|
Items in cart [0] |
Questions? Call 888-624-8373 |
PAPERBACK Free PDF Access |
||||||||||||||||
|
||||||||||||||||
|
|
|||||||||||||||
| ||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||
| Copyright © 2009. National Academy of Sciences. All rights reserved. Terms of Use and Privacy Statement |
Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter.
Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.
OCR for page 203
6
Nickel
Raghupathy Ramanathan, Ph.D.
NASA-Johnson Space Center Toxicology Group
Habitability anc!Environmental Factors Branch
Houston, Texas
BACKGROUND
The International Space Station (ISS) will use stainless steel plumbing
systems extensively in the wastewater and processed-water distribution
lines, the humidity heat exchanger, and the collection and dispenser lines.
Nickel is one ofthe key components ofthese systems. The lines carry water
containing various levels of iodine, which can corrode the lines, and thus
nickel canbe foundintheprocessedwaters. Although the in-line conductiv-
ity monitors might be able to flag such leaching, and the ion exchange
resins can actively eliminate nickel, high nickel levels can foul these sys-
tems. In NASA's ground-based human testing (NRC 2000, Ch. 2) for the
development of ISS water-processing hardware, nickel concentrations were
found in the processed water through the analysis of archived samples.
Because studies in experimental animals (inhalation and injections) and
epidemiological studies have shown that nickel and nickel-containing sub-
stances are carcinogenic (cancers of the lung and nasal cavities), and be-
cause nickel has been implicated as a cause of chronic dermatitis, it was
necessary to assess if an appreciable health risk exists for the presence of
nickel as soluble nickel salts in the spacecraft drinking water. Nickel also
203
OCR for page 204
204
Spacecraft Water Exposure Guidelines
TABLE 6-1 Physical and Chemical Properties of Nickel and Soluble
Nickel Compounds
CAS registry no.
Atomic number
Synonyms
Oxidation states
Nickel chloride (CAS registry no.)
Nickel oxide (CAS registry no.)
Structural formulas
Water solubility
7440-02-0
28
None
1, 2, 3, and 4
77 1 8-54-9
13 13-99-1
Ni, NiCl2, NiO, NiS04, Ni(NO3)2,
Ni(CH3 C02)2
Ni (insoluble); NiO (1.1 mg/L at 20°C);
NiCl2 (642 g/L at 20°C)
seems to affect the absorption of iron. The requirement for nickel as an
essential trace element for humans is inconclusive.
Nickel is a lustrous hard metal and exists in several salt forms, some
soluble and some insoluble in water. The most common soluble forms are
the chlorides, sulfates, and the nitrate. This document will discuss the health
effects of nickel in drinking water; therefore, only the soluble forms will
be discussed. Nickel dust or insoluble forms such as nickel sulfides will not
be considered.
Occurrence and Use
Nickel salts are used extensively in electroplating and in the manufac-
ture of alloys, catalysts, and high capacity batteries. Metallic nickel is used
in the manufacture of stainless steel. Nickel is present in the earth's crust
at 0.018% as the free form but predominantly as sulfides, oxides, arsenides,
antimonides, and silicates in ores.
Nickel is very commonly found in surface waters and groundwaters,
mostly originating from industrial activities and anthropogenic discharges.
In water, nickel mostly occurs as Ni2+. In an aerobic environment, at a pH
below 9, nickel will form soluble compounds with hydroxides, carbonate,
sulfate, and naturally occurring organic ligands. An EPA survey reported
that the concentrations in surface water range from 3.9 micrograms per liter
(~g/L) to 672 ~g/L,and groundwater levels ranged from 2.95 ~g/L to 440
~g/L. Most potable waters contain <40 ~g/L of nickel (EPA 1983~. Thus,
OCR for page 205
Nickel
TABLE 6-2 Physical and Chemical Parameters of Other Nickel
Compounds
205
Molecular Nickel Content
Form Weight (NO)
Nickel 58.69 100
Nickel chloride (monohydrate) (NiCl2) 129.60 45.29
Nickel chloride hexahydrate (NiCl2 6H2O) 238.00 25
Nickel sulfate (NiS04) 154.75 37.9
Nickel sulfate hexahydrate (NiSO4 6H2O) 262.8 22.3
Nickel acetate (Ni(CH3C00~2) 176.80 33.20
Nickel nitrate hexahydrate (Ni(NO3~2 6H2 O) 290.81 20.2
Source: Merck 1989.
several surveys found that community water supplies, surface waters, drink-
ing waters, and tap water samples contained nickel. Nickel may leach into
drinking water from plumbing materials. It is important to note that dietary
nickel forms a significant portion of the human exposure/body burden. A
wide range of nickel intake through diet has been reported (IOM 2001~.
According to the U.S. Food and Drug Administration total diet study of
1984, the mean adult daily nickel consumption from diet ranges from 74 fig
per day (~) to 100 ~g/d (Pennington and Jones 1987~. On the contrary, a
national survey from five Canadian studies during 1986-1988 reported a
dietary nickel consumption of 207-406 ~g/d for adults (Dabeka and
McKenzie 1995~.
PHARMACOKINETICS AND METABOLISM
Absorption
The major route of nickel intake is ingestion, although inhalation and
dermal absorption are also routes of exposure. Most ofthe data for ingestion
comes from animal studies in which nickel salts were added to the diet.
From the available studies it can be inferred that the bioavailability of
nickel from dietary sources is different than that from drinking water
sources. In general, it has been reported that in animals 1-10% of nickel
administered as nickel salts either in the diet or by gavage is absorbed (Sun-
OCR for page 206
206
Spacecraft Water Exposure Guidelines
TABLE 6-3 Nickel Levels in Various Processed Water Samples in NASA
Investigations
Nickel (vigil)
Sample Source Minimum Maximum Frequency of Occurencea
Phase II A (60 d) 1.2 265 44/81
PhaseIII (90 d) 0 328 47/58
Mir missions
Mir-18-Mir-25 5.6 157
Mir water ferried 1.2 79.3
from ground
22/29
7/7
around above method quantifiable levels.
Source: Data fromNASA-Johnson Space Center Water and Food Analysis Labora-
tory.
derman 1970~. On the basis of urine excretion data, Ho and Furst (1973)
reported that female rats given nickel chloride (NiCI2) in dilute acid solution
by oral intubation absorbed only 3-6% of doses at 4,16, or 64 milligrams
per kilogram (mg/kg). Sunderman et al. (1989) reported that absorption of
nickel from food was much lower than from water in humans (n = 8) who
ingested 12,18, or 50 grams (g) of nickel as nickel sulfate (NiSO4) in food
or in water (27% absorption from water and 0.7% from food). The subjects
were fasted 12 hours (h) before the dose was administered, and those
recieving the dose in water were fasted an additional 3 h after being dosed.
The bioavailability of nickel, as measured by serum nickel levels, was simi-
larly elevated in fasted subjects given NiSO4 in drinking water (peak in-
crease within 3 h) but not when nickel was given in food (Solomons et al.
