EPA-540/1-86-018
Office of Emergency and
Remedial Response
Washington DC 20460
Superfund
vvEPA
Off'ce of Research and Development
Office of Health and Environmental
Assessment
Environmental Criteria and
Assessment Office
Cincinnati OH 45268
HEALTH EFFECTS ASSESSMENT
FOR NICKEL
-------
EPA/540/1-86-018
September 1984
HEALTH EFFECTS ASSESSMENT
FOR NICKEL
U.S. Environmental Protection Agency
Office of Research and Development
Office of Health and Environmental Assessment
Environmental Criteria and Assessment Office
Cincinnati, OH 45268
U.S. Environmental Protection Agency
Office of Emergency and Remedial Response
Office of Solid Waste and Emergency Response
Washington, DC 20460
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DISCLAIMER
This report has been funded wholly or In part by the United States
Environmental Protection Agency under Contract No. 68-03-3112 to Syracuse
Research Corporation. It has been subject to the Agency's peer and adminis-
trative review, and 1t has been approved for publication as an EPA document.
Mention of trade names or commercial products does not constitute endorse-
ment or recommendation for use.
11
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PREFACE
This report summarizes and evaluates Information relevant to a prelimi-
nary Interim assessment of adverse health effects associated with nickel.
All estimates of acceptable Intakes and carcinogenic potency presented In
this document should be considered as preliminary and reflect limited
resources allocated to this project. Pertinent toxlcologlc and environ-
mental data were located through on-Hne literature searches of the Chemical
Abstracts, TOXLINE, CANCERLINE and the CHEMFATE/OATALOG data bases. The
basic literature searched supporting this document 1s current up to
September, 1984. Secondary sources of Information have also been relied
upon 1n the preparation of this report and represent large-scale health
assessment efforts that entail extensive peer and Agency review. The fol-
lowing Office of Health and Environmental Assessment (OHEA) sources have
been extensively utilized:
U.S. EPA. 1980b. Ambient Water Quality Criteria for Nickel, with
Errata for Ambient Water Quality Criteria Documents dated June 9,
1981 (Updated: February 23, 1982). Environmental Criteria and
Assessment Office, Cincinnati, OH. EPA 440/5-80-060. NTIS PB
81-11715.
U.S. EPA. 1983a. Health Assessment Document for Nickel. Environ-
mental Criteria and Assessment Office, Research Triangle Park, NC.
EPA 600/8-83-012A. NTIS PB 83-213827.
U.S. EPA. 1983b. Re.portable Quantity for Nickel (and Compounds).
Prepared by the Environmental Criteria and Assessment Office,
Cincinnati, OH, OHEA for the Office of Solid Waste and Emergency
Response, Washington, DC.
U.S. EPA. 1985. Drinking Water Criteria Document for Nickel.
Prepared by the Environmental Criteria and Assessment Office,
Cincinnati, OH, OHEA for the Office of Drinking Water, Washington,
DC. (Final draft)
The Intent 1n these assessments Is to suggest acceptable exposure levels
whenever sufficient data were available. Values were not derived or larger
uncertainty factors were employed when the variable data were limited 1n
scope tending to generate conservative (I.e., protective) estimates. Never-
theless, the Interim values presented reflect the relative degree of hazard
associated with exposure or risk to the chemlcal(s) addressed.
Whenever possible, two categories of values have been estimated for sys-
temic toxicants (toxicants for which cancer Is not the endpolnt of concern).
The first, the AIS or acceptable Intake subchronlc, 1s an estimate of an
exposure level that would not be expected to cause adverse effects when
exposure occurs during a limited time Interval (I.e., for an Interval that
does not constitute a significant portion of the Hfespan). This type of
exposure estimate has not been extensively used or rigorously defined, as
111
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previous risk assessment efforts have been primarily directed towards expo-
sures from toxicants 1n ambient air or water where lifetime exposure Is
assumed. Animal data used for AIS estimates generally Include exposures
with durations of 30-90 days. Subchronlc human data are rarely available.
Reported exposures are usually from chronic occupational exposure situations
or from reports of acute accidental exposure.
The AIC, acceptable Intake chronic, Is similar In concept to the ADI
{acceptable dally Intake). It Is an estimate of an exposure level that
would not be expected to cause adverse effects when exposure occurs for a
significant portion of the Hfespan [see U.S. EPA (1980a) for a discussion
of this concept]. The AIC 1s route specific and estimates acceptable
exposure for a given route with the Implicit assumption that exposure by
other routes 1s Insignificant.
Composite scores (CSs) for noncarclnogens have also been calculated
where data permitted. These values are used for ranking reportable quanti-
ties; the methodology for their development Is explained In U.S. EPA (1983c).
For compounds for which there Is sufficient evidence of carclnogenlclty,
AIS and AIC values are not derived. For a discussion of risk assessment
methodology for carcinogens refer to U.S. EPA (1980a). Since cancer 1s a
process that Is not characterized by a threshold, any exposure contributes
an Increment of risk. Consequently, derivation of AIS and AIC values would
be Inappropriate. For carcinogens, q-|*s have been computed based on oral
and Inhalation data 1f available.
1v
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ABSTRACT
In order to place the risk assessment evaluation In proper context,
refer to the preface of this document. The preface outlines limitations
applicable to all documents of this series as well as the appropriate Inter-
pretation and use of the quantitative estimates presented.
Human occupational data Indicate that nickel refinery workers experience
an elevated Incidence of tumors of the nasal cavities and lungs. The spe-
cific compounds Involved 1n the etiology of cancer 1n these workers have not
been positively Identified; however, nickel carbonyl, nickel sulfate,
nitrate and chloride have been Implicated. Animal Inhalation data Indicate
an association between certain nickel compounds and lung neoplasms.
The human epldemlologlcal data have been used to calculate a q-j* of
1.2 (mg/kg/day)'1 based on lung and laryngeal tumors In two epldemlologl-
cal studies. This q-j* Is more conservative than that calculated from the
Incidence of lung tumors 1n animals or than that calculated from the Inci-
dence of total lung, laryngeal and nasal tumors In the two epldemlologlcal
studies.
Evidence Is considered Inadequate to consider nickel to be carcinogenic
by the oral route. An oral AIS of 1.4 mg/day has been estimated based on a
6-week feeding study using rats. An oral AIC of 0.7 mg/day has been esti-
mated based on a 2-year feeding study In rats. There are some uncertainties
concerning absorption of nickel from the gastrointestinal tract which are
reflected In an additional uncertainty factor. In addition, the toxlclty
data base 1s considered limited.
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ACKNOWLEDGEMENTS
The Initial draft of this report was prepared by Syracuse Research
Corporation under Contract No. 68-03-3112 for EPA's Environmental Criteria
and Assessment Office, Cincinnati, OH. Or. Christopher DeRosa and Karen
Blackburn were the Technical Project Monitors and Helen Ball was',the Project
Officer. The final documents 1n this series were prepared for the Office of
Emergency and Remedial Response, Washington, DC.
