a specific copper/nickel transport site
(Dolovich et al. 1984).
The mechanism of nickel dermatitis includes diffusion of nickel
through the skin, binding of nickel ions with proteins and other skin
components, and immunological response to the nickel-macromolecule
complex (NAS 1975). The development of nickel sensitivity occurs most
frequently during the teenage years as a result of dermal contact to
nickel-containing items, e.g., earrings (Grandjean 1986). Once an
individual is sensitized, even minimal exposure to nickel can result in
a reaction. The condition may persist after the removal of obvious
sources of exposure.
The topographical distribution pattern of nickel dermatitis
according to Calnan (1956) is as follows: (1) primary: areas in direct
contact with nickel; (2) secondary: spreading of dermatitis in a
symmetrical fashion; and (3) associated: afflicted areas having no
relation to contact areas. The classical patch test in determining
nickel dermatitis may reflect a primary irritation instead of
sensitivity (EPA 1986a). A more reliable screening technique may be
transformation of cultured human peripheral lymphocytes.
4.3.2.4 Other immunological effects
Inhalation, human. No studies are available.
Inhalation, animal. Acute exposures to nickel have been shown to
affect the immune system and immune system components. In a study by
Adkins et al. (1979), a 2-h inhalation exposure to nickel chloride at
500 /ig/ra-* nickel enhanced the mortality of mice exposed to an aerosol of
viable Streptococcus pyogens. The exposure, thus, represents a FEL Port
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50 Section 4
et al. (1975) observed that an intratracheal injection of nickel oxide
at 1, 2.5. or 5 mg (<5 MM in size) significantly increased the mortality
of hamsters treated 48 h before with influenza A/PR/8 virus.
In a study by Graham et al. (1978), mice exposed to NiCl2 at 250
Mg/m3 nickel (LOAEL) for 2 h showed significant immunosuppression as
measured by a hemolytic plaque technique used to determine the number of
specific antibody-producing spleen cells.
Atrophy of the thymus and spleen was observed in rats and mice
exposed to 10 or 5 mg/ra3 Ni3S2 (7.3 or 3.7 mg/m3 nickel) 6 h/day for 12
days (Benson et al. 1987). Rats also exhibited atrophy of bronchial
lymph nodes at these exposure concentrations. No effects on the thymus
or spleen were noted at concentrations <2. 5 mg/m3 Ni3S2 (<1.8 mg/m^
nickel). In rats exposed to NiS04'6H20, lymphocyte depletion in the
spleen was observed at concentrations >7 mg/m3 (1.6 mg/m3 nickel)
(Benson et al. 1988). This effect was not observed in mice that survived
NiS04'6H20 exposure.
Haley et al. (1987) found that instillation of nickel subsulfide in
the lungs of cynomologus monkeys at 0.6 /jmol/g per lung resulted in
suppression of pulmonary alveolar macrophage function and a secondary
increase in NK-cell-mediated killing of target cells.
Spiegelberg et al. (1984) examined the effect of inhaled NiO
particles (produced by the pyrolysis of nickel acetate, MMAD - 0.35-0.42
Mm) on alveolar macrophages and humoral immunity. Groups of 12 male rats
were exposed to NiO continuously at 50, 100, 200, 400, and 800 Mg/m3
nickel for 4 weeks or at 25 or 150 Mg/m3 for 4 months. Control rats were
maintained in nickel-free air. In the 4-week study, the number of
macrophages were similar to control levels at 50 and 100 Mg/m3, with
significant decreases at 400 and 800 Mg/m3. The 800-pg/m3 concentration
resulted in a high fraction of dead macrophages. Macrophage size was
increased at 100 Mg/m3, with enhanced phagocytic activity observed at
400 Mg/m3 and reduced activity at 800 Mg/m3. In the 4-month study, 25
Mg/m3 resulted in increased numbers and activity of alveolar macro-
phages, while at 150 Mg/m3, there were fewer macrophages with activity
greater than controls. Antibody production by spleen cells in response
to injected sheep red blood cells was reduced significantly in rats
exposed to >200 Mg/m3 for 4 weeks and in rats exposed to 150 Mg/m3 for 4
months. The results showing more severe effects at a lower exposure
concentration in the longer study indicate that the early changes may be
precursors of more severe effects. Because effects are duration- and
dose-related, the 4-month exposure study may be more relevant for
defining dose-response relationships. In the 4-month study, increased
activity and number of macrophages observed at 50 Mg/m3 may represent a
normal physiological response to particulates in the lung; therefore,
this concentration can be considered a NOAEL for intermediate exposure.
The LOAEL is 150 Mg/m3, a concentration at which humoral immune response
was significantly reduced. Because this study identifies a NOAEL and a
LOAEL for immune effects in a study of subchronic duration, it is
considered a key study.
Oral, human. No studies are available.
-------
Toxicological Data 51
,io7,v mnl"*J- As "ported in abstract form, Ashrof and Sybers
(1974) observed hypoplasia of the bone marrow, thymus, and spleen in
rats fed diets containing increasing concentrations of nickel acetace
(from 0.1 to 1.0%) over several weeks. It was not clear if these effects
occurred at all dietary concentrations.
Dieter et al. (1987) provided groups of at least 10 female B6C3F1
mice drinking water containing nickel sulface at 0 1 5 or 10 e/L (0
0^4. 19, or 4 g/L nickel) for 180 days. The investigators determined '
that the mice consumed nickel sulfate at 0, 115.7, 285 7 or 395 7
mg/kg/day (0. 43.9. 108.4, or 150.1 mg/kg nickel per day} for the 0. 1.
5. and 10 g/L dose.groups, respectively. This treatment resulted in a
dose-related decrease in thymus weights, which was not associated with
other indices of T-cell toxicity (e.g., spleen cell lymphoproliferative
responses to T-cell specific raitogens). A series of assays were
completed to examine immune function response. A dose-related reduction
in spleen lyraphoproliferative responses to the B-cell mitogen LPS was
found, with values significantly (P < 0.01) below controls for all three
dose groups. The drinking water concentration of 1 g/L nickel sulfate
(43.9 mg/kg nickel per day) can be considered a LOAEL for immune system
effects in this study.
Dermal. No studies are available.
General discussion. Injection studies have also observed
immunological effects. Graham et al. (1978) found that mice injected
intramuscularly with NiSO* (3.9 Mg/g nickel) or NiCl2 (9.25 ^g/g nickel)
showed significant immunosuppression as measured by a hemolytic plaque
technique used to determine the number of specific antibody-producing
spleen cells. Smialowicz et al. (1985) found that natural killer cell
activity was significantly depressed in mice treated with a single
intramuscular injection of nickel chloride at 18.3 mg/kg This effect
was not associated with a significant reduction in spleen cellularity or
in the production of suppressor cells.
In vitro studies by Fishelson and Muller-Eberhard (1982) and
Fishelson et al. (1983) found that nickel can replace magnesium in the
complement enzymes C3b.Bb and C4b,2a. If this happens in vivo, it may
lead to a weakened defense against pathogens. In vitro studies indicate
that nickel affects immune system cells. Nickel(II) stimulates both
immunologically immature thymocytes and immunocorapetent peripheral
lymphocytes of children of different ages (Nordlind and Henze 1984). The
ability of human polymorphonuclear leukocytes (PMN) to phagocytize and
kill Scaphylococcus epidermis was reduced by 50% during an 18-h exposure
to nickel at 0.05 ^raol/L (Rae 1983).
4.3.2.5 Renal effects
Inhalation, human. No studies are available.
Inhalation, animal. In a study by Clary (1977), groups of 30 rats
were exposed to airborne nickel chloride at 1 mg/m3 nickel. 5 days/week
for 3 or 6 months. Necropsy at 3 and 6 months revealed nickel
accumulation in the kidneys, but no lesions.
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52 Section 4
Oral, human. No'studies are available.
Oral, animal. Ashrof and Sybers (1974) observed renal tubular
degeneration in rats fed diets containing increasing concentrations of
nickel acetate (from 0.1 to 1.0%) over several weeks. It was not clear
from the study, which was reported in abstract form, if this effect
occurred at all dietary concentrations. In a study by Dieter et al.
(1987), a treatment-related increase in mild nephrosis was observed in
mice provided with nickel sulfate in their drinking water at 5 and 10
g/L for 180 days. Renal lesions were not observed at 1 g/L.
Dermal. No studies are available.
General discussion. Although the data for renal effects due to
inhalation, oral, and dermal exposure to nickel are sparse, they are
supported by studies in which nickel was administered parenterally. For
example, aminoaciduria and proteinuria, indicative of renal dysfunction,
were observed in rats injected intraperitoneally with nickel chloride
(Gitlitz et al. 1975). Ultrastructural examination indicated that the
glomerular epithelium was the target site. Foulkes and Blanck (1984)
found that reabsorption of aspartate was reduced in rabbits injected
with nickel chloride, indicating impaired renal function.
4.3.2.6 Hematological and hematopoietic effects
Inhalation. No studies are available.
Oral, human. No studies are available.
Oral, animal. American Biogenics (1986) dosed groups of 30 rats
per sex by gavage with nickel chloride hexahydrate at 0, 5, 35, or 100
mg/kg nickel for 91 days. By day 78, all 100-rag/kg rats had died. White
blood cell (WBC) counts were significantly increased in 35-mg/kg males
and slightly increased in 5- and 35-mg/kg females at an interim
sacrifice. WBC counts were comparable to controls at the final
sacrifice. A statistically significant increase in platelet count and a
decrease in glucose were observed in 35-mg/kg females at the final
sacrifice. The dose of 5 mg/kg/day can be considered a NOAEL and 35
nig/kg/day a LOAEL for hematological effects in this study. A study by
Whanger (1973) supports these findings. Groups of six weanling brown
rats were fed nickel acetate in the diet at 0, 100, 500, or 1000 ppra
nickel for 6 weeks. No significant effects were noted at 100 ppm. At 500
and 1000 ppm, hematological changes (decreased hematocrit and hemoglobin
concentrations) were noted.
Dieter et al. (1987) found a 25% decrease in bone marrow
cellularity in mice provided with nickel sulfate in their drinking water
at 5 and 10 g/L (5000 and 10,000 mg/L or ppra) for 180 days. Changes in
stem cell proliferative responses were also noted with granulocyte-
raacrophage progenator cells affected beginning at 1 g/L (1000 mg/L) and
multipotential stem cells affected at levels >5 g/L. These changes in
stem cell responsiveness were associated with a decrease in glucose-6-
phosphate dehydrogenase, an important enzyme in leukocytes.
In a study by Ambrose et al. (1976), dogs fed nickel sulfate in the
diet for 2 years had histological lesions in the bone marrow at 2500
ppm, but not at
-------
Toxicological Data 53
Dermal. No studies are available.
