NTP Study Reports
Abstract for TR-451 - Nickel Oxide
TR-451
Toxicology and Carcinogenesis Studies of
Nickel Oxide (CAS No. 1313-99-1) in F344 Rats and
B6C3F1 Mice (Inhalation Studies)
Chemical Formula: NiO
Nickel oxide (NiO) "sinters" are used in stainless steel and alloy steel production. Nickel oxide was nominated by the National Cancer Institute to the NTP for testing because exposure to this form of nickel is prevalent in the nickel industry. Increased incidences of lung and nasal sinus cancers have occurred among workers in certain nickel refining facilities, and nickel oxide was studied as part of a class study of nickel compounds. Male and female F344/N rats and B6C3F1 mice were exposed to nickel oxide (high temperature, green nickel oxide; mass median diameter 2.2 ± 2.6 mm; at least 99% pure) by inhalation for 16 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in peripheral blood of B6C3F1 mice exposed to nickel oxide for 13 weeks.
16-DAY STUDY IN RATS
Groups of five male and five female
F344/N rats were exposed to 0, 1.2, 2.5, 5, 10, or 30 mg nickel
oxide/m3(equivalent to 0, 0.9, 2.0, 3.9, 7.9, or 23.6
mg nickel/m3) by inhalation for 6 hours per day, 5
days per week for a total of 12 exposure days during a 16-day
period. Additional groups of five male and five female rats were
exposed to 0, 1.2, 5, or 10 mg/m3 for tissue burden
studies. All core study rats survived until the end of the study,
final mean body weights of exposed male and female rats were similar
to those of the controls, and there were no clinical findings
related to nickel oxide exposure. Absolute and relative lung weights
of male and female rats exposed to 10 or 30 mg/m3 were
significantly greater than those of the controls. Pigment particles
in alveolar macrophages or within the alveolar spaces were observed
in the lungs of exposed groups of males and females. Chronic-active
inflammation and accumulation of macrophages in alveolar spaces
of the lungs and hyperplasia in the respiratory tract lymph nodes
were most severe in 10 and 30 mg/m3 males and females.
Hyperplasia of bronchial lymph nodes occurred in 30 mg/m3
rats. Atrophy of the olfactory epithelium was observed in one
male and one female exposed to 30 mg/m3. The concentrations
of nickel oxide in the lungs of exposed groups of rats were greater
than those in the lungs of control groups (males, 42 to 267 mg
nickel/g lung; females, 54 to 340 mg/g lung).
16-DAY STUDY IN MICE
Groups of five male and five female
B6C3F1 mice were exposed to 0, 1.2, 2.5, 5, 10, or 30 mg nickel
oxide/m3 by inhalation for 6 hours per day, 5 days
per week for a total of 12 exposure days during a 16-day period.
Additional groups of five male and five female mice were exposed
to 0, 1.2, 2.5, or 5 mg/m3 for tissue burden studies.
No exposure-related deaths occurred among core study mice, and
final mean body weights of exposed male and female mice were similar
to those of the controls. There were no chemical-related clinical
findings. Pigment particles were present in the lungs of mice
exposed to 2.5 mg/m3 or greater. Accumulation of macrophages
in alveolar spaces was observed in the lungs of 10 and 30 mg/m3males and females. The concentrations of nickel oxide in
the lungs of exposed groups of mice were significantly greater
than those in the lungs of control animals (males, 32 to 84 mg
nickel/g lung; females, 31 to 71 mg/g lung).
13-WEEK STUDY IN RATS
Groups of 10 male and 10 female
F344/N rats were exposed to 0, 0.6, 1.2, 2.5, 5, or 10 mg nickel
oxide/m3 (equivalent to 0, 0.4, 0.9, 2.0, 3.9, or 7.9
mg nickel/m3) by inhalation for 6 hours per day, 5
days per week for 13 weeks. Additional groups of 18 male and 18
female rats were exposed to 0, 0.6, 2.5, or 10 mg/m3
for tissue burden studies. No exposure-related deaths occurred
among core study rats, final mean body weights of exposed male
and female rats were similar to those of the controls, and no
clinical findings in any group were related to nickel oxide exposure.
Lymphocyte, neutrophil, monocyte, and erythrocyte counts; hematocrit
values; and hemoglobin and mean cell hemoglobin concentrations
in exposed rats were minimally to mildly greater than those of
the controls; these differences were most pronounced in females.
Mean cell volumes in exposed rats were generally less than those
in the controls. Absolute and relative lung weights of exposed
groups of males and females were generally significantly greater
than those of controls.
Chemical-related nonneoplastic
lesions were observed in the lungs of male and female rats exposed
to concentrations of 2.5 mg/m3 or higher, and the severity
of these lesions generally increased with exposure concentration.
