Barium and barium compounds
13
8. EFFECTS ON LABORATORY
MAMMALS AND IN VITRO TEST SYSTEMS
8.1
Single exposure
Acute oral LD
50
values in rats for barium chloride,
barium carbonate, and barium sulfide range from 118 to
800 mg/kg body weight (IPCS, 1990; ATSDR, 1992).
Acute effects include fluid accumulation in the trachea,
intestinal inflammation, decreased liver/brain weight
ratio, darkened liver, increased kidney/body weight ratio,
and decreased body weight (Borzelleca et al., 1988). No
data were available regarding the lethality of barium
sulfate in laboratory animals.
In rabbits administered single intratracheal doses
of
147
Ba (85% barium sulfate) in the range of 0.015–
0.6 ml/kg body weight, soft X-rays of the lungs revealed
dose-related shadows, and transient bronchopneumonia,
bronchitis, or bronchiolitis was observed (Uchiyama et
al., 1995).
Barium sulfate instilled in the trachea or bronchus
of laboratory animals was present in the lungs for up to
126 days after administration and induced local increases
in the number of polymorphonuclear leukocytes 1 day
post-instillation, followed by an increase in macro-
phages. Small foci of atelectasis or emphysema were
seen post-instillation, whereas hyperplasia and/or
granulomas in bronchial tissue (without evidence of
pulmonary fibrosis) appeared between days 7 and 42
post-instillation (Huston & Cunningham, 1952; Willson
et al., 1959; Nelson et al., 1964; Stirling & Patrick, 1980;
Ginai et al., 1984; Slocombe et al., 1989). None of the
investigators reported systemic effects.
Intravenous infusion of barium chloride into
anaesthetized dogs (0.5–2 µmol/kg body weight per
minute) or guinea-pigs (1.7 mg/kg body weight per
minute) resulted in increased blood pressure and cardiac
arrhythmias (Roza & Berman, 1971; Hicks et al., 1986).
The study in dogs also reported skeletal muscle
flaccidity and paralysis (Roza & Berman, 1971).
Determination of plasma potassium concentrations in the
dogs revealed severe hypopotassaemia, which was
attributed to an extracellular-to-intracellular shift of
potassium. Simultaneous infusion of potassium into the
dogs abolished the cardiac effects and the skeletal
muscle flaccidity but did not affect hypertension. The
hypertension did not appear to be mediated through the
renin–angiotensin system, because it was not prevented
by bilateral nephrectomy of the dogs. Dose-dependent
cardiac arrhythmias were also noted in conscious rabbits
following infusion of barium chloride (Mattila et al.,
1986).
8.2
Irritation and sensitization
Barium hydroxide is strongly alkaline and therefore
corrosive. Topical and ocular applications (24-h
exposure) of barium nitrate and barium oxide in rabbits
caused mild skin irritation and severe eye irritation
(RTECS, 1985). No data are available on skin or eye
irritation caused by barium sulfate. However, the
physicochemical properties of barium sulfate and the
lack of reports of skin or eye irritation in humans despite
its widespread use, particularly for X-ray purposes,
suggest that barium sulfate is not irritating or corrosive
to either skin or eyes.
Useful information on the sensitization potential of
barium compounds was not identified.
8.3
Short-term exposure
Increased blood pressure was reported in rats
exposed to barium chloride in drinking-water for 1 month
at an estimated daily dose of 7.1 mg barium/kg body
weight (Perry et al., 1983, 1985, 1989). No chemically
related adverse effects were seen in rats exposed to up to
2000 mg barium chloride dihydrate/litre in drinking-water
(average daily doses of up to 110 mg barium/kg body
weight) for 15 days. In mice similarly exposed to up to
692 mg/litre (average daily doses of up to 70 and 85 mg
barium/kg body weight in males and females,
respectively), the only significant adverse effect was an
increased relative liver weight in high-dose males (NTP,
1994).
Muller (1973) exposed rats to barium sulfate dust at
an exposure level of 40 mg/m
3
(particle size 1–2 µm), 5
h/day, 5 days/week, for up to 8 weeks. Following a single
exposure period, thickening of the alveolar septa, loss of
ciliated epithelial cells, and formation of multicellular
epithelium were noted. At 14 days of treatment, rats
exhibited normal alveolar septa. However, the
investigator reported unspecified changes in bronchiolar
epithelium that were still present following a 28-day
recovery period.
8.4
Medium-term exposure
NTP (1994) treated groups of rats (10 per sex per
group) with barium chloride dihydrate in drinking-water
at concentrations of 0, 125, 500, 1000, 2000, or
4000 mg/litre for 13 weeks (average daily doses of 0, 10,
30–35, 65, 110–115, or 180–200 mg barium/kg body
weight). Effects observed in the 4000 mg/litre rats
Concise International Chemical Assessment Document 33
14
included reduced water consumption, significantly
reduced final mean body weights, and death of three
males and one female during the last week of the study.
