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OCR for page 60
B1~111~1 111
Bismuth (Bi) is a pinkish-white, lustrous, crystalline, brittle metal
widely distributed in small quantities throughout the world. Bismuth
occurs naturally as a metal, oxide, sulfide, and carbonate and until
about 1775 was often confused with tin and lead. Most bismuth destined
for use in the Western Hemisphere today is obtained as a by-product of
copper-, lead-, and tin-refining processes. The most significant physical
property of bismuth is its expansion upon solidification (Hempe! and
Hawley, 1973~. Accordingly, bismuth alloys are especially suited to use
in safety devices such as plugs in compressed gas cylinders, automatic
fire spunkier systems, and firedoor releases. While bismuth has been
used in the treatment of venereal disease, contemporanly, bismuth is
used as a colonng agent in decorative cosmetics (Beaver and Burr,
1963), in ointments for burns, to delineate viscous surfaces in X-ray
analyses, as a fungicide, in the treatment of warts, and to regulate stool
odor and consistency in colostomy patients (Burns et al., l974~.
ESSENTIALITY
Despite rather extensive experience with bismuth as a therapeutic
agent for gastrointestinal disturbances, no evidence exists to indicate
that bismuth is an essential nutrient.
60
OCR for page 61
Bismuth
METABOLISM
61
Metallic bismuth is poorly absorbed; however, several organic forms of
bismuth are absorbed from parented administration sites as well as
through' skin and mucous membranes. A dark brown to black pigment
frequently occurs in the skin, gum line, and mucosa of bismuth-treated
individuals (Wachstein and Zak, 1946~. This pigment is believed to
represent precipitation and accumulation of bismuth sulfide (Urizar and
Vernier, 1966~. Some aspect of bismuth metabolism, in man at least,
results in a reversible myoclonic encephalopa~y following administra-
tion of bismuth subnitrate (Cambieret al., 1974; Ehermitte et al., 1975~.
This indicates the blood brain battier is permeable to bismuth. Another
bismuth-related phenomenon is the development of intranuclear inclu-
sion bodies within proximal renal tubule cells in humans and animals
exposed to bismuth (Wachstein, 1949~. These inclusions are spherical,
eosinophilic, slightly acid-fast, electron dense, homogenous structures
that, by X-ray microanalysis, have been demonstrated to contain
bismuth (Fowler and Goyer, 1975~.
SOURCES
The potential for animal exposure to parenteral compounds has greatly
diminished since the advent of penicillin and other antibiotics that
replaced basic bismuth chloride and other bismuth compounds as anti-
syphilitic agents. Additional bismuth compounds, bismuth aluminate,
bismuth oxide, bismuth subnitrate, bismuth subgallate, and bismuth
tannate have been and/or continue to be used as gastrointestinal protec-
tives at levels of 0.3 to 2 g for dogs and up to 15 to 30 g for horses and
cattle. Some of the -above preparations and bismuth iodosubgallate,
bismuth iodide oxide, bismuth sodium tartrate, and bismuth subcarbo-
nate are still used as external astringents, on buccal warts (Urizar and
Vernier, 1966) as topical antiseptics, and in cosmetics. The industrial or
manufacturing uses for bismuth include the 'manufacture of dry cell
cathodes, industrial catalysts, disinfectants, magnets, semiconductors,
glazes, and carriers for 23sU (Hempel and Hawley, 19731.
OCR for page 62
62 MINERAL TOLERANCE OF DOMESTIC ANIMALS
TOXICOSIS
LOW LEVELS
There are numerous reports of iatrogenic bismuth toxicosis in humans,
but data from natural or experimental bismuth toxicoses in animals are
very limited.
Lechat et al. (1968) orally administered bismuth substrate to rabbits
at a rate equivalent to 70 to 74 mg of bismuth per kilogram of body
weight for up to 34 weeks without any noticeable effect regardless of
whether the vehicle used for diluting and carrying the bismuth was
saccharose, mann~tol, or sorbitol. Elevations in urinary and renal con-
centrations of bismuth were noted during the experiment but dis-
appeared soon after cessation of the bismuth administration. Of major
significance in this experiment was the absence of any inclusion bodies
in the kidneys. Similar studies conducted by Lechat et al. (1968) with
rats yielded comparable results.