1982~. Food constituents such as fibers, phytate, and some metal-ion bind-
ing components may bind nickel, influencing the availability. These data
indicate that the presence of food significantly decreased the absorption of
nickel. Absorption from solutions was higher for more soluble nickel com-
pounds (Ishimatsu et al. 1995~. A detailed study by Nielsen et al. (1999) on
the kinetics of nickel absorption from food end wafer and of nickel elimina-
tion reported that the maximum nickel levels observed 1 h after ingestion
in water were 13 times higher than those observed when nickel was given
with food and water. The cumulative amount of nickel excreted increased
with an increase in the interval between the meal and nickel administration
OCR for page 207
Nickel
207
in water. From the experimental design and conclusions, it is clear that
under normal circumstances, when one ingests food once every 4 h and
drinks water intermittently, the existing food in the stomach will affect
nickel absorption. In the same study, Nielsen et al. (1999) indicated that
women absorb less nickel, and the authors propose that the difference in
absorption is due to a gender-related difference in gastric emptying time,
which is longer in women than in men.
Nickel is believed to play a role in physiologic processes as a cofactor
in the absorption of iron from the intestine. The interaction between nickel
and iron occurs only under certain conditions. Nickel increased the absorp-
tion of iron from the diet in iron deficient rats (female), but interaction was
seen only when dietary iron was in the unavailable ferric form, whereas a
mixture of ferrous and ferric sulfates (60% ferric to 40°/0 ferrous) as a sup-
plement to the diet did not elicit any effect (Nielsen et al. 1980~. Talikvist
et al. (1994) examined nickel-iron interactions both in vivo after an oral
dose and in vitro using isolated perfused jejunal and ileal segments from
iron deficient and iron sufficient rats. In both cases, enhanced nickel absorp-
tion from iron deficient rats was evident. Furthermore, Talikvist and Tjalve
(1997) observed increased nickel uptake in several tissues of the
iron-deficient rats following gastric intubation of nickel. This indicates, at
least in part, that nickel is taken up by the same absorptive mechanism for
iron in the intestinal epithelium. In a study using monolayers of epithelial
coco-2 cells, derived from human colonic adenoma carcinoma in bicameral
chambers, Talikvist and Tjalve (1998) observedthatboth transportation and
accumulation of nickel (63NiCI2) were depressed when the monolayer cul-
tures were loaded with iron, indicating strong interaction between nickel
and iron.
However, an important concern is whether increased doses of nickel (by
ingestion) will affect iron status (decrease in iron absorption and tissue
levels) in subjects with sufficient iron in the diet, eventually resulting in
anemia. Nielsen et al. ( 1979) conducted a fully crossed two-way Pictorially
designed experiment in female SD rats in which the interaction of nickel
and iron was studied in rats at varying doses of nickel in the diet (0, 5, and
50 Agog) for 9 weeks (wk), and the changes in levels hematocrit and hemo-
giobin levels were reported. The results showed that when iron is present
at borderline deficient levels or at normal levels, nickel did not affect the
above parameters. Similarly, Oosting et al. ( 1991 ) reported that the addition
of 0, 3, 50, or 100 ~g/kg in the diet to rats had no major impact on iron
concentrations in plasma, liver, kidneys, spleen, or femur.
OCR for page 208
208
Spacecraft Water Exposure Guidelines
Distribution
The total amount of nickel found in the human body has been estimated
to be 86 ~g/kg for a 70-kg person (Sumino et al. l 975~. Serum nickel levels
peaked at 2.5 h to 3 h after ingestion of NiSO4 (Sunderman et al. 1989~. In
workers who accidentally drank nickel-contaminated drinking water, the
serum half-life was 60 h (Sunderman et al. 1988~. In short-term and
long-term studies of animals administered various soluble nickel salts
orally, nickel was found primarily in the kidneys. Whanger ~ 1973) reported
that there was a dose-dependent increase in the retention of nickel from the
diet when rats were fed diets containing nickel at 0,10,50, or 100 mg/kg/~.
The relative tissue concentrations were kidneys > lungs > liver > heart >
testes (Ambrose et al. 1976; Dieter et al. 1988; Ishimatsu et al. 1995;
Whanger 1973.) Oral administration of radioactive 63Ni2+ to mice resulted
in higher accumulation of 63Ni2+ in the spinal cord than in the cerebellum or
frontal cortex (Borg and Tjalve 1989~. In control rats, there appeared to be
a difference in the levels of nickel in bones between males and female
rats 0.53 parts per million (ppm) and <0.096 ppm, respectively (Ambrose
et al. 1976~. Casey and Robinson (1978) reported that the levels of nickel
in the liver, heart, and muscles were similar in human fetuses and in adults.
When pregnant rats were fed nickel salts at 1,000 ppm in the diet (50 ma/
kg/~), their newborn pups had a total tissue concentration of 22-30 ppm; the
levels in decreasing order were bone > spleen > kidneys > heart > intestine
> blood > testes, indicating transplacental transfer of nickel (Phatak and
Patwar~han 1950, as cited in EPA 1995~. When NiCI2 was injected
subcutaneously into lactating SD rats, a dose-dependent increase of nickel
in milk was observed (Dostal et al. 1989~. When nickel at 5 ppm (0.41
mg/kg/d, soluble salt not specifiers was added in drinking water, however,
the rats did not accumulate significant amounts in tissues (Schroeder et al.
1974~.
Metabolism
In humans and animals, serum albumin is the main carrier of nickel in
the serum. In human serum, nickel was found to bind to albumin, L-his-
tidine, and alpha-2-macrogIobulin (Sarkar 1984~. The low-molecular-
weight complex of albumin-histidine-nickel can be transported across cellu-
lar membranes. Nickel bound to the alpha-2-macrogIobulin (nickeloplas-
min) pool is considered a nonexchangeable pool (Nomoto and Sunderman
1989~. Serum albumin in dogs does not have the specific Ni+2 binding site
OCR for page 209
Nickel
209
(Glennon and Sarkar 1982), and hence, most of the nickel in dog serum is
not protein-bound. It has been shown that there are large species variations
in the proportions of ultraf~Itrable and protein-bound serum nickel (Hendel
and Sundennan 1972~.
Excretion
In humans, most ingested nickel is not absorbed and is eliminated pre-
dominantly in the feces. Some of the nickel absorbed from the gastrointes-
tinal tract is excreted in the urine and is associated primarily with low-
molecular-weight complexes that contain amino acids. In humans, nickel
can also be eliminated through sweat and milk. Sunderman et al. (1989)
reported that in humans who ingested 12, 1 8, or 50 fig of nickel from NiSO4
in food or water, 26% of the dose given in water was excreted in the urine
and 76% was excreted in the feces by 4 d poet-treatment. Ofthe dose given
via food, only 2% was excreted in the urine and almost all the rest was
excreted in the feces. A 40-fold difference was seen in the absorption of
nickel from drinking water and from food; absorption was higher from the
drinking water. Hansen et al. (1994) reported that excretion of nickel fol-
lowing a single oral dose given to women after an overnight fast was found
to decrease with increasing age, suggesting that nickel absorption may
decrease with age. Ho and Furst (1973) reported that 1 ~ after administra-
tion of NiCI2 to rats, about 95°/O was excreted in the feces and about 3-6%
in the urine. Similarly, in dogs given NiSO4 in the diet for 2 years (y), only
1% to 3% of the dose was excreted in the urine (Ambrose et al. 1976~.