Scientists from the following U.S. EPA offices provided review comments
for this document series:
Environmental Criteria and Assessment Office, Cincinnati, OH
Carcinogen Assessment Group
Office of Air Quality Planning and Standards
Office of Solid Waste
Office of Toxic Substances
Office of Drinking Water
Editorial review for the document series was provided by:
Judith Olsen and Erma Durden
Environmental Criteria and Assessment Office
Cincinnati, OH
Technical support services for the document series was provided by:
Bette Zwayer, Pat Daunt, Karen Mann and Jacky Bohanon
Environmental Criteria and Assessment Office
Cincinnati, OH
v1
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TABLE OF CONTENTS
1. ENVIRONMENTAL CHEMISTRY AND FATE
2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS . . . .
2.1.
2.2.
ORAL
INHALATION
3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1.
3.2.
3.3.
3.4..
SUBCHRONIC
3.1.1. Oral
3.1.2. Inhalation
CHRONIC
3.2.1. Oral
3.2.2. Inhalation
TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral
3.3.2. Inhalation
TOXICANT INTERACTIONS
"4. CARCINOGENICITY
4.1.
4.2.
4.3.
4.4.
HUMAN DATA
4.1.1. Oral
4.1.2. Inhalation
BIOASSAYS
4.2.1. Oral
4.2.2. Inhalation
OTHER RELEVANT DATA
WEIGHT OF EVIDENCE
5. REGULATORY STANDARDS AND CRITERIA
1
1
. . 1
. . 1
1
. . 1
. . 1
. . 1
1
. . 1
, , 1
1
. . 1
, , 1
. . 1
1
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TABLE OF CONTENTS (cont.)
6. RISK ASSESSMENT
6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS)
6.1.1. Oral
6.1.2. Inhalation
6.2. ACCEPTABLE INTAKE CHRONIC (AIC)
6.2.1. Oral
6.2.2. Inhalation
Page
10
10
10
10
10
10
10
6.3. CARCINOGENIC POTENCY (qi*) 10
6.3.1. Oral 10
6.3.2. Inhalation 10
7. REFERENCES 10
APPENDIX: Summary Table for Nickel 10
V111
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LIST OF TABLES
No. Title Page
3-1 Subchronlc Toxlclty of Orally Administered Nickel 5
3-2 Subchronlc Toxlclty of Inhaled Nickel 6
3-3 Chronic Toxlclty of Orally Administered Nickel 8
3-4 Chronic Toxlclty of Inhaled Nickel 10
4-1 Mortality by Cause and Year of First Employment, Clydach
Nickel Refinery, Wales 15
4-2 Carclnogenlclty Studies Involving Chronic Inhalation
Exposure to Nickel 17
1x
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LIST OF ABBREVIATIONS
ADI Acceptable dally Intake
AIC Acceptable Intake chronic
AIS Acceptable Intake subchronlc
BCF Bloconcentratlon factor
bw Body weight
CAS Chemical Abstract Service
CS Composite score
DNA Deoxyrlbonuclelc acid
LOAEL Lowest-observed-adverse-effect level
NOEL No-observed-effect level
ppb Parts per billion
ppm Parts per million
RNA Rlbonuclelc acid
SO Standard deviation
STEL Short-term exposure limit
TLV Threshold limit value
TWA Time-weighted average
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1. ENVIRONMENTAL CHEMISTRY AND FATE
Nickel is a metal that belongs to the first transitional series of the
periodic table. Elemental nickel has a CAS Registry number of 7440-02-0.
In the environment, nickel almost always occurs in the 0 and +2 valence
states (Cotton and Wilkinson, 1980). Besides a variety of Inorganic
compounds, nickel forms a number of complexes with organic Ugands. Both
Inorganic and organic nickel compounds have a variety of uses (Antonses,
1981).
In the atmosphere, nickel 1s expected to be present as dusts and fumes
from nickel smelting and processing facilities, coal burning and dlesel oil
combustion (Flshbein, 1981). The atmospheric fate of nickel has not been
studied comprehensively. Any chemical Interaction of nickel compounds 1n
the atmosphere 1s likely to result in the conversion of nickel to nickel
oxide and not Its direct removal through decomposition, as frequently occurs
with organic compounds. For example, nickel carbonyl 1s likely to be oxlda-
tlvely converted to nickel oxide 1n the atmosphere (U.S. EPA, 1983a). The
principal removal mechanisms for atmospheric nickel are wet and dry deposi-
tion (Flshbein, 1981). The atmospheric half-life for the physical removal
mechanism 1s expected to depend on the particle size and particle density of
atmospheric nickel or Its compounds. In one study, enrichment of nickel
from coal-fired power plants was found to occur In partlculate fractions of
diameter <1 vm (U.S. EPA, 1983a). Partlculate nickel 1n such small sizes
is expected to have a long lifetime in the atmosphere. No estimate of the
atmospheric lifetime for nickel 1s available.
The aquatic fate of nickel has been studied extensively (Callahan et
al., 1979). In most aerobic aquatic environments, nickel may exist 1n
-1-
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solution as hydroxide, carbonate, sulfate and organic complexes (Callahan et
al., 1979). Some of the nickel 1n solution may be copredpltated with
hydrous metal oxides or sorbed onto organic material, or 1t may undergo 1on
exchange with crystalline minerals. The ratio of the dissolved and precipi-
tated nickel In an aquatic medium may be dependent upon the nature of the
medium. In general, 1t appears that 1n pristine waters sorptlon to hydrous
Iron or manganese oxides controls dissolved nickel concentrations, while In
polluted waters a higher concentration of dissolved nickel Is expected
(Callahan et al., 1979). No estimate of the aquatic half-life of nickel 1s
available 1n the literature.
The fate of nickel In soil has been studied Inadequately; however, the
fate may be dependent upon the nature of soil. Soils containing relatively
higher proportions of Iron and manganese oxides may sorb nickel
significantly. Soils rich 1n organic matter content may enhance the
mobility of nickel through complexatlon. Although nickel has not been
detected at appreciable concentration In most groundwaters (Flshbein, 1981),
Page (1981) reported the detection of nickel 1n almost 100% groundwater at a
median concentration of 3 ppb.
The BCFs for nickel In aquatic organisms have been determined by several
Investigators and have been found to vary from <20 for marine plankton to
40,000 1n an algae (Callahan et al., 1979). The bloaccumulatlon factor In
edible fish, however, may not exceed 100 (Callahan et al., 1979).
-2-
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2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS
2.1. ORAL
A number of studies Indicate that 1n animals, 1-10% of the nickel
Ingested 1n the diet or in aqueous solution is absorbed by the gastrointes-
tinal tract (Horak and Sunderman, 1973; Nodiya, 1972; Nomoto and Sunderman,
1970; Perry and Perry, 1959; Tedeschl and Sunderman, 1957).
2.2. INHALATION
Nickel can be Inhaled either In gaseous form, as nickel carbonyl or 1n
particulate form. Sunderman and Selln (1968) reported that nickel carbonyl
was readily absorbed by rats exposed to 100 mg N1/8. air for 15 minutes.
WHhin 4 days after treatment, 26% of the administered dose was excreted in
the urine.
