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Barium and barium compounds

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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. 



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