General discussion. Hematological effects (such as increased WBC
counts, decreased hemoglobin concentration, and decreased hematocrit)
and hematopoietic effects (such as histological lesions in the bone
marrow) have been observed in animals treated orally with nickel
compounds. As reviewed by EPA (1986a), erythrocytosis has been produced
in rats injected intrarenally with nickel compounds. The erythrocytosis
is associated with marked erythroid hyperplasia of bone marrow and may
be mediated by enhanced erythropoietin production. Several of the
studies showing hematological effects also reported decreased body
weight gain. In the study by Whanger (1973), a reduction in body weight
gain was observed in the rats receiving nickel acetate in the diet at
500 and 1000 ppm nickel but not at 100 ppm. Ashrof and Sybers (1974)
observed a reduction in growth in rats fed diets containing increasing
concentrations of nickel acetate (from 0.1 to 1.0%) over several weeks.
In the study by American Biogenics (1986), body weight gain and food
consumption were reduced in the rats at 35 and 100 mg/kg/day, but not at
5 mg/kg/day. In the study by Ambrose et al. (1976), body weight gain was
reduced in dogs at 2500 ppm, but not at 1000 or 100 ppm, and in rats at
1000 and 2500 ppm, but not at 100 ppm. In addition, Price et al. (1986)
found depressed food intake and decreased body weight gain in rats
exposed to nickel chloride in drinking water at 500 ppm (mg/L) nickel
for 90 days. Assuming that rats consume a daily amount equal to 5% of
their body weight, the 500- and 100-ppm dietary levels are equivalent to
25 and 5 mg/kg bw per day, respectively. Thus, the LOAEL for depressed
body weight gain is 25 mg/kg bw per day in the studies by Whanger
(1973), and the NOAEL is 5 mg/kg bw per day in the studies by Whanger
(1973), American Biogenics (1986), and Ambrose et al. (1976).
4.3.2.7 Endocrine and neurotoxic effects
Injection studies reviewed by EPA (1986a) indicate that the
nickel(II) ion affects carbohydrate metabolism in animals. Transitory
hyperglycemia has been observed following parenteral exposure of
rabbits, rats, and domestic fowl to nickel (Horak and Sunderman 1975a,b;
Freeman and Langslow 1973; Clary and Vignati 1973; Kadota and Kurita
1955). Horak and Sunderman (1975a) found that the injection of nickel
chloride (2 or 4 mg/kg) produced prompt elevations in plasma glucose and
glucagon levels with a return to normal 2 to 4 h later. These results
suggest that hyperglucagonemia may be responsible for the acute
hyperglycemic response to nickel(II).
Nickel has also been shown to decrease the release of prolactin
from rat and bovine pituitary gland (LaBella et al. 1973a). This effect
is discussed in Sect. 4.3.4.4 on reproductive toxicity in its possible
relation to reproductive effects.
In vitro studies (Dormer et al. 1973, Dormer and Ashcroft 1974)
indicate that nickel(II) is an inhibitor of secretion of the parotid
(amylase), islets of Langerhans (insulin), and pituitary (growth
hormone). Dormer et al. (1973) hypothesized that nickel may block
exocytosis by interfering with either secretory granule migration or
membrane fusion and microvillus formation.
-------
54 Section 4
Although little is known about the neurotoxicity of nickel, it can
enter the brain, but. compared with kidney, endocrine glands, lung, and
liver, relatively little lodges in neural tissue (EPA 1986a). This is
consistent with the low neurotoxic potential of nickel and its inorganic
compounds as indicated by NAS (1975) and NIOSH (1977).
4.3.2.8 Studies showing no effects
Early oral studies of the subchronic oral toxicity of nickel
compounds did not reveal toxic effects. Phatak and Patwardhan (1950)
provided nickel carbonate, nickel soaps, or nickel catalyst (Raney
nickel) in the diets of young rats at 250, 500, and 1000 ppm for 8
weeks. No effect on growth rate was noted. The same nickel compounds
given to monkeys (Macaca sinicus) in the diet at nickel levels of 250,
500, or 1000 ppm for 24 weeks also resulted in no adverse effects. No
ill effects were observed in dogs and cats given oral doses of nickel
metal at 4 to 12 rag/kg/day for 200 days (Stokinger 1963). In a study by
Schroeder et al. (1964), groups of 50 mice per sex were given nickel
acetate in the drinking water at 5 ppm throughout their lifetime. The
mice were fed diets low in metals including chromium. No changes in
survival, growth, or tumor incidences were observed. Similar results
were observed in a repeat of this study (Schroeder and Mitchener 1975)
except the mice used were not chromium-deficient. Schroeder et al.
(1974) provided groups of 52 rats per sex with an unspecified soluble
nickel salt in their drinking water throughout their lifetime. The
results indicated that nickel at 5 ppm was nontoxic and did not result
in increased tumor incidences.
4.3.3 Developmental Toxicity
4.3.3.1 Inhalation
Human. Warner (1979) reported that there were no clinical data on
developmental effects from women working at a nickel refinery in Wales.
Animal. A reduction in fetal body weight was observed in rats
exposed to nickel oxide by inhalation throughout gestation at 1.3 and
2.5 mg/m3 nickel but not at 0.6 mg/m3 (Weischer et al. 1980). No effect
on the number of fetuses/litter was observed.
4.3.3.2 Oral
Human. No studies are available.
Animal. Berman and Rehnberg (1983) provided pregnant mice with
drinking water containing nickel chloride at 500 or 1000 ppm (mg/L)
nickel on gestation days 2-17. No effects were observed at 500 ppm. At
.1000 ppm, a loss of maternal weight, a reduction in mean birth weights
of pups and an increased incidence of spontaneous abortions were
observed. Thus, for mice, the 500-ppm level is a NOAEL for developmental
effects and 1000 ppm is a PEL.
In a two-generation study, groups of -30 rats per sex were given
nickel chloride in the drinking water (filtered/delonized, 0 ppm nickel)
at 0, 50. 250. or 500 ppm nickel (0. 7.3, 30.8. or 51.6 mg/kg/day.
estimated) (RTI 1987). At 500 ppm. a significant decrease in maternal
-------
Toxicological Data 55
body weight and decreases in absolute and relative liver weights were
observed, with no maternal effects noted at 250 ppm. In the Fla and Fib
generations, the number of. live pups per litter was significantly
decreased, pup mortality was significantly increased, and average pup
weight was significantly decreased at 500 ppm. In the Fib generation,
increased pup mortality and decreased live litter size were observed at
50 and 250 ppm. An independent statistical evaluation by EPA indicated
that the increased pup mortality in the 50- and 250-ppm groups was not
statistically significant when compared with controls. The decreased
live litter size was statistically significant when compared with
concurrent controls but not when compared with historic litter sizes.
Results of the mating of the Fl generation included depressed body
weight of dams and F2 pups and increased postnatal mortality at 500 ppra.
At 250 ppm, body weight and water intake of dams were transiently
depressed. There was a significant increase in short ribs in the F2
offspring at 50 ppm but not at the higher doses; therefore, the absence
of a dose-related trend suggests that the effect in the 50-ppm group is
spurious and not compound-related. Furthermore, no significant
difference between the 50-ppm group and the controls was observed when
the incidence of short ribs was analyzed using the litter rather than
the offspring as the unit of comparison. Since the independent
statistical evaluation suggested no compelling evidence of nickel-
related effects in any but the high dose group, the 50- and 250-ppm
levels are NOAELs for developmental toxicity.
Ambrose et al. (1976) failed to find a NOAEL in a three-generation
study in which rats were fed nickel sulfate hexahydrate at dietary
levels of 0, 250, 500, or 1000 ppm nickel. The number of pups born dead
was increased at all nickel levels in just the first generation and the
number of pups per litter showed a dose-related decrease. This study
incorporated some statistical design limitations, including small sample
size and use of pups rather than litters as the unit for comparison,
making it difficult to interpret.
Schroeder and Mitchener (1971) reported increased perinatal
mortality and increased numbers of runts at 5 ppm nickel in a three -
generation drinking water study in rats. This study is weak because the
end results are based on five mat ings that were not random1. In addition.
the rats had access to food and water containing minimal levels of
essential trace metals. Because of the interaction of nickel with other
trace metals, the restricted exposure (chromium was estimated as
inadequate) may have contributed to the effects observed.
4.3.3.3 Dermal
No studies are available.
4.3.3.4 General discussion
Exposure of animals to nickel salts is associated with delayed
fetal development and increased resorptions. There are no studies
regarding the teratogenicity or fetotoxicity of nickel in humans.
Studies of nickel compounds administered to animals by parenteral
routes have also reported developmental effects. For example, decreased
-------
56 Section 4
mean fetal body weight was found in the offspring of rats injected
intramuscularly with nickel subsulfide (Sunderman et al. 1978).
Intraperitoneal injection of nickel chloride in pregnant mice resulted
in a dose-related increase in abnormalities (Lu et al. 1979). Perm
(1972) found increased resorptions and malformations in embryos from
hamsters injected intravenously with nickel acetate. The relevance of
injection studies on developmental effects to human exposure is not
clear.
Findings of in utero effects of nickel compounds are not surprising
because nickel readily crosses the placenta. Whole-body levels of 22 to
30 ppm were found in neonatal rats from dams that were fed various
nickel compounds in the diet at 1000 ppm (Phatak and Patwardhan 1950).
Transplacental transfer also occurs in mice and has been shown to occur
throughout gestation (Lu et al. 1976, Jacobsen et al. 1978, Olsen and
Jonsen 1979). Although developmental effects have not been reported in
humans, several reports indicate that nickel crosses the placenta in
humans. Relatively high levels of nickel have been found in teeth,
liver, heart, and muscle of human fetuses, neonates, and stillbirths
(Stack et al. 1976, Casey and Robinson 1978). In a study of maternal-
fetal tissue levels of trace elements in eight selected U.S.
communities, Creason et al. (1976) reported geometric mean nickel levels
of 2.2 Mg/100 g in placenta, 3.8 /ig/100 mL in maternal blood, and 4.5
jig/100 mL in cord blood. These studies are reviewed in EPA (1986a).
4.3.4 Reproductive Toxicity
4.3.4.L Inhalation
Human. No studies are available.
Animal. Degeneration of the germinal epithelium of the testes was
observed in male rats exposed to nickel sulfate at concentrations >7
mg/m3 (>1.6 mg/m3 nickel) for 12 days (Benson et al. 1987a). No
testicular effects were observed in rats at 3.5 mg/m3 (0.7 mg/m3 nickel)
or in mice at any exposure concentration. Testicular degeneration was
also observed in male mice and rats exposed to nickel subsulfide at
concentrations >2.5 mg/m3 NijS2 (£1.8 mg/m3 nickel); no testicular
effects occurred at 1.2 mg/m* Ni3S2 (0.9 mg/m3 nickel) (Benson et al.
1987b).
4.3.4.2 Oral
Human. No studies are available.