On the other hand, particulate nickel in the form of nickel oxide is not
readily absorbed by inhalation. Leslie et al. (1976) exposed rats to nickel
In welding fumes (8.4 yg/m3) -and observed no clearance from the lungs- or
elevation of nickel levels 1n the blood within 24 hours of treatment.
Similarly, Wehner and Craig (1972) exposed hamsters to nickel oxide
particles (2-160 yg/8.; 1-2.5 ym mass median aerodynamic diameter) and
measured the deposition of nickel in the lungs. Of the 20% of the admin-
istered dose deposited in the lungs, 50% remained at 45 days post-treatment.
Furthermore, levels of nickel in the tissues did not Increase, Indicating
that absorption was negligible.
In contrast, mice exposed to an aerosol of nickel chloride cleared 75%
of the administered dose within 4 days of treatment (Graham et al., 1978),
Indicating appreciable absorption. The discrepancy between this and the
previously mentioned studies can probably be accounted for 1n terms of the
greater solubility of nickel chloride as compared with that of nickel oxide.
-3-
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3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral. Studies pertaining to the subchronlc toxldty of orally
administered nickel are summarized 1n Table 3-1.
Whanger (1973) exposed weanling rats to 0, 100, 500 or 1000 ppm nickel
(as nickel acetate) 1n the diet for 6 weeks. Assuming that a weanling rat
consumes a quantity of food equivalent to 10% of Us body weight/day, these
dietary levels can be converted to doses of 0, 10, 50 and 100 mg/kg bw/day.
No significant effects were reported at the 10 mg/kg bw/day level, while
rats exposed to >50 mg/kg bw/day had hematologlcal changes (decreased
hematocrit and hemoglobin concentrations), decreased cytochrome oxldase
activity and a reduction In the rate of gain of body weight. A NOEL of 10
mg/kg bw/day can thus be established from these data.
In the subchronlc studies by Clary (1975) and Waltschewa et al. (1972),
effects (see Table 3-1) were observed 1n rats exposed to drinking water-con-
taining 225 ppm nickel (22.5 mg N1/kg bw/day, assuming that a rat consumes
0.035 8, water/day and weighs 0.35 kg), and 1n rats treated by gavage with
25 mg N1/kg bw/day, respectively.
3.1.2. Inhalation. Studies pertaining to the subchronlc toxldty of
Inhaled nickel are summarized 1n Table 3-2. The salient feature here 1s
that adverse effects (particularly pulmonary effects) were seen at all the
levels of exposure (0.04-0.594 mg/kg/day) employed 1n four different studies
(Welscher et al., 1980; Ottolenghl et al., 1974; Blngham et al., 1972;
Johansson et al., 1981). The lowest level of exposure that produced effects
was reported for rats by Blngham et al. (1972). Unfortunately, these
Investigators do not report the numbers of animals treated nor the actual
length of exposure ("up to several months").
-4-
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TABLE 3-1
Subchrontc Toxlclty of Orally Administered Nickel
1
Ift
1
Species Number Vehicle Compound
weanling 24 diet nickel
rats acetate
Rats 10/group drinking nickel
water chloride
Rats NR gavage nickel
sulfate
Dose Duration Effects
100, 500, 1000 6 weeks 100 ppra, no effects; 500 or 1000
ppm N1 ppm, decreased body weight gain.
hematologlcal changes .reduced cyto-
chroine oxtdase activity In heart.
significantly reduced Iron content
In red blood cells
225 ppm N1 4 months Reduced body weight and lower levels
of serum Itptd and cholesterol at the
time of sacrifice
0, 25 mg/NI/kg 120 days Degenerative cellular changes In the
bw/day liver and kidney, and testlcular
changes
References
Uhanger. 1973
Clary. 1975
Ualtschewa
et al., 1972
NR - Not reported
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TABLE 3-2
Subchronlc Toxlclly of Inhaled Nickel
Species Number Compound Dose as Nickel*
Rat NR nickel oxide 200. 400. 800
iig/m3 (0.148,
0.297. 0.594 mg/kg
bw/day)
Rat 120 N and nickel sulflde 0 or 0. 97^0. 18
104 F/group dust mg/m' (0 or 0.13
mg/kg bw/day)
Rat NR nickel oxide 120 vq/m» (-0.04
, mg/kg bw/day)
v
\
Rat NR nickel chloride 109 pg/m" (-0.04
mg/kg bw/day)
Rabbit 6/group nickel dust 0 or 1.0 mg/m3
(0 or 0.2S mg/kg/day)
Duration
continuously for
120 days
6 hours/day.
5 days/week
for 78 weeks
• 12 hours/day
up to several
months
12 hours/day. 6
days/week up to
several months
6 hours/day, 5
days/week for
6 months
Effects
all levels, decreased kidney
weights and growth rates; In-
creased lung weight and urinary
alkaline phosphatase activity;
severe lung, liver and kidney
lesions
significantly Increased mor-
tality beyond 52 weeks; pul-
monary lesions; 28/208 treated
animals had tumors as compared
with 2/115 controls
thickening of alveolar walls
and respiratory bronchi
hyperplastlc eplthella
changes In lung macrophage
morphology; evidence of pneu-
monia In all 6 treated rabbits
as compared with 1 control
References
Melscher et
al., 1980
Ottolenghl
et al.. 1974
Blngham et
al.. 1972
Blngham et
al., 1972
Johansson
et al.. 1981
'The values In parentheses are calculated by the following equation:
dose In mg/kg/day = [Concentration In mg/m« x (hours exposed/24 hours) x (days exposed/7 days) x (Inhalation rate In mVday)]
_ * the body weight of the animal In kg
where: Inhalation rate = 0.26 mVday for rats and 1.6 mVday for rabbits
body weight = 0.35 kg for rats and 1.13 kg for rabbits
NR = Not reported
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3.2. CHRONIC
3.2.1. Oral. Two studies regarding the chronic toxldty of orally admin-
istered nickel are summarized 1n Table 3-3. Schroeder et al. (1974) exposed
rats to 5 ppm nickel (unspecified compound) In drinking water for life and
observed an ultimate reduction In mean body weight (p<0.025), compared to
controls.
Ambrose et al. (1976) exposed rats to 0, 100, 1000 or 2500 ppm nickel
(as nickel sulfate hexahydrate) 1n the diet (equivalent to 0, 5, 50 and 125
mg/kg bw/day) for 2 years. At levels >1000 ppm (>50 mg/kg/day), effects on
body weight and on the ratio of organ-to-body weight were observed. A NOEL
was established at 100 ppm (5 mg/kg bw/day). The U.S. EPA (1985) conducted
an Independent statistical analysis of these data and found the only sig-
nificant effect to be a lower mean body weight 1n the 1000 ppm dietary dose
group.
In a 3-generat1on reproductive study, Ambrose et al. (1976) exposed 20
female W1star-der1ved rats to 0, 250, 500 or 1000 ppm nickel (as nickel
sulfate hexahydrate) In the diet. Assuming that rats consume the equivalent
of 5% of their body weight In food/day, these levels can be converted to
doses of 0, 12.5, 25 or 50 mg/kg bw/day. At all levels of treatment, a
higher Incidence of fetal mortality compared with controls was observed 1n
the F- generation, but not 1n the F_ or F~ generations. Furthermore,
I a i o
weanling body weight was reduced at the highest level of exposure for all
generations.
