BROMIDE ION
EXPLANATION
Inorganic bromide has not been previously evaluated by the JMPR,
but the Meeting in 1966 established an ADI for man of 0-1.0 mg/kg bw,
based on a minimum pharmacologically effective dosage in humans of
about 900 mg of KBr, equivalent to 600 mg of bromide ion.
Since then toxicological studies with animals as well as human
volunteers have become available and are summarized and evaluated in
this monograph.
EVALUATION FOR ACCEPTABLE INTAKE
BIOLOGICAL DATA
Biochemical Aspects
Absorption, distribution, and excretion
Mice
Single doses of an aqueous solution of 82Br-ammonium bromide
were injected into tail veins of pregnant albino mice 2 days before
parturition. The mice were sacrificed after 5 or 20 min, 1, 2, 4, 24
or 48 hrs and the distribution of the 82Br in the tissues of the
dams and the foetuses had been studied by autoradiography. The
distribution of 82Br was similar at the various time periods
studied. The radioactivity was excreted slowly, which resulted in only
slight decreases in concentration with increasing time periods. Blood
levels remained high and exceeded those recorded for most organs and
tissues. Bromide gradually accumulates in the central nervous system.
The level in the thyroid was relatively high but did not exceed levels
in the blood. Bromide showed transplacental passage and most of the
radioactive bromide was found in the bones of the foetuses, but the
level was not as high as in the cartilage of the dams (Söremark &
Ullberg, 1960).
Rats
Thirty females Wistar SPF rats received diets containing 2000 ppm
sodium bromide for 3 weeks. Mean bromide concentration at the
beginning of the bromide administration was 0.55 ± 0.46 mmol/l. After
the 3 weeks of bromide administration it was 8.57 ± 0.57 mmol/l. The
animals were then divided into 5 groups. Group 1 received a normal
diet and tapwater as drinking water; Group 2 was fed a "salt free"
diet and tapwater as drinking water; and Groups 3, 4 and 5 received a
"salt free" diet and drinking water containing various concentrations
of NaCl. The resulting chloride intake was 91, 10, 28, 55 and
144 mg/day, respectively. Plasma bromide levels were determined in all
rats after 1, 2, 3, 4, 9 and 14 days. Bromide half-lives varied from
2.5 days at high-chloride intake, via 3.5 days at normal dietary
chloride intake, to 25 days at low-chloride intake (Rauws & van Logten,
1975). It can be concluded that since bromide half-life is about 10
times longer at a low-chloride intake than at the highest chloride
intake, the accumulation level in the first case will be about 10
times higher than in the latter case.
In the reproduction study, a third litter (F1c) in the first
generation was used for the investigation of the transplacental
transport of bromide. Bromide concentrations in the kidneys of
corresponding dams and foetuses were found almost equal, showing the
absence of a distinct placental barrier in the developing foetus.
The accumulation of bromide was also studied in the 90-day
toxicity rat studies (see "Short-term toxicity" section). After the
administration of normal and low chloride diets plasma bromide
concentrations rose to a plateau within 3 and 12 weeks, respectively.
Except for the highest dose groups in both studies, these plateaus
were directly proportional to the bromide concentration in the diet.
The same levels were reached at bromide concentrations in the low
chloride diet, which were about 10 times lower then in the normal
chloride diet. In these experiments total halogenide levels (Cl-
and Br-) remained the same in the normal diet study and were
significantly decreased at the highest dose in the low chloride study
only (van Logten et al., 1976; Rauws, 1983).
Toxicological studies
Special studies mutagenicity
Sodium and ammonium bromide were studied in an Ames test with
Salmonella typhimurium strains TA-98 and TA-100. At dose levels of
0.001-10 mg/plate, both with and without metabolic activation, no
mutagenic effect was observed (Voogd, 1988).
