Document 8OKBgYkLL631bLMdoq2Rywapm

BOARD OF DIRECTORS MEETING New York, N.Y. May 12, 1949 A luncheon and meeting of the Eoard of Directors of the Lead Industries Association v;as held on Thursday, May 12, 1949, at 12:50 ?.M., at the Down Town Association, New York, N.Y. PRESENT REPRESENTING Norman Hickman K. C. Brownell J. A. Costello Clarence Glass J. A. Martino F. E. Ylormser G. H. LeFevre The American Metal Co. Ltd. American Smelting 5: Refining Co. Ethyl Corp. International Smelting & Refining Co. Anaconda Sales Co., Agents National Lead Co. St. Joseph Lead Co. United States Smelting Fefining & Mining Co. Inc. OTHERS VI. E. Clancy D. A. Merson C. M. Chapin, Jr. American Smelting Sc Refining Co. National Lead Co. St. Joseph Lead Co. Robert L. Ziegfeld, Secretary-Treasurer Mr. Normser occupied the chair. The minutes of the previous meeting of April 3, 1949, were approved. AMENDMENT TO BY-LAWS By letter ballot and vote in person, the following amend ment to Article IV, Executive Committee, Sec. 1 of the By-Laws, which was recommended at the Eoard meeting on April 3, 1949, was approved: "Article IV, Executive Committee, Sec. 1, shall be amended to strike out "five (5)" in the first sen tence and substitute therefor "six (6)." It was decided to table the election of the sixth member of the Executive Committee for the position created by the foregoing amendment until a later meeting. A suggestion was also made that the secretary investigate the possibility of arranging for rotation of the members of the Board and Executive Committee so that a certain number of members would be automatically retired each year and not be eligible for reelecticn until a certain specified period had elapsed. Board of Directors Meeting Minutes i qdo AHHUALHETTIIIG - 1950 Plans for th= 1959 annual meeting of the Lead Indus tries Associati'n v;ere discussed and it sas generally felt that the secretary should try to make arrangements, at least for next year, somewhat similar to those made during 1942. It ".'as decided that Chicago would be the best place to hold the meeting and that the secretary should work closely with the secretary of the American / i n p Institute so that members wishing to attend meetings of both organizations could do so with a minimum loss of time. HYGIENE AML SAFETY Educational Film on Lead Poisonino - The secretary re- or' Tv rtner on mmrestion :at it might be advantageous to make a motion picture on the diagnosis, eatment and cre ation of leao poisoning 'or the education of medical students, mecica.1i ,,m,,e,,n, -w..eohafltvh, authorities and others interested. He ex plained that he was suite sure that the sponsorship cf the American -'edical Association could be enlisted and that if such a film were made, it should be with the advice of a committee of top-ranking medical authorities in the field. He reported that preliminary investigations indicated that the cost, in color, of a ."H-minuts film >f this type would run from .-?5,0C0 to J, COO, V*, 4. black and would probably suffice and would r; :C'' ce cost 'rom 3 sercent. IP m- strusted to ir:ve. further. 'ohr.s Hookins University - The question o: ar. acwitional grant to Johns Hopkins University to continue the research on antidotes for lead poisoning, under the direction of Ir. Alscph H. Corwin, was discussed. Correspondence is attached as Exhibit "A.n The secretary reported that in pre liminary conference with the Research Corporation, that organi zation had indicated a probable willingness to subscribe half cf the *5,000 fund requested if the Lead Industries Association subscribed the other half. He further explained that the *,500 grant from the Lead Industries Association could be made from the 1949 approved budget without a subscription of additional funds. The grant of f,500 to be matched by a similar grant of the Pesearch Corporation to carry on this work for another year was aouroved. Research at Harvard College and Children's Hospital - The secretary made a brief report of the work conducted under a Lead Industries Association grant to Harvard College and the Children' Hospital in toston over the past year. He stated that fifteen cases had ;een studied and that of these, six had been proven not LIA0C362 Board of Directors Meeting Minutes May 12, 1949 3 to be lead poisoning after urinalyses were made from the funds granted, already justifying the north of the project. Four of these six had previously been diagnosed as lead poisoning by the X-ray examination. He explained that it was the desire of those conducting the work to continue it in order to provide a broader statistical background and that this could be done for one year from June 30, when the present grant expires, at a cost of $2,200. The Board approved a grant of $1,100 from the current budget, without additional subscriptions, to continue this work from July 1, to December 31, 1945, further conside ration to be given later in the year as to the continuation of the work in 1950. Research at the University of Colorado - A request for financial assistance for research on the use of strontium and pyrocatechindisulfonate as antidotes for lead poisoning from Dr. Princi of the University of Colorado (attached as Exhibit "B") was tabled. Research by Memorial Hosnital and New York State Depart ment of Labor - An invitation to cooperate, without financial assistance, in a study of lead poisoning by the New York State Department of Labor and the Memorial Hospital, New York, was discussed.