The U.S. EPA (1985) has Identified several design limitations Including
small sample size (17-20 females mated/generation) and use of pups rather
than litters as the unit for comparison (the Incidence of stillborn pups can
be markedly elevated by a single stillborn Utter). Furthermore, the
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TABLE 3-3
Chronic Toxlclty of Orally Administered Nickel
Species
Rat
Number
52 N and 52
F/group
Vehicle Compound
drinking NR
water
Dose*
0, 5 ppm N1
(0. 0.5 ing/
kg/day)
Duration Effects
lifetime at 18 months mean body weight of
treated animals was significantly less
(p<0.025) than controls; no Increased
Incidence (p<0.025) of focal myo-
cardlal ftbrosls compared with
controls.
References
Schroeder et
al.. 1974
CO
I
Rat 25 N and 25 diet nickel 0. 100. 1000. 2 years 100 ppm, no significant effects;
F/group sulfate 2500 ppm N1 1000 ppm, significant reduction In
hexahydrate (0. 5. 50, body weight for females at 6 weeks
125 mg/kg/day) and >26 weeks (p<0.05); 1000-2500
ppn, females had significantly higher
heart-to-body weight ratios and signif-
icantly lower Itver-to-body weight
ratios (p<0.05) than controls; both
males and females had significantly
reduced body weight at 2500 ppm.
Ambrose et
al., 1976
"Dose values In parentheses were calculated by multiplying the dietary level (ppm) by the fraction of body weight consumed as food/day (0.05
for a rat) OR by multiplying the level In water by the fraction of body weight consumed as water/day (0.035 ml/day * 0.35 kg).
NR = Not reported
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results are equivocal and do not clearly define a NOAEL or LOAEL. The Inci-
dence of stillborn pups did not exhibit a consistent dose-response relation-
ship, the Incidence of stillborn pups In the 250 ppm (12.5 mg N1/kg bw)
groups was Increased 1n the F, but not the F,. generation and the
i a ID
elevated Incidences of stillborn pups observed in the first generation did
not occur 1n the subsequent two generations.
In another 3-generat1on study, Schroeder and MHchener (1971) exposed
five pairs of Long-Evans BLV(LE) rats to either 0 or 5 ppm nickel (unspeci-
fied salt) 1n drinking water. Assuming that rats consume the equivalent of
10% of their body weight in drinking water/day (0.035 mil/day * 0.35 kg),
these levels are equivalent to doses of 0 or 0.50 mg/kg bw/day. In all
three generations, neonatal mortality was significantly Increased compared
with controls. Furthermore, the number of runts was significantly Increased
1n the first and third generations. In their review of this study, U.S. EPA
(1985) states:
The ambient water criteria was originally based on this study
(U.S. EPA, 1980) but the criterion was subsequently revised because
a number of design problems precluded the use of the Schroeder and
MHchener (1971) study for risk assessment purposes (U.S. EPA,
1982). Design problems Included small sample size (five females
were mated to produce the F] generation), use of diets low 1n
trace metals (deficient 1n chromium) and use of animals rather than
Utters as the unit for statistical analysis. An attempt was made
to duplicate these results, however, the Investigators were unsuc-
cessful.
3.2.2. Inhalation. Chronic Inhalation data for nickel are summarized In
Table 3-4. In both studies (Hueper, 1958; Wehner et a!., 1975), severe
effects, Including death and pathological changes 1n the respiratory system,
were seen at the levels of exposure employed (15 mg/m3 In the Hueper
study, 53.2 mg/m3 1n the Wehner et al. study). It should be noted that
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TABLE 3-4
Chronic Toxlclty of Inhaled Nickel
1
0
1
Species Number
Guinea pig 32 N. 10 F
Rat 50 H. 110 F
Mouse 20 F
Hamster 102
Compound
nickel
(metallic dust)
nickel
(metallic dust)
nickel
(metallic dust)
nickel oxide
Dose as Nickel
(mg/m»)
15
15
15
53.2
Duration
6 hours/day, 5 days/
week for 21 months
6 hours/day. 5 days/
week for 21 months
6 hours/day, 5 days/
week for 15 months
7 hours/day, 5 days/
week for life
Effects
early death, pulmonary edema.
hyperemla, hemorrhage, liver
necrosis
early death, pleurisy, pneu-
monia, congestion, edema,
bronchi ectasts
early death, hemorrhaglc
lungs, congested liver
lung lesions (pneumoconlosis),
emphysema, early death,
References
Hueper ,
195B
Uehner et
al.. 1975
bronchial hyperplasla
-------
these levels are well above the TLVs recommended by the ACGIH (1983) for
metallic nickel (1 mg/m3) or soluble compounds of nickel (0.1 mg/m3) 1n
the workplace.
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral. Pertinent data regarding the teratogenldty of orally
administered nickel could not be located 1n the available literature; how-
ever, other reproductive effects associated with oral exposure to nickel
have been discussed 1n Section 3.2.1.
3.3.2. Inhalation. Sunderman et al. (1959) Investigated the teratogenl-
dty of nickel carbonyl vapors 1n F1scher-344 rats. Pregnant rats were
exposed to 0.08, 0.16 or 0.30 mg/S. nickel carbonyl for 15 minutes on days
7, 8 or 9 of gestation. Pups were either removed from dams on day 20 of
gestation or were born naturally. Of those pups born to mothers exposed to
0.30 mg/8, nickel carbonyl on day 7 of gestation, 25% had eye malforma-
tions. Of the pups delivered by Caesarian section, 64 of 433 had eye mal-
formations. Furthermore, the highest incidence of eye malformations was
found 1n pups removed from dams exposed to 0.30 mg/ms, on day 7 of gesta-
tion. A significant number of anomalies was also seen 1n fetuses delivered
from mothers exposed to 0.16 mg/s. on day 7 of gestation. Furthermore, two
fetuses of dams exposed to 0.08 mg/2. had anomalies (the total number of
fetuses was not specified 1n the secondary source). There were no malforma-
tions in fetuses delivered from sham-treated dams or from dams exposed to
carbon monoxide. Thus, inhalation of nickel carbonyl produced dose-related
teratogenic effects 1n rats.
3.4. TOXICANT INTERACTIONS
Nickel appears to antagonize the arrhythmias Induced by cardiac glyco-
sldes such as dlgltoxln, presumably by competing with calcium at the
membrane binding site (Prasad et al., 1980).
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Nickel also seems to have a synerglstlc effect on the cardnogenlclty of
polycycllc aromatic hydrocarbons (Maenza et al., 1971; Kasprzak et al.,
1973), and may also play a role 1n the cardnogenlclty associated with
asbestos (NAS, 1975; Morgan et al., 1973) and cigarette smoke (Kreyberg,
1978).
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4. CARCINOGENICITY
4.1. HUMAN DATA
4.1.1. Oral. Data pertaining to the carclnogenlcHy of orally Ingested
nickel could not be located 1n the available literature.