The kinetics of 63Ni2+ metabolism was studied in rats end rabbits follow-
ing an intravenous injection of 63NiCI2 to develop a compaWnental model
useful in predicting nickel concentrations under various circumstances
(Onkelinx et al. 1973~.63Ni2+ was rapidly cleared from plasma and serum
during the first 48 h after injection and was cleared at a much slower rate
from 72 h to 168 h. The model developed was tested and validated in other
separate experiments in which NiCI2 was either perfused or injected daily
for 14 ~ (Onkelinx et al. 1973~.
TOXICITY SUMMARY
Available evidence indicates that the natural concentrations of nickel
present in water, soil, and food do not constitute a threat to humans (NAS
1977~. Toxicity studies have demonstrated that significant differences can
OCR for page 210
210
Spacecraft Water Exposure Guidelines
exist based on the chemical form of the nickel salt. That is probably be-
cause the estimated absorbed fraction of each ofthe nickel compounds was
increased with the increased solubility of the nickel compound (Ishmatsu
et al. 1995~. Furthermore, although parenteral injections of nickel salts are
very toxic, nickel salts have relatively low toxicity in various species of
animals when administered orally. Soluble nickel compounds are more
toxic than less soluble nickel compounds. For example, although the oral
LD50s (doses lethal to 50°/O of subjects) for less soluble nickel oxide (NiO)
and nickel subsurface (Ni3S2) were 4 g/kg, the oral LD50 in female rats for
NiSO4 was 39 mg/kg, and the LD50s for nickel acetate were 1 16 mg and 136
mg for female rats and mice, respectively (Hero et al. 1968; Mastromatteo
1986~.
The available literature indicates that, following a high oral exposure
to nickel in rats and mice, some of the most common effects reported are
decline in body-weight gain, reduced water intake, hepatic and renal weight
changes, gastrointestinal effects, adverse hematologic effects, and some
central nervous system (CNS) effects at high doses. In addition to those
effects, allergic reactions (hypersensitivity) to nickel have been reported in
individuals with nickel allergic contact dermatitis (ACD).
Acute Toxicity (1 d)
Daldrup et al. (1983, as cited in ATSDR 1997) reported that a 2.5-y-old
child died of cardiac arrest after ingesting an oral dose of NiSO4 crystals.
The dose was calculated to be 250 mg/kg. In a study that was designed to
find the absorption and elimination kinetics of nickel in humans,
Sunderman et al. (1989) reported that 7 h after a single dose of nickel as
NiSO4 (0.05 mg/kg) in drinking water, a male volunteer developed left
hemianopsia for 2 h (Ioss of sight in the corresponding lateral half of the
eye). However, when the dose was lowered in other subjects to 12 ~g/kg
or 18 ~g/kg, that effect was not observed.
Short-Term Toxicity (2-10 d)
During a 2-y nickel-feed study in dogs, Ambrose et al. (1976) observed
that during the first 3 ~ all dogs ingesting nickel at 2,500 ppm in their diet
(37 mg/kg/~) vomited, indicating gastrointestinal distress. The concentra-
tion of nickel in the diet was raised from 1,500 to 1,700, 2,100, and the
target level of 2,500 ppm (37 mg/kg/~) at 2-wk intervals with no further
OCR for page 211
Nickel
211
evidence of emesis. The final dose was 37 mg/kg/d (Ambrose et al. l 976),
which was continued for the rest of the 2-y duration.
Acute gastrointestinal effects were also reported by Sunderman et al.
(1988~. Thirty-two workers in an electroplating factory who accidentally
drank water from a water fountain contaminated with nickel suffered from
acute gastrointestinal (nausea, vomiting, abdominal discomfort, diarrhea)
and neurologic (headache, shortness of breath, giddiness) symptoms. The
amount was determined to be 1.63 g/L as NiCI2 and NiSO4. The authors
estimated that intake ranged from 0.5 g to 2.5 g in 20 workers who had
these symptoms. Symptoms lasted for a few hours and up to 2 ~ in some
workers. Even though boric acid was also present at 68 mg/L in the water,
the authors concluded that nickel was the primary cause for the observed
effects. In three of 10 workers who were hospitalized, a transient increase
in serum bilirubin (indicative of hepatotoxicity), a transient increase in urine
albumin (indicative of renal toxicity), and a transient increase in hematocrit
were reported.
Other toxic responses to short-term doses of nickel are the allergic
dermatologic reactions to nickel ingestion, such as flare-up of eczema and
dose-related erythema, seen only in individuals who are aireadypredisposed
to nickel ACD. This is discussed in a separate section later in the docu-
ment.
Subchronic Toxicity (10-100 d)
Weber and Reid ~ 1969) reported significant reductions in body-weight
gain, decreased body weight, and signs of hepato- and renal toxicities in
animals as a result of daily exposure to nickel via diet or gavage. Nickel
as nickel acetate at 0,1,100, or 1,600 ppm administered in the diet to male
and female mice for 4 wk resulted in decreases in body weight at 100 and
1,600 ppm in females, whereas that change was seen only at 1,600 ppm in
males (Weber and Reid 1969~. Liver and heart cytochrome oxidase, liver
isocitric dehydrogenase, and kidney and heart maleic dehydrogenase were
also decreased. A LOAEL (Iowest-observed-adverse-effect level) of 143
mg/kg/d for reduction in body weight and reduced enzyme activities was
identified.
Weischer et al. (1980) reported that oral administration of nickel as
NiCI2 in male rats over a period of 28 d at concentrations of 2.5, 5.0, and
10.0 ~g per milliliter (mL) in drinking water (0.38, 0.75, or 1.5 mg/kg/d)
resulted in significant dose-dependent hyperglycemia, decreases in serum
OCR for page 212
212
Spacecraft Water Exposure Guidelines
urea, and significant increases in urine urea. Increased leukocytes observed
at 0.75 mg/kg were not observed at lower doses. Water consumptions were
significantly lower than controls at all doses. These effects were noted at
extremely small doses compared with other reports; hence, this study was
not considered for AC derivation because of lack of confidence in the data.
In weanling rats (n = 24) fed a diet containing nickel as nickel acetate
at 100, 500, or 1,000 ppm (10, 50, or 100 mg/kg/~) for 6 wk. significant
reductions in weight gain in the mid-dose group and loses of weight in the
100-mg/kg group were noted (Whanger 1973). Reduced blood hemoglobin
and packed cell volume (PCV) were also noted. Significant reductions in
plasma alkaline phosphatase and in cytochrome oxidase activities in liver
and heart were seen in the 100-mg/kg group. Significantly elevated levels
of iron in many tissues, particularly in the kidneys and liver, were observed
in both the 50-mg/kg group and the 100-mg/kg group. These effects were
not seen in the 10-mg/kg group. The influence of nickel on tissue iron
levels was not clear.