~ (Attached as Exhibit nCn) The secretary was in structed to cooperate as far as possible with the New York State Department of Labor and the Memorial Hospital in its projected study of lead poisoning. USEFUL INFORMATION AEOUT LEAD The secretary reported that the work of revising the original publication of "Useful Information About Lead," pub lished by the Association in 1931, was now about complete and reminded the Board that a reserve of $4,000 had been set aside for a new edition several years ago but that present printing costs indicated that a new edition of 10,000 copies would probably cost about $6,000. In view of this, he explained that he had discussed with the McGraw-Hill Company the possi bility of the book being published by the McGraw-Hill Book Company with the Association guaranteeing to purchase a certain number of copies. Arrangements had been made to discuss this further with the McGraw-Hill Company and it was, therefore, de cided to postpone any action on printing the book until a report of the conferences with the McGraw-Hill Company could be con sidered by the Board. PROCEEDINGS ANNUAL MEETING - 1949 The secretary reported that the Proceedings of the Annual Meeting, held in Chicago in April, had gone to the printer and should be ready for distribution in about a week. He stated L IA0C363 ".1**r* Beard of Directors Meeting Minutes -4- May 12, 1949 that he proposed to distribute free copies to the entire membership mailing list of the Association and to anyone who attended the meeting if he was not on the mailing list. He requested instruction as to the general distribution of the Proceedings. It was decided that they be offered for sale at a price not to exceed $2.00, to cover the cost, ohe actual price to be left to the discretion of the secretary. REINVESTMENT OF FUNDS The secretary was instructed to reinvest the $34,000 which would be realized on maturity of the O.S. Certificates of Indebtedness in which the funds are now invested, on June 1, in new short term Certificates of Indebtedness. RESIGNATION - GENERAL LEAD MANUFACTURING COMPANY The secretary read a letter of resignation from the As sociation from the General Lead Manufacturing Company of Denver, Colo., as follows: nI have ycur statement before me for second quarter subscription. For some time, especially since the Plumbing Promotion Program has been discontinued, I have felt that we are receiving but little benefit from our membership. It is therefore with regret that we feel obli gated to cancel our further membership in the Lead Industries Association, having been one of the early members and staunch supporters." and explained that he had written the Company asking that its decision be held in abeyance on the ground that the Plumbing Promotion Program of the Association had not been discontinued but had merely been curtailed, and that a new program was to be considered sometime during the current year. The Board decided to take no action on the resignation until a reply had been received from the General Lead Manu facturing Company. LIA00364 Board of Directors Meeting Minutes From Manfred. Bowditch To Mr. Ziegfeld Exhibit nAn May 12, 1949 May 9, 19U9 Subject: Summary of statement by Dr. A. K. Corwin, Hay 9, 19U9, Development of an Antidote for Lead Poisoning Studies in 19Ul under the residue of a grant from the Rockefeller Founda tion led to interest in antidotes for heavy metal poisoning through the ob servation that it was possible to extract mercury from biological tissues by means of the reagent "dithizone." Financial aid from the Research Corporation enabled pursuit of this sub ject, leading to the determination that, while dithizone itself was not prac tical as an antidote, the symmetrical meta-dicarboxyl derivative, in the form of the sodium salt, had apparent possibilities. It was tried against cadmium, mercury, silver, arsenic, antimony and finally lead. The results against lead' poisoning were sufficiently encouraging to warrant concentration on this metal. Joint support by the Research Corporation and the Lead Industries Association was then secured. Chemically, efforts to develop even more watersoluble compounds were unsuccessful, but are believed to merit renewal* - Bio logically, 'using strains of pure-bred mice, these results vrere attained: 1. The dicarbaxy dithizone antidote was shown to be no more toxic than table salt. (This is in marked contrast to EAL, British Anti-Lewisite, which was thought to give great promise as a lead antidote.) 