School of Advanced Nutritional and Medical Research

Pharmacy and Chemistry
Vol. 157, no. 4

J.A.M.A., Jan 22, 1955
Pages 341 and 342

Carl M. Peterson, M.D., Secretary,

R.T. Stormont, M.D., Secretary,

The enthusiasm that has greeted the development of a satisfactory compound of edathamil (Calcium Disodium Versenate, ethylenediaminetetraacetic acid, EDTA) for clinical trial in the therapy of lead poisoning, and the recent flood of experimental and case reports concerning its use, furnish ample testimony to the alertness of physicians regarding new means of alleviating human disease and distress. These professional responses also focus attention anew on the sad fact that the incidence of this ancient disease is unduly high, despite the availability of adequate and practical methods for the recognition and control of hazardous absorption of lead by industrial employees and other persons in the general population. It is not common knowledge that there are in the United States some thousands of cases of lead encephalopathy annually among children up to 3 years of age that the mortality rate within this group, so far as it is recorded, exceeds 25%.¹ Therefore, it is understandable that effective preventive measures have not been demanded and applied. There is, however, no justification for the frequency with which obviously hazardous industrial exposure to lead persists, nor for the failure o industry generally to employ the measures that have banished hazardous exposure to lead form some industrial operations.

There are signs that a promising remedial agent, edathamil calcium-disodium, may be misused and perhaps discredited in advance of a full exploration of the potentialities of its proper usage. For this reason physicians may need to be reminded of the role of preventive medicine in the lead trades and of their duty to keep the responsibility for the safety of the industrial environment in the hands of industrial management, where it belongs. The hazards of the lead-using occupations are measurable by reliable methods. Thus, when the physician in industry undertakes, by medical means, to palliate the effects of the absorption of demonstrably dangerous quantities of lead by industrial employees, he must look at his reasons for doing so and in all humility and professional integrity ask himself where the welfare of his industrial wards may lie. His function is to know the extent of the danger and to portray the facts to industrial management so that their meaning is clear. He must also set up satisfactory and practical criteria for the safe conditions that are to be achieved. When he fails in his critique and in his insistence on the necessity of adequate control of exposure to lead (or to other occupational hazards), he contributes to the risks to which workmen are subjected and becomes a party to their existence.

The nature of the projected misuse of edathamil calcium-disodium is the old story of naively optimistic application of prophylactic therapy in the lead trades. Attempts on the part of physicians and others to mitigate the effects of current excessive absorption of lead by industrial workmen have been numerous. Milk,² ascorbic acid,³ laxatives and purgatives, and lemonade fortified by acid⁴ have had their proponents, if not always their persistent vogue. Recourse to the procedure of the "fixation" of lead in the skeleton during exposure, followed periodically, in some instances, by prophylactic "mobilization" of lead from the skeleton,⁵ was based on the investigations of Aub and his associates.⁶ Because of the inadequacies of the methods of analysis available at the time, this led to the mistaken belief that these opposed effects on the lead metabolism could be affected by shifts in the calcium metabolism in the corresponding direction. That these and other comparable methods, which have been employed in prophylactic (and curative) therapy, are essentially ineffectual⁷ is beside the point. The fault is that they were often used in lieu of the adequate measures of environmental control that are dictated by considerations of sound industrial hygiene and by decent regard for the safety and welfare of human beings. It is to be expected that industrial management should favor and be unduly impressed by the magic of simple and relatively inexpensive medical prophylactic procedures rather than face the stern and often costly necessities of safe process design and plant engineering. If a physician, brashly or innocently wandering beyond his professional province, will bear the responsibility of the threatened health of industrial employees, many managers will relinquish it gladly, at least until the facts of life overtake them in the form of the resentment of employees and increases in compensation costs.

The administration by proper means of eh appropriate salt of edathamil, in contrast with may if not all of such medical measures of prophylaxis proposed and employed in the past, offers certain intriguing prospects for beneficial effects. Its use to achieve such benefits, under appropriate safeguards, in competent and conscientious hands, and under certain carefully weighed circumstances, eventually may be found to be advantageous. Only careful and thorough investigation, however, can determine whether this is feasible, and whether the immediate beneficial effects outweigh, in the long run, certain hazards of its use.

Experience has shown that the intravenous or intramuscular administration of edathamil calcium-disodium, in limited dosage and over brief periods of time, is an essentially safe medicament. That it can be relied on for the relief of symptoms or for saving life has not been established,⁸ but it is well tolerated by adults and even by infants during episodes or more prolonged periods of acute and potentially lethal lead intoxication.⁹ Its action, described superficially of necessity, is as follows: It combines with lead in the soft tissues of the body, forming a stable soluble, nonionized compound. Because of the rapid excretion of this compound, principally by way of the kidney, it virtually sweeps the lead form the soft tissues¹⁰; however, the compound seems unable to penetrate into erythrocytes. Therefore, lead concentration in the blood is not decreased as substantially and abruptly as it is after the administration of dimercaprol (BAL).¹¹ The details of the biochemical process and its remote effects are not clear at this time and remain to be established by investigation. This applies, with special significance, to the extent to which other metals are taken out of the body. For this reason, the prolonged administration of the drug, even intermittently, is fraught with unknown potentialities for the derangement of the mineral metabolism of the body.

It is obvious that the use of the drug for purposes of prophylaxis in industry would be facilitated greatly by its administration by mouth, and such a preparation is available for use in this manner. Thus it could be given to industrial employees without inconvenience or objection on their part, and in a form that would not suggest that a somewhat drastic therapy was being employed. The beneficial results that are assumed to follow the use of this procedure would be those of a considerable increase in the over-all rate of excretion of lead and the maintenance of an appreciable reduction, as compared with that expected otherwise, in the concentration of lead in the soft tissues. Unfortunately, however, the absorption of the drug from the alimentary tract is comparatively poor.¹² Although there is evidence of a slight to moderate increase in the urinary excretion of lead,¹³ there is also evidence indicating that this increase occurs in association with a corresponding decrease in the output of lead from the alimentary tract.¹⁴ In that case, the end-result is a failure to expedite the elimination of lead from the body. Even if there should be some over-all increase in the rate of elimination of lead, the quantities of lead involved, in relation to the total quantities absorbed and retained in the body under the conditions of potentially hazardous exposure to lead, probably would be too small to be of practical significance. Certainly, if a significant increase in elimination were to be achieved, the virtually continuous use of the prophylactic agent would be required. From the aspect of effective use of the drug, there is no information that would enable even the most enthusiastic proponent of such a regimen to anticipate what might be its consequences, whether overt or insidious. Under these circumstances the subjection of men to such a regimen, except for the purpose of cautious investigation surrounded by appropriate technical and ethical safeguards, could only be regarded as rash and irresponsible.