4.1.2. Inhalation. A number of studies provide evidence that nickel
refinery workers have an Increased risk of contracting cancer of the nasal
cavities and lungs by Inhalation. The nickel compounds Implicated 1n car-
dnogenesls Include nickel subsulflde and nickel oxide dusts; vapors of
nickel carbonyl; and soluble aerosols of nickel sulfate, nickel nitrate and
nickel chloride (Sunderman, 1977). These cases have been reviewed exten-
sively by numerous authors (NIOSH, 1977; IARC, 1976; NAS, 1975; Sunderman,
1977). Two of these studies (Doll et al., 1977; Pedersen et al., 1973),
summarized below, were used by the U.S. EPA Carcinogen Assessment Group 1n
the quantitative assessment of carcinogenic risk (U.S. EPA, 1983a).
An ep1dem1olog1cal study of the Increased risk of cancer in a nickel
refinery at Clydach, Wales, was reviewed and updated by Doll et al. (1977).
At this plant, the Mond refining process for nickel had been used since
1900, and the mortality of the workers was monitored continuously. Between
1900 and about 1930, the concentration of airborne nickel was 20-25 mg
N1/m3 In areas of high exposure (International Nickel Co., 1976). Workers
employed during this period of time had a higher Incidence of cancer of the
nasal cavities and lungs than would be expected 1n the general population.
After 1925, however, the Clydach plant made basic changes 1n the refinery
process, which resulted 1n pollution control and a subsequent decrease 1n
exposure to nickel. Concomltantly, a reduction 1n the number of observed
vs. expected cancers of the nasal cavity and lungs was observed among
-13-
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workers employed 1n or after 1930. These results are summarized in Table
4-1. As a further note on this study, there has been some speculation that
arsenic, a component of the nickel matte feed material, was the causal agent
1n cardnogenesls. Evidence from a Norwegian study of occupational expo-
sure, however, Implicates nickel as the causal agent (Pedersen et a!., 1973,
1978; Andersen et al., 1980; Kreyberg, 1978; Torjussen et al., 1979), as
does a study by Sutherland (1959), who observed a high Incidence of lung
cancer In an Ontario nickel refinery where arsenic was not a component of
the feed material.
Pedersen et al. (1973) reported on the incidence of lung and nasal
cavity cancers among workers employed at a Norwegian nickel refinery. The
cohort analyzed (1916 men) had started working at the plant at least 3 years
prior to 1961 and were followed through 1971 . The results were similar to
those reported for the Clydach workers prior to 1930; the risks of lung
cancer and nasal cavity cancer were increased 3.75- and 27-fold, respec-
tively. In a 1980 update (Andersen et al., 1980), 2247 persons were fol-
lowed from 1953-1979. Among these, there were 21 cancers of the nasal
cavities as opposed to the 0.88 expected, and 82 lung cancers as opposed to
the 22 expected. In a further analysis of these same data, Kreyberg (1978)
reported that exposed workers still had a higher incidence of lung cancer
even if cigarette smoking was taken Into account. In addition, Torjussen
and Andersen (1979) reported finding a higher mean concentration of nickel
in the nasal mucosa of nickel workers (279.9+ SO 412.1) than in controls
(12.9+ SO 20.3). Unfortunately, the variance about the mean is large.
4.2. BIOASSAYS
4.2.1. Oral. Data specifically pertaining to the carcinogenlcity of
orally administered nickel could not be located in the available literature.
-14-
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TABLE 4-1
Mortality by Cause and Year of First Employment. Clydach Nickel Refinery. Hales3
1
en
i
Year of First
Employment
Before 1910
1910-1914
1915-1919
1920-1924
1925-1929
All periods
before 1930
1930-1944
No. of
Nen
119
150
105
285
103
762
205
Han-Years
of Risk
1980.0
2665.5
2204.0
7126.5
2678.0
6655.0
4538.5
No. of Deaths From
Nasal Sinus Cancer'*
QC
14
24
11
7 (1)
0 (1)
56 (2)
0
Ed
0.036
0.137
0.025
0.071
0.026
0.195
0.034
0/E
389
649
440
99
0
287
0
No. of Deaths
From Lung Cancer
OC
24
34
20
50
9
37
8
E«»
2.389
3.267
3.070
9.642
3.615
1.983
5.463
0/E
10.0
10.4
6.5
5.2
2.5
6.2
1.5
No. of
Deaths From Other
malignant neoplasma
OC
10
10
10
27
7
64
11
E««
14.637
13.549
8.064
20.902
7.247
64.399
8.786
0/E
0.68
0.74
1.24
1.29
0.97
0.99
1.25
No. of Deaths
From Other Diseases
OC
69
69
48
25
44
55
58
Ed
84.95
75.99
44.28
15.63
41.02
61.87
46.14
0/E
0.81
0.91
1.08
1.08
1.07
0.98
1.25
aSource: Doll et al.. 1977
Number of cases of nasal sinus cancer referred to as an associated cause of death
""Observed
Expected _
-------
The following discussion of the Issue Is excerpted from U.S. EPA (1985):
A number of reviews have discussed the cardnogen1c1ty of
nickel compounds (U.S. EPA, 1980; NIOSH, 1977; IARC, 1976; NAS,
1975; Sunderman, 1981, 1979, 1977a, 1976, 1973). It 1s apparent
from these reviews that the chemical form and route of exposure are
Important factors 1n determining the carcinogenic potential of
nickel. The soluble nickel salts do not generally appear to be
carcinogenic, although repeated 1.p. Injections of nickel acetate
at a dose of 360 mg/kg Induced lung carcinomas 1n mice (Stoner et
al., 1976).
The results of several oral studies suggest that 5 ppm nickel
1n drinking water 1s not carcinogenic to rats and mice (Schroeder
et al., 1974; 1964; Schroeder and Mltchener, 1975). Schroeder et
al. (1974) exposed a group of 52 male and 52 female weanling Long-
Evans rats to 0 or 5 ppm nickel 1n drinking water for life. The
diet for both control and treated groups contained an estimated
0.44 yg N1/g of food. Assuming the average dally food and water
consumption of the rats was -5% and 7.8% bw, respectively, average
dally doses can be calculated as 0.02 and 0.41 mg N1/kg bw for
control and exposed rats, respectively. Tumor Incidences were
determined after natural death of the experimental animals.
Longevity of control and exposed rats was similar. There were no
significant differences In tumor Incidences (sarcomas, lymphomas or
carcinomas) between the exposed and control groups.
In an earlier study with mice, Schroeder et al. (1964) exposed
50 male and 54 female Charles River mice to 5 ppm nickel 1n drink-
Ing water. This 1s a dally dose of -0.85 mg N1/kg bw assuming mice
consume water at a rate equivalent to 17% of their bw/day. No
estimate of dietary nickel Intake was provided, although the Inves-
tigators stated that It was low. Causes of death were determined
at autopsy 1n 33 and 41 treated females and males, respectively,
and 60 female and 44 male controls. The number of deaths from all
tumor types was significantly (p<0.01) lower 1n treated females
compared with controls. No other statistically significant differ-
ences In causes of death or longevity were observed. Early mortal-
ity was observed In both the exposed and control groups.