2. By colonic irrigation, it proved very effective in controlling intestinal lead colic. 3. Evidence was adduced to justify the belief that further experimentation would demonstrate effective control of lead poisoning. Since the termination of the R.C.-L.I.A. grant, further 'work by doctoral candidates has resulted in: 1. Standardization of the technique for experimental intoxication with lead. 2. Establishment of the structure of dithizone on firm ground. 3. Resolution of the debated question of the nature of the chemical bonding between heavy metal compounds and dithizone. hm Determination of the chemistry of the poisoning and antidote reactions. 5. Doubling of yields in synthesis of the needed compounds. Publications on two of these subjects have been prepared and a third is planned. ]S 611-01 LIA00365 Mr. Ziegfeld >2- Hay 9, 19U9 Before the outcome of this work can have the hoped-for results in the treatment of human lead poisoning, throe further steps are deemed essential: 1. The yield of the synthesis must be further stepped up to accumulate a working reserve of the antidote. 2. Its efficacy on animals must be further studied. 3. Its stability in air, hitherto unsatisfactory, must be materially improved. Doctor Corwin believes that each of these three requisites can be accomplished and asks a grant ox CoOOO for this purpose, $1*500 for the full-time services of a skilled organic chemist for one year and 0500 for chemicals and equip ment Supplementary: The initial Research Corporation grant was authorized on February 3, 1 ?);)| and a total of 03995 was expended. The work was started on February H* and continued for somewhat more than a year. The Research Corporation-Lead Industries Association grant was author ized on January 22, 191*6 in the amount of 072OO. The full amount, of which each organization contributed one-half, was expended. The work was started on July 1 and-continued for somewhat more than a year,' U. S. Patent Mo, 2,14*1,31*6, which is freely available to the public, resulted. Doctor Corwin has advised me of his belief that the work now contem plated car. be completed within a one year period. He would hope to start the work on July 1 or October 1, depending on the availability of a quali fied chemist. Llf>0C3fcb DEVELOP! ZNT OF All ANTIDOTE FOR I,DAD POISONING Alsoph H. Corwin The Johns Hopkins University I wish to present for the consideration of the Lead Industries Association a statement concerning the work which has been completed in ahis laboratory on the general subject of antidotes for heavy metal poisoning end a proposal for further stucty" >7ith the particular problem of lead poisoning as the major consideration. The program which I shall present could bo carried forward most efficiently if the services of a full-time and skilled organic chemist were available for the work. he estimate that his services would require a salary of eU,500 per year and that he would require an additional *-500 for chemicals and equipment during the year. Our Early Vnork on Heavy Metal Poisoning The work which vrf.ll bo reviewed here was performed with the collaboration of the following investigators: Dr. Lewis Sargent, Dr. iilvir. Sharp, Dr. Kurt Kraus, !.irs. l!;rtha Pelletier, Dr. James Webb, Dr. Sylvia Halm, Dr. George Jackson, ISrs* Jean Arrington, Dr. V/ilhelm Frisoll, Dr. John Rcinheimer, and iir. Iqbal Singh Bhatia, These collaborators have worked for periods of on,, to three ye:vrs each on the problem at different times during its development. In 1911 wo were studying the action of heavy metals on bio logical systems under the residue of a grant from the Rockefeller Foundation. Our interest in the subject of .antidotes for heavy metal poisoning began v.ith the observation that it was possible to extract mercury from tissues and from organic mercurials by means of the heavy metal reagent "dithizone" yrfthout preliminary destruction of the tissues, 'do did not investigate this reaction quantitatively for the purpose of chemical .analysis. Instead we decided to explore its possible use in the formulation of an antidote for heavy metal poison ing. Research Corporation Grant - Cadmium Poisoning Research Corporation extended us financial aid for the general investigation of heavy metal poisoning. We first attempted to use dithizone itself as an antidote, wo soon found that it w.ns so insoluble in body fluids that its use.was impractical, wo then attempted to in crease its solubility and found that the symmetrical mcta-dicarboxyl derivative had quite satisfactory solubility in the form of the sodium salt. It was also found that this compound had sufficient affinity for heavy metals to bo of use as an antidote. The material has the following chemical formula: / CO O // I