Animal. In the two-generation reproduction study in rats (RTI
1987) (see Sect. 4.3.3.2, developmental toxicity from oral exposure in
animals), nickel chloride in the drinking water at 0, 50, 250, or 500
ppm (mg/L) nickel resulted in nonsignificant but dose-related deaths of
parental females due to pregnancy complications. Results of matings
showed no statistically significant differences among groups for the
percent mated females, percent fertile matings, or percent live litters.
The percent viable litters from postnatal days 1 to 4 and 4 to 21 showed
a dose-related reduction in the Fib pups that was significant at 500
ppm. A dose-related increase in deaths of Fl rats occurred during
postnatal days 22 to 42, with most deaths occurring in the 250- and
-------
Toxicological Data. 57
500-ppm groups. Because of higher temperatures during parts of this
study, the results cannot be validated as genuine adverse effects.
In the three-generation study by Ambrose et al. (1976) (see Sect.
4.3.3.2, developmental toxicity from oral exposure in animals), no
adverse effects on fertility, gestation, viability, and lactation were
noted in rats maintained on diets containing nickel sulfate hexahydrate
at 0, 250, 500, or 1000 ppra nickel. A consistent reduction in offspring
body weight at weaning in the 1000-ppm group was noted in all three
generations, although recovery was noted by mating. The number of pups
per litter and the number weaned per litter showed a concentration-
related decrease at all concentrations. This study was severely limited
by small sample size, statistical design limitations, and use of pups
rather than litters as the unit of comparison.
4.3.4.3 Dermal
Human. No studies are available.
Animal. In a study using eight rats per group, tubular damage of
the testis and sperm degeneration were observed in shaved rats given a
daily dermal application of nickel sulfate hexahydrate at 60 and 100
mg/kg nickel (FELs) for 30 days (Mathur et al. 1977). The testicular
effects noted were less severe following 15 days of treatment, and no
effects were noted in rats treated at 40 mg/kg nickel (NOAEL). In this
study, the rats treated at 60 and 100 mg/kg nickel per day also had
liver effects (swollen hepatocytes, focal necrosis) and skin effects,
but rats treated at 40 mg/kg/day did not. The study does not indicate
that the rats were prevented from licking the skin, so the effects
observed may be a result of ingested nickel rather than from nickel
absorbed through the skin.
4.3.4.4 General discussion
In the two-generation study by RTI (1987), rats had pregnancy
complications. LaBella et al. (1973a,b) found that nickel(II) inhibits
the release of prolactin from rat pituitary both in vivo and in vitro.
The inhibition of prolactin release could affect interactions between
the hypothalamus and the pituitary gland needed to maintain pregnancy
(Grandjean 1986).
A number of studies in which nickel compounds were administered
parenterally also report effects on fertility in males. In a study by
Jaquet and Hayence (1982), untreated superovulated female mice were
mated with male mice given an injection of nickel nitrate at 40 or 56
mg/kg. Embryos collected from the female mice and cultured to the
blastocyst stage indicated that doses of 40 mg/kg had no effect on the
fertilization capacity of the spermatozoa or the ability of the
fertilized eggs to cleave. At 56 mg/kg, a significant proportion of the
eggs were not fertilized (uncleaved); fertilized eggs were capable of
developing into blastocysts. These results suggest an effect on
spermatogenesis. Nickel chloride and nickel nitrate injected
intraperitoneally in male mice resulted in a decreased pregnancy rate
and an increase in preimplantation loss (Deknudt and Leonard 1982).
Subcutaneous and intratesticular injections of nickel compounds resulted
in atrophy of seminiferous tubules, disintegration of spermatozoa.
-------
58 Section 4
exfoliation, and lysis of the seminiferous epithelium (Hoey 1966 Kamboi
and Kan 1964). ' J
In the multigeneration studies cited above, effects were seen in
pups after birth. -It -is not clear if these effects were a result of in
utero exposure or via milk of the exposed dams.
4.3.5 Genotoxicity
4 . 3 . 5 . 1 Human
Tests for chromosome aberrations and sister chromatid exchange
(SCE) in cultured human lymphocytes or human bronchial epithelial cells
exposed to nickel sulfate and nickel sulfide consistently gave positive
results (Table 4.2). Waksvik and Boysen (1982), however, failed to find
increased frequencies of chromosomal aberrations and SCE in the
lymphocytes of two groups of refinery workers exposed to nickel compared
with a group of controls (Table 4.3). The first group consisted of 9 men
exposed to 0.1 to 1.0 mg/ra3 nickel for 7 to 29 years (mean - 21.2 years)
and who had a nickel plasma concentration of 1 to 7 Mg/L. The second
group consisted of 10 workers exposed to 0.1 to 0.5 mg/ra3 nickel for an
average of 25.2 years and who had a mean plasma nickel concentration of
5.2
4.3.5.2 Nonhuman
Studies on the in vitro genotoxicity of nickel and its compounds in
prokaryotes, eukaryotes, and cultured mammalian cells are presented in
Table 4.2. Tests for gene mutations have been equivocal, while most
tests for DNA damage, SCE, chromosome aberrations, and cell
transformation were positive. Studies of the in vivo genotoxicity of
nickel and its compounds are presented in Table 4.3. Consistently
negative results were obtained for in vivo tests of chromosome
aberrations, micronuclei formations, and dominant lethality in mice and
rats and for gene mutations and recessive lethality in Drosophila
melanogaster .
4.3.5.3 General discussion
As indicated in Tables 4.2 and 4.3, the compounds that have been
tested in genotoxicity studies are predominantly soluble nickel chloride
and nickel sulfate. Therefore, generalizations relating solubility and
ge no toxic activity cannot be made.
The equivocal results of mutagenicity tests in bacteria probably
reflect the variation in sensitivity of bacterial strains and different
conditions of the studies. The only study showing positive results for
gene mutations in mammalian cells in vitro that is adequately reported
is that of Amacher and Paillet (1980). Results of chromosome aberration
tests in cultured mammalian cells generally indicate a positive
response; however, the studies of chromosome aberrations in vivo
indicate that nickel compounds are not clastogenic. Nickel, however,
appears to be toxic to male germ cells in vivo, resulting in reduced
fertility (see Sect. 4.3.4.4, reproductive toxicity) . The studies of SCE
in cultured mammalian cells and cultured human lymphocytes are positive.
Negative results were obtained for SCE and chromosome aberrations in the
-------
Toxicological Data 59
TaMc 4.2. Geooloxicity of nickel and compounds in ritro
End point
Gene mutation
DNA damage
SCE
Chromosome
aberration
Cell
transformation
Species/test system
Salmonella typhimunum
EschericHia coll
Cornebactenum sp
Saccharomyces cerevisiae
CHO cells
Mouse lymphoma cells
Chinese hamster V79 cells
Bacillus subulu
CHO cells
Hamster cells
Human lymphocytes
Hamster cells
Human lymphocytes
Human bronchial
epithelial cells
Hamster cells and
C3H/1OTI/2 cells
Compound
Nickel chloride
and sulfate
Nickel chloride
Nickel chloride
Nickel sulfate
Nickel chloride
Nickel chloride
Nickel chloride
Nickel oxide
and tnoxidc
Crystalline NiS
Nickel chloride
Nickel sulfate
Nickel chloride
Nickel sulfate
Nickel sulfide
Nickel sulfate
Nickel chloride
Nickel sulfate
Nickel sulfate
Nickel subsulfide
Nickel chloride
Nickel, nickel
oxide or trioxide
Result' References
Mixed LaVelle and Witmer 1981. Arlauskas et al 198S
- Green et al 1976
+ Pikalek and Necasek 1983
- Singh 1984
Inconclusive Hsie et al 1979
+ Amacher and Paillet 1980
Inconclusive Miyaki et al. 1979
- Kanemaisu et al 1980
+ Patierno and Costa 1985
+ Ohno et al. 1982. Larremendy et al
+ Wulf 1980. Larremendy et al 1981.
Andersen 1983. Saxholm et al 1981
+ Sen and Costa 1986. Larremendy et
+ Larremendy et al 1981
+ Lechner et al. 1984
+ Dipaolo and Casto 1979, Costa et al
Hansen and Stern 1982. Saxholm et
1981
al 1981
1982.
al 1981
'Metabolic activation is not an issue for nickel compounds.
TabfcO. feootoxlcity of akkel and c
End point
Gene mutation
Recessive lethal
Chromosome aberra-
tions and SCE
Chromosome
aberrations
Micronucleus test
Dominant lethal
Species/test system
Drosophtla melanogaster
D melanogaster
Human lymphocytes
Rat bone marrow and
spermatogomal cells
Mouse bone marrow cells
Mouse
Compound
Nickel nitrate
or chloride
Nickel sulfatc
Nickel
Nickel sulfate
Nickel chloride
Nickel acetate
mnpoundu la vivo
Result References
— Rasmuson I98S
- Rodriguez- Arnaiz and Ramos 1986
Waksvik and Boysen 1982
Mathur el al 1978
- Oeknudt and Leonard 1982
- Deknudt and Leonard 1982
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60 Section 6
only in vivo study in humans; therefore, in vivo data are insufficient
to rule out a possible clastogenic effect in humans. Because of the
suggestive evidence for nickel-induced gene mutations and chromosome
effects, the positive results for cell transformation in cultured
mammalian cells may be due to somatic mutations. EPA (1986a) reviewed
studies of biochemical genotoxicity that indicate that nickel compounds
induce genotoxic effects such as binding to the DNA, DNA strand breaks,
and misincorporations of nucleotide bases in DNA. It is not clearly
understood, however, how these biochemical effects translate into actual
mutations.
4.3.6 Care inogenic ity
4.3.6.1 Inhalation
Human. NAS (1975) summarized epidemiological studies completed
before 1975. The studies showed an increased risk of pulmonary and nasal
cavity cancers among nickel refinery workers. The most common types of
respiratory cancer found in nickel refinery workers have been
epidermoid, anaplastic, and pleomorphic carcinomas. Three cases of
respiratory tract cancers in persons involved in nickel plating and
grinding were also reported (NAS 1975).
EPA (1986a) reviewed numerous epidemiology studies which found an
association between employment in nickel refining and respiratory
cancers. This section presents data only on those studies on which EPA
(1986a) based a unit risk slope.
Enterline and Harsh (1982) studied the disease risks of three
groups of workers: 266 workers hired before 1947, who had worked >1 year
in the refinery and who were working there at some time during 1948;
1589 workers as defined above, but who had worked in the refinery area
for <1 year; those hired after 1946 (<1 year before the calciners were
shut down). Exposures varied from 5 mg/rn^ nickel for refinery workers to
0.01 to 0.75 mg/m^ nickel for other workers. The period of follow-up was
29 years, January 1, 1948, to December 31, 1977. Expected values were
determined using 5-year age- and calendar-specific national and local
mortality rates. The results showed an excess risk of nasal sinus cancer
in nickel refinery workers [standardized morbidity ratio (SMR) - 2443].
An overall excess of lung cancer was not noted, but analysis of data by
mg/m^ nickel-months indicated a significant dose-response relationship
for nickel refinery workers but not other workers.