It may be noted that the 4000 mg/litre (180–200 mg
barium/kg body weight) dose is comparable to the LD
50
of 180 mg barium/kg body weight in rats. There were no
clearly chemical-related clinical findings of toxicity or
cardiovascular (heart rate, systolic blood pressure,
electrocardiogram) effects. Toxicologically significant (P
#
0.01) organ weight changes consisted of increased
absolute and relative kidney weights in 2000 and
4000 mg/litre female rats, increased relative kidney
weights in 4000 mg/litre male rats, and decreased
absolute and/or relative liver weights in 4000 mg/litre rats
of both sexes. Organ weight changes in the kidney were
considered to be associated with chemical-induced renal
lesions consisting of minimal to mild, focal to multifocal
areas of dilatation of the proximal convoluted tubules
seen in three rats of each sex at the 4000 mg/litre
exposure level. Crystals were not present in the kidney
tubules. Decreased liver weights and lymphoid
depletions in spleen, thymus, and/or lymph nodes of
4000 mg/litre rats were attributed to reduced body weight
and stress. There were no biologically significant
changes in serum electrolytes or haematology values
that were considered to be chemical related. Significant
decreases in the magnitude of undifferentiated motor
activity were observed at day 90 in 4000 mg/litre rats of
both sexes. Marginal decreases in undifferentiated motor
activity were seen in all other barium-exposed groups
except the 1000 mg/litre female rats. No significant or
dose-related changes were observed in other neuro-
behavioural end-points. Although NTP (1994) con-
sidered the no-observed-adverse-effect level (NOAEL)
to be 115 mg/kg body weight per day (the 2000 mg/litre
exposure level), US EPA (1998) suggested that this level
might be considered a lowest-observed-adverse-effect
level (LOAEL), based on significant (P
#
0.01) increased
kidney weight in female rats and an observed LD
50
of 118
mg/kg body weight in rats (RTECS, 1985). The NOAEL
would then be 65 mg/kg body weight per day (the 1000
mg/litre exposure level).
NTP (1994) also treated groups of mice (10 per sex
per group) with barium chloride dihydrate in drinking-
water at concentrations of 0, 125, 500, 1000, 2000, or 4000
mg/litre for 13 weeks (average daily doses of 0, 15, 55–60,
100–110, 200–205, or 450–495 mg barium/kg body
weight). Adverse effects in the 4000 mg/litre groups
included death of 6 males and 7 females, chemical-related
nephropathy in 10 males and 9 females, significantly
reduced body weights in both sexes, reduced absolute
kidney weight in males, and increased relative kidney
weight in females, relative to controls. Kidney lesions
were characterized by tubule dilatation, renal tubule
atrophy, tubule cell regeneration, and the presence of
crystals, primarily in the lumen of the renal tubules.
Relative and absolute thymus weights were decreased in
both sexes. Lymphoid depletions in spleen, thymus,
and/or lymph nodes of 4000 mg/litre mice were attributed
to reduced body weight and stress. A significant
decrease in forelimb grip strength of 4000 mg/litre female
mice, observed at 90 days, was attributed to debilitation;
no significant dose-related changes were observed in
other neurobehavioural end-points. Cardiovascular tests
were not performed in mice. The LOAEL is 495 mg/kg
body weight per day, based on nephropathy and
mortality at the 4000 mg/litre exposure level; the NOAEL
is 205 mg/kg body weight per day.
Tardiff et al. (1980) exposed male and female
Charles River rats continuously to barium chloride in
drinking-water for up to 13 weeks. The authors estimated
doses as 0, 1.7, 8.1, or 38.1 mg barium/kg body weight
per day for males and 0, 2.1, 9.7, or 45.7 mg barium/kg
body weight per day for females. Rats were fed a diet of
Tekland mouse/rat diet pellets, which contributed a
baseline dose of 0.5 µg barium/kg body weight per day.
The only reported adverse effects were depressed water
consumption in the high-dose groups of both sexes and
slight decreases in relative adrenal weights in mid-dose
males at 8 weeks and in all exposed groups of females at
13 weeks; these changes were not dose related. Blood
pressure and end-points sensitive for glomerular damage
(electron microscopic examination or urinary excretion of
protein) were not investigated.
In a series of longer-term histological, electron
microscopic, electrocardiographic, and blood pressure
studies (McCauley et al., 1985), CD Sprague-Dawley rats
were given barium in drinking-water for various
durations and fed Purina rat chow (containing 12 mg
barium/kg) or Tekland rat chow (insignificant barium
intake). In the histology studies, three exposure regi-
mens were used with the Purina rat chow diet, and the
estimated total barium intakes were 1, 1.15, 2.5, 16, or 38.5
mg/kg body weight per day for 36–68 weeks. Histo-
logical evaluations of an extensive number of tissues did
not reveal barium-related lesions. No alterations in
haematocrit levels were observed. A retinal lesion (“focal
absence of the outer layers of the retina”) was observed
but did not appear to be dose or duration related; its
relationship to barium exposure is uncertain. No
significant increases in incidences of neoplasms were
observed in the barium-exposed rats, but the study dura-
tion is less than a lifetime and may not have been of
sufficient duration for the detection of late-developing
tumours.