SH A/-A//'-/- COO'a /c C^ N 611.02 LIA0C367 The next step was the investigation of different heavy metals. We made a quick survey of toxic metals and soon found that the activity of the new antidote against cadmium was quite easily established. For this reason we concentrated our studies on cadmium poisoning for some time. We studied increased dosages, auxiliary treatments, time "f successful administration and other variables. One of the most important variables which we found was the temperature of exposure of the experimental animals, which were nice. In mice the influence of a toxic substance may be radically altered by the temperature of the animals before and during the administration of the drug and during the time of survival after the dose. We chose to control this variable rather than to abandon mice as ezrperimentsl animals because of the relative cheapness of mice and because of the high degree of biological homogeneity obtainable, le do not consider statistical experimentation with dogs and other large animals to be reliable for establishing curative action unless very large samples are taken to establish both the lethal dose and the curative dose. Since each of these actions is an independent variable with genetic variation, over all curative action is a second order variable and large numbers of experimental animals would be required to arrive at sound conclusions. With animals having great biological homogeneity, similar large numbers are not required and experimentation is relatively more rapid. In addition to this, experimentation with large animals would not have been feasible with a compound as difficult to procure as ours has been. In addition -to our work on cadmium, we worked somewhat on mercury, silver, arsenic, antimony, and finally lead. The antidote was of no value with either arsenic or antimony, as was predicted from the known lack of action of dithizone on these metals. Contradictory results -were obtained on various organic mercurials. More light has now been thrown on these results by our later experimentation and we believe that the mercury field should be reinvestigated. The results against lead poisoning were encouraging and because of the interest in it as a health hazard, we decided to work further on lead poisoning. Research Corporation - Lead Industries Association Grant Lead Poisoning At this time we applied for an extension of the grant from Research Corporation. They suggested a joint grant with the Lead Industries Association and this was arranged. Our experimentation under this joint grant was of two types, chemical and biological. On the chemical side we attanpted to prepare compounds of still greater water solubility. In this search we were partially successful. New compounds were found which were more soluble in water than the dicarboxy-dithizone. On the other hand, the groups necessary to obtain this increase in solubility were found to diminish the activity of the compounds. The end result of this chemical study LIAOC368 J was a return to our original compound. Wo have not yet explored .all the possibilities for securing more soluble compounds but wo believe that information uncovered in our biological studies warrants still further investigation of the present antidote. Experimental Lead Poisoning On the biological side, we made numerous studies of the lethal action of lead when given in large doses both with and without antidote, we found that it was most difficult to obtain a reproducible intoxication in the laboratory with tnis memal. Attempts at chronic intoxication gave quite variable results and attempts at acute intoxication, while not so variable, were still far removed from the results obtainable with cadmium. Since the termination of the grant we have succeeded in standardizing the technique of experimental intoxication with lead. The difficulty in lead intoxication is that the injection of soluble lead salts usually results in the rapid precipitation of the lead in a quite insoluble and variably toxic mass. This action can be observed best in the peritoneal cavity. Out studies show that this precipitation can be prevented by the use of a mixture of citrate and thiosulfate administered with the lead. These substances form stable- load complexes which are broken up slowly and fairly raproducibly by the body so that a reasonably predictable intoxication can to secured. Incidentally, the toxicity of lead administered in this fora is several times as great as when administered as the nitrat; or acetate* Many of our early failures in the attempted use cf antidotes were duo. to the fact that wo were administering up to five times the lethal dose of lead and that the antidotes had the power to mobilizing the load so laid down. A large amount ef lcad-dithizone was then thrown on the kidney for excretion and the material was not sufficiently soluble to permit its elimination. It was this observation which led us to desire more water-soluble compounds, .