Doll et al. (1977) reported a mortality study of 937 nickel
refinery workers in Wales who worked at the plant for at least 5 years
during 1902 to 1944, with follow-up to 1971. In this cohort, 145 lung
and 56 nasal cancer cases were identified. SMRs were calculated using
age and tine-specific rates for England and Wales. For lung cancer, SMRs
by starting date were 750 (<1925); 950 to 1005 (<1915); 570 to 630
(>1915); and 250 (1925 to 1929). For nasal sinus cancer, the risks were
very high: 38,900 (<1910); 64,900 (1910 to 1914); 44,000 (1915 to 1919);
and 9900 (1920 to 1924). Virtually no cases of nasal sinus cancer were
found in workers who started after 1924, perhaps due to the use of
respirators since 1922.
-------
ToxicologLcal Data 61
Chovil et al. (1981) studied a cohort of 495 Copper Cliff sincer
workers who were alive in 1963 and had been exposed at some time between
1948 and 1962. There were 54 cases and 37 deaths of lung cancer compared
with 6.38 and 4 25 expected, respectively.
Magnus et al. (1980) studied a cohort of 2247 refinery workers
starting employment before 1966 who were alive on January 1, 1953, and
who had been employed for at least 3 years. Expected cancer deaths were
calculated from age-specific national mortality rates. Risks of nasal
cancer were increased in all job categories, with the highest SMR (4000)
in roasting/smelting (R/S) workers followed by electrolysis workers
(2600). An excess risk of laryngeal cancer was observed in R/S workers
(SMR - 670) and other specified process workers (SMR - 330). The highest
excess of lung cancer was observed in electrolysis workers (SMR - 550),
followed by other specified process workers (SMR - 390) and R/S workers
(SMR - 360). An assessment of the combined effects of smoking and nickel
exposure on the risk of lung cancer led the authors to state that the
effects are likely to be additive. A number of epidemiology studies in
which workers were exposed to nickel metal (Goldbold and Tompkins 1979,
Cox et al. 1981, Cornell and Landis 1984, Redmond 1984, Cornell 1984,
Cragle et al. 1984) have not reported increased cancer risks. These
studies are also summarized in EPA (1986a).
Animal. Nickel subsulfide was carcinogenic in a long-term
inhalation study in rats (Ottolenghi et al. 1974), which is summarized
in Table 4.4. This is the most relevant animal study to human exposure
because it studied a large number of rats of both sexes for the life
span, used a relevant route of exposure, and demonstrated a positive
response. The study is limited, however, because only one exposure level
was used. Other inhalation studies of nickel or nickel compounds, which
gave negative or equivocal results, are summarized in Table 4.5.
The finding of cancer in animals after inhalation of nickel
subsulfide supports the conclusion that nickel subsulfide is
carcinogenic in humans via inhalation. It is interesting to note that
nickel refinery dust is -50% nickel subsulfide (EPA 1986a).
4.3.6.2 Oral
Human. No data were available.
Animal. Data from chronic oral studies of nickel compounds are
inadequate to reach conclusions regarding the carcinogenicity of nickel
by that route. In chronic oral studies (Schroeder et al. 1964, Schroeder
and Mitchener 1975), the administration of nickel acetate in the
drinking water of mice at 5 ppm throughout their lifetime did not result
in increased tumor incidences The Schroeder et al. (1964) and Schroeder
and Mitchener (1975) studies are limited because they examined only one
dose level, which may not have been a maximum tolerated dose.
No treatment-related tumors were observed in rats given nickel
sulfate hexahydrate in their diets at 0, 100. 1000, or 2500 ppm nickel
for 2 years (Ambrose et al. 1976) Beagle dogs similarly treated also
did not have treatment-related tumors, but 2 years is an inadequate
duration for a carcinogenicity study in dogs.
-------
62 Section
Table 4.4. Hyperplastic and neoplastic changes in lungs of
rats exposed to nickel subsulfide"
Controls
Pathologic changes
Typical hyperplasia
Atypical hyperplasia
Squamous metaplasia
Tumors
Adenoma
Adenocarcmoma
Squamous cell carcinoma
Fibrosarcoma
Males
(108)f
26 (24)
17(16)
6 (6)
0 (0)
1 (1)
0 (0)
0 (0)
Females
(107)'
20(19)
11 (10)
4 '(4)
1 (1)
0 (0)
0 (0)
0 (0)
Nickel sulfide*
Males
(110)'
68 (62)
58(53)
20(18)
8 (7)
6 (5)
2 (2)
1 (1)
Females
(98 )c
65 (66)
48 (49)
18(18)
7 (7)
4 (4)
1 (I)
0 (0)
"Values represent the number of affected animals in each group; percen-
tage of affected animals is given in parentheses.
*Exposures were to 0.97 mg/m3 nickel, 6 h/day. 5 days/week for 78 to 84
weeks with a 30-week observation period
'Number of animals.
Source- Ottolenghi et al. 1974, EPA 1986a.
-------
Table 4.5. Inhalation carcinogenicity studies of nickel and compounds
Compound
Animals
Nickel metal (powder)
Nickel powder
Nickel oxide
Rats, mice,
guinea pigs
Rats, hamsters
Hamsters
Nickel oxide
Rats
Exposure
15 mg/m3, 6 h/duy,
4 to 5 days/week for >2 years
Concentration not clearly staled
53.2 mg/m3, 7 h/day,
5 days/week for <2 years
0 6 and 8 0 mg/m3, 6 h/day,
5 days/week for I month, 20 months
observation
Response
No clear carcinogenic
response
No tumors
Two osteosarcomas and
one rhabdomyosarcoma
in 120 exposed hamsters,
no tumors of these
types in 51 control
hamsters
One adenocarcmoma in
five rats at 0 6 mg/m3,
no tumors in control or
8 0-mg/m3 group
References
Hueper 1958
Hueper and Payne 1962
Wehnerel al 1975
Hone el al 1985
n
o
O
to
t—
rt
to
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64 Section 6
4.3.6.3 Dermal
No data in animals or humans were available.
4.3.6.4 General discussion
In addition to the studies summarized above, EPA (1986a) reviewed
numerous studies in which nickel compounds were injected into animals
In general, these studies have found tumors only at the site of
injection, although a few distant site responses were also seen.
Injection studies are not particularly relevant to human exposure but
can be used to support the hypothesis of carcinogenic potential. They
may also provide insights into properties of nickel compounds that
result in a carcinogenic effect. Sunderman (1984a) reports the results
of intramuscular injection studies of 18 nickel compounds in male
Fischer rats given a single injection of a nickel compound (14 mg nickel
per rat). The results indicated that the compounds fell into five
categories: class A compounds (nickel subsulfide, nickel monosulfide,
and nickel ferrosulfide) resulted in injection site sarcomas in 100% of
the rats; class B compounds [nickel oxide, nickel subselenide (Ni3Se2).
nickel sulfarsenide (NiAsS), nickel disulfide (NiS2), and nickel
subarsenide (Ni5As2)] produced sarcomas in 85-93% of the rats; class C
compounds (nickel dust, nickel antimonide (NiSb), nickel telluride
(NiTe), nickel monselenide (NiSe), and nickel subarsenide (NillAsS)]
induced sarcomas in 50-65% of the rats; class D compounds [amorphous
nickel monosulfide and nickel chrornate (NiCr04)] resulted in sarcomas in
6-12% of the rats; and class E compounds [nickel monoarsenide (NiAs),
nickel titanate (NiTi03), and ferronickel alloy] did not result in any
sarcomas. Rank-correlation tests showed a significant (p - 0.02)
relationship between sarcoma incidences and nickel mass-fraction and a
significant (p < 0.0001) relationship between sarcoma incidences and the
ability of nickel compounds to induce erythrocytosis in rats after
intrarenal injection. The correlation between erythrocytosis and
carcinogenicity in rats does not necessarily indicate that the two
effects are related in their pathogenesis. Significant relationships
were not observed between sarcoma incidences and dissolution rates of
nickel compounds in rat serum or renal cytosol, or to the phagocytosis
of the compounds in vitro by rat macrophages.
It has been suggested that the carcinogenic potency of nickel is
dependent on the selective phagocytosis of nickel compounds (Costa and
Heck 1984). The data by Sunderman (1984a) seem to contradict this
suggestion, although Sunderman did find that the ability of nickel
compounds to induce erythrocytosis was significantly (p - 0.04) related
to the phagocytosis of nickel compounds, a finding which Sunderman
(1984a) stated and supported the conclusion that "phagocytosis plays an
important role in the cellular uptake and metabolism of particulate
nickel compounds."
Based on human epidemiological data, nickel refinery dust from
pyrometallurgical sulfide nickel matte refineries is classified as a
Group A carcinogen (a known human carcinogen) according to the
classification scheme of the Carcinogen Assessment Group (EPA 1986b
The data from the study by Ottolenghi et al. (1974) and in vitro
studies, along with the fact that nickel subsulfide is a major component
-------
Toxicological Data 65
of nickel refinery dust, are sufficient to classify nickel subsulfide as
a Group A carcinogen as well. According to EPA (1986a), "The
carcinogenic potential of other nickel compounds remains an important
area for further investigation. Some biochemical and in vitro
toxicological studies seem to indicate the nickel ion as a potential
carcinogenic form of nickel and nickel compounds. If this is true, all
nickel compounds might be potentially carcinogenic, with potency
differences related to their ability to enter and make the carcinogenic
form of nickel available to a susceptible cell. However, at the present
time, neither the bioavailability nor the carcinogenesis mechanism of
nickel compounds is well understood." The negative but inadequate
evidence that nickel and its compounds are not carcinogenic by the oral
route may reflect poor gastrointestinal absorption (see Sect. 4 2 2 on
distribution).
Data reviewed in Sect. 4.3.5 on genotoxicity suggest that nickel
and its inorganic compounds may be mutagenic and clastogenic processes
that are thought to be related to carcinogenesis.
4.4 INTERACTIONS WITH OTHER CHEMICALS
A number of antagonistic and sytrergistic interactions have been
reviewed by EPA (1986a). Vitamin C co-administered with nickel orally to
weanling rats protected against the effects of nickel on growth and
enzyme activities (Chatterjee et al. 1980). Spears and Hatfield (1977)
reported that nickel protects against adverse effects of copper, but
Ling and Leach (1979) found no evidence of an interaction between nickel
and copper, iron, zinc, or cobalt on growth rate, mortality, or anemia.
Zinc(II) protected rats against lethal doses of injected nickel chloride
and offset the degree of kidney damage (Waalkes et al. 1985). Prasad et
al. (1980) found that nickel(II) antagonized arrythmias induced by
digoxin in the hearts of rats, rabbits, and guinea pigs. Smialowicz
(1985) reported that manganese antagonized the suppression of natural
killer cell activity caused by nickel chloride, which may be important
in understanding the antagonism of manganese for nickel-induced cancer.