The chronic studies with bismuth conducted by Steinfeld and Meyer
(1886) involved rabbits, cats, and dogs. Rabbits weighing 0.75 to 1 kg
were subcutaneously injected with 15 mg of bismuth oxide per day on
4 different days. Cats weighing 2.3 to 3.4 kg were injected subcutane-
ously with 10 to 20 mg bismuth oxide daily for 4 consecutive days. In
each of these species, bismuth toxicosis was manifested by lassitude,
stomatitis, salivation, anorexia, weight loss, diarrhea, fever, albumin-
uria, and tetanic convulsions. At necropsy, the bismuth-intoxicated
animals had ulceration and necrosis of the mucosa of the large intestine.
Low-leve} bismuth toxicity studies have been conducted with labora-
tory rodents for periods of up to 2 years. Wilson (1975a) observed no
effect of 1 to 2 ml tripotassium dicitrato bismuthate (TDB) administered
daily for 30 days to rats weighing 190 to 215 g. In similar studies with
TDB in 100- to 120-g rats, Wilson (1975b) revealed that administering 4
to 32 mg TDB/lEg per day by gavage for 40 days caused no toxic
effects, while the highest level was effective in decreasing the healing
time of experimentally induced ulcers. Preussmann and Ivankovic
(1975) found no carcinogenic or other toxic effects of bismuth oxychlo-
ride administered at the rates of 1 to 5 percent in the diets of rats for a
period of 2 years.
Haddow and Horning (1960) were concerned about the carcinogenic
effect of bismuth and reported that bismuth dextran, administered to
mice in weekly subcutaneous injections at the rate of 1 mg per week for
23 weeks was not carcinogenic. The mice were observed for a total
period of 10 months. The same results were obtained with hamsters
OCR for page 63
Bismuth
63
administered the above dosage of bismuth dextran intramuscularly for
the same period. Innes et al. (1969) orally dosed mice with bismuth
dimethylthiocarbonate at a rate equivalent to 34 ppm bismuth without
producing toxic effects.
HIGH LEVELS
Acute studies of bismuth toxicity were conducted by Steinfeld and
Meyer (1886) using rabbits, cats, dogs, and frogs. Rabbits weighing
about 1 kg were injected subcutaneously with 72 mg bismuth as Bi203,
and cats weighing 2. ~ to 3.5 kg were similarly given 3~900 mg bismuth
as Bi2O3. The effects in both species included increased respiration
rates, slowed heart rate, convulsions, and death. One dog weighing 6.2
kg was also given two 40 mg subcutaneous injections of bismuth oxide.
In addition to many of the above signs, the dog also exhibited vomition
and tenesmus. Frogs injected in the dorsal lymph sack with 7 to 2,700
mg of bismuth as Bi2O3 exhibited the same effects as the rabbits and
cats. The effects of parenterally administered bismuth subnitrate in
rabbits have been studied by Langhans (1886~. He was the first to report
on the "wismuthcellen," the bismuth-induced intranuclear and intra-
cytoplasmic inclusion bodies in the renal tubular epithelium.
The acute toxic elects of orally administered bismuth have been
observed in cats by Noval~ and Gutig (19081. These workers found 10
g of bismuth subnitrate (7.0 to 7.4 g Bi) administered in a single oral
dose cause cyanosis, methemoglobinemia, and death. This response is
typical of nitrate poisoning. The same dosage of bismuth subnitrate
administered orally to dogs was reported to be without effect (Dalche
and Villegean, 1887, as cited by Mayer and Baehr, 1912~.
Acute bismuth toxicity studies in rodents have been conducted by
Wilson (1975a) using TDB. Rats weighing about 200 g were not affected
by oral administration of 1 to 5 m} of TDB per 100 g of body weight in a
Manhour period. Similarly, mice weighing 24 to 32 g were not affected by
0.2 to 0.9 ml orally administered TDB per 100 g of body weight during a
24-hour period.