-hen wc had found the proper dose level for the production of actue lead poisoning in the laboratory, the picture changed and better results wore obtained. Blandnoss of the Dithizone Antidote One biological finding made at this time was of the greatest importance with respect to the possible use of dicarboxy dithizone as an antidote. This was the ostnoiishmont of the lack of toxic action of the proposed drug in mice, wo fed mice vat^r containing the antidote from the time of their weaning throueh their entire lifetimes and found that they were capable of raising normal young when given no untreated water, wc established the fact that the drug is comparable in blandnoss to table salt. When th~ latter substance is given in sufficiently high concentra tion it causes an upset in the osmotic balance and consequent deleterious action. The antidote required a solution of similar strength to cause toxic action and it was found that this 'was also duo to upset of the osmotic relationships. This is one of th.. few drugs that vo have dealt LI A00369 -u- with that is to be classified as being harmless as salt and we have no hesitation in using it. As a further example- of the mildness of this drug, '..'a have found that a two per cent solution is not irritating to the eyes. This discovery led to the use of the material in colonic irrigation. Control of Lead Colic Animals poisoned with lead exhibit more or less severe symptoms on intestinal colic, when the intoxication is severe, extensive capillary hemorrhage can be observed in the intestines. ri?e have observed that the intestinal colic can be controlled very effectively by colonic irrigation with tiie dithizone antidote. In severe poisoning, the capiulary hemorrhage is also controlled, so that colonic irrigation adds materially to the efficacy of the- treatment of experimental lead poisoning. Contrast Between BAL and Dicarboxy Dithizone The outstanding property of BAL `.hich is notes in experimentation with it is its revolting odor. This contrasts with the dithizone antidotes which ar odorless. BAL can be tolerated in doses of only 3 mg./kg. without discomfort. In much larger doses it caus-s increasingly severe psychic symptoms. Our dithizone antidote has been given parenterally at the level of liOO mg./kg./day for four wo-ks without perceptible physiological altera tion and at the level of 2500 mg./kg./day by mouth throughout the entire life span of animals without porceptibl2 interference with physiological functions. BAL has not proved effective as or antidote for lead poisoning in the first, trials which have been made with it. Survival times of intoxicated animals were shortened when it was administered. In our antidote tests on -animals receiving what we now know to hav. been approx imately five times the minimum lethal dose cf l^aa, the survival times we-r more than doubled. Beth drugs mobilize lead reserves of the animal. This appears to bo the cause of the observed shortening of survival times in animals treated vith BAL. The mobilization of lead to the kidney does not obscure the antidote action in the caso of dicarboxy dithizone, however. On this basis wo feel encouraged to bolievo that further experi mentation with smaller doses of lead will demonstrate effective control of poisoning. Use of Longer Animals During this period we also did a limited mount of experimen tation on larger animals but wa, .are not in a position to draw final con clusions from it. Because of its lack of stability in solution, our anti dote has to be standardized biologically. The only reliable method for doing this is to test its power as -an antidote for cadmium poisoning. We v.'; . able to establish the fact that it acts as an mtidote in rabbits just it docs in mice but the work lacks the precision of the mouse work LIA 0037 0 -5- because of the smaller number of animals that we were forced to use. This arises from the difficulties encountered in preparing the antidote in larger quantities. We were not able to progress beyond the point of standardization of the antidote on cadmium with a limited number of rabbits and cannot report its effectiveness in lead poisoning in rabbits. Later Chemical Work Since the termination of the grant by Lead Industries Association and Research Corporation, we have succeeded in standardizing the dosage of lead for laboratory investigations, as was pointed out above, and have made extensive chemical investigations, through the medium of the work of doctoral candidates. The chemical work has been of several types, all contributing to a better understanding of the chemistry fundamental to the antidote reaction. Our first problem was to establish the structure of dithizone with certainty, he found that most preparations ere quite impure and it is possible to conclude that the yields of chemical degradation products obtained by