Nickel ions and nickel sulfate have been found to enhance the
transformation frequency and mutagenicity of benzo[a]pyrene in hamster
embryo cells, and nickel compounds may be cocarcinogenic with other
organic carcinogens (Barrett et al. 1978; Rivedal and Sanner 1980, 1981;
Toda 1962; Maenza et al. 1971; Kasprzak et al. 1973).
The interactions between cadmium and nickel in causing kidney
toxicity have been examined in laboratory animals. Tandon et al. (1982)
found that pretreatment of animals with nickel protects against cadmium
nephrotoxicity. In contrast, Khandelwal and Tandon (1984) found that
rats given an intramuscular injection of cadmium followed by three daily
intraperitoneal injections of nickel have more marked enzymuria,
proteinuria, and aminoaciduria than are caused by either metal alone.
From their results, the authors hypothesized that kidney "cells damaged
by cadmium are more vulnerable to nickel toxicity or that cells other
than those damaged by cadmium are affected by nickel."
Studies reviewed in Anke et al. (1984) concerning the essentiality
of nickel in which animals were fed nickel-deficient diets indicate that
nickel interacts with iron, calcium, and zinc. Rats fed nickel-deficient
-------
66 Section 4
diets had reduced hemoglobin and hematocrit values which were not
affected by iron supplementation (Schnegg and Kirchgessner 1976a,b,
Nielsen et al. 1979;. Nielsen and Shuler 1981). These studies also found
reduced iron absorption in nickel-deficient rats.
Anke (1974) found that nickel-deficient miniature pigs excreted
more urinary calcium than control animals. The nickel-deficient pigs
also had less calcium in their bones compared with controls. The effects
of nickel deficiency on calcium were confirmed by Kirchgessner and
Schnegg (1980), who also found that magnesium was incorporated into bone
instead of calcium. Nickel deficiency has also been shown to lead to
zinc deficiency in goats (Anke et al. 1980), miniature pigs (Anke 1974),
and rats (Schnegg and Krichgessner 1976b). Anke et al. (1981) found that
zinc absorption from the rumen of nickel-deficient goats was reduced.
-------
67
5. MANUFACTURE, IMPORT. USE, AND DISPOSAL
5 . 1 OVERVIEW
Primary nickel is recovered from mined ore and nickel matte, and
secondary nickel is recovered from scrap metal. The only nickel mine and
letter In Deration in the United States has been ^^^^ '
More nickel is recovered from metal scrap than is obtained from both
domestic and imported ore combined. Nickel is used primarily in the
production of steels and alloys and in electroplating.
5 . 2 PRODUCTION
During 1985 1736 million pounds of nickel ores were mined in the
UniteS Stages, from which 10.4 million pounds of nickel were recovered,
and 114 million pounds of nickel were recovered from ferrous and
nonferrous scrap respectively (Chamberlain 1987) Refinery production
of ntckel from imported matte in 1985 was 62.3 million pounds
Chamberlain 1987). Nickel mined in the United States is in the form of
earnie"te a lateritic nickel silicate (EPA 1986a) . Lateritic ores are
Drocessed by pyrometallurgic or hydrometallurgic methods (Tien and
Sowson 1981). Secondary nickel can also be recovered from scrap metal
(Hawley 1981). For a description of the nickel mining process, see
Grandjean (1986) .
itsmei uacesea
Curing 85 was half that of 1984 (Chamberlain 1987). On January 7
1987,gHanna Co. announced that it was Permanently closing lj^«*.
operations in Riddle. Oregon; AMAX Nickel closed its Port Nickel
refinery (which refined Imported nickel matte) in Braithhwaite ,
Lou siana November 30. 1985. In 1985. the U.S. consumption of nickel by
use was as follows: steel. 47.4%; alloys •^.•"P-"1^' "l'^..
electroplating. 15.2%; cast iron. 1.9%; chemicals and eh e™i«l us e
1 2%' electric magnet. 0.5; other uses. 1% (Chamberlain 1987, U.S D.I.
1987).
5.3 IMPORT
During 1985, 315.4 million pounds of nickel were imported for
consumption in the United States (Chamberlain 1987).
5.4 USES
The domestic use pattern for nickel in 1985 was as follawi
(Chamberlain 1987): stainless and heat-resistant steels *2% *ign
nickel heat- and corrosion-resistant alloys. 15%; electroplating.
-------
68 Section 5
alloy steels. 15%; superalloys, 8%; other uses, 5%. Other uses include
use in cast irons, ceramics, nickel-placing, batteries, and fuel cells,
in chemical production, and as an industrial catalyst, particularly in
the food industry (Chamberlain 1987, Tien and Howson 1981).
5.5 DISPOSAL
Nickel has been designated as a priority pollutant by EPA (Passow
1982). EPA requires that persons who generate, transport, treat, store,
or dispose of this compound comply with regulations of the Federal
Resource Conservation and Recovery Act (RCRA). Nickel products that are
to be disposed of should be routed to a metal salvage facility for
profitable reuse or sale as scrap (EPA-NIH 1987, NLM 1987). Methods for
disposing of nickel-containing sludge are landspreading, landfilling,
incineration, and ocean disposal (EPA 1985a).
-------
69
6. ENVIRONMENTAL FATE
6.1 OVERVIEW
The primary source of nickel in the atmosphere is from the burning
of fuel oil. Nickel emissions from the combustion of fossil fuels appear
to be primarily in the form of nickel sulfate, followed by lesser
amounts of nickel oxide and complex oxides of nickel. Nickel levels in
soils may be elevated by application of nickel-containing sewage sludge,
use of certain fertilizers, and deposition of aerosol particles.
Industrial pollution and waste disposal practices are responsible for
higher levels of nickel found in surface water or groundwater. Nickel is
continuously transferred between air, water, and soil by natural
chemical and physical processes, such as weathering, erosion, runoff,
precipitation, stream/river flow, and leaching. Nickel aerosols are
removed from the atmosphere primarily by wet and dry deposition The
average residence time for nickel in the atmosphere is 7 days. Over this
period of time, long-distance transport is expected to take place.
Nickel is extremely persistent in both water and soil. Oceans act as the
ultimate sink for nickel in the environment. The residence time for
nickel in deep oceans and near shore coastal waters has been estimated
to be 23,000 and 19 years, respectively. Nickel may be removed from
oceans in sea spray aerosols.
6.2 RELEASE TO THE ENVIRONMENT
Estimated worldwide atmospheric emission rates for nickel from both
point and non-point sources are listed in Table 6.1. Since the worldwide
consumption of residual and fuel oil and the mining and refining of
nickel (Chamberlain 1987) have not changed significantly in recent
years, the emission pattern should remain largely unchanged. It has been
speculated that most of the nickel emitted into the atmosphere from
fossil fuel combustion is primarily in the form of nickel sulfate (EPA
1986a), with lesser amounts of nickel oxide and complex oxides of nickel
also being released (EPA 1986d). Nickel levels in soils depend on
mineral constituents of the soil. These levels may be elevated as the
result of land application of sewage sludge, use of commercial
fertilizers with a high nickel content (e.g., phosphates), and
deposition of airborne particulate matter (Grandjean 1984). Any nickel
found in surface waters or groundwaters is likely to occur at very low
concentrations unless its presence is mainly the result of industrial
pollution or waste disposal (NAS 1975, Sunderman 1986).
6.3 ENVIRONMENTAL FATE
In the atmosphere, nickel exists predominantly in the aerosol form
(Schmidt and Andren 1980). Airborne nickel particles will remain aloft
in the atmosphere for varying periods of time depending upon such
-------
70 Section 6
Table 6.1. Worldwide emissions of nickel into the atmosphere
Source
Natural
Windblown dust
Volcanoes
Vegetation
Forest fires
Meteoric dust
Sea salt
Anthropogenic"
Residual and fuel oil consumption
Nickel mining and refining operations
Incineration
Steel production
Gasoline and diesel fuel combustion
Nickel alloy production
Coal combustion
Cast-iron production
Cu-Ni alloy production
Total
% of total
emissions
93
4.9
1 6
04
0.4
<0 1
52.0
14.0
10.0
23
1 8
1 4
1.3
0.6
<0.l
100
Emission rate
(106 kg/year)
48
2.5
0.82
0 19
0 18
0.009
26.7
7.2
5.148
1.2
0.9
07
0.66
0.3
0.04
51 347
"Estimated emission rate during mid-1970s.
Source: Schmidt and Andren, 1980.
-------
Environmental Face 71
factors as the concentration of nickel in the atmosphere, the density
and size of the particles, and precipitation The average residence time
of nickel in air is 7 days, with typical residence times ranging from 1
to 21 days (Nriagu 1980a). Larger-size aerosols are expected to settle
out relatively quickly and deposit near the emission source; however,
smaller particles may be transported for hundreds or even thousands of
kilometers before being removed from the atmosphere (Davidson 1980)
Physical removal of nickel by wet or dry deposition is expected to be
the primary fate process in air (Cupitt 1980) The dry deposition flux
of nickel has been measured to range from 0.5 to 12 ng/cm'/day onto
artificial surfaces in semiurban and rural areas (Davidson 1980). Dry
deposition accounts for 30 to 60% of the total or bulk depostion of
nickel. Wet deposition rates of 2.4 to 114 ng/L in urban areas (median
12 A»g/L) have been measured (EPA 1986a) .
Little information is available on the chemistry of nickel in air.
The predominant nickel species present in the atmosphere appears to be
nickel oxide, nickel sulfate, complex oxides of nickel and other metals
(chiefly iron), and to a much lesser extent, metallic nickel, and nickel
subsulfide (EPA 1986d). Nickel carbonyl has been shown to form under
certain conditions, but it is very unstable with a half-life of -100 s
(Schmidt and Andren 1980, EPA 1986a).
Nickel persists in water with an estimated residence time of 23,000
years in deep oceans and 19 years in near-shore coastal waters (Nriagu
1980a). Nickel exists in numerous soluble and insoluble forms depending
upon chemical and physical properties of the water. The transport of
nickel in the major rivers of the world is estimated as follows: 0.5% in
solution, 3.1% adsorbed, 47% as a precipitated coating, 14.9% in organic
solids, and 34.4% as crystalline material (Snodgrass 1980). The mobility
of nickel in aquatic media is controlled by complexation,
precipitation/dissolution, adsorption/desorption, and oxidation/
reduction reactions (Richter and Theis 1980). Limited data suggest that
in pristine environments nickel may exist primarily as hexahydrate ions
that are subsequently coprecipitated or sorbed by hydrous oxides of
iron, silica, and manganese, leading to decreases in mobility and
bioavailability. In more organo-rich polluted waters, organic materials
will keep nickel solubilized by complexation, and approximately half may
exist as simple inorganic salts and half as stable organic complexes,
e.g., with huraic acids. In water where anaerobic conditions exist,
nickel will precipitate out of solution as nickel sulfide in the
presence of sulfides (Callahan et al. 1979, Sunderman and Oskarsson
1987). The results of one study indicate that although amorphous oxides
of iron and manganese generally control the mobility of nickel in
aqueous media, variation in such properties as sulfate concentration,
pH, and iron oxide surface area could affect the mobility of nickel
(Richter and Theis 1980).
