Document rY4Vy5JrVG198a6EG0ZLqJwE

V. . . N. . ... V'T-^|. : f ^ J S& Q%gg$ F T <"* E ? r MEMORANDUM ON THE LEAD ALKYL COMPOUNDS The compounds in this series that have been studied vith respect to their toxicity consist of lead tetra ethyl, lead tetra methyl and the tri, di, and mono configurations of these tvo radicals. The formulae, the densities, and per cent of composition of lead in the molecule, the vapor pressure at 25 C, and the tcxici'ties of these compounds administered orally upon the skin are given in the table below. The data on oral toxicity demonstrate that these compounds have a toxicity of the- same order of magnitude, varying to some, degree probably in accordance with their ease of absorption from the alimentary tract; vith the exception of tetra methyl, they are absorbed through the skin to such a degree as to produce fatalities. For some reason which is not 'clear, telra methyl is absorbed only slightly and not in sufficient dosage to cause fatalities in experimental animals . This is not the consequence purely of its volatility, since its application to the skin even under conditions that have prevented volatilization have not produced acute illness and death. From the point of view of inhalation ,the lethal con- 12 to 18 y centration of lead tetra ethyl for / houis of exposure is of the order of magnitude of d .32 mgs. (expressed in terms of lead} per liter in air. Concentrations of much lesser magnitude of lead tetra ethyl will produce fatal results on prolonged expo sure. A concentration approximating .0.l8mgs. per liter will produce .fatal results after three exposures of 6 hours per 2 day on successive days. (Experimental animal here is the rabbit.) The study of inhalation exposures in the case of the other* compounds has been limited, but the Indications are that they are all of the same order of toxicity when the concentration is expressed in terms of lead. (Pb) From this fact alone one would assume that the toxicity of these compounds is referrable to their content of lead. How ever', other experimental evidence justifies this conclusion still more strongly. In particular, the distribution of lead in the organs in acute intoxication is that of a fat soluble com pound . High concentrations are found in the brain, liver, muscle, and fatty depots, with negligible quantities in the skeleton. The concentration in the brain which coincides with fatal poisoning is of the same general order of magnitude, regardless of the com pound emt)loyed. (Eeference here is made only to the compounds listed in the first sentence, since these are the only ones In the alkyl scries that have been investigated.; These organic lead compounds are decomposed in the body, the first result of this decomposition being that volatile l e a d ' compounds can no longer be reclaimed from the tissues after a few hours following their administration. A further decomposition takes place as shown by the fact that within about 1^ days of the administration of a sublethal dose the distribution of lead in the tissue corresponds to that of water soluble lead compounds rather than to that characteristic of tetraethyl lead. The clinical pictur-e of tetraethyl lead Intoxication, as veil as that produced by the other compounds mentioned pre viously, is that of an acute central nervous system intoxication and with hyperreflexia/agltatlon, which progresses into convulsions and coma. This picture can best be described in terms of the fatal human cases of poisoning. In such cases the clinical picture is the same substantially, regardless of the length of time required in terms of exposure to produce toxic concentra tions in the body . Even In those cases in which exposure to small concentrations has occurred over a period of months, the clinical picture ha3 been the came. Chronic lead poisoning has never been seen in association vith exposure to these organic lead compounds. No microscopic changes occur in the cellular elements of the blood- That is to say, there is no stippling, no anemia, and no evidence of disturbance of the bone marrow. The intoxicated individual x h si x develops mental abberations characterised by a dream-like state with wild representations, confusion, personality distortions, and hallucinosis. Ay the intoxication develops, the confusion increases and the state of acute mania may ensue, followed by convulsions, exhaustion, coma, and death. In mild cases the mental