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    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)