No data have been found which would suggest that nickel compounds
volatilize from water (Callahan et al. 1979).
It has been shown that the free aqua species of nickel [Ni(H20)62*l
predominates at pH 9 in most aerobic waters, and soluble nickel
compounds will form as a result of nickel complexation with naturally
occurring ligands (OH">S042'>C1'>NH3) (Richter and Theis 1980). In
-------
72 Section 6
aerobic environments at pH <9, these nickel compounds are sufficiently
soluble to maintain aqueous Ni^+ concentrations at >10'^ M (Callahan et
al. 1979). At pH >9, the hydroxide and/or carbonate species will
precipitate out of solution (Callahan et al. 1979). Under anaerobic
conditions, sulfide ions present in water will control the solubility of
nickel (Richter and Theis 1980). A fuller discussion of the fate of
nickel in water can be found in Nriagu (1980b) and EPA (1986a).
No data have been found which suggest that nickel undergoes any
biological transformation process by microorganisms in water (Callahan
et al. 1979).
Nickel is significantly bioaccumulated in some, but not all,
aquatic organisms. Typical bioconcentration factors (BCFs) for some
organisms are as follows: marine phytoplankton, <20-8000; freshwater
plants, 100; freshwater fish, 40; seaweeds, 550-2000; algae, 2000-
40,000; marine fish, 100; and skipjack tuna, 50 (Callahan et al. 1979).
A BCF of <1000 suggests that bioaccumulation would not be significant
(Kenaga 1980).
The average residence time of nickel in soil is estimated to be
2400 to 3500 years (Nriagu 1980a, Grandjean 1984). Although nickel is
extremely persistent in soil, it also has the potential to leach through
soil and subsequently enter groundwater (Tyler and McBride 1982). The
sorption of nickel in soils has been found to correlate with suspension
pH, total iron, and surface area (Sadiq and Enfield 1984a,b). Organic
complexing agents in soil appear to restrict the movement and
availability of nickel in soil by forming organo-nickel complexes (Tyler
and McBride 1982). Nickel may also be immobilized in soil as nickel
ferrite since carbonate, sulfates, and halides of nickel are too soluble
to precipitate out of solution in soil (Sadiq and Enfield 1984a,b).
There is no evidence which suggests that nickel compounds volatilize
from soil surfaces.
The speciation of nickel in soil is expected to be similar to that
in water (Richter and Theis 1980). Nickel ferrite (NiFe204) appears to
be the most probable nickel species to precipitate in soil (Sadiq and
Enfield 1984a,b).
Nickel is reasonably mobile in low pH and cation exchange capacity
mineral soils, but less mobile in basic mineral soils and soils with
high organic content. Nickel present in dump sites will have higher
mobility under acid rain conditions and will be more likely to
contaminate the aquifer. The extractable nickel content of soil affects
its uptake by plant roots. This extractability is influenced by physical
factors (e.g., soil texture, temperature, and water content), chemical
factors (e.g., pH, organic content, and redox potential), and biological
factors (e.g., plant species variability and microbial activity). In
soil derived from serpentine rocks (which contain higher concentrations
of nickel), the extractable nickel concentration can reach 70 mg/kg,
which is toxic to most plants. Alkalization of such soils decreases the
nickel uptake by plants and reduces the likelihood of their exhibiting
nickel toxicity (Sunderman and Oskarsson 1978, Tyler and McBride 1982).
Nickel is an essential constituent in such urease-rich plants as
Jack beans and soybeans; the concentration of nickel in these plants is
-------
Environmental Face 73
very high. Numerous species of nickel-accumulating planes have been
identified. One such plant, Sebercia acuminaca, native to nickel-rich
New Caledonia, contains an exceptionally high concentration of nickel
(10 g/kg dry weight in leaves and 250 g/kg in latex). Such plants
usually contain elevated concentrations of citric acid and malic acids.
The solubilization of nickel due to complexation may be involved in the
transport and storage of nickel in these plants (Sunderman and Oskarsson
1987).
No data pertaining to the biodegradation of nickel in soil were
found in the available literature.
A fuller discussion of the fate of nickel in soil can be found in
EPA (1986a) and Nriagu (1980b).
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75
7. POTENTIAL FOR HUMAN EXPOSURE
7 . 1 OVERVIEW
Nickel is a naturally occurring element which cannot be degraded in
the environment. Environmental fate processes may transform one nickel
expire. lnt° an°ther> ^ *' niCkel im StiU ™^1* for
fooHc™6 8!n"^ population is exposed to nickel in ambient air, in many
foods, in drinking water, and in various consumer products Nickel
dermatitis, as a result of skin contact with nickel products is the
n^rS'S; 3dVerSe1effeCC °f "ickel -on g the general population.
Segments of the general population who are more likely to exhibit nickel
M«ir n7 "e bourWiVeS 3nd individu*l* prediposed due to familial
history. Unusually frequent contact with nickel may result from wearine
jewelry or working with nickel-containing or nlck.l-pl.ted tooTs or
appliances .
Ca S dai^ intake for numans is estimated to range from 120
3n
om
83 to 94ot ^°Ch1UHrba" and rural areas' Dl.t typically contributes
ILlr ? i u ly consumPci°n °f nickel. Segments of the
general population who may be exposed to higher levels of nickel include
people whose diets contain foods naturally high in nickel, people Uving
in the vicinity of a nickel processing facility, people who are *
occupationally exposed to nickel, and people who smoke tobacco It is
estimated that 0.2% of the workforce in the nickel-producing and
nickel -using industries may be exposed to airborne nickel at
concentrations at or near levels of 0.1 to 1 mg/ra3 .
7.2 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT
7.2.1 Air
* "*imt ^ haVe been mon^ored in a number of
3reaS °f Che United States and th. world.
20 n / , air typically range from approximately 1 to
t w h •
et al. 1985. Schmidt and Andren 1980. Bennett 1984). Average
concentrations of nickel have been found to be higher (>100 ng/m3) Ln
o« , (Bennett 1984.
ean 1984). As much as 2000 ng/m3 nickel has been monitored in the
atmosphere near a large nickel -producing facility (Crandjean 1984).
Nickel in its elemental state can be measured in ambient air-
however, measurement of specific nickel compounds is very difficult
ntne!r i^ " 3nalySiS *-«ally break inorganic compounds down
their ionic or atomic states, thus changing the form of the
-------
76 Section 7
compound in an attempt to determine the total concentration of the
element (EPA 1986d).
Assuming that ^he average breathing rate is 20 m^/day, typical
values for the average daily exposure to nickel by inhalation have been
estimated to be 20 to 200 ng/day in rural areas and 200 to 1200 ng/day
in urban areas. Although people do not spend 26 h/day outside, the 20-
m-vday breathing rate is commonly used to approximate daily exposures to
pollutants, and the resulting doses should be considered as best guess
upper limits.
7.2.2 Water
Nickel has been monitored in surface, ground, and drinking waters
and in sediments throughout the United States and the world. The
concentration of nickel in seawater typically ranges from 0.1 to 0.5
Mg/L (NAS 1975). The typical concentration of nickel in surface waters
averages between 15 and 20 pg/L (Sunderman 1986) . The concentration of
nickel in groundwater in the United States is highly variable. Mean
concentrations ranged from 3.0 to 4630 /jg/L in 1982. The typical
concentration in groundwater was <50 pg/L (EPA 1986a). Drinking water
usually contains <10 /ig nickel/L (Sunderman 1986). The average
concentration of nickel in municipal drinking water near a large open-
pit mine was found to be -200 /ig/L (Grandjean 1984).
Based on a typical concentration of <10 /jg/L nickel in drinking
water (Sunderman 1986) and assuming that the average intake of water by
a human adult is 2 L/day, the average daily exposure to nickel in
drinking water has been estimated to be <20 ng/day.
7.2.3 Soil
The concentration of nickel in agricultural soils typically ranges
between 5 to 500 Mg/g. with a typical level of 50 pg/g. In
nonagricultural soil, its concentration is generally in the range of 4
to 80 pg/gi with a median of 26 ng/g (Bennett 1984). Levels as high as
24,000 ng/g soil have been found in soils near metal refineries (EPA
1986a).
7.2.4 Other
The following are typical concentrations of nickel found in various
food categories: grains, vegetables, and fruits, 0.02 to 2.7 pg/g;
meats. 0.06 to 0.4 /ig/g; and seafoods, 0.02 to 20 ng/g (Sunderman 1986).
Cow's milk has been found to contain nickel concentrations of <100 jig/L,
and the typical concentration of nickel in mother's milk ranges between
20 and 500 pg/L, (Grandjean 1984). Data regarding the level of nickel
found in various food items, including seafood, are presented in Table
7.1. Dietary intake of nickel has been estimated to range from 100 to
500 /ig/day (Bennett 1984). Foods with mean nickel concentrations >1
mg/kg are oatmeal, wheat, bran, dried beans, soya products, hazelnuts,
peanuts, sunflower seeds, licorice, cocoa, and dark chocolate. Nickel
intake from consumption of large amounts of such foods occasionally
could reach 900 ng/day (Sunderman and Oskarsson 1987).
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Potential for Human Exposure 77
Table 7.1. Nickel concentrations in various foodstuffs
Food
Concentration
(ppm)
All-purpose wheat flour
Wheaties cereal
Oat, precooked, quick
Rice, American, polished
Spinach
Peas
Tomato
Orange
Pear
Clam, fresh
Shrimp, fresh-frozen
Haddock, frozen
Pork chop
Egg, whole
Tea, orange pekoe
Beer, canned
Salt, table
Sugar, cane
Cinnamon
0 30-0 54 fresh weight
3.00 fresh weight
2.35 fresh weight
0.47 fresh weight
2.4-4 6 dry weight
2.25 dry weight
0.154 dry weight
0.16 dry weight
0.90 dry weight
0.58 fresh weight
0.03 fresh weight
0.05 fresh weight
0 02 fresh weight
0.03 fresh weight
7.6 fresh weight ,
0.01 fresh weight
0.35 fresh weight
0.03 fresh weight
0.74 fresh weight
Source: NAS. 1975
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78 Section 7
It has been speculated that nickel transfer from kitchen utensils
and metal plumbing due to leaching processes could occasionally add 1
mg/day to daily oral .intake (Grandjean 1984).
Nickel is found in tobacco at a concentration that corresponds to 1
to 3 /ig per cigarette. Approximately 10 to 20% of the nickel in
cigarettes is released in the smoke stream, possibly as nickel carbonyl
(Bennett 1984). Nickel levels in pipe tobacco, cigars, and snuff are
reported to be of the same magnitude as found in cigarettes (NAS 1975).