Accumulation of alveolar macrophages, many of which contained
black, granular pigment, was generally observed in all exposed
groups of males and females, and increased incidences of inflammation
occurred in males and females exposed to 2.5 mg/m3
or higher. In addition, lymphoid hyperplasia and pigment occurred
in the bronchial and mediastinal lymph nodes of 2.5, 5, and 10
mg/m3 males and females.
The concentration of nickel oxide
in the lungs of 0.6, 2.5, and 10 mg/m3males was greater
than in the lungs of controls at 4, 9, and 13 weeks, and nickel
continued to accumulate in the lung at the end of the 13-week
exposures (4 weeks, 33 to 263 mg nickel/g lung; 9 weeks, 53 to
400 mg/g lung; 13 weeks, 80 to 524 mg/g lung).
13-WEEK STUDY IN MICE
Groups of 10 male and 10 female
B6C3F1 mice were exposed to 0, 0.6, 1.2, 2.5, 5, or 10 mg nickel
oxide/m3 by inhalation for 6 hours per day, 5 days
per week for 13 weeks. Additional groups of six male and six female
mice were exposed to 0, 0.6, 2.5, or 10 mg/m3 for tissue
burden studies. No exposure-related deaths occurred among core
study animals, final mean body weights of exposed male and female
mice were similar to those of the controls, and no clinical findings
in any group were related to nickel oxide exposure. Hematocrit
values and erythrocyte counts in 5 and 10 mg/m3 females
were minimally greater than those of the controls, as was the
hemoglobin concentration in 5 mg/m3 females. Absolute
and relative lung weights of 10 mg/m3 males and females
were significantly greater than those of controls, and absolute
and relative liver weights of 10 mg/m3 males were significantly
less than those of controls.
Accumulation of alveolar macrophages,
many of which contained pigment particles, occurred in all groups
of mice exposed to nickel oxide. Inflammation (chronic active
perivascular infiltrates or granulomatous) occurred in 2.5, 5,
and 10 mg/m3 males and females. In addition, lymphoid
hyperplasia and pigment occurred in the bronchial lymph nodes
of males and females exposed to 2.5 mg/m3 or higher.
The concentration of nickel in
the lung was greater than that of controls in 0.6, 2.5, and 10
mg/m3 males at 13 weeks (42 to 736 mg nickel/g lung).
2-YEAR STUDY IN RATS
Survival, Body Weights,
Clinical Findings, and Hematology
Groups of 65 male and 65 female
F344/N rats were exposed to 0, 0.62, 1.25, or 2.5 mg nickel oxide/m3
(equivalent to 0, 0.5, 1.0, or 2.0 mg nickel/m3)
by inhalation for 6 hours per day, 5 days per week for 104 weeks.
Survival of exposed male and female rats was similar to that of
the controls. Mean body weights of 1.25 mg/m3 females
and 2.5 mg/m3 males and females were slightly lower
than those of the controls during the second year of the study.
No chemical-related clinical findings were observed in male or
female rats during the 2-year study. No chemical-related differences
in hematology parameters were observed in male or female rats
at the 15-month interim evaluation.
Pathology Findings
Absolute and relative lung weights
of 1.25 and 2.5 mg/m3 males and females were significantly
greater than those of the controls at 7 and 15 months. At 2 years,
there were exposure-related increased incidences of alveolar/bronchiolar
adenomas alveolar/bronchiolar adenoma or carcinoma (combined)
in males and females. Incidences of atypical alveolar epithelial
hyperplasia in the lungs generally increased with increasing exposure
concentration in male and female rats. Chronic inflammation of
the lung was observed in most exposed rats at 7 and 15 months
and at 2 years; the incidences in exposed males and females at
2 years were significantly greater than those in the controls,
and the severity of the inflammation increased in exposed groups.
The incidences of pigmentation in the alveolus of exposed groups
of males and females were significantly greater than those of
the controls at 7 and 15 months and at 2 years.
Pigmentation in the bronchial
lymph nodes similar to that in the lungs was observed in all exposure
groups with the exception of 0.62 mg/m3males and females
at 7 months. Lymphoid hyperplasia was observed in the bronchial
lymph nodes of 1.25 and 2.5 mg/m3 males and females
at 7 and 15 months, and the incidence at 2 years generally increased
with exposure concentration.
At 2 years, there was an exposure-related
increase in the incidence of benign pheochromocytoma in males
and females. The incidences of benign pheochromocytoma and adrenal
medulla hyperplasia in 2.5 mg/m3 females and the incidence
of benign or malignant pheochromocytoma (combined) in 2.5 mg/m3
males were significantly greater than those in the controls.