In a 90-d rat gavage study (American Biogenics Corporation 1988, as
cited in IRIS 1996), 30 male and female CD rats received a daily gavage
dose of nickel as NiCI2 (hexahydrate) at 0, 5, 35, and 100 mg/d (1.2, 8.6,
and 25 mg/kg/~. Various symptoms of toxicity, such as lethargy, ataxia,
irregular breathing, hypothermia, salivation, and loose stools, were ob-
served in the 10- mg/kg/d group, and increased mortality (52/60 rats in the
high-dose group and 2/60 in the low-dose group) was observed during the
regimen. All animals in the 100-mg/kg group and 14 of 60 in the 35-mg/kg
group died. Decreased body weights, decreased food intake, and clinical
signs of toxicity, including ataxia, lethargy, altered breathing, lower body
temperature, and discoloration of the extremities, were observed. Kidney,
liver, and spleen weights were lower in the mid-dose and high-dose groups.
A dose of 1.2 mg/kg/d appeared to be a NOAEL (no-observed-adverse-
effect level) in this study.
Waltschewa et al. (1972, as cited in EPA 1985) reported that daily oral
intubations of nickel as NiSO4 at 25 mg/kg for 4 months (mo) in male rats
resulted in degenerative cellular changes in the liver and kidneys.
Obone et al. (1999) reported that in adult male Sprague-Dawley rats
given NiSO4 (hexahydrate) at 0°/O, 0.02%, 0.05°/O, and 0.1%, or 0, 44.7,
111.75, and 223.5 mg/L, respectively (estimated doses of 0,5,12.5, and 25
mg/kg/~), in their drinking water for 13 wk. both the absolute and relative
liver weights in the 12.5-mg/kg and 25-mg/kg groups were significantly
decreased. Total plasma proteins, plasma albumin and globulins, and
plasma glutamic pyruvic transaminase activity were significantly decreased
OCR for page 213
Nickel
213
in the highest-dose group. In the splenic lymphocyte subpopulations (T-
celis and B-celis), the ratio of CD4 to CDS cells was suppressed signif~-
cantly in the highest-dose group (223.5 mg/L). There were also significant
decreases (about 20%) in B-celis. A significant decrease in urine volume
and an increase in blood urea nitrogen (BUN) were observed at the highest
dose. Other nephrotoxic indices, such as excretion of urinary protein, N-
acetyI-beta-D-glucosaminidase, and gamma-glutamy! transpepeptidase,
were unaltered. Biochemical analysis of bronchoalveolar ravage fluid and
lung tissue showed some lung damage.
The 1988 American Biogenics Corporation study reported changes in
heart weight in rats exposed to nickel as NiCI2 at 8.6 mg/kg/d by the oral
route for 91 d. One study indicated that nickel ingestion could be neuro-
toxic. Nation et al. (1985) fed adult male rats food containing nickel as
NiCI2 at 0, 10, or 20 mg/kg/d for a total of 75 d. Fourteen days after the
exposure started the animals were trained over 61 ~ to get their food from
a lever-press operand machine. Rats receiving 20 mg/kg/d lever-pressed at
a significantly lower rate than the 1 0-mg/kg/d group and the control group,
thus showing behavioral effects. A dose of 10 mg/kg/d (as NiCI2) seems to
be a NOAEL, and 20 mg/kg/d a LOAEL, for 75 d.
Chronic Toxicity (>100 d)
Male albino rats (n = 10, body weight = 80 g, strain not specified) re-
ceived drinking water containing nickel as NiCI2 at 225 mg/L for 4 mo
(estimated dose of about 32 mg/kg/~) (CIary 1975~. Significant reductions
inbody weights, serum lipids, serum cholesterol, urinary calcium, end urine
outputs compared with controls were reported in this study. Many of the
biochemical changes were secondary to loss in body weight. Water intake
was not measured, and the authors assumed that decreased urine output
(50°/O decrease) by the end of 4 mo might be due to decreased water intake.
A 50°/O decrease in urine output is a serious adverse effect, and there is no
dose-response data to identify a NOAEL. Because there are other drinking
water studies using nickel that provide dose-response data that can be used
for AC development, this study was not considered for AC derivation.
Dieter et al. (1988) conducted a study to evaluate tissue disposition,
myelopoietic responses, and immunologic responses in female B6C3F,
mice after long-term exposure to nickel as NiSO4 in drinking water at 0, 1,
5, or 10 g/L (0, 44, 108, 150 mg/kg/~) for 180 d. Water consumption, con-
centration of nickel in blood and tissue, body and organ weights, histo-
pathology, immune responses, bone marrow cellularity and proliferation,
OCR for page 237
Nickel
237
for species extrapolation, nickel sensitivity, and time extrapolation from 90
~ to 100 4, respectively, the 100-d AC for potential nephrotoxic effects
(increased albuminuria) was calculated as follows:
(7.6 mg/kg/d x 70 kg) t10 x 2 L/d x 3 x (100/90~] = ~ mg/L.
As usual, the calculation assumes a 70-kg person ingesting 2 L of wafer per
day.
100-d AC for Behavioral Effects
Adult male rats were fed NiCI2 at 0, 10, or 20 mg/kg/d via a 10 g daily
food ration. Following 14 ~ of exposure, animals were trained over a period
of 61 ~ to lever-press for food on a VI-2 operant training schedule while
continuing to ingest the indicated daily doses of nickel (Nation et al. 1985~.
Rats in the 20-mg/kg/d group lever-pressed at a significantly lower rate than
those in the 10-mg/kg/d and control groups, thus indicating behavioral
effects. A LOAEL of 20 mg/kg/d and a NOAEL of 10 mg/kg/d were identi-
fied. As the authors presented the data in a graphic form, numerical data for
BMD calculation were not available. Applying a factor of 10 for species
extrapolation, a factor of 3 for nickel sensitivity, and a factor of 1.333 for
time extrapolation from 75 ~ to 100 4, the 100-d AC for behavioral effect
was calculated as follows:
(10 mg/kg/d x 70 kg) (10 x 2 L/d x 3 x 1.333) = 9 mg/L.
Ingestion for 1,000 d
A 13% increase in focal myocardial fibrosis was observed in a life-term
study of rats ingesting nickel at 5 ppm as NiCI2 in drinking water for 18 mo
(Schroeder et al. 1974~. However, the experiments were done in a
metal-free environment, which may have made the animals more sensitive.
These data could not be used due to the lack of dose- and time-response
data.
Two 2-y drinking water studies were considered for calculating the
1,000-d ACs. They are two-generation and three-generation reproductive
and developmental studies using NiCl2 andNiSO4 in drinking water, respec-
tively. Microscopic examination of ovaries and testes of rats and dogs that
OCR for page 238
238
Spacecraft Water Exposure Guidelines
received NiSO4 and NiCI2 by the oral route for 2 y did not indicate any
abnormality (Ambrose et al.1976; American Biogenics Corporation 1988~.