U.S. EPA (1985) concluded that there 1s Insufficient evidence to support the
cardnogenldty of nickel via the oral route.
4.2.2. Inhalation. Four cardnogenldty studies Involving chronic expo-
sure to nickel compounds via Inhalation are summarized in Table 4-2. Hueper
(1958) reported that nickel powder was tumorlgenlc 1n rats and guinea pigs.
-16-
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TABLE 4-2
Carclnogenlclty Studies Involving Chronic Inhalation Exposure to Nickel
Species/
Strain Number
Rats/Wlstar 50 N, 50 F
Rats/ 60 F
NIH black
Compound
nickel powder
(<4 i»ni in diameter)
Dose Duration
15 mg/m" 6 hours/day. 4-5
days/week for up
to 21 months
Effects References
128/160 died within 15 months; Hueper. 1958
15/50 rats of both strains were
found to have adenomatold lung
lesions (benign neoplasms) but
no excess of neoplasms In other
organs.
Guinea pigs/ 32 N, 10 F
NR
Rats/Wlstar
Rats/Wlstar
Rats/
Fischer 344
nickel powder 15 mg/m>
(<4 iim In diameter)
64 N
32 N
41 controls
285 N
70 N controls
nickel carbonyl
nickel carbonyl
nickel carbonyl
0.03 mg/t
0.06 mg/t
0.03 mg/t
226 H and F nickel subsulflde 1 mg/m*
241 controls (70X <1 lira In dla- average
meter, 25X 1-1.5
urn In diameter)
6 hours/day. 4-5
days/week for up
to 21 months
30 minutes. 3 times/
week for 12 months
30 minutes. 3 times/
week for 12 months
30 minutes, 3 times/
week until death
6 hours/day. 5
days/week for 78
weeks
23 animals survived >12 months,
2 survived >18 months; At death
nearly all animals had abnormal
adenomatold formations In the
alveolar and broncheolar
eplthella.
All animals were dead within
30 months of the first exposure;
4/9 rats surviving 2 years had
lung neoplasms; none of the
controls had pulmonary tumors.
8 treated rats survived >2
years, of these 1 had a pul-
monary adenocarcinemas with
metastases; 44 controls
survived >2 years, none had
pulmonary carcinomas.
Significantly higher number of
benign and malignant lung tumors
(p<0.01) In treated animals
(14X) than In controls (IX);
treated animals. 10 adeno-
carclnomas, 3 squamous cell
carcinomas, 1 fIbrosarcoma;
Control animals. 1 adenocar-
clnoma.
Sunderman et
al.. 1957. 1959
Sunderman and
Donnelly. 1965
Ottolenghl
et al.. 1974
NR = Not reported
-------
In studies by Sunderman et al. (1957, 1959) and Sunderman and Donnelly
(1965), animals exposed to nickel carbonyl had lung neoplasms, but the
numbers of animals examined were small (due to excessive mortality). The
study by Ottolenghl et al. (1974) conclusively demonstrated that Fischer
rats chronically exposed to 1 mg nickel subsulf1de/m3 developed a signifi-
cantly higher number of lung tumors (p<0.01) than did controls.
Other studies regarding the carclnogenlcHy of Inhaled nickel have been
summarized by IARC (1976). These studies either were Inconclusive because
of confounding factors (Hueper and Payne, 1962), gave negative results (52
yg/N10/S, to hamsters for life) (Wehner, 1974; Wenner et al., 1975) or
failed to employ controls (Kasprzak et al., 1973).
These animal bloassays studies Indicate that nickel subsulflde, and
possibly nickel carbonyl, are carcinogenic to animals (IARC, 1982).
4.3. OTHER RELEVANT DATA
Nickel chloride and nickel sulfate (soluble 1n water) have been shown to
be mutagenlc 1n eukaryotlc systems (Mlyakl et al., 1979; Amacher and
Palllet, 1980; Wulf, 1980). Nickel chloride was not mutagenlc In EscheM-
chla coll (Green et al., 1976) or Bacillus subtnis (Kanematsu et al., 1980;
Nlshloka, 1975).
Nickel compounds have also been shown to Inhibit DNA or RNA synthesis
(Beach and Sunderman, 1970; Leonard et al., 1981) and have Induced DNA
breakage and repair 1n hamster cells Iji vitro (Roblson and Costa, 1982;
Roblson et al., 1982).
4.4. WEIGHT OF EVIDENCE
IARC (1982) concluded that the evidence for carclnogenlcHy to humans Is
limited for nickel and certain nickel compounds, but sufficient for nickel
refining.
-18-
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According to the IARC criteria for evaluating the overall weight of evi-
dence of carc1nogen1c1ty to humans, nickel and nickel compounds are classi-
fied as Group 2A chemicals, while nickel refining 1s classified as Group 1
(IARC, 1982). The corresponding classifications using the criteria for
evaluating weight of evidence proposed by the Carcinogen Assessment Group of
the U.S. EPA (Federal Register, 1984) are Group A for nickel refining and
Group B2 for nickel and compounds. These classifications are based on
occupational and hence Inhalation exposure.
The lack of data concerning the oral cardnogenldty of nickel would
correspond to an IARC group 3 or a CAG group 0.
-19-
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5. REGULATORY STANDARDS AND CRITERIA
In the June 1981 Errata for Ambient Water Quality Criteria Documents
(U.S. EPA, 1980b), a criterion of 632 yg nickel/a water was recommended,
based on the study of Ambrose et al. (1976).
The ACGIH (1983) has recommended TLVs for Inhalation exposure to nickel
and nickel compounds 1n the workplace. These Include a TWA-TLV of 0.35 mg
N1/m3 for nickel carbonyl (to protect from chronic and acute Intoxication
and to minimize potential carcinogenic effects), a TWA-TLV of 1 mg N1/m3
for nickel sulflde roasting fumes and dust (with the cautionary note that
cancer may be caused at levels below this value), a TWA-TLV of 1 mg/m3 for
nickel metal and a TWA-TLV of 0.1 mg/m3 with an STEL of 0.3 mg/m3 for
soluble compounds of nickel (based on the observation that soluble compounds
of nickel may be carcinogenic while Insoluble compounds are not).
NIOSH (1977) has adopted a TL.V of 0.007 mg/m3 for nickel carbonyl,
based upon Us carcinogenic potential.
-20-
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6. RISK ASSESSMENT
6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS)
6.1.1. Oral. As discussed 1n Section 4.2.1., evidence Is currently
Inadequate to consider nickel carcinogenic by the oral route. Therefore, H
1s appropriate to develop an AIS. The only subchronlc study available which
demonstrates a NOEL 1s a 6-week study 1n which weanling rats were admin-
istered nickel acetate 1n the diet. The low dose, estimated to be equiva-
lent to 10 mg/kg bw/day, was a NOEL while the mid-dose, estimated to be 50
mg/kg bw/day, resulted In depressed weight gain and hematologlcal changes
(Whanger, 1973).
Two other subchronlc studies defined effect, but not no-effect levels.