symptoms predominate and may develop and disappear without the more serious manifestations of chemical Intoxication. Even in the most acute cases the evi dences of organic intoxication are limited largely to circulatory manifestations in which there is a very low systolic and diastolic blood pressure* slow pulse andhypopyrexia . Following exposure there i3 a long lag in the appearance of symptoms. Varying with the dosage this lag varies from 2A hours to 7 or 3 days. B y reason of this lag In relation to an Incident of exposure and by reason of the bizarre clinical picture 0003421 4 the diagnosis of lead poisoning has never* been made by any physician who has not had first-hand experience previously. From the point of view of chemical warfare tactics, insofar as the writer has any familiarity with previous concepts, it would seem that this group of compounds offers little or no - promise. From the point of view of dosage, large quantities of material would be required to produce an effect. Moreover, the rime lag between exposure and the induction of symptoms is so great that disability would be greatly delayed. It is apparent tha t effective concentrations could be obtained and maintained in a combat area, a very considerable amount of incapacitation of sizable numbers of men would be brought about. However, the quantities of material that would be required, to produce this situation would be very great indeed Ho experience has been had with the higher homologues of the compounds referred to in this memorandum. Actually such compounds as have been synthesized even in small quantities, have merely been the subject of scientific curiosity with respect to their physical and chemical properties. No commercial uses have been found for them, and therefore-no effort has been expended on studies of their toxicity and mode of action. Judging from the facts available, one would assume that the toxicity of such homologues would be of the same order of magnitude as those that have been investigated, and that their properties as chemical warfare agents would be less rather than more satisfactory. The reference above to the quantities required to pro duce an effect is considered in a relative 3ense. Obviously, 0003422 5 fck less material that has to be handled the more effective should be the results, all other factors being similar. In this connection the extremely high toxicity of ricin come3 to mind, in that only the lowest concentrations of this material need be available to produce prompt and highly dramatic effects. As compared with such a material lead tetra ethyl and Its homologues must be regarded as very tame substances. } ___________________ Ro b er t A. Xeh oe, Li.D. I'ecember 12, 1994 0003423 'ijir'i',* ! 1t < 't >V 1 Vf>vV` Toxicity and Certain Properties of Alkyl Lead Compound <v Compound )erisity Lead Content Ma. Hg, Aoproximate M.L.D. In mptn/Ki? as Pb at Saf Percent___ 25.Q- Intrav. Sub.q , Oral Percutaneous indefi d; tetraethyl k' *#'. fy.f*.isw %. d- t e tramethyl Af't ^ '. 1.66 1 1.99 64..0 77.5 0.5 17.0 7O.O kO to 110* 75O rabbi t rabbit rabbit rabbit 0.2 pe $0.0 40 65-7O 20 not absorbed rabbi t rabbit with fatal results MK&ylX diethyl 1.79 70.2 $.0 10 rabbi t 150 rabbit trim ethylethyl . 1<t r i`e t h y l peth yl 1.88 I . 7I 73.7 67.O 10.0 V. 1.0 15 rabbit 25 rabbi t 210 rabbit 150 rabbit Lon apparently result of carrier, Toxicity and Certain Properties of Alkyl Lead Compounds ity Lead Content n. Hg. Approximate M.L.D. in t at Percent 2<5C Intrav. Su b ,a . Oral as Pb Concentrat Safe for Percutaneous indefinite time Lethal 66 ' 6^,0 *5 I7. 0 70.0 ifO to 110* 750 rabbi t rabbi t rabbit rabbit 0.2 per cu.m. 99 77.5 19 i 88 70,2 73.7 3O.O 3 .O 10.0 i+0 65-70 20 not absorbed rabbi t rabbit with fatal results 10 rabbit 150 rabbit 15 rabbit 210 rabbi t 4 .5 pe rab 71 67.0 1.0 25 rabbit 150 rabbit htly result of carrier. Toxicity and Certain Properties of Alkyl Lead Compou Tonicity and Certain Properties of Alkyl Load Compounds isity Lead Content lik. Hq , Aopmxifsate ll.L.D. in mara/K as Pb Concentr ' 4 Percent at Safe for 25C Xntrav. Sub.a. Oral Percutaneous indefinite time Letha 66 64.0 0.5 I7.O 70.0 k O to 110 750 rabbit rabbit rabbit rabbit 0 .2 per cu.m. 77.5 3O.O 40 65-7O 20 not absorbed rabbit rabbit with fatal results .79 70.8 3 .O 10 rabbit 150 rabbit 4 .5 r .88 73.? 10.0 15 rabbit 210 rabbi t .71 67.O 1.0 25 rabbit 150 rabbit htly result of carrier.