early investigators right hav^ stormed from the impurities instead of from the dithizone itself. We have now established the structure of dithizone on firm ground. A publication on this subject, has been submitted to aha Journal of the American Chemical Society. The next problem was to establish th.. nature of the chemical bending in the compounds between heavy metals and dithizone. The litera ture presents no agreement on this subject, to believe that v/e have been able to doom up the debatable points and hope to be in a position to publish our findings in this field in the near future. The third problem eras to establish the chemistry of the poisoning reaction and of the mtiiote reaction on firmer ground. This has "Iso been accomplished and a publication on this subject has bean completed and is being submitt,,d to the Journal of the American Chemical Society, Next in order ".'as to improve the yields in the synthesis of the necessary compounds for physiological study, te have been partially successful in this stud;/, having doubled the yields of the compounds desired, even this increase in yield leaves a considerable distance to go and further studies on the by-products of the dithizone reaction and their elimination are necessary before these substances will be readily available for our biological studies. Finally, we have worked on the chemical staoilization of ditnizone and its derivatives. This work has not yet yialdea definitive results. New derivatives have been prepared which are quite stable chemically but which are not effective antidotes. The field has not been exhausted and there is still a goou possibility of preparing derivatives that will be stable to the air and still be effective antidotes. LIA00371 - 6- ruturs Experimentation At the present time, the most pressing need is to make available a larg: quantity of our antidote for a definitive series of animal experi ments . The chemical work which would be necessary would involve a series of studios on the improvement of yields in she preparation of the material with consequent accumulation of a working reserve, with this, experiments could be run on a large enough seal- to make certain of the limits of efficacy of the antidote in lead poisoning. The next most important investigation is the production of an air stable material. This would involve further work along the lines already laid down, consisting of the selective chemical reaction of the oxidizablo group on the molecule to secure stabilization. Vve have reason to believe, from past experience 'with selective chemical procedures, that a method can be found for the production of the desired substances. ..e should propose, t:nn, to concentrate our research upon three lines of investigation; first., the. improvement of the synthesis of our present antidote and the accumulation of a working reserve; second, the study of this material on animals to determine decisively its efficacy as an antidote; third, the possible improvement in the compound-to secure a material which would be stable in the air. (signed) Alsoph H. Corwin hay 5, 19h9 LI A0C37 2 Board of Directors Meeting Minutes Exhibit "B" May 12, 1949 From: Manfred Bov/ditch To: Mr. Ziegfold May 6, 19 49 Subject: Dr. rrinci's proposal, aated Liarch 2, i?US Thvj following arc condensed comments on the subject proposal, based upon extended discussions nith Drs. J, C. Aub, ... H. Corwin, R. A. Kehoc and S. H. Pinto, briefer talks vath Drs. R. K. Byers, T. L. Shipman, J. J. Daring end Dr. Princi himself, and my own knowledge of animal experimenta tion of thw type outlined. 1. There is question whether both treatment and prophylaxis should have simultaneous consideration. Treatment is by far the more probably fruitful of the two. 2. There is next to no enthusiasm for strontium among the authorities, somewhat more for pyrocatechindisulfcnate, but nothing approaching unanimity. 3. Should dogs be used, or mice? .gain there is difference of opinion. Dr. Cora,in favoring nice on the ground that strains of knev/n suscep tibility to load are available. Dr. Kchoo voting for dogs because of their more adequate blood supply, and Dr. ,.ub seeing both sides. Dr. Princi is not interested unless he can use dogs. A. Though I would question some details, I do not consider Dr. Princi^ overall cost figure excessive for a single year. I an quite certain, however, that he '(/ill want to continue the work beyond that period. 5. Quito apart from the above considerations is the question of lending a haid to a now and promising laboratory. There are tod;.y all too few reliable institutions *w!ra such work can bo done and the potential value to industry of a worth-while addition to the list is obvious. 6. iy conclusion is that, unless wo aum prepared t~ support both the work of Dr. Corwin and that of Dr. Princi, we should chose in favor of the former. Dr. Pinto, Dr. Princi's prime supporter, is in agreement as to this. N 611.03 LI A 0 C373 University of Colorado Medical Center h200 East Ninth Avenue Denver 7, Colorado December 31, 19U8 Mr. R, L. Ziegfeld, Sec.