7.3 OCCUPATIONAL EXPOSURES
Inorganic nickel levels in workroom atmospheres usually range
between 0.1 and 1 mg/m-*, which may be hundreds of times greater than
natural levels in ambient air. Significant exposure from inhalation at
or near permissible levels may occur in a wide variety of occupations
including battery makers, ceramic makers, dyers, electroplaters,
enamelers, glass workers, jewelers, magnet makers, metal workers, nickel
mine workers, refiners and smelters, paint makers, sand blasters, spray
painters, and welders (Grandjean 1984). It is estimated that -0.2% of
the work force in the nickel-producing and nickel-using industries may
be exposed to considerable amounts of airborne nickel. Nickel release
into cutting oils and skin contact with nickel-containing or nickel-
plated tools and other items may add significantly to the number of
people occupationally exposed. NIOSH has estimated that 250,000 people
may be exposed annually to inorganic nickel in occupational settings
(Grandjean 1984).
7.4 POPULATIONS AT HIGH RISK
Nickel dermatitis is the most prevalent adverse effect of nickel in
the general population. Surveys indicate that 2.5 to 5.0% of the general
population may be nickel sensitive. This group includes individuals
predisposed to sensitization of nickel by virtue of familial history. In
addition, it has been found that housewives are more likely to be
sensitive than men or other women (EPA 1986a).
Conflicting data are available on the contribution of nickel toward
various respiratory disorders associated with smoking (EPA 1986a).
Nickel-containing alloys are used in various items which may be
implanted into medical patients (i.e., joint prostheses, plates and
screws for fractured bones, pacemakers). It is believed that nickel
leaching may occur from slow corrosion of the alloys. Insufficient data
are available to determine the significance of leaching from nickel-
alloy implants (Grandjean 1984). Nickel may also contaminate intravenous
fluids. During normal operations, the average nickel uptake in
intravenous fluid has been estimated to be 100 ng per dialysis
(Grandjean 1984).
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79
8. ANALYTICAL METHODS
8.1 ENVIRONMENTAL MEDIA
Analytical methods and detection limits for nickel in various
environmental media are given in Table 8 1 EPA methods 249 1 and 249 2
are required by the EPA Contract Laboratory Program for the analysis of
nickel in water and wastewater. The most common analytical method used
for nickel is atomic absorption spectrometry (AAS), while
dimethylglyoxime-sensitized differential pulse anodic stripping
voltammetry (DPASV) is reportedly the most sensitive analytical method.
The detection limit for nickel, when employing the DPASV method, is
<0.002 ng/g (Stoeppler 1984) Spectrophotometry, alone or in combination
with enrichment procedures, was frequently used in earlier analytical
work on nickel; however, this technique has been almost completely
replaced by atomic spectroscopic or other recent methods. Other
analytical methods which have limited use include catalytic reactions,
mass spectrometry, neutron activation analysis, different kinds of X-ray
fluorescence analysis, and gas chromatography after conversion into
chelates (Stoeppler 1984). Nickel carbonyl can be quantitatively
analyzed in air samples and exhaled breath by gas chromatography or
chemiluminescence techniques (Sunderman and Oskarsson 1987).
Total nickel can be measured in the environment; however,
determination of specific nickel compounds is difficult to achieve (EPA
1986a). Therefore, available data on the monitoring of nickel in the
environment are expressed in terms of total nickel and not the actual
form in which it occurs.
Table 8.1 lists analytical methods for detection of nickel in air,
water, soil, and food.
i
8.2 BIOMEDICAL SAMPLES
8.2.1 Fluids/Exudates
Analytical methods and detection limits for nickel in
fluids/exudates and tissues are identified in Table 8.1. A number of
other techniques (including separation of complexed nickel with high-
performance liquid chromatography columns and spectrophotometric
detection, X-ray fluorescence spectrophotometry of ashed samples,
particle-induced X-ray emission (PIXE) spectrophotometry of dried
samples, neutron and charged particle activation analysis, and isotope-
dilution mass spectrometry) have been employed for the analysis of
nickel in biological samples. These techniques are insufficiently
sensitive or prohibitively expensive or require instrumentation not
generally available to most laboratories The electrothermal atomic
absorption spectrophotometry of methyl isobutyl ketone (MIBK)-extracted
-------
80 Section 8
Table 8.1. Methods for analysis of nickel
Sample
Water, wastewater
Air
Soils, groundwater,
solid waste
Soil
Corn
Hair
Hair, nails
Blood, serum
Urine
Liver tissue
Orchard leaves,
bovine serum
Sample preparation*
Acidify filtrate with
1 1 HNO, to a pH <2
Cellulose membrane filter
collection, wet ashing
Digested with concentrated
HNO, to dryness, and
residue dissolved in dilute
HNO, or HC1
Dry ashed and residue
digested in HNO,
Dried for 48 h at 100'C,
milled com digested in
HNO, or HC1
Wet ashed with HNO, or
HC1O., diluted with HC1
Dned at 45°C for 16 h;
washed samples ashed in
plasma asher and dissolved
in 1% HC1
Extracted from digested
samples with APDC/MIBK
Extracted from digested
samples with APDC/MIBK
Digested with HC1/HNO, at
IOO±20°C
Wet ashed with acid mixture
complexed with funldoxime
Analytical method*
Direct aspiration and
AAS(2491 CLP-M)orthe
furnace method (249 2 CLP-M)
Graphite atomization-AAS
with background correction
Direct aspiration and
AAS or the furnace method
Graphite furnace AAS
Flame AAS
Inductively coupled argon
plasma emission spectroscopy
AAS
Rame AAS
Flame AAS
unne
Rame AAS
Spectrophotometry at 435 nm
(NBS method)
Detection limit
0 04 mg/L (direct
aspiration) and
1 Mg/L (furnace)
OOOUSmg/m1
(200 L air sample)
1 (ig/L (furnace
method) 004 mg/L
(aspiration)
NR*
0 4 rag/kg
NR
-------
Analytical Methods 81
ammonium pyrrolidine di-thiocarbamate (APDC)-complexed nickel is probably
the most sensitive, accurate, reliable, and commonly available cutrent
method for the determination of nickel in biological samples (Sunderman
1984b).
The detection limits amd accuracy for nickel can be improved
further by advanced instrumentation. For example, the detection limits
by electrothermal AAS with Zeeman background corrections are 0.45 ^g/L
in urine, 0.1 ng/L in whole blood, 50 ng/L in serum and plasma, and 10
ng/g dry wt in tissues and food. The detection limit for analysis of
nickel using DPASV with a dimethylglyoxime-sensitized mercury electrode
is 1 ng/L in whole blood, urine, saliva, and tissue homogenate
(Sunderman and Oskarsson 1987).
For reviews on the analysis of nickel in biological samples, refer
to Sunderman (1984) and Tsalev and Zaprianov (1983). Contamination of
biological samples may occur from use of stainless steel apparatus to
collect the samples or from containers used to store specimens. Since
human sweat contains relatively high concentrations of nickel, such
contamination should be avoided. Solvents and reagents used for nickel
analysis should be free from contamination. To analyze certain
biological samples such as urine, long-term storage is necessary for
comparison between samples. In such cases, nickel may adsorb
significantly onto precipitates in solution or onto sample containers,
resulting in an unrepresentative sample. Urine samples should be
acidified with ultrapure nitric acid and frozen until analysis. Other
biological samples should be stored at freezing temperatures (EPA 1986a,
Sunderman 1984).
8.2.2 Tissues
Analytical methods and detection limits for nickel in tissues are
listed in Table 8.1.
-------
9. REGULATORY AND ADVISORY STATUS
9.1 INTERNATIONAL (WORLD HEALTH ORGANIZATION)
The World Health Organization has not advised a limit for nickel in
drinking water (IRPTC 1987).
9.2 NATIONAL
9.2.1 Regulations
The OSHA permissible exposure limit for nickel and soluble nickel
compounds is 1 mg/m3 (OSHA 1985).
Federal law (CERCLA 103a and 103b) requires that the National
Response Center be notified when there is a release of a hazardous
substance in excess of the reportable quantity (RQ). The RQs for nickel
metal (diameter < 100 pm), nickel carbonyl, and nickel cyanide are 1 Ib;
the RQ for nickel hydroxide is 1000 Ib; and the RQs for nickel ammonium
sulfate, nickel chloride, nickel nitrate, and nickel sulfate are 5000 Ib
(EPA 1985b). These RQs are subject to change when the assessment of
potential carcinogenicity and/or chronic toxicity is completed.
Federal law (Sect. 302 of SARA) requires any facility to notify the
State emergency planning commission when an extremely hazardous
substance is present in excess of the threshold planning quantity (TPQ).
TPQs for nickel and nickel carbonyl are 10,000 and 1 Ib, respectively
(EPA 1987c). Federal law (Sect. 304 of SARA) also requires that releases
of hazardous substances be reported immediately to local emergency
planning committees and the State emergency planning commission.
Releases of 1 Ib of nickel and nickel carbonyl must be reported (EPA
1987c).
9.2.2 Advisory Guidance
9.2.2.1 Air
AGENCY ADVISORY
NIOSH Time-weighted average-threshold limit value (TWA-TLV) - 15 pg/m3
for elemental nickel and all nickel compounds except
organonickel compounds with a covalent carbon-nickel bond, for
example, nickel carbonyl (NIOSH 1977). This value is the lowest
reliably detectable concentration of nickel measurable by the
methods recommended by NIOSH (1977).
-------
84 Section 9
ACGIH TWA-TLV - nickel dust - 1 mg/m3
insoluble compounds - 1 mg/m;?
soluble compounds - 0 1 mg/raj
nickel sulfide roasting - 1 mg/ra-* (ACGIH 1986)
EPA
Unit Risk Slope - 2.4 x 10'4 (jig/m3)'1 for nickel refinery dust,
4.8 x 10'4 (pg/m3) for nickel subsulfide (EPA 1986a)
9.2.2.2 Water
AGENCY ADVISORY
EPA 10-day health advisory (HA) (child) - 1.0 mg/L
10-day HA (adult) - 3.5 mg/L
Adjusted acceptable daily intake (AADI) (lifetime) - 0.35 mg/L
(EPA 1985a)
EPA Ambient water quality criterion (AWQC)--According to EPA (1980),
the AWQC for the protection of human health from the toxic
properties of nickel ingested through water and contaminated
aquatic organisms is 632 MgA- The AWQC for the protection of
human health from the toxic .properties of nickel ingested
through contaminated aquatic organisms alone is 4.77 mg/L.
9.2.2.3 Food
FDA (1983) confirmed that nickel is generally recognized as safe
(GRAS) as a direct human food ingredient.