The acute toxic effects of bismuth cymol administered parenterally to
rats have been studied by Pappenheimer and Maechling (19341. They
gave 77 to 3,930 mg/kg in one to four intramuscular injections. This
caused renal tubular degeneration and the formation of the inclusion
bodies previously mentioned. The ~D50 for a single oral dose of bismuth
as Bi203 in mice has been calculated from unpublished data by Preuss-
mann and Ivankovic (1975) to be 19.3 g/kg. These workers never found
OCR for page 64
64 MINERAL TOLERANCE OF DOMESTIC ANIMALS
a high enough level of bismuth oxide to effect an LD50 for rats.
Vu Ngoc and Garcet (1967) have indicated the rat gastric mucosa is
hypersensitive to bismuth.
FACTORS AFFECTING TOXICITY
The limited data from the rather wide variety of bismuth compounds
used in the reviewed toxicity experiments herein preclude meaningful
statements on factors influencing toxicity. The data, however, suggest
that rodents are rather refractive to several bismuth compounds but do
develop bismuth nephrotoxicity. Of the larger species, dogs seem less
susceptible to bismuth toxicity than cats, but this species difference in
bismuth toxicity may be a simple difference in the rates of bismuth
administration to these two species.
TISSUE LEVELS
Data on tissue levels of bismuth are fragmentary at best. While specific
concentrations are lacking, evidence for the persistence of bismuth in
tissue comes from experience with chronic use of bismuth medicaments
in humans (Mayer and Baehr, 1912; Burr et al. 1965~. Randall e! al.
(1972) demonstrated that cases of bismuth nephrotoxicity and inclusion
body formation have followed the topical use of bismuth preparations
and that the bismuth inclusion bodies are very persistent' being present
in 86 percent of the kidneys of humans treated with bismuth prepara-
tions 30 years previously (Beaver and Burr, 1963~. Fowler and Goyer
(1975) demonstrated that bismuth is concentrated in these inclusions
but gave no quantitative estimates.
The blood levels of bismuth are more transient than bismuth renal
inclusion bodies. Kruger et al. (1976) noted levels of 10 to 16 me
bismuthldl in the venous blood of patients using bismuth skin creams
and found no detectable bismuth in blood within 3 weeks after the
bismuth creams were discontinued. Similar levels have been found by
Buge et al. (1974) in serum, blood, and plasma of bismuth-toxic
humans.
MAXIMUM TOLERABLE LEVELS
There seems to be insufficient continuity or similarity among the vari-
ous bismuth toxicity experiments conducted to make any definitive
OCR for page 65
Bismuth 65
statements on the maximum tolerable levels. Extrapolating from the
bismuth toxicity data from rabbits, one can calculate that 2,31~3,360
ppm of bismuth as bismuth subnitrate are below the MTL. If one uses a
100-fold margin-of-safety factor for cross-species extrapolation in con-
junction with the work of Preussmann and Ivankovic (1975) indicating
40,000 ppm of bismuth was a no-effect level in rats, the MTE for the
domestic animals may approximate 400 ppm of bismuth.
SUMMARY
Overt signs of experimental bismuth toxicosis (lassitude, salivation,
anorexia, diarrhea, fever, and convuIsions) have been demonstrated in
rabbits, cats, and dogs, with the latter species being perhaps the least
susceptible of the three. Rodents appear to be quite resistant to bis-
muth toxicosis as indicated by the fact that the calculated tD50 for
bismuth oxychlor'&e in mice is 21.5 g/kg and that no overt signs
of bismuth toxicosis in rodents were reported at lesser levels of admin-
istration. Bismuth gradually induces nephrotoxicity characterized by
the formation of intranuclear inclusion bodies in renal tubular epi-
thelium and the persistence of these inclusions for perhaps the life of
the host.
OCR for page 66
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OCR for page 69
Bismuth
REFERENCES
69
Beaver, D. L., and R. E. Burr. 1963. Bismuth inclusions in the human kidney. Arch.
Pathol. 76:89.
Buge, A., G. Rancurel, M. Poisson, and J. Dechy. 1974. Encephalopathies myocloniques
par les sets de bismuth. Nouv. Presse Med. 3:2315.
Burns, R., D. W. Thomas, and V. J. Barron. 1974. Reversible encephalopathy possibly
associated with bismuth subgallate ingestion. Br. Med. J. 1:220.
Burr, R. E., A. M. Gotto, and D. L. Beaver. 1965. Isolation and analysis of bismuth
inclusions. Toxicol. Appl. Pharmacol. 7:588.