Clary (1975) administered 225 ppm nickel 1n the drinking water to rats for 4
months (estimated 22.5 mg/kg/day). These animals showed reduced body
weights as well as lower serum I1p1d and cholesterol levels. Waltschewa et
al. (1972) administered 25 mg N1/kg bw/day by gavage for 120 days. These
animals exhibited degenerative cellular changes 1n the liver, kidneys and
testes.
U.S. EPA (1985) has postulated that various dietary components may
retard nickel absorption by the gastronlntestlnal tract. They have pointed
out that this may be a particular concern for human exposures by nickel 1n
drinking water. Since the comparability of nickel absorption by laboratory
animals of nickel 1n feed to human absorption of nickel from water or the
human diet 1s uncertain, they have suggested an additional uncertainty
factor of 0.2 be applied when extrapolating from animal dietary exposures.
An AIS can be estimated from the rat NOEL of 10 mg/kg bw/day established
1n a 6-week feeding study (Whanger, 1973). Multiplying by an assumed human
body weight of 70 kg, by 0.2 to account for possible absorption differences
-21-
-------
and dividing by an uncertainty factor of 100 (10 for Interspedes extrapola-
tion and 10 for 1nter1nd1v1dual variability) results In an AIS of 1.4 mg/day.
6.1.2. Inhalation. Nickel and compounds have been shown to be carcino-
genic to humans and data are sufficient for computation of a q^*. It 1s
Inappropriate, therefore, to calculate an AIS for these chemicals.
6.2. ACCEPTABLE INTAKE CHRONIC (AIC)
6.2.1. Oral. As discussed 1n Section 4.2.1., evidence Is Inadequate to
consider nickel carcinogenic by the oral route. Therefore, 1t 1s appropri-
ate to develop an AIC for oral exposure. As a result of design and statis-
tical deficiencies In the Schroeder and MHchener (1971) study and the
3-generat1on portion of the Ambrose et al. (1976) study as discussed 1n
Section 3.2.1., U.S. EPA (1985) has determined that the study of Ambrose et
al. (1976) In which rats were administered nickel 1n the feed for a period
of 2 years provides the soundest basis for an AIC estimate. In this study,
rats were fed diets containing 0, 100, 1000 or 2500 ppm nickel (estimated to
provide doses of 0, 5, 50 and 125 mg/kg bw/day). A reanalysls of the data
from this study Indicated a significantly lower body weight In the 1000 ppm
group (U.S. EPA, 1985). U.S. EPA (1985) considered the reduced body weight
to be an adverse effect and chose the 100 ppm dietary dose (5 mg/kg bw/day),
designated a NOAEL, as the basis for ADI calculation. Following this pre-
cedent, assuming a 70 kg human body weight, multiplying by 0.2 to account
for possible absorption differences (see Section 6.1.1.), and dividing by an
uncertainty factor of 100 (10 for Interspedes extrapolation and 10 for
1nter1nd1v1dual variability) results 1n an AIC of 0.7 mg/day. This estimate
should be reevaluated when more complete data concerning both toxldty and
absorption are available.
-22-
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6.2.2. Inhalation. Nickel and compounds have been shown to be carcino-
genic to humans and data are sufficient for computation of a q,*. It 1s
Inappropriate, therefore, to calculate an AIC for these chemicals.
6.3. CARCINOGENIC POTENCY (q^)
6.3.1. Oral. The lack of data pertaining to the cardnogenldty of
orally Ingested nickel precludes assessment of carcinogenic risk.
6.3.2. Inhalation. The U.S. EPA (1983a) derived cancer-based risk
assessment for human exposure to nickel, based on the animal study of
Ottolenghi et al. (1974) and the human ep1dem1olog1cal studies by Doll et
al. (1977) and Pedersen et al. (1973).
Based on lifetime exposure to 1 yg nickel sulf1de/m3, the upper
limit risk calculated from the Ottolenghi et al. (1974) data 1s 4.8xlO~3
(yg/m3)"1. From the Pedersen et al. (1973) study and the Doll et al.
(1977) study, the upper limit lifetime unit carcinogenic risks for lung and
nasal cancers were calculated as 6.3xlO~4 and 8.1xlO~4 (yg/m3)"1,
respectively. Taking the geometric mean of these values gives a lifetime
unit carcinogenic risk of 7.1xlO~4 (yg/m3)""1 for total lung, larynx
and nasal cancers. This Is only slightly less than the unit risk calculated
from the animal studies (4.8xlO~3).
U.S. EPA (1983a) also derived a value for lifetime unit carcinogenic
risk, based only on lung and larynx cancers rather than on total lung,
larynx and nasal cancers. This was established by taking the midpoint of
the range of the geometric mean of the lifetime unit risks from the studies
of Pedersen et al. (1973) and Doll et al. (1977) (7.5xlO~s, 5.8xlO~4).
-23-
-------
Assuming a 70 kg man and a human Inhalation rate of 20 m3/day, the mid-
point, 3.3xlO~4 (yg/m3)""1, 1s adjusted to 1.2 (mg/kg/day)'1 by the
following formula:
3.3xlO~4(yg/m3)"1x70 kg •=• (20 m3)x!0~3 mg/yg.
A complete discussion of the derivation of q *s from various data bases
has been reported In U.S. EPA (1983a).
-24-
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7. REFERENCES
ACGIH (American Conference of Governmental Industrial Hyglenlsts). 1983.
Threshold Limit Values for Chemical Substances and Physical Agents 1n the
Workroom Environment with Intended Changes for 1983-84. Cincinnati, OH.
p. 27.
Amacher, D. and S. Palllet. 1980. Induction of tMfluorothymldlne-resIs-
tant mutants by metal Ions In L5178Y/TKt/" cells. Mutat. Res. 78:
279-288. (Cited In U.S. EPA, 1985)
Ambrose, A.M., P.S. Larson, J.R. Borzelleca and G.R. Hennlgar, Jr. 1976.
Long-term toxlcologlc assessment of nickel 1n rats and dogs. J. Food Scl.
Techno!. 13: 181-187. (Cited In U.S. EPA, 1985)
Andersen, A., A. Hogetvelt and K. Magnus. 1980. A follow-up study among
Norwegian nickel workers. In.: Nickel Toxicology, S. Brown and F.W. Sunder-
man, Ed., Academic Press, London, p. 31-32. (Cited 1n U.S. EPA, 1983a)
Antonses, D.H. 1981. Nickel compounds. In.: Klrk-Othmer Encyclopedia of
Chemical Technology, 3rd ed., Vol. 15, M. Grayson and E. Eckroth, Ed. John
Wiley and Sons, Inc., NY. p. 801-819.
Beach, D.J. and F.W. Sunderman, Jr. 1970. Nickel carbonyl Inhibition of
RNA synthesis by a chromatln-RNA polymerase complex from hepatic nuclei.
Cancer Res. 30: 48-50. (Cited 1n U.S. EPA, 1985)
-25-
-------
Blngham, E., W. 'Barkley, M. Zerwas, K. Stemmer and P. Taylor. 1972.