NASA has not considered using developmental toxicity data for determin-
ing SWEGs.
The only other long-term study, a 2-y feeding study in rats and dogs, is
that of Ambrose et al. (1976~. Rats of both genders (25 per gender per
group) were given NiSO4(hexahydrate) at 0,100,1,000, and2,500 ppm (0,
5, 50, and 125 mg/kg/~. Although significant depression in growth, de-
creases in body weights, and decreases in liver- and heart-to-body weight
ratios were noted at the 1,000-ppm and 2,500-ppm doses, no such effects
were noted at the 100-ppm dose. A parallel study in dogs indicated that at
higher doses hemoglobin and hematocrit values tended to be lower, and the
dogs showed lung and bone marrow lesions. NASA has not used the dog
data, because nickel is not bound to albumin in dogs the way it is in humans
and rodents. The pharmacokinetics, and hence the toxicologic mechanisms,
may be different in dogs.
1,000-d ACs Based on Dieter et al.'s (19XX) lX0-d Study
Dieter et al.'s (1988) 180-d drinking water study was used after apply-
ing a time factor. In that study, female B6C3F~ mice were given NiSO4 at
0, 44, 108, and 150 mg/kg/d in drinking water for 180 d. Significant
changes in the immune system, decreases in water consumption, decreases
in bone marrow cellularity, mild renal tubular damage, and thymic atrophy
were significant toxic effects noted at the two highest doses. A 1,000-d AC
was calculated using a time-extrapolation factor of 5.555 (1,000/180~.
Factors of 10 and 3 were applied for species extrapolation and nickel sensi-
tivity, respectively. A spaceflight factor of 3 was added to the calculations
for hematologic end points. A LOAEL-to-NOAEL factor of 10 was in-
cluded in calculations that used the LOAEL. The calculations assumed a
70-kg person ingesting 2 L of water per day. (See Table 6-15 for ACs.)
The most sensitive parameters seem to be the lymphoproliferative re-
sponse and the granulocyte macrophage colony forming response both
end points give a 1,000-d AC of 0.3 mg/L.
OCR for page 239
239
hi
¢
J O
Cat O O
V
¢
A_
o
Cat
o
V
Al
Cat
¢
to
to
to
8 ~ oo oo ~
o
Do
~ 2=
Z VO
C) ~
~ .
VO
sat
Cot
o ~
.
En
Cat
.O
C)
Vat
Cal
. ~ _
To
:== ~ E E ~ ~ ~
5^~^ ~ got ~ ~ O 4.= ~ 4= bold
~ ¢~ ~ ¢= O ~ ~ ¢.~o ~ ~ ~ ~ ~ ~ ~
of .> ~ ~ ~
z ~ ~ a ~ · ~ ~ ' a 5
OCR for page 240
240
5
A
V
V
¢
Cal
Cal
o
Cat
to
to
to
to
o
to
~ 2=
O
==
Cal
o
.
En
Cal
.O
Via
¢ ¢
O O
Cal
.~
o
. -
· X
Ed
Do ~
. ~
O ~ ~
~ =^ ~t ~ ~ ~ =^
¢ ~ ¢ o O~ ~ ~
O ¢~ O ~ ho ¢=
Cal
Cal ~ ~
C) cx3 cat
at a ~ 5 ~
~ ~ ~ lo.- ~
o
Cal
vO
- ~
c~
.
~ ~ ·^
.~o ~
~ ~ ~o
s~ ~ c)
. c)
o o=>
c) ~ v
·= ~ ~
(~, ~ ·^
~_1-g
~ v ~
~ ¢ ·p
~ o ~
.
o ~ ~
~ s^ ~
o =~
s~ ~
.
~ o
,
o ~
o
c~ ~
c~ ~
o o
c) · s~
~ ~o
o c~
c)
. c~ ~
E~ ~
vl
. ~
~ .
o
·=
c~ .
~ ~o
o ~
o ~
~ o
..
o ~
.~ ~
~ . -
=¢ ~
OCR for page 241
Nickel
TABLE 6-15 1,000-d ACs Calculated for Various End Points Using
Data from the Dieter et al. (1988) Study
241
BMDLo~ NOAEL LOAEL ACs (mg/L)
Parameter (mg/kg) (mg/kg) (mg/kg) BMDLo~ NOAEL
Spleen cellularity 63.8 108 150 4.5 7.5
Lymphoproliferative 7.9 NA 44 0.55 0.3
response to LPS
Bone marrow 9.8 44 108 0.7 3.08
cellularity
Granulocyte 12 NA 44 0.8 0.3
macrophage CFUs
Stem cell proliferation 7.6 44 108 0.5 3
CFUs
Abbreviations: AC, acceptable concentration; BMDLo~, the lower 95°/O confidence
limit on the benchmark dose corresponding to a 1% risk; CFU, colony forming unit;
LPS, lipopolysaccharide.
REFERENCES
Ambrose, A.M., P.S. Larson, J.F. Borzelleca et al.1976. Long-term toxicological
assessment of nickel in rats and dogs. J. Food Sci. Technol. 13:181-187.
American Biogenics Corporation. 1988. Ninety-day gavage study in albino rats
using nickel. Final report to U. S. Environmental Protection Agency. Ameri-
can Biogenics Corporation, Decatur, IL.
ATSDR (Agency for Toxic Substances and Disease Registry).1997. Toxicological
Profile for Nickel (Update). U.S. Department of Health and Human Services,
Agency for Toxic Substances and Disease Registry, Atlanta, GA.
Biggart, N.W., and M. Costa. 1986. Assessment of the uptake and mutagenicity
of nickel chloride in Salmonella tester strains. Mutat. Res. 175:209-215.
Borg, K., H. Tjalve. 1989. Uptake of 63Ni in the central and peripheral nervous
system of mice after oral administration. Effect oftreatment with halogenated
8-hydroxyquinolines. Toxicology 54:59-68.
Burrows, D., S. Creswell, and J.D. Merrett.1981. Nickel, hands, and hip prosthe-
sis. Br. J. Dermatol. 105:437-444.
Burrows D.1992. Is systemic nickel important? J. Am. Acad. Dermatol.26~4~:632-
635.
Casey, C.E., M.F. Robinson.1978. Copper, manganese, zinc, nickel, cadmium and
lead in human fetal tissues. Br. J. Nutr. 39:639-634.
Clary, J.J. 1975. Nickel induced metabolic changes in the rat and the guinea pig.
Toxicol. Appl. Pharmacol. 31 :55-65.
OCR for page 242
242
Spacecraft Water Exposure Guidelines
Christensen, O.B., and H. Moller.1975. Nickel allergy and hand eczema. Contact
Dermatitis 1~3~:129-35.
Christensen, O.B., and H. Molter. 1975. External and internal exposure to the
antigen in the hand eczema of nickel allergy. Contact Dermatitis 1 :136-141.
Christensen, O.B., and V. Langesson. 1981. Nickel concentration of blood and
urine after oral administration. Ann. Clin. Lab. Sci. 11: 119- 125.