-Treas. Lead Industries Association ii20 Lexington Avenue New York 17, New York Dear Mr. Ziegfeld: For some time this laboratory has been interested in the treatment and prophylaxis of lead intoxication, <7e have recently been working with two substances which seem to show promise. One is Strontium and the other is Sodium pyrocatechindisulfonate. Since we are able to work on the problems only in our spare time it would naturally take years to arrive at any successful conclusions. Dr, Sherman Pinto, of this city, has suggested that your organization might be interested in promoting research of this type. If you think that such a project is worth while and would like to have more information concerning our plans, I would be very glad to outline in detail what we propose to do, how we expect to carry it out and the approximate cost, Mr, Manfred Bowedtch of your organization is familiar with our laboratories and with some of the work which we are carrying on here, and I am certain hu will be able to give you any general inform ation you might desire. I shall be glad to answer any questions that you might have at any time. Very sincerely. Frank Princi, M.D., Director Division of Industrial Medicine LIA0C37A N 611.04 Although load absorptions ind load intoxications have long boon recognized as serious industrial hazards, the state of knowledge concerning the treatment or prophylaxis of this condition is wholly unsatisfactory. Recent in vestigations have shown that none of the drugs or substances in common use in the treatment of lead absorption have any actual effect on the metabolism of lead. It is a well knovm fact, however, that strontium in solution at pH 7.5 to 3.0 re moves lead fretn solution either by adsorption or absorption (in vitro). If t'nc strontium as an ion or as the- lactate molecule forms a complex with the lead ions in the blood and thus prevents deposition in the bone and facilitates -excretion in the kidney or intestinal tract, then it is readily conceivable that strontium will act as a do-leading agent. If, however, the strontium removes lead from solution only by co-precipitation, adsorption or absorption, it is difficult to visualize (a) how the body would react to the presence of such insoluble material in the blood stream and (b) a mechanism by means of which undissolved material could be removed from the blcoa by excretion. However, other workers hav,, found tha^ in the Serum of dogs fed strontium lactate the filterable strontium is always low and often entirely absent even when the total strontium, is fairly high. Haldane reports that the toxicity of strontium varies with the species of animal, being tolerated in relatively larger amounts in humans, McCancc and YJiddowscn found the kidney to be the main organ of excretion for strontium in human subjects. They wore able- to recover approximately half the injected strontium in two days, about 90% was in the urine. Feeding experiments on dogs in this laboratory have shown us thdt these animals can ingest considerable amounts of strontium lactate -without apparent change in physical condition. Sodium pyre Catichin, Di-sulfonate- (di-catichin) is a compound'which has been used in The past as an analytical reagent for the estimation of iron in micro quantitie-s. The similarity of the di-catichin reaction 'with iron to BAL's reaction with mercury led Borghero in Italy to test its effects on lead. 7aeir results were very meager and inconclusive, but showed great promise of having the same type of reaction with lead as dees 3AL with mercury. If this is true, di--catichin should act as a therapeutic and/or prophylactic drug for lead in toxications, Experiences in this laboratory- with di-catichin have shown that it is not acutely toxic to dogs or mice; that of several he-avy metals tested in vitro only iron forms a colored complex and lead a turbid solution. All others gave no reaction whatsoever. `Ye propose to study the therapeutic value of both strontium and dicatichin by direct animal experimentation. Five groups of dogs will be used. Cne group 'will be given lead only. One '.Till be giver, lead and strontium. One group will be given lead and di-catichin. One group v.ill be given strontium only and one group di-catichin only. By this means we hope to (1) determine any cumulative toxicity of strontium; (2) determine any cumulative toxicity of di-catichin; (3) determine whether or not strontium has any effect in preventing clinical signs and symptoms of lead poisoning and if it has any effect in removing lead from the body; (u) determine whether or not di-catichin has any effect in preventing clinical signs ana symptoms of lead poisoning ana if it has any effect in removing lead from the body, host of the above items