Responses of alveolar macrophages to metals. I. Inhalation of lead and
nickel. Arch. Environ. Health. 25: 406-414. (Cited 1n U.S. EPA, 1983b)
Callahan, M.A.. M.W. Sllmak, N.W. Gabel, et al. 1979. Water-Related Envi-
ronmental Fate of 129 Priority Pollutants. Vol. I., U.S. EPA, Office of
Water Planning and Standards, Office of Water and Waste Management, Washing-
ton, DC. EPA 440/4-79-0293.
Clary, J.J. 1975. Nickel chloride-Induced metabolic changes 1n the rat and
guinea pig. Toxlcol. Appl. Pharmacol. 31: 55-65. (Cited In U.S. EPA, 1985)
Cotton, F.A. and G. Wilkinson. 1980. Nickel. In: Advanced Inorganic
Chemistry. A Comprehensive Text, 4th ed. John WHey and Sons, Inc., NY.
p. 783-798.
Doll, R., J.D. Mathews and L.G. Morgan. 1977. Cancers of the lung and
nasal sinuses 1n nickel workers: A reassessment of the period of risk. Br.
J. Ind. Med. 34: 102-105. (Cited 1n U.S. EPA, 1983a)
Federal Register. 1984. Environmental Protection Agency. Proposed
guidelines for carcinogenic risk assessment. 49 FR 46294-46299.
F1shbe1n, L. 1981. Sources, transport and alterations of metal compounds:
An overview. I. Arsenic, beryllium, cadmium, chromium and nickel. Environ.
Health. Perspect. 40: 43-64.
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Graham, J.A., F.J. Miller, M.J. Daniels, E.A. Payne and D.E. Gardner. 1978.
Influence of cadmium, nickel and chromium on primary Immunity 1n mice.
Environ. Res. 16: 77-87. (Cited U.S. EPA, 1983a)
Green, M.H.L., W.J. Muriel and B.A. Bridges. 1976. Use of a simplified
fluctuation test to detect low levels of mutagens. Mutat. Res. 38: 33-42.
(Cited 1n U.S. EPA, 1985)
Horak, E. and F.W. Sunderman, Jr. 1973. Fecal nickel excretion by healthy
adults. CUn. Chem. 19: 429-430. (Cited 1n U.A. EPA, 1983a)
Hueper, W.C. 1958. Experimental studies In metal cardnogenesls. IX.
Pulmonary lesions 1n guinea pigs and rats exposed to prolonged Inhalation of
powdered metallic nickel. Arch. Pathol. 65: 600-607. (Cited In NIOSH,
1977)
Hueper, W.C. and W.W. Payne. 1962. Experimental studies 1n metal cardno-
genesls—Chromium, nickel, Iron, arsenic. Arch. Environ. Health. 5:
445-462. (Cited 1n NIOSH, 1977)
IARC (International Agency for Research on Cancer). 1976. Nickel and
nickel compounds. In: Cadmium, Nickel, Some Epoxldes, Miscellaneous Indus-
trial Chemicals and General Considerations on Volatile Anaesthetics. IARC
Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man.
IARC, WHO, Lyon, France. 11: 75-112.
-27-
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IARC (International Agency for Research on Cancer). 1982. Results and
conclusions. In: Chemicals, Industrial Processes and Industries Associated
with Cancer 1n Humans. IARC Monographs on the Evaluation of the Carcino-
genic Risk of Chemicals to Humans. IARC, WHO, Lyon, France. Vol. 1-29
(Suppl. 4). p. 167-169.
International Nickel Company. 1976. Nickel and Its Inorganic compounds
Including nickel carbonyl. Unpublished supplementary report submitted to
NIOSH. p. 126. (CHed 1n U.S. EPA, 1983a)
Johansson, A., P. Camner and B. Robertson. 1981. Effects of long-term
nickel dust exposure on rabbit alveolar epithelium. Environ. Res. 25:
391-403. (CHed 1n U.S. EPA, 1983b)
Kanematsu, N., M. Hara and T. Kada. 1980. Rec-assay and mutagenlcHy
studies on metal compounds. Mutat. Res. 77: 109-116. (Cited 1n U.S. EPA,
1985)
Kasprzak, K.S., L. Marchow and J. Breborowlcz. 1973. Pathological reac-
tions 1n rat lungs following Intratracheal Injection of nickel subsulphlde
and 3,4-benzpyrene. Res. Commun. Chem. Pathol. Pharmacol. 6: 237-245.
(Cited 1n IARC, 1976)
Kreyberg, L. 1978. Lung cancer 1n workers 1n a nickel refinery. Br. J.
Ind. Med. 35: 109-116. (CHed In U.S. EPA, 1983a)
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Leonard, A., G.B. Gerber and P. Jacquet. 1981. Carclnogenldty, mutagenlc-
Hy and teratogenldty of nickel. Mutat. Res. 87(1): 1-15.
Leslie, A.C.D., J.W. Winchester, F.W. Leysleffer and M.S. Ahlberg. 1976.
Prediction of health effects of pollution aerosols. In.: Trace Substances 1n
Environmental Health - X, D.O. Hemphlll, Ed. Univ. Missouri, Columbia, MO.
p. 497-504. (Cited In U.S. EPA, 1983a)
Maenza, R.M., A.M. Pradhan and F.W. Sunderman, Jr. 1971. Rapid Induction
of sarcomas 1n rats by combination of nickel sulflde and 3,4-benzypyrene.
Cancer Res. 31: 2067-2071. (Cited 1n U.S. EPA, 1983a)
M1yak1, M., N. Akamatsu, T. Ono and H. Koyama. 1979. MutagenlcHy of metal
cations In cultured cells from Chinese hamsters. Mutat. Res. 68: 259-263.
(Cited In U.S. EPA, 1985)
Morgan, A., A.E. Lally and A. Holmes. 1973. Some observations on the
distribution of trace metals 1n chrysotlle asbestos. Ann. Occup. Hyg. 16:
231-240. (Cited U.S. EPA, 1983a)
NAS (National Academy of Sciences). 1975. Nickel. National Academy of
Sciences Committee on Medical and Biologic Effects of Environmental Pollut-
ants. Washington, DC.
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APPENDIX
Summary Table for Nickel
Carcinogenic
Potency
Inhalation
Oral
Species Experimental
Dose/Exposure
human 20-25 mg/m3
occupational
Effect
nasal, laryngeal
and lung tumors
qi* Reference
1.2 (ing/kg/day)'1 Doll et al., 1977;
Pederson et al., 1975;
U.S. EPA, 1983a
ND
I
CO
Route
Species
AIC
rat
Inhalation
Experimental
Dose/Exposure
Effect
6 weeks (0.
10, 50, 100
mg/kg bw/day)
0, 100, 1000,
2500 ppm diet/
2 years (0, 5,
50, 125 mg/kg
bw/day)
body weight,
hematologlcal
changes
decreased
body weight
at 50 mg/kg
Acceptable Intake
(AIS or AIC)
Reference
Oral
AIS
rat 0, 100,
1000 ppr
500,
n diet/
>50 mg/kg
decreased
1.4 mg/day
Whanger, 1973
0.7 mg/day
ND
Ambrose
et al., 1976
ND = Not derived
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