Christensen, O.B., C. Lindstrom, H. Lolberg, and H. Mohler.1981. Micromorph-
ology and specificity of orally induced flare-up reactions in nickel-sensitive
patients. Acta Derm. Venereol. 61 :505-510.
Cronin, E., A. Di Michiel, and S.S. Brown. 1980. Oral Nickel challenge in
nickel-sensitive women with hand eczema. Pp.149- 152 in Nickel Toxicology,
S.S. Brown and F.W. Sunderman Jr., eds. New York, NY: Academic Press.
Coogan, T.P., D.M. Latta, E.T. Snow, and M. Costa.1989. Toxicity and carcinoge-
nicity of nickel compounds. CRC Crit. Rev. Toxicol. 19:341-384
Costa, M. 1991. Molecular mechanisms of nickel carcinogenesis. Annul Rev.
Pharmacol. Toxicol. 31: 321 -337.
Dabeka, R.W., and A.D. McKenzie. 1995. Survey of lead, cadmium, fluoride,
nickel, and cobalt in food composites and estimation of dietary intakes ofthese
elements by Canadians in 1986-1988. J. AOAC Int. 78~4~:897-909.
Daldrup, T., K. Haarhoff, S. Szathmary. 1983. Fatal nickel sulfate poisoning [in
German]. Beitr. Gerichtl. Med. 41:141-4.
Dally, H., and A. Hartwig, (1997~. Induction and repair inhibition of oxidative
DNA damage by nickel(II) and cadmium(II) in mammalian cells.
Carcinogenesis 18: 1021 - 1026.
Dieter, M.P., C.W. Jameson, A.N. Tucker, M.I. Luster, J.E. French, H.L. Hong, and
G.A. Boorman. 1988. Evaluation oftissue disposition, myelopoietic and im-
munologic responses in mice after long-term exposure to nickel sulfate in the
drinking water. J. Toxicol. Environ. Health 24:356-372.
Dostal, L.A., S.M. Hopfer, S.M. Lin, and F.W. Sunderman Jr. 1989. Effects of
nickel chloride on lactating rats and their suckling pups, and the transfer of
nickel through rat milk. Toxicol. Appl. Pharmacol. 101~2~:220-31
EPA (U.S. Environmental Protection Agency).1983. Nickel occurrence in drink-
ing water, food and air. Office of Water, U.S. Environmental Protection
Agency, Washington, DC.
EPA (U.S. Environmental Protection Agency).1985. Drinking water criteria docu-
ment for nickel. NTIS PB86-117801. Environmental Criteria and Assessment
Office, U.S. Environmental Protection Agency, Cincinnati, OH.
EPA (U.S. Environmental Protection Agency). 1995. Nickel. Drinking Water
Health Advisory. Office of Water, U.S. Environmental Protection Agency,
Washington, DC.
EPA (U. S. Environmental Protection Agency). 1996. Drinking water regulations
and health advisories. EPA 822-R-96-001. Of fice of Water, U.S. Environmen-
tal Protection Agency, Washington, DC.
Fletcher, G.G., F.E. Rossetto, J.D. Turnbull, and E. Nieboer. 1994. Toxicity, up-
OCR for page 243
Nickel
243
take, and mutagenicity of particulate and soluble nickel compounds. Environ.
Health Perspect. 102(Suppl. 3~:69-79.
Gawkrodger, D.J., S.W. Cook, G.S. Fell et al.1986. Nickel dermatitis: The reaction
to oralnickel challenge. Br. J. Dermatol. 115:33-38.
Glennon, J.D., B. Sarkar.1982. The non-specificity of dog serum albumin and the
N-terminal model peptide glycylglycyl-L-tyrosine N-methylamide for nickel
is due to the lack of histidine in the third position. Biochem. J. 203 :25-31.
Haber, L.T., B.C. Allen, and C.A. Kimmel. 1998. Non-cancer risk assessment for
nickel compounds: Issues associated with dose-response modeling of inhala-
tion and oral exposures. Toxicol. Sci. 43~2~:213-29.
Haber, L.T., G.L. Diamond, Q. Zhao, L. Endreich, and M.L. Dourson.2000. Haz-
ard identification and dose response of ingested nickel-soluble salts. Regul.
Toxicol. Pharmacol. 31:231-241.
Haro, R.T., A. Furst, H.L. Falk.1968. Studies on the acute toxicity of nickelocene.
Proc. West. Pharmacol. Soc. 11 :39-42.
Hindsen, M., O.B. Christensen, H. Moller. 1994. Nickel levels in serum and urine
in five different groups of eczema patients following oral ingestion of nickel.
Acta Derm. Venereol. 74: 176- 178.
Hendel, R.C., and F.W. Sunderman Jr.1972. Species variations in the proportions
of ultrafiltrable end protein-bound serum nickel. Res. Commun. Chem. Pathol.
Pharmacol. 4:141-146.
Ho, W., A. Furst. 1973. Nickel excretion of rats following a single treatment.
Proc. West. Pharmacol. Soc. 16:245-248.
Hopfer, S.M., and F.W. Sunderman Jr.1988. Hypothermia and deranged circadian
rhythm of core body temperature in nickel chloride-treated rats. Res.
Commun. Chem. Pathol. Pharmacol. 62:495-505.
Horak, E., and F.W. Sunderman Jr.1973. Fecal nickel excretion by healthy adults.
Clin. Chem. 19:429-430.
IARC (International Agency for Research on Cancer).1990. Pp.318-411 in IARC
Monographs on the Evaluation of Carcinogenic Risks to Humans, Vol. 49.
Lyons, France: IARC.
IOM (Institute of Medicine). 2001. Dietary Reference Intakes for Vitamin A,
Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese,
Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington, DC: Na-
tional Academy Press.
IRIS (Integrated Risk Information System).1996. Nickel, soluble salts. Integrated
Risk Information System, U.S. Environmental Protection Agency, Washington,
DC [Online]. Available: http://www.epa.gov/iris/subst/0271.htm.
Ishimatsu, S., T. Kawamoto, K. Matsuno,and Y. Kodama. 1995. Distribution of
various nickel compounds in rat organs after oral administration. Biol. Trace
Elem. Res. 49~1~:43-52.
Jackson, A.L., R. Chen, and L.A. Loeb.1998. Induction of microsatellite instabil-
ityby oxidative DNA damage. Proc. Natl. Acad. Sci. USA 95: 12468-12473.
Jasim, S., and H. Tjalve.1986. Effect of sodium pyridimethione on the uptake and
OCR for page 244
244
Spacecraft Water Exposure Guidelines
distribution of nickel, cadmium and zinc in pregnant and non-pregnant mice.
Toxicology 38: 327-350
Jordan Jr., W.P.,and S.E. King. 1979. Nickel feeding in nickel-sensitive patients
with hand eczema. J. Am. Acad. Dermatol. 1 :506-508.
Kakela, R., A. Kakela, and H. Hyvarinen. 1999. Effects of nickel chloride on
reproduction of the rat and possible antagonistic role of selenium. Comp
Biochem Physiol. Pharmacol. Toxicol. Endocrinol. 123:27-37.
