Topical Review
Journal of Occupational Medicine
(Vol.3, pp380, 383)
August 1961
Modern Trends in the
Treatment of Lead Poisoning
A Review of the Literature on the Use of Edathamil Calcium-Disodium
Elston L. Belknap, M.D., Milwaukee, Wis.*A
LTHOUGH lead absorption, which when presented in excess produces clinical lead poisoning, has been know from the time of Hippocrates, there has been no specific treatment available until the last decade. As one reviews the 10 years of development of the use of edathamil (ethylenediaminetetraacetic acid) as a specific therapeutic agent for the treatment of lead absorption in adults, one is struck by the fact that changing trends in such treatment involve largely details, such as dosage, frequency, and duration, whereas the basic principles underlying the use of chelating agents for treating lead absorption have not varied the world over.In fact, the principle of Chelation itself is not new, for citrate Chelation dates back to 1941. Its most effective application to the problem of the elimination of lead from the human organism with the use of edathamil calcium disodium (monocalcium disodium ethylenediaminetetraacetate; also called calcium EDTA and Versene) is, however, relatively new. The last 10 years have seen the use of this drug for the treatment of lead absorption become worldwide.
Basis of Action
The basis of action of this new drug is that it chelates or binds a metal ion, like lead, by complexing the metal in a ring structure so tightly that the complex is nonionizable. The resultant end-product is a metal chelate which is a stable, water-soluble, readily excreted, non-toxic compound. The successful employment of chelating agents for the control of undesirable cations in solution and thus making chemically clean large containers in industry, suggested the use of the same chelating agent, edathamil, as a means of mobilization of certain toxic metallic ions in man. While at first the sodium salt of edathamil was used, the calcium salt is now used to avoid the marked serum-calcium lowering when the unbound edathamil sodium is used. This thus avoids the development of tetany which arises when the serum calcium is dropped rapidly by the edathamil sodium, as found by Popovici and colleagues as early as 1950 and by Spencer in 1953.
The "solubilizing" property of edathamil suggested its use for mobilizing heavy metal in bone. The edathamil forms a much stronger bond with lead than does the citrate which was previously used for Chelation. The lead displaces calcium from the combination of edathamil calcium because of the greater stability constant of edathamil lead, as studied by Foreman about 1950 and reported at the conference on lead poisoning at the Massachusetts General Hospital in Boston, Mass., on Feb. 8, 1952. Following animal studies with carbon-labeled edathamil, Foreman showed that 60% to 80% of the drug is excreted within 6 hours and 95% to 99% within 25 hours when given intravenously.
First Clinical Case
The first human patient actually to be treated in Calcium Disodium Versenate was studied and treated by Bessman, Reid, and Rubin, after his entrance to the hospital (children’s Hospital, Washing, D.C.) on June 1, 1951. Their report on this case was published in March, 1952. The dosage on the 20th hospital day was 0.750mg per day in three divided doses, without apparent toxicity and no recurrence . . .
* * * * *
. . .form of an oral tablet, was first suggested by Didbury, Bynum, and Fetz in their publication of January, 1953, after giving the drug to five adults and two children with excessive lead absorption. In comparing the intravenous and oral administration, they found that with the intravenous route there was a 10- to 40-fold increase in the urinary lead excretion promptly on the first day of therapy, with subsequent values of a lower magnitude but never less than three times the observed pretreatment level; when the drug was given orally, the rise in excretion was more gradual with maximum excretion on the third or fourth day of therapy, with a 5- to 10-fold increase in 24 hour urinary lead above the observed control value. The treatment by either route was well tolerated and effective in producing a significant increase in excretion of lead together with a prompt alleviation of symptoms. Gastrointestinal absorption of lead-edathamil was suggested by the increase in urinary lead following oral therapy, and they admitted that the formation of the lead-edathamil complex in the gastrointestinal tract with subsequent absorption could not be ruled out.
In 1954, Cotter stated that he felt that his four lead-poisoned patients treated orally had good symptomatic results borne out by satisfactory lean in urine values.
To disprove the efficacy of the oral treatment with edathamil calcium-disodium, Rieders and Brieger, in February, 1955, stated before the American Academy of Occupational Medicine, that the orally administered edathamil calcium-disodium is apparently not absorbed as such. In the intestine a portion of the drug exchanges its calcium for such heavy metals as lead, iron, and copper. These chelates are then absorbed and excreted in the urine. The total effect is a transfer of metal from the intestinal to the urinary rout of excretion without appreciable removal of metal from tissues.
A favorable report, however, was made in 1955 by Manville and Moser on the apparently successful effect of oral edathamil calcium-disodium treatment given to 12 patients from a battery works. Tablets containing 250mg of the drug were given, and then dosage was on the basis of 60mg a day of edathamil calcium-disodium per kilogram of body weight. The tablets were given for the first five days of each week, and the daily intake was divided into four doses. Symptomatically, there was relief of fatigue and constipation, and lessened fatigability. The authors reported that satisfactory lead levels in the blood and urine had not been achieved at the end of two weeks of the drug administration but their men who had excreted and average of 1.974mg of lead before treatment, were excreting 3.6mg after treatment, an increase of 82%. Stippled cells and porphyrin had practically disappeared at the end of three weeks. They recommended, however, the intermittent administration of edathamil by mouth.
Likewise, in May, 1956, Shiels and co-workers, of Australia, reported the apparently favorable effect of the oral use of edathamil calcium-disodium in five industrial lead cases and the case of one small boy, using 2gm twice a day for several days followed by a rest period of seven days and by a second course similar to the first. They noted marked increase in concentration of lead in the urine. If such a patient is still at work in a lead hazard and swallowing as well as inhaling lead compounds, the effect of the drug if given orally would probably be to convert this lead into readily soluble and absorbable lead. The result would be to increase the urinary excretion of lead but not to serve any useful purpose in doing so. However, in the case of a person who may be removed from the lead hazard for some time, they felt that the amount of lead which might be absorbed from the alimentary tract during the oral treatment is only a small fraction of the increased lead excretion. The found no serious untoward effect, and they felt that the oral method was capable of causing removal of lead from the bone.
Similarly, in April, 1956, Bell and co-workers,of Denver, reported the same apparently beneficial effect of oral edathamil calcium-disodium on urinary and fecal lead excretion in three lead poisoning cases treated daily with 3gm of the compound or intravenously. In these cases the combined urinary and fecal lead excretion response was approximately two-thirds as much on oral as on intravenous therapy, but it was felt that the oral administration caused a significant increase in both fecal and urinary lead excretion.
In January, 1958, Pagnotto, Elkins, and Bayka reported on oral administration of edathamil calcium-disodium and concluded that the statement may not be entirely true that the increased excretion of lead following oral administration of edathamil is due solely to the absorption in the intestine of lead which would otherwise be excreted by the gastrointestinal tract.
Nephrotoxicity of Edathamil
In regard to possible contraindications to th use of
edathamil calcium-disodium the question of damage to the kidneys from its use
warrants special study. The first two cases of severe . . .
_____________________________________________________
*Dr. Belknap is Professor and Director of the
Department of Occupational and Environmental Medicine, Marquette University
Medical School.
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