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Spring 2001

Bismuth Toxicity

By Joseph R. DiPalma, M.D.

Of the heavy metals including lead, mercury, arsenic and bismuth it is the latter which has salts which are relatively the least toxic. This is probably because of the great insolubility of many bismuth salts, which prevents their absorption. In addition they have physical qualities which are demulcent and protective of mucous membranes and skin. They also have modest antibiotic properties, which may be useful in surface inflammation and for deodorizing fecal material. It is no wonder that bismuth salts have been widely used since antiquity and still hold a secure place in medicinal therapy today.

In industry bismuth metal has occupational exposure in the manufacture of alloys, catalysts, ceramics, cosmetics, magnets, paints, pharmaceuticals, semiconductors and x-ray contrast media. However, cases of poisoning from this source are seldom reported. In contrast toxicity from medicinal use is not uncommon and may even occur in epidemic form. In the U.S.A. Pepto Bismol (and many imitators) contains bismuth subsalicylate, 262 or 524 mg/ml, widely used and available without prescription (otc) for dyspepsia, nausea, stomach ulcer and diarrhea. Bismuth subgallate, Devrom® 200 mg tablets is also available otc for controlling the fecal odor in colostomy patients. Heliac® a prescription medication composed of bismuth subsalicylate 250 mg, tetracycline 500 mg and metroniadazole 200 mg is used for Heliobactor pylori infections. These are the only bismuth containing preparations in the U.S.A which are FDA approved. The many other products containing bismuth as an active ingredient are now available from other countries or underground sources.(see , Federal Register, Vol 57, No165/ Tuesday August 15, 1992) A classical example is Balmex Ointment widely sold for over 30 years for diaper rash. A zinc oxide ointment it also contained bismuth subnitrate as an active ingredient. The FDA forced the manufacturer to remove the bismuth salt from the preparation because it could not be proven to be safe and effective.

In the seventies and the eighties there was an epidemic of bismuth poisoning mostly confined to France and Australia. This was generally attributed to sales promotions of cosmetic preparations containing bismuth salts. Another factor was the increased use of bismuth to treat the increasing number of colostomy patients. Naturally such therapy is long term and this greatly increases the chance of bismuth intoxication.

Before 1950, syphilis and other parasitic diseases were treated with soluble salts of bismuth by a parental route. Naturally this led to severe toxicity and the therapy could only be given by using rest periods between courses. This experience emphasizes the importance of solubility of the bismuth salts in relation to toxicity. Table I has a useful classification of commonly used salts of bismuth and their toxicity potential. An important additional factor is that some salts of bismuth have the additional toxicity potential of the anion apart from the metal component. The average dose of bismuth subsalicylate contained in Pepto-Bismol has a dose of of salicylate almost equal to that of an aspirin once the compound dissociates in the stomach. Those allergic to aspirin may suffer as well as children subject to Reyes syndrome and with prolonged dosage actual salicylism has occurred. Likewise, preparations containing bismuth subnitrate taken orally may cause nitrite poisoning.

Bismuth toxicity like that of other heavy metals is attributable to its predilection to combine with sulhydril groups. Since sulhydril groups are components of many vital enzymes the effect of bismuth is to denature and destroy the function of these enzymes Thus bismuth is toxic for all living organisms which depend on these enzymes. There is little selective toxicity for a particular cell type and the degree of injury depends upon the concentration which develops in a particular organ. Renal toxicity in acute poisoning is early evident because bismuth is excreted mainly by this route only 10% appearing in the feces after a parenteral dose. In chronic poisoning all organs are affected. In the skin a lichen planus-like rash, in the mouth stomatitis with a blue black gum line. Inflammation and inclusion bodies in the liver, kidney.and bone are characteristic. In the brain the lesions will cause encephalitis.

Diagnosis of bismuth intoxification is usually easily made from the history of ingestion of a bismuth containing oral preparation or the use of a cosmetic compound. Colostomy patients are obviously suspect. Physical signs in chronic poisoning include poor oral hygiene with a blue-black gum line, lichen planus-like skin rashes, weight loss, Gastrointestinal symptoms, signs of encephalopathy including confusion, disorientation and rarely seizures, and black stools. Specific diagnosis by blood levels is difficult because of the extremely low blood levels found in normals as well as those poisoned. The normal blood level is on the average less than 1 ug/dl while poisoned subjects average 3 ug/dl. Much more reliable is the urine level which averages 0-20 mmol/L in normals and as high as 400mmol/L or more in poisoning..In appropriate cases a simple flat plate of the abdomen will reveal the bismuth in the intestine since it is almost as dense as lead.

A bedside test which is simple, reliable and fast is the modified Reinsch's test. It can identify mercury, arsenic, antimony and bismuth. Use 10 to 15 g of gastric contents or tissue homogenate. Add 3 ml of concentrated hydrochloric and insert a copper wire spiral. Heat gently for 2 hours. A silvery deposit =mercury, shiny black=bismuth, dull black=arsenic and purple=antimony. Confirmatory tests such as The Gutzeit test can confirm each deposit and they can even be quantified. ( For details, see Kaye, S. Handbook of Emergency Toxicology, Charles C. Thomas, Springfield, IW. 1980, pp55,84.)

Prevention of bismuth toxicity can be easily achieved by avoiding bismuth medications and cosmetics. Pepto-Bismol type preparations have been popularized by its use in , Travelers Diarrhea where it enjoys a good reputation. As long as therapy is not continued beyond 3 or 4 days there is little danger of poisoning. Therapy of colostomy patients with bismuth preparations is more apt to lead to poisoning as the treatment is often prolonged for months and years.

For severe acute and chronic poisoning chelation therapy with BAL is often recommended. However, many experts prefer to treat conservatively and expectantly allowing the bismuth to be gradually excreted. In support of this view there is evidence that chelation therapy which solubilizes the bismuth leads to an increased concentration in the brain. Thus some harm can be done by the attempt to rapidly excrete the bismuth. Other authorities feel that penicillamine is a safer chelator for bismuth. It is practical to conclude that only life threatning cases of bismuth poisoning should receive chelation therapy.

Table 1. Relationship of solubility of bismuth salts to their potential toxicity

* The reason that group IV is of relatively low toxicity is that such organic salts hydrolyze easily and become either subchlorides or sulphides which like Group I are both water and lipid insoluble.

References:
1. DiPalma,J.R. Bismuth Toxicity, American Family Physician, 36:244-246,1988
2. Haddad, L.M. Shannon, M.W. Winchester,J.F. Clinical Managing of Poisoning and Drug Overdose. 3rd Edition, W.B. Saunders Company, Philadephia,1998
3. Bradley,B. Singleton, M. Li Wan Po, A. Bismuth Toxicity-A Reassesment. Journal of Clinical Pharmacy. 14: 424-441, 1989.

Joseph R. DiPalma, M.D. Emeritus Professor of Pharmacology and Medicine, MCP/Hahnemann University.

ELECTRON MICROSCOPE

The Philadelphia Crime Laboratory (PCL) has donated an electron microscope to the FRFRF. A special thank you goes to Lew Brenner of the PCL for assisting in obtaining and transferring this equipment.

One of the immediate applications for the electron microscope will be in the Forensics Mentors Institute's summer program for 2001. A few projects that will be investigated this summer include 1.) evaluation of selenium exposure in patients and 2.) hair morphologic changes associated with drugs of abuse. The foundation along with Dr. Fredric Rieders wants to express our appreciation to the PLC for this instrument.