Kodell, R.L., and R.W. West. 1993. Upper confidence limits on excess risk for
quantitative responses. Risk Anal. 13~2~: 177-82.
Lee, Y.W., C. Pons, D.M. Tummolo, C.B. Klein, T.G. Rossman, andN.T. Christie.
1993. Mutagenicity of soluble and insoluble nickel compounds at the apt locus
in G12 Chinese hamster cells. Environ. Mol. Mutagen. 21 :365-371.
Lynn, S., F.H. Yew, K.S. Chen, and K.Y. Jan. 1997. Reactive oxygen species are
involved in nickel inhibition of DNA repair. Environ. Mol. Mutagen. 29:
208-216.
La Bella, F.S., R. Dullar, P. Lemon et al. 1973. Prolactin secretion is specifically
inhibited by nicker. Nature245:330-332.
Mastromatteo, E. 1986. Yant memorial lecture. Nickel. Am. Ind. Hyg. Assoc. J.
47:589-601.
Menne, T.1994. Quantitative aspects of nickel dermatitis: Sensitization and elicit-
ing threshold concentrations. Sci. Total Environ. 148:275-281.
Mantovani, A. 1993. Reproductive risks from contaminants in drinking water.
Ann. Ist. Super. Sanita 29~2~:317-26.
Muhle, H., B. Bellmann, S. Takenaka, R. Fuhst, U. Mohr, and F. Pott. 1992.
Chronic effects of intratracheally instilled nickel-containing particles in ham-
sters. In Nickel and Human Health, Current Perspectives. E. Nieboer and J.O.
Nriagu, eds. New York, NY: John Wiley and Sons Inc.
Nation, J.R., M.F. Hare, D.M. Baker, D.E. Clark, and A.E. Bourgeois. 1985. Di-
etary administration of nickel: Effects on behavior and metallothionein levels.
Physiol. Behav. 34:349-53.
Nielsen, F.H., T.R. Shuler, T.J. Zimmerman, M.E. Collings, andE.O. Uthus. 1979.
Interaction between nickel and iron in the rat. Biol. Trace Elem. Res. 1 :325-
335.
Nielsen, F.H., T.R. Shuler, T.G. McLeod et al. l 984. Nickel influences iron metab-
olism through physiologic, pharmacologic and toxicologic mechanisms in the
rat. J. Nutr. 114: 1280-1288.
Nielsen, G.D., L.V. Jepson, and P.J. Jorgensen. 1990. Nickel-sensitive patients
with vesicular hand eczema: Oral challenge with a diet high in nickel. Br. J.
Dermatol. 122:299-308.
Nielsen, G.D., U. Sodserberg, P.J. Jorgensen, D.M. Templeton, S.N. Rasmussen,
K.E. Andersen, and P. Granjean. 1999. Absorption and retention of nickel
from drinking water in relation to food intake and nickel sensitivity. Toxicol.
Appl. Pharmacol. 154:67-75.
Nicogossian, A.E., C.F. Sawin, C.L. Huntoon.1994. Overall physiologic response
OCR for page 245
Nickel
245
to space flight. In Space Physiology and Medicine, 3rd Ed., A.E. Nicogossian,
C.L. Huntoon, and S.L.Pool, eds. Philadelphia, PA: Lea and Febiger.
Nomoto, S., M.I. Decsy, J.R. Murphy, and F.W. Sunderman Jr. 1973. Isolation of
63Ni-labeled nickeloplasmin from rabbit serum. Biochem. Med. 8: 171 -81.
NRC (National Research Council).1977. Drinking Water and Health. Washington
DC: National Academy Press. Pp 285-289
NRC (National Research Council). 2000. Methods for Developing Spacecraft
Water Exposure Guidelines. Washington, DC: National Academy Press.
NTP (National Toxicology Program).1996. NTP technical report on the toxicology
and carcinogeneis studies of nickel sulfate (CAS No. 10101-97-0) in F344/N
rats and B6C3F1 mice (inhalation studies). NTP-TRS number 454. National
Toxicology Program, Research Triangle Park, NC.
Obone, E., S.K. Chakrabarti, C. Bai, M.A. Malick, L. Lamontagne, and K. S.
Subramanian. 1999. Toxicity and bioaccumulation of nickel sulfate in
Sprague-Dawley rats following 13 weeks of subchronic exposure. J. Toxicol.
Environ. Health 57(Part A):379-401.
Onkelinx, C., J. Becker, F.W. Sunderman Jr.1973. Compartmental analysis of the
metabolism of 63Ni(II) in rats and rabbits. Res. Commun. Chem. Pathol.
Pharmacol. 6:663-76.
Oosting, J.S., A.G. Lemmens, G.J. Van den Berg, and A.C. Beynen. 1991. Iron,
copper, and zinc status in rats fed supplemental nickel. Biol. Trace Elem. Res.
31 :63-70.
Pennington, J.A., and J.W. Jones. 1987. Molybdenum, nickel, cobalt, vanadium,
and strontium in total diets. J. Am. Diet. Assoc. 8 7( 1 2~: 1 644- 1 650.
Phatak, S.S., and V.N. Patwardhan. 1950. Toxicity of nickel. J. Sci. Ind. Res.
9B(3~:70-76.
Poirier, L.A., J.C. Theiss, L.J. Arnold, and M.B. Shimkin. 1984. Inhibition by
magnesium and calcium acetates of lead subacetate- and nickel acetate-induced
lung tumors in strain A mice. Cancer Res. 44~4~:1520-1522.
Pool-Zobel, B.L., N. Lotzmann, M. Knoll, F. Kuchenmeister, R. Lambertz, U.
Leucht, H-G. Schroeder, and P. Schmezer. 1994. Detection of genotoxic ef-
fects in human gastric and nasal mucosa cells isolated from biopsy samples.
Environ. Mol. Mutagen. 24:23-45.
Pott, F., R.M. Rippe, M. Roller, M. Csicsaky, M. Rosenbruch, and F. Huth. 1992.
Carcinogenicity studies on nickel compounds and nickel alloys after
intraperitoneal injection in rats. In Nickel and Human Health, Current Perspec-
tives. E. Nieboer and A. Altio, eds. New York, NY: John Wiley and Sons.
Reid, T.M., D.I. Feig and L.A. Loeb.1994. Mutagenesis by metal-induced oxygen
radicals. Environ. Health Perspect. 102(Suppl. 3~:57-61.
Robinson, S.H., and M. Costa. 1982. The induction of DNA strand breakage by
nickel compounds in cultured Chinese hamster ovary cells. Cancer Lett.
15:35-40.
RTI (Research Triangle Institute). 1986. Two-generation reproduction and fertility
study of nickel chloride administered to CD rats in the drinking water. Interim
report. Ninety-day toxicity study of nickel chloride administered to CD rats in
OCR for page 246
246
Spacecraft Water Exposure Guidelines
the drinking water. Report to Office of Solid Waste, U.S. Environmental Pro-
tection Agency, Washington, DC, by Research Triangle Institute, Research
Triangle Park, NC.