Special studies on reproduction
In a 3-generation reproduction study (2 litters/generation)
groups of Wistar rats (10 males and 20 females/group) were fed diets
containing 0, 75, 300, 1200, 4800 or 19200 ppm NaBr. Observations
included behaviour, growth, food and water consumption, leucocyte
count and differentation, T3 and T4 levels in serum, bromide in
blood and thyroid, litter size and weight, reproduction parameters as
fertility, viability and lactation index, organ weights and
macroscopic examination.
Complete infertility was observed at the highest dose whereas at
4800 ppm the fertility as well as the viability of the offspring was
significantly reduced. Therefore the second and third generations were
bred only from the groups dosed at up to end including 1200 ppm. No
treatment-related effects were observed in reproductive performance,
viability and body weight of the offspring in these groups.
Haematological examinations revealed significantly increased
neutrophil count and decreased lymphocytes in F0 females at 19200
and 4800 ppm. Serum thyroxine concentrations (T4) were significantly
decreased in F0 males at all dose groups and in F0 females at the
2 highest dose groups after 6 weeks of administration. After 12 weeks
of administration similar effects were observed.
Body and organ-weight determinations did not reveal a clear
pattern of dose-related effects in the successive generations. Only
relative adrenal weight was significantly reduced in F0 females at
4800 and 1200 mg/kg food. In order to investigate the reversibility of
the observed effects, an additional litter was bred with parent
animals fed a diet containing 19200 ppm NaBr for 7 months followed by
a control diet for 3 months before mating. No differences were
observed in breeding results in the "reversibility" study between
control and exposed rats (van Leeuwen et al., 1983a;
van Logten et al., 1979).
Special studies on thyroid function and endocrine parameters
Male Wistar rats (10 animals/group/period) were fed diets
containing 0, 20, 75, 300 or 1200 ppm NaBr (purity 99.5%) for 4 or 12
weeks. An additional experiment using the same protocol with 0 and
19200 ppm NaBr was carried out. Observations included body weight,
serum hormone concentrations, weight and histopathological examination
of testes, thyroid and pituitary gland. Both latter organs were also
studied immunocytochemically. Significantly decreased body weight was
observed at the highest dose (19200 ppm) after 4 and 12 weeks of
administration. Relative thyroid weight was significantly increased at
1200 mg ppm after 4 weeks and significantly increased at the highest
dose group after both 4 and 12 weeks of administration. An activation
of the thyroid gland and a decreased spermatogenesis in the testes was
observed microscopically in the highest dose group after 4 as well as
after 12 weeks. After 4 weeks of treatment T4 (thyroxine) levels
were significantly decreased at 1200 and 19200 ppm. A significant
decrease of T4 was also observed at the highest dose after 12 weeks.
TSH (thyroid-stimulating hormone) levels were significantly increased
at the highest dose both after the 4- and the 12- week treatment.
Insulin levels were significantly increased and growth hormone (GH)
(after 12 weeks), testosterone and corticosterone levels were
decreased at the high dose level.
It was postulated that NaBr acts directly on certain endocrine
organs such as the thyroid, adrenals and testes, thereby inducing
alterations in the pituitary gland by feedback mechanisms (van Leeuwen
et al., 1983b; Loeber et al., 1983).
In an experiment on the time dependency of the effect of bromide
on the thyroid gland in rats, significantly decreased thyroxine
concentrations were found as soon as 3 days after feeding diets
containing 4800 or 19200 ppm NaBr. This decrease was observed and
remained constant during an experimental period of 12 weeks
(van Leeuwen et al., 1983a).
The uptake of radiolabelled iodide by the thyroid was measured
in a "chloride-free" experiment 6, 24 and 48 hours after a single
intraperitoneal injection of iodine-131 to rats (g/group) fed diets
containing 0, 125, 500 or 2000 ppm NaBr for 90 days. At levels
of 125 ppm NaBr and greater the iodine uptake was increased
(significantly at 500 ppm). At 500 ppm the uptake was greater than at
2000 ppm; in the latter group the release, measured between 24 and 48
hours, seemed to be enhanced compared to the 500 ppm dose level. The
explanation for this is probably that two opposite effects of bromide
on the thyroid exist (activation and inhibition of uptake)
(van Leeuwen et al., 1983a).