Tissue Burden Analyses
Nickel concentrations in the lungs
of exposed rats were greater than those in the controls at 7 and
15 months (7 months, 173 to 713 mg nickel/g lung; 15 months, 262
to 1,116 mg/g lung), and nickel concentrations increased with increasing
exposure concentration and with time.
2-YEAR STUDY IN MICE
Survival, Body Weights,
Clinical Findings, and Hematology
Groups of 74 to 79 B6C3F1 mice
were exposed to 0, 1.25, 2.5, or 5 mg nickel oxide/m3
by inhalation for 6 hours per day, 5 days per week for 104 weeks.
Survival of exposed male and female mice was similar to that of
the controls. Mean body weights of 5 mg/m3 females
were slightly lower than those of the controls during the second
year of the study. No chemical-related clinical findings were
observed in male or female mice during the 2-year study. No chemical-related
differences in hematology parameters were observed in male or
female mice at the 15-month interim evaluation.
Pathology Findings
At 2 years, the incidence of alveolar/bronchiolar
adenoma in 2.5 mg/m3 females was significantly greater
than that of the controls, as was the incidence of alveolar/bronchiolar
adenoma or carcinoma (combined) in 1.25 mg/m3 females.
Generally, incidences of chronic inflammation increased with exposure
concentration in males and females at 7 and 15 months. Bronchialization
of minimal severity in exposed animals and proteinosis were first
observed at 15 months. At 2 years, the incidences of chronic inflammation,
alveolar epithelial hyperplasia, and proteinosis in exposed groups
of males and females were significantly greater than those of
the controls. The severity of chronic inflammation increased with
exposure concentration in females, and proteinosis was most severe
in 5 mg/m3 males and females. Pigment occurred in the
lungs of nearly all exposed mice at 7 and 15 months and at 2 years,
and the severity increased with exposure concentration.
Lymphoid hyperplasia occurred
in two animals after 7 months; at 15 months, lymphoid hyperplasia
occurred in males exposed to 2.5 and 5 mg/m3 and in
all exposed groups of females. At 2 years, lymphoid hyperplasia
occurred in some control animals, but this lesion was still observed
more often in exposed males and females and the incidence increased
with exposure concentration. Pigmentation was observed in the
bronchial lymph nodes of exposed males and females at 7 and 15
months and in nearly all exposed animals at 2 years.
Tissue Burden Analyses
Nickel concentrations in the lungs
of exposed mice were significantly greater than those in the controls
at 7 and 15 months (7 months, 162 to 1,034 mg nickel/g lung; 15
months, 331 to 2,258 mg/g lung), and nickel concentrations increased
with increasing exposure concentration and with time.
GENETIC TOXICOLOGY
No increase in the frequency of
micronucleated normochromatic erythrocytes was observed in peripheral
blood samples from male or female mice exposed to nickel oxide.
CONCLUSIONS
Under the conditions of these
2-year inhalation studies, there was some evidence of carcinogenic
activity of nickel oxide in male F344/N rats based on increased
incidences of alveolar/bronchiolar adenoma or carcinoma (combined)
and increased incidences of benign or malignant pheochromocytoma
(combined) of the adrenal medulla. There was some evidence
of carcinogenic activity of nickel oxide in female F344/N
rats based on increased incidences of alveolar/bronchiolar adenoma
or carcinoma (combined) and increased incidences of benign pheochromocytoma
of the adrenal medulla. There was no evidence of carcinogenic
activity of nickel oxide in male B6C3F1 mice exposed to 1.25,
2.5, or 5 mg/m3. There was equivocal evidence of
carcinogenic activity of nickel oxide in female B6C3F1 mice
based on marginally increased incidences of alveolar/bronchiolar
adenoma in 2.5 mg/m3 females and of alveolar/bronchiolar
adenoma or carcinoma (combined) in 1.25 mg/m3 females.
Exposure of rats to nickel oxide
by inhalation for 2 years resulted in inflammation and pigmentation
in the lung, lymphoid hyperplasia and pigmentation in the bronchial
lymph nodes, and hyperplasia of the adrenal medulla (females).
Exposure of mice to nickel oxide by inhalation for 2 years resulted
in bronchialization, proteinosis, inflammation, and pigmentation
in the lung and lymphoid hyperplasia and pigmentation in the bronchial
lymph nodes.
Synonyms: Bunsenite; C.I. 77777;
green nickel oxide; mononickel oxide; nickel monoxide; nickel
oxide sinter 75; nickel protoxide; nickel (II) oxide; nickel (T+)
oxide; nickelous oxide
Report Date: July 1996
Pathology Tables, Survival and Growth Curves from NTP 2-year Studies
Target Organs & Incidences from 2-year Studies
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