RTI (Research Triangle Institute).1988a. Two-generation reproduction and fertility
study of nickel chloride administered to CD rats in the drinking water: Fertility
and reproductive performance of the Fo generation. Final study report (II of
III). Report to Office of Solid Waste, U.S. Environmental Protection Agency,
Washington, DC, by Research Triangle Institute, Research Triangle Park, NC.
RTI (Research Triangle Institute).1988b. Two-generation reproduction and fertility
study of nickel chloride administered to CD rats in the drinking water: Fertility
and reproductive performance of the Fit generation. Final study report (III of
III). Report to Office of Solid Waste, U.S. Environmental Protection Agency,
by Research Triangle Institute, Research Triangle Park, NC.
Sarkar, B.1984. Nickel metabolism. Pp.367-384 in IARC Publication # 53. Lyon,
France: International Agency for Research on Cancer (IARC).
Santucci, B., F. Manna, A. Cristaudo, C. Cannistraci, andM. Picardo.1988. Nickel
sensitivity: Effects of prolonged oral intake ofthe element. Contact Dermatitis
19:202-205.
Santucci, B., F. Manna, C. Cannistraci, A. Cristaudo, R. Capparella, A. Bolasco,
and M. Picardo. 1994. Serum and urine concentrations in nickel-sensitive
patients after prolonged oraladministration. Contact Dermatitis 30~2~:97-101.
Schafer, S.G., and W. Forth.1983. The influence oftin, nickel, and cadmium on the
intestinal absorption of iron. Ecotoxicol. Environ. Saf. 7:87-95.
Schroeder, H.A., J.J. Balassa, W.H. Vintin Jr. 1964. Chromium, lead, cadmium,
nickel, and titanium in mice. Effect on mortality, tumors, and tissue levels. J.
Nutr. 83:239-250.
Schroeder, H.A., M. Mitchner, and A.P. Nasaon.1974. Life-term effects of nickel
in rats: Survival, tumors, interactions with trace elements and tissue levels. J.
Nutr. 104:239-243.
Seidenberg, J.M., D.G. Anderson, and Becker. 1986. Validation of an in vivo de-
velopmental toxicity screen in the mouse. Teratog. Carcinog. Mutagen. 6:
361-74.
Shirakawa, T., Y. Kusaka, N. Fujimura, M. Kato, S. Heki, and K. Morimoto.1990.
Hard metal asthma: Cross immunological and respiratory reactivity between
cobalt and nickel? Thorax 45~4~:267-71.
Smith, M.K., J.A. George, J.A. Stober, and H.A. Feng. 1993. Perinatal toxicity
associated with nickel chloride exposure. Environ. Res. 61 :200-211.
Sobti, R.C., end R.K. Gill.1989. Incidence of micronuclei and abnormalities in the
head of spermatozoa caused by the salts of a heavy metal nickel. Cytologia
(Tokyo) 54:249-254.
Solomons, N.W., F. Viteri, T.R. Shuler, and F.H. Nielsen.1982. Bioavailability of
nickel in man: Effects of foods and chemically defined dietary constituents on
the absorption of inorganic nickel. J. Nutr. 112~1~:39-50.
Storeng, R., and J. Jonsen. 1981. Nickel toxicity in early embryognesis in mice.
Toxicology 20:45-51.
OCR for page 247
Nickel
247
Sumino, K., K. Hayakawa, T. Shibata et al. 1975. Heavy metals in normal Japa-
nese tissues. Amounts of 15 heavy metals in 30 subjects. Arch. Environ.
Health 30:487-494.
Sunderman Jr., F.W. 1984. Nickel in the Human Environment. IARC Scientific
Publications #53. Lyon, France: International Agency for Research on Cancer
(IARC).
Sunderman Jr., F.W. 1986. Sources of exposure and biological effects of nickel.
Vol. 8. Some metals: As, Be, Cd,Cr, Ni, Pb, Se,Zn. In IARC Scientific
Publications #71. Lyon, France: International Agency for Research on Cancer
(IARC).
Sunderman Jr, F.W., B. Dingle, S.M. Hopfer, and T. Smith. 1988. Acute nickel
toxicity in electroplating workers who accidentally ingested a solution of
nickel sulfate and nickel chloride. Am. J. Ind. Med. 14:257-266.
Sunderman Jr., F.W., S.M. Hopfer, K.R. Sweeney, A.H. Marcus, B.M. Most, and
J. Creason. 1989. Nickel absorption and kinetics in human volunteers. Proc.
Soc. Exp. Biol. Med. 191:5-11.
Synder, R.D. 1994. Effects of metal treatment on DNA repair in polyamine-de-
pleted HeLa cells with special reference to nickel. Environ. Health Perspect.
162(Suppl. 3~:51-55.
Tallkvist, J., A.M. Wing, and H. Tjalve. 1994. Enhanced intestinal nickel absorp-
tion in iron-deficient rats. Pharmacol. Toxicol. 75:244-249.
Tallkvist, J., and H. Tjalve.1997. Effect of dietary iron-deficiency on the disposi-
tion of nickel in rats. Toxicol Lett. 92: 131-138.
Tallkvist, J., and H. Tjalve.1998. Transport of nickel across monolayers of human
intestinal Caco-2 cells. Toxicol. Appl. Pharmacol. 151:117-122.
Veien, N.K., T. Hattel, O. Justesen, and A. Norholm. 1987. Oral challenge with
nickel and cobalt in patients with positive patch tests to nickel and/or cobalt.
Acta Derm. Venereol. 67:321-325.
Verma, A., S. Ohshima, J. Ramnath, K.N. Thakore, and J.R. Landolph. 1999. Pre-
dictions and correlations of carcinogenic potentials of nickel compounds by
short-term in vitro assays using C3H IOT1/2 mouse embryo cells. Environ-
mental Mutagen Society 30th annual meeting. Washington, DC. March
27-April 1, 1999. Environ. Mol. Mutagen. 33(Suppl. 30~:66.
Vyskocil, A., C. Viau, and M. Cizkova. 1994. Chronic nephrotoxicity of soluble
nickel in rats. Hum. Exp. Toxicol. 13 :257-261.
Waltschewa, W., M. Slatewa, and I. Michailow. 1972. Testicular changes due to
long-term administration of nickel sulfate in rats [in German]. Exp. Pathol.
(Jena) 6:116-120.
Weischer, C.H., W. Kodel, and D. Hochrainer.1980. Effects of NiC12 end NiO in
Wistar rats after oral uptake and inhalation exposure respectively. Zentrabl.
Bakteriol. Mikrobiol. Hyg. [B] 171 :336-351.
Weber, C.W., and B.L. Reid. 1969. Nickel toxicity in young growing mice. J.
Anim. Sci. 28:620-623.
Whanger, P.D. 1973. Effects of dietary nickel on enzyme activities and mineral
content in rats. Toxicol. Appl. Pharmacol. 25:323-331.
Representative terms from entire chapter:
water exposure