will bo deter mined by clinical means. It is also planned to determine lead lev*;Is in the body '"uias throughout the experiment on all animals. N 6U-05 LIA00375 V -2- This can be done for ,9,1.60.00, which is .distributed as follows: board and room for dogs for one year Z 960.00 Aninal Custodian 2lt00.G0 Chemist (Part time) 1300.00 Supplies (chemicals, pqper, notebooks, etc.) 300.03 vie believe the above proposal to be worthy cf your consideration. Any further questions which might arise in your mind will be answered promptly, or if you have any suggestions or criticisms of the abovi please communicate them to us. March 2, 19U9 Frank Princi, M.D., Director Division of Industrial Medicine 61A003 ?6 k Board of Directors Meeting Minutes COPY Exhibit "C" May 12, 1949 STATS OF NS< YORK DEPARTMENT OF L_i30R Albany NEW YORK OFFICE 80 CENTRE STREET May 6, 19ii9 New York, ...Y- Division of Industrial r^'giene and Safety Standards' Mr, Manfred Bowditch Director of Health and Safety Lead Industries Association it20 Lexington Avenue New York, New York Dear Mr, Bowditch: In line with our telephone conversation last week, I am presenting you with a brief resume of our projected lead study for consideration by the Lead Industries Association at their next meeting on May 12th. It is, as you will see, primarily an effort to find better methods than are now available for the early detection of leal absorption or l^ad intoxica tion as an aid to prevention--methods which ara also less subject to error from contamination of samples. Present inaccuracies stem largely from the fact that cne is attempting to obtain accurate quantitative estimations of minute amounts of load in blood or urino, for example, where the very substance to be measured is also the contaminant. Another ocjcctivo is to obtain furtnor data on some of the more obscure physiological and biochemical mechanisms involved. The stuefy will include briefly: 1) A determination of coproporphyrins in the urine, both by the usual raDid field method and a more detailed research method, in order to check ano relative accuracy of the former and develop further information as to the pnysiological significance of this test, 2) Special studies to demonstrate abnormal physiology in red blood ceils which may load to a simple field tost for evidences of early lead intoxica tion. 3) Selected blood chemistry determinations. N 611.06 \_1A003W 5. ' t r-A Mr. Manfred Bowditch Page Two May 6, 19u9 Ii) The usual occupational histories; physical examinations; nenatological studies including stipple cell count and basophile aggregation tests; and chemical estimations of the lead content of blood and urine oy standard methods. 5) Air lead determinations to evaluate the exposure cf the workers under study. In order to properly evaluate the significance and usefulness of the newer procedures contemplated* we believe it will be necessary to careful_y correlate all such findings with the mere familiar laboratory and clinical data now available vdth reference to lead absorption, lead poisoning anu lead exposure, for that reason, v.re propose to include the conventional studies listed under k). We believe we are fortunate in having the cooperation of the Memorial Hospital in How York City in connection v-lth the coproporphyrin determinations First, they have a metabolism research laboratory which is -working full time on porphyrins in relation to cancer; and they are using chemical methods which arc quantitatively far more .accurate than anything in use elsewhere either here or abroad. Since ether extraction is a necessary part of their method and the quantities of ether necessary are large, no industrial hygi ne or public health laboratory could possibly take on the potential explosion hazard-involved in its use. Furthermore, it will be an opportunity for us tc contribute tc cancer research in providing Memorial Hospital with data on workers exposed to lead for comparison with all of thuir ether data on a large variety of cancer patients* It seems to us that tnis is a golden opportunity for a scientific study in which the Lead Industries Association could also participate. in so doing, they would be malting a ccneriouticn to a. better scientific understanding of lea.d poisoning, which is on- of their important oejectives, as I understand it. Needless to say, their cooperation vould gr_atly simplify our problem of getting the necessary scries of lead -workers for the study, and w<. woulu .appreciate this assistance greatly* If you were not personally connected with the LanaIndustries Associa tion at this time, it would probably not h.nv._ occurred to ustc suggest this as a cooperative project. But I think you wile agree vdth me that it is worthy rf consideration. If any questions -arise which I can clarify, please let me know. Very sincerely yours, s/ ;.I:y ft. layers MRM:MK t/ lay ft. Layers, M.D. Chief, Medical Unit L1A00371