Acute toxicity
The acute toxicity to mice and rats is summarized in Table 1.
Bromide exerts a very low acute toxicity upon oral administration.
Table 1. Acute toxicity of bromide
Species Route LD50 Reference
Mouse oral 5020 mg/kg bw Vase et al., 1961
Mouse oral 7000 mg/kg bw Graff et al., 1955
Rat oral 3500 mg/kg bw Smith et al., 1925
Short-term toxicity
Rats
In a range-finding study 5 groups of 4 female Wistar rats
received 0, 300, 1200, 4800 or 19200 ppm NaBr (purity 99.5%) for 4
weeks. High dose level rats did not groom themselves sufficiently and
showed signs of motor incoordination in their hind legs. No clear
influence on growth, food or water intake was observed. At 19200 ppm
NaBr, about 50% of the chloride in the plasma, brain, kidneys and
liver had been replaced by bromide, while there was no marked
influence on the total halogenide concentration. Also in the other
treatment groups there was a dose-related replacement of chloride by
bromide. Plasma bromide concentration reached a plateau level by the
third week of treatment. Relative kidney weight was significantly
increased in high dose level rats. Compound related histopathological
changes were not observed (van Logten et al., 1973a; 1973b).
In another range-finding study, groups of 5 male and 5 female
Wistar rats received doses of 0, 75, 300, 1200, 4800 or 19200 ppm NaBr
in a low chloride diet (by leaving out NaCl and KCl, but adding 1%
potassium sulphate) for 4 weeks. The chloride content was about
3 g/kg, whereas the normal diet contained 11 g/kg.
All high dose level rats and 3 male and 2 female rats at 4800 ppm
died within 12 and 22 days, respectively. Food intake and growth were
significantly decreased at 4800 and 19200 ppm. Kidney weight was
significantly increased in males at all dose groups (Kroes et al.,
1974).
Groups of Wistar-SPF rats (10 animals/sex/group) were fed diets
containing 0, 75, 300, 1200, 4800 or 19200 ppm NaBr (purity 99.5%) for
90 days. Grooming was depressed in rats at 19200 ppm NaBr and the
animals showed motor incoordination of their hind legs. Body weight
gain was significantly decreased in high dose level males during the
entire study and in females during the first 6 weeks. Haematological
and biochemical parameters were not affected except for an increase in
the percentage of neutrophilicranulocytes at 19200 ppm. Relative
thyroid weight was significantly increased in male and female rats at
19200 and also in females at 4800 and 1200 ppm. Relative adrenal
weight was significantly increased in high dose level male rats and
relative testes and prostate weights were significantly decreased at
4800 and 19200 ppm. A significantly decreased thymus weight was
observed in high dose level females. Upon histopathological
observation, dose-related effects on endocrine organs were found at
the two highest dose levels. The thyroid gland showed activation,
characterized by a reduction in follicle size along with an increase
in the height of the follicular epithelium in the two highest dose
groups. In the adrenals, in all dose groups, there was strikingly less
vacuolisation of the zona fasciculata, compared with the controls
although this was not clearly dose-related. At the highest dose the
ovaries showed an indication of a lower number of corpora lutea. In
addition, spermatogenesis was decreased in the testes at 19200 ppm and
less secretory activity of the prostate was observed (suggesting a
diminished production of gonadotropic hormones) at 4800 ppm and
19200 ppm (van Logten et al., 1973; 1974; 1976).