9.2.3 Data Analysis
9.2.3.1 Reference dose
EPA (1987a) has proposed an oral reference dose (RfD) of O.o:
tng/kg/day or 1.2 mg/day for a 70-kg human based on the 2-year Ceding
study in rats by Ambrose et al. (1976), using decreased body weight gain
as the effect of concern. The RfD is calculated according to the methods
of Barnes et al. (1987) as follows:
RfD - 5 mg/kg/day/100 x 3 - 0.02 mg/kg/day ,
where 5 mg/kg/day - NOAEL. 100 - uncertainty factor appropriate for use
with NOAEL from animal data (interspecies and intraspecies
extrapolation), and 3 - modifying factor to account for^hVun"""^
regarding developmental effects due to inadequacies in the reproductive
studies by RTI (1987) and Ambrose et al. (1976). During the Station
and postnatal development of Fib Utters in the RTI (1987) study, high
room temperatures confounded the results. Statistical design
limitations, small sample size, and use of pups rather than litters as
the unit of comparison severely limited the Ambrose et al. (1976)
reproductive study.
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Regulatory and Advisory Scacus 85
9.2.3.2 Carcinogenic potency
The Carcinogen Assessment Group (CAG) of EPA has developed a
quantitative unit cancer risk estimate based upon various
epidemiological data.(EPA 1986a) Using additive and multiplicative
excess risk models and four sets of data (Enterline and Marsh 1982, Doll
et al 1977, Chovil et al. 1981, Magnus et al 1980), a range of
incremental unit risks from 1 1 x 10'5 (jig/m3)'1 to 4 6 x 10'1 (/ig/m3)'1
were calculated Using the midpoint of this range, incremental unit risk
estimates of 2.4 x 10'^ (jjg/m3)'^ for nickel refinery dust and 4 8 x
10"^ (jjg/m3)"! for nickel subsulfide were calculated. These risk
estimates were verified by the EPA agency-wide Carcinogen Risk
Assessment Verification Endeavor (CRAVE) work group on April 1, 1987
(EPA 1987b).
Nickel refining has been classified by IARC (1982) in Group 1
(i.e., data are sufficient to support a causal association between
exposure of humans and cancer). IARC (1982) has classified nickel and
certain nickel compounds (nickel powder, subsulfide, oxide, hydroxide,
carbonate, carbonyl, nickelocene, nickel iron-sulfide matte, nickelous
acetate) in Group 2A (limited evidence in humans, sufficient evidence in
animals).
According to the guidelines of EPA (1986c), nickel refinery dust
and nickel subsulfide have been classified by CAG in Group A: human
carcinogen (EPA 1986a). This category is for agents for which there is
sufficient evidence to support the causal association between exposure
of humans and the agents for cancer. The classification was verified by
the CRAVE work group on April 1, 1987 (EPA 1987b).
9.3 STATE
No state regulations were available.
-------
87
10. REFERENCES
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88 Section 20
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Solomons NW, Viteri F, Shuler TR, Nielsen FH. 1982. Bioavailability of
nickel in man: Effects of foods and chemically defined dietary
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Spears JW, Hatfield EE. 1977. Role of nickel in animal nutrition.
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107
11. GLOSSARY
Acute Exposure--Exposure to a chemical for a duration of 14 days or
less, as specified in the Toxicological Profiles.
Bioconcentration Factor (BCF)--The quotient of the concentration of a
chemical in aquatic organisms at a specific time or during a discrete
time period of exposure divided by the concentration in the surrounding
water at the same time or during the same time period.
Carcinogen--A chemical capable of inducing cancer.
Ceiling value (CL)--A concentration of a substance that should not be
exceeded, even instantaneously.
Chronic Exposure--Exposure to a chemical for 365 days or more, as
specified in the Toxicological Profiles.
Developmental Toxicity--The occurrence of adverse effects on the
developing organism that may result from exposure to a chemical prior to
conception (either parent), during prenatal development, or postnatally
to the time of sexual maturation. Adverse developmental effects may be
detected at any point in the life span of the organism.
Embryotoxicity and Fetotoxicity--Any toxic effect on the conceptus as a
result of prenatal exposure to a chemical; the distinguishing feature
between the two terms is the stage of development during which the
insult occurred. The terms, as used here, include malformations and
variations, altered growth, and in utero death.
Frank Effect Level (FEL)--That level of exposure which produces a
statistically or biologically significant increase in frequency or
severity of unmistakable adverse effects, such as irreversible
functional impairment or mortality, in an exposed population when
compared with its appropriate control.
EPA Health Advisory--An estimate of acceptable drinking water levels for
a chemical substance based on health effects information. A health
advisory is not a legally enforceable federal standard, but serves as
technical guidance to assist federal, state, and local officials.
Immediately Dangerous to Life or Health (IDLH)--The maximum
environmental concentration of a contaminant from which one could escape
within 30 min without any escape'impairing symptoms or irreversible
health effects.
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108 Section 11
Intermediate Exposure--Exposure to a chemical for a duration of 15-364
days, as specified in the Toxicological Profiles.
Immunologic Toxicity--The occurrence of adverse effects on the immune
system that may result from exposure to environmental agents such as
chemicals.
In vitro--Isolated from the living organism and artificially maintained,
as in a test tube.
In vivo--Occurring within the living organism.
Key Study—An animal or human toxicological study that best illustrates
the nature of the adverse effects produced and the doses associated with
those effects.
Lethal Concentration(LO) (LCLO)--The lowest concentration of a chemical
in air which has been reported to have caused death in humans or
animals.
Lethal Concentration(SO) (LCSO)--A calculated concentration of a
chemical in air to which exposure for a specific length of time is
expected to cause death in 50% of a defined experimental animal
population.
Lethal Dose(LO) (LDLO)--The lowest dose of a chemical introduced by a
route other than inhalation that is expected to have caused death in
humans or animals.
Lethal Dose(50) (LDso)--The dose of a chemical which has been calculated
to cause death in 50% of a defined experimental animal population.
Lovest-Observed-Adverse-Effect Level (LOAEL)--The lowest dose of
chemical in a study or group of studies which produces statistically or
biologically significant increases in frequency or severity of adverse
effects between the exposed population and its appropriate control.
Lovest-Observed-Effect Level (LOEL)--The lowest dose of chemical in a
study or group of studies which produces statistically or biologically
significant increases in frequency or severity of effects between the
exposed population and its appropriate control.
Malformations--Permanent structural changes that may adversely affect
survival, development, or function.
Minimal Risk Level--An estimate of daily human exposure to a chemical
that is likely to be without an appreciable risk of deleterious effects
(noncancerous) over a specified duration of exposure.
Mutagen--A substance that causes mutations. A mutation is a change in
the genetic material in a body cell. Mutations can lead to birth
defects, miscarriages, or cancer
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Glossary L09
Neurotoxicity--The occurrence of adverse effects on the nervous system
following exposure to a chemical.
No-Observed-Adverse-Effect Level (NOAEL)--That dose of chemical at which
there are no statistically or biologically significant increases in
frequency or severity of adverse effects seen between the exposed
population and its appropriate control. Effects may be produced at this
dose, but they are not considered to be adverse.
No-Observed-Effect Level (NOEL)--That dose of chemical at which there
are no statistically or biologically significant increases in frequency
or severity of effects seen between the exposed population and its
appropriate control.
Permissible Exposure Limit (PEL)--An allowable exposure level in
workplace air averaged over an 8-h shift.
q^ --The upper-bound estimate of the low-dose slope of the dose-response
curve as determined by the multistage procedure. The q * can be used to
calculate an estimate of carcinogenic potency, the incremental excess
cancer risk per unit of exposure (usually /*g/L for water, mg/kg/day for
food, and pg/m-> for air).
Reference Dose (RfD)--An estimate (with uncertainty spanning perhaps an
order of magnitude) of the daily exposure of the human population to a
potential hazard that is likely to be without risk of deleterious
effects during a lifetime. The RfD is operationally derived from the
NOAEL (from animal and human studies) by a consistent application of
uncertainty factors that reflect various types of data used to estimate
RfDs and an additional modifying factor, which is based on a
professional judgment of the entire database on the chemical. The RfDs
are not applicable to nonthreshold effects such as cancer.
Reportable Quantity (RQ)--The quantity of a hazardous substance that is
considered reportable under CERCLA. Reportable quantities are: (1) 1 Ib
or greater or (2) for selected substances, an amount established by
regulation either under CERCLA or under Sect. 311 of the Clean Water
Act. Quantities are measured over a 24-h period.
Reproductive Toxiclty--The occurrence of adverse effects on the
reproductive system that may result from exposure to a chemical. The
toxicity may be directed to the reproductive organs and/or the related
endocrine system. The manifestation of such toxicity may be noted as
alterations in sexual behavior, fertility, pregnancy outcomes, or
modifications in other functions that are dependent on the integrity of
this system.
Short-Term Exposure Limit (STEL)--The maximum concentration to which
workers can be exposed for up to 15 min continually. No more than four
excursions are allowed per day, and there must be at least 60 min
between exposure periods. The daily TLV-TWA may not be exceeded.
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110 Section 11
Target Organ Toxicity--This term covers a broad range of adverse effects
on target organs or physiological systems (e.g., renal, cardiovascular)
extending from those arising through a single limited exposure to those
assumed over a lifetime of exposure to a chemical.
Teratogen--A chemical that causes structural defects that affect the
development of an organism.
Threshold Limit Value (TLV)--A concentration of a substance to which
most workers can be exposed without adverse effect. The TLV may be
expressed as a TWA, as a STEL, or as a CL.
Time-weighted Average (TWA)--An allowable exposure concentration
averaged over a normal 8-h workday or 40-h workweek.
Uncertainty Factor (UF)--A factor used in operationally deriving the RfD
from experimental data. UFs are intended to account for (1) the
variation in sensitivity among the members of the human population,
(2) the uncertainty in extrapolating animal data to the case of humans,
(3) the uncertainty in extrapolating from data obtained in a study that
is of less than lifetime exposure, and (4) the uncertainty in using
LOAEL data rather than NOAEL data. Usually each of these factors is set
equal to 10.
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Ill
APPENDIX: PEER REVIEW
A peer review panel was assembled for nickel. The panel consisted
of che following members: Dr. Herbert Cornish, Professor, Department of
Toxicology, University of Michigan (retired); Dr. Theodore J. Kniep,
Professor and Director, Laboratory of Environmental Studies, New York
University of Environmental Studies, New York University Medical Center;
and Dr. F. William Sunderman, Jr., Chair of Toxicology, University of
Connecticut Medical School. These experts collectively have knowledge of
nickel•s physical and chemical properties, toxicokinetics, key health
end points, mechanisms of action, human and animal exposure, and
quantification of risk to humans. All reviewers were selected in
conformity with the conditions for peer review specified in the
Superfund Amendments and Reauthorization Act of 1986, Sect 110.
A joint panel of scientists from ATSDR and EPA has reviewed the
peer reviewers' comments and determined which comments will be included
in the profile. A listing of the peer reviewers' comments not
incorporated in the profile, with a brief explanation of the rationale
for their exclusion, exists as part of the administrative record for
this compound. A list of databases reviewed and a list of unpublished
documents cited are also included in the administrative record.
The citation of the peer review panel should not be understood to
imply their approval of the profile's final content. The responsibility
for the content of this profile lies with the Agency for Toxic
Substances and Disease Registry.
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