Cambier, J., M. Masson, and R. Dairou. 1974. Encephalopathie myoclonique et intoxica-
tion par les sets de bismuth. Nouv. Presse Med. 3:2662.
Fowler, B. A., and R. A. Gayer. 1975. Bismuth localization within nuclear inclusions by
X-ray microanalysis. Effects of accelerating voltage. J. Histochem. Cytochem. 23:722.
Haddow, A., and E. S. Horning. 1960. On the carcinogenicity of an iron-dextran com-
plex. J. Natl. Cancer Inst. 24:109.
Hempel, C. A., and G. G. Hawley. 1973. The Encyclopedia of Chemistry, 3rd ed. Van
Nostrand Reinhold Co., New York.
Innes, J. R. M., B. M. Ulland, M. G. Valerio, L. Petrucelli, L. Fishbein, E. R. Hart,
L. Pallotta, R. R. Bates, H. L. Falk, J. J. Gart, M. Klein, I. Mitchell, and J. Peters.
1969. Bioassay of pesticides and industrial chemicals for tumorigenicity in mice. A
preliminary note. J. Natl. Cancer Inst. 42:1101.
Kruger, G., D. J. Thomas, F. Weinhardt, and S. Hoyer. 1976. Disturbed oxidative
metabolism in organic brain syndrome caused by bismuth in skin creams. Lancet
176:485.
Langhans, T. 1886. Pathologisch-anato~rusche Befunde Bei mit Bismuth um subnitricum
vergifteten thieren 2. Chirurgie 13:263.
Lechat, P., L. Morel-Maroger, R. Cluzan, P. Flouvat, and J. Fontagne. 1968. Etude
experimentale des effete de ['ingestion prolonger de soul-nitrate de bismuth associe a
des doses. Therapie 23:445.
Lhermitte, F., C. F. Degas, and J. L. Signoret. 1975. Encephalopathies reversibles par
les sets insolubles de bismuth, cinq nouveaux cast Nouv. Presse Med. 4:419.
Mayer, L., and G. Baehr. 1912. Bismuth poisoning. A clinical and pathological report.
Surg. Gynecol. Obstet. 15:309.
Novak, J., and C. Gutig. 1908. Nitritvergiftung durch Bismutun subnitricum. Ber. Klin.
Wochenschr. 45:1764.
Pappenheimer, A. M., and E. H. Maechling. 1934. Inclusions in renal epithelial cells
following the use of certain bismuth preparations. Am. J. Pathol. 10:577.
Preussmann, R., and S. Ivankovic. 1975. Absence of carcinogenic activity in so rats after
oral administration of high doses of bismuth oxychloride. Food Cosmet. Toxicol.
13:543.
Randall, R. W., R. J. Osheroff, S. Bakerman, and J. G. Setter. 1972. Bismuth nephro-
toxicity. Ann. Intern. Med. 77:481.
Steinfeld, W., and H. Meyer. 1886. Untersuchungen uber die toxischen und therapeuti
schen Wirkungen des Bismuths. Arch. Exp. Pathol. Pharrnakol. 20:40.
Urizar, R., end R. L. Vernier. 1966. Bismuth nephropathy. J. Am. Med. Assoc. 198:187.
Vu Ngoc, H., and S. Garcet. 1967. Hypersensitivity of the rat gastric mucosa to repeated
administration of bismuth. Sem. Ther. 43:34.
Wachstein, M., and G. F. Zak. 1946. Bismuth pigmentation. Its histochemical identifica-
tion. Am. J. Pathol. 22:603.
OCR for page 70
70 MINERAL TOLERANCE OF DOMESTIC ANIMALS
Wachstein, M. 1949. Studies on inclusion bodies. I. Acid-fastness of nuclear inclusion
bodies that are induced by ingestion of lead and bismuth. Am. J. Clin. Pathol. 19:608.
Wilson, T. R. 1975a. The pharmacology of tn-patassium di~itrato bismuthate (]DB).
Postured. Med. J. 51:18.
Wilson, T. R. 1975b. Eject of tri-potassium di~itrato bismuthate (TDB) on the healing of
experimental gastric ulcers in rats. Postgrad. Med. J. 51(Suppl. 5~:22.
Representative terms from entire chapter:
bismuth toxicity