Groups of Wistar-SPF rats (10 animals/sex/group) were fed low
chloride diets containing 0.4-0.7 g Cl- and 1% potassium sulphate/kg
for 90 days. The dose levels were 0, 8, 31, 125, 500 or 2000 ppm NaBr
(purity 99.5%), respectively. Observations included body weight, food
intake, clinical chemical determinations in blood, urine and liver,
bromide and total halogenide in plasma and several organs, organ
weights and histopathology. In the highest dose group, 3 male and 3
female rats died during the experiment. At 2000 ppm NaBr grooming was
depressed, motor incoordination of the hind legs was observed and the
weight gain was significantly decreased. Percentage and total number
of neutrophilic granulocytes and the total leucocyte count were
increased at the highest dose. Corticosterone in blood was lower at
the two highest dose levels (significantly at 2000 ppm). At 2000 ppm
the relative weight of heart, brain, spleen, adrenals, thyroid and
pituitary gland were increased in males, whereas the relative prostate
weight was decreased. In high dose level females, relative heart and
brain weight were increased and relative pituitary and uterus weight
were decreased. Upon histopathology, in the two highest dose groups
activation of the thyroid, absence of nephrocalcinosis in female rats,
less vacuolisation in the zona fasciculata of the adrenals and less
zymogen granulae in the pancreas were observed. In the highest dose
groups, fewer corpora lutea, retardation in maturation of the uterus,
inhibition of spermatogenesis and less secretory activity of the
salivary glands were observed (van Logten et al., 1976; Rauws
et al., 1977).
The toxicity of NaBr in rats on a low chloride diet is about 10
times higher, in comparison with the toxicity for rats on a normal
diet. The highest dose in the low chloride study (2000 ppm) is more
toxic than the highest dose (19200 ppm) in the study for rats on a
normal diet (mortality: 6/20 and 1/20 respectively).
Observations in humans
Since bromide was introduced as a medicine, clinical symptoms of
bromide intoxication have been reported. Large doses of bromide cause
nausea and vomiting, abdominal pain, coma and paralysis. The chronic
state of bromide intoxication is reported as bromism. The signs and
symptoms are referable to the nervous system, skin, glandular
secretions and gastrointestinal tract (van Leeuwen & Sangster, 1988).
Sodium bromide at a dose of 1 mg Br/kg/day was administered
orally to 20 healthy volunteers (10 females not using oral
contraceptives and not pregnant and 10 males) during 8 weeks. In the
females, bromide was administered during 2 full menstrual cycles.
Special attention was paid to the endocrine system. The results of the
full medical history and physical examination taken at the start and
end of the study showed no differences. The measured haematological,
biochemical and urine parameters did not change during the experiment.
Plasma bromide concentrations rose in females and males from 0.08 +
0.01 mmol/l to 0.97 ± 0.18 mmol/l and from 0.08 ± 0.01 mmol/l to 0.83
± 0.09 mmol/l, respectively. No changes were observed in the serum
concentrations of thyroxine, free thyroxine, thyroxine-binding
globulin, triiodothyronine, cortisol, testosterone, estradiol and
progesterone. Also no changes were observed in the serum concentration
of thyroid-stimulating hormone (TSH), prolactin, luteinizing hormone
(LH) and follicle-stimulating hormone (FSH). These hormones were
measured before as well as 20 and 60 minutes after the administration
of thyrotropin-releasing hormone (TRH) and LH-releasing hormone (LHRH)
(Sangster et al., 1981; 1982a).
In another study, healthy volunteers were repeatedly given sodium
bromide in oral doses of 0, 4 or 9 mg Br/kg/day using a double blind
design. Groups of seven males received the treatment for 12 weeks and
groups of seven non-pregnant females (not using oral conceptives) over
three full cycles. Special attention was paid to possible effects on
the endocrine and central nervous systems. At the start and end of the
study, a full medical history, the results of physical examination,
haematological studies and standard clinical chemistry and urine
analyses were recorded for each subject. Except for incidental nausea,
no changes were observed. Mean plasma bromide concentrations at the
end of treatment were 0.07, 2.14 and 4.30 mmol/l for males and 0.07,
3.05 and 4.93 mmol/l for females of the 0-, 4- and 9-mg Br/kg/day
groups, respectively. Only in the females receiving 9 mg Br/kg/day was
there a significant increase in serum thyroxine and triiodothyronine
at the end of the study compared to pre-administration values, but all
concentrations remained within normal limits. No changes were observed
in serum concentrations of free thyroxine, thyroxine-binding globulin,
cortisol, oestradiol, progesterone or testosterone, or of thyrotropin,
prolactin, luteinizing hormone (LH) and follicle-stimulating hormone
before or after the administration of thyrotropin-releasing hormone
and LH-releasing hormone. Analysis of neurophysiological data (EEG and
visual evoked response) showed shifts in the power of various spectral
bands and a shift in mean frequency in the groups on 9 mg Br/kg/day.
All findings were, however, within normal limits (Sangster et al.,
1982b; 1983).
A limited replication study was carried out to confirm the
findings in the former study. Three groups of 15 females received
(double blind) doses of 0, 4 and 9 mg Br/kg/day during three menstrual
cycles. After the administration period the 45 females were observed
for another three cycles. Mean plasma bromide concentrations at the
end of the treatment were 0.07, 3.22 and 7.99 mmol/l, respectively. In
none of the three groups were significant changes observed in the
serum thyroxine concentration, free thyroxine, triiodothyronine,
thyrotropine and thyroxine-binding globulin. Clinical observation did
not show effects on the thyroid or on the central nervous system.
Quantitative analysis of the electroencephalogram (EEG) showed only a
marginal effect in females receiving 9 mg Br/kg/day (Sangster et al.,
1986).
COMMENTS
After oral ingestion bromide is rapidly and completely absorbed
in the gastrointestinal tract and distributed almost exclusively in
the extracellular fluid. The similarity of bromide to chloride gives
rise to an important pharmacokinetic interaction. The two ions compete
for reabsorption in the kidney. High chloride reabsorption will lead
to higher bromide excretion and vice versa. The biological half-life
of bromide can be decreased by administration of chloride. A normal
half-life of bromide in the rat of 3 days will increase to 25 days on
a chloride-free diet.
Bromide exerts various toxicological effects in rats. At high
doses effects on the central nervous system were observed. In
short-term toxicity studies motor incoordination of the hind legs and
inhibition of grooming were found. The main effects of bromide are on
endocrine organs. It is assumed that bromide acts directly on organs
such as the thyroid, adrenals and testes, thereby inducing alteration
in the pituitary gland by feed-back mechanisms. The effect on the
thyroid may be explained by interaction with iodide uptake and is the
most sensitive effect in animal experiments.
In a short-term toxicity study with rats at a normal chloride
intake, effects were found on most endocrine organs, while in special
studies decreased levels of a number of hormones (thyroxine, growth
hormone, testosterone and corticosterone) were observed. On the other
hand, TSH and insulin were increased. A NOAEL based upon all available
data on the effects on the thyroid of 300 ppm sodium bromide (240 ppm
bromide), equivalent to 12 mg bromide/kg bw/day could be established.
In a reproduction study in rats, complete infertility was
observed at the highest dose level of 19200 ppm sodium bromide whereas
at 4800 ppm fertility and viability of the offspring were reduced. At
1200 ppm no effects on reproduction were observed. The effects on
fertility were reversible. Bromide was not mutagenic in the Ames test.
Studies with sodium bromide in human volunteers did not show
neurophysiological or endocrinological changes: the NOAEL was 9 mg
bromide/kg bw/day.
TOXICOLOGICAL EVALUATION
LEVEL CAUSING NO TOXICOLOGICAL EFFECT
Rat: 240 ppm, equivalent to 12 mg bromide/kg bw/day
Human: 9 mg bromide/kg bw/day
ESTIMATE OF ACCEPTABLE DAILY INTAKE FOR MAN
0-1 mg/kg bw
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See Also:
Toxicological Abbreviations
Bromide ion (FAO/PL:1968/M/9/1)
Bromide Ion (FAO/PL:1969/M/17/1)
Bromide ion (Pesticide residues in food: 1981 evaluations)
Bromide Ion (Pesticide residues in food: 1983 evaluations)