Tobacco Documents Online

Tnj: t'our:cu. Torr TouACCo RESEAItCH-U.S.A.. Bc. 1Narch 10, 1975 Grant Application Nb. 869A PHARPMCOLO;,I' 1D: The Committee comprising Drs. Feldmaxi, Meier and Seaaa'ers (Gardner) SZMJECT: Ronald P. Rubin, Ph.D., Medical College of Virginia, Richmond Continuation application No. b69A "The Action of Nicotine rua the Adrenal Gland" (See Stone's memora_ndmn of January 16, 1975) Dr. Gardner commented on this app].ication that r'the levels of nicotine used seem high --- 60-600 micro molar," and Dr. Lisanti, as monitor, asked Rubin what considerations led him to adopt the levels used. A copy of his reply is attached. Comaents. Of course it is legitimate for a pharmacologist to use large doses to find out what kinds of things can happen, but sooner or later he has to reduce the conditions to those that could occur in ordinary life, in order to appraise their actual significance. Because of the way Rubin reparts his experiments, it is difficult to detex7nine the nicotine concentrations actually present in the reaction media. A 6 micro molar solution of nicotine containsc,yT31+ g. of nicotine per liter or0.0009734 g• per ml. A 60 micro molar solution contains 9.734 g./liter or 0.009734 g./m1. (9•734 mg./ml) and a 600 micro molar solution contains 97.34g./liter oro.09734 g. fml. We are told that the test media contained 250,000 cells per milliliter but are not given the volumes of solution at outset nor the volumes of nicotine solutions added. Rubin states that his nicotine concentrations were "in the order of 1-10 micrograms/ml -- approxinating those fou.-id in blocd and tissue after chronic exposure to tobacco snoke" citing Larson and Silvette, Tobacco , Suppl. II. (I do not find the figure he quotes in the reference citedf Wolf et al. working back in 191+8 with the laborious steam distillation - cyanogen bromide technique, found nicotine levels of 0.1-0.28 ncg./rall in the blood, of human smokers. Desoille et al., using the same method in 1963 reported 1 to 9.8 mcg/ml. His values have been considere3 doubtful because they are so far out of line with many others. None of the earlier workers, however, appears to have been fully aware of the rapidity wich which nicotine is metabolized and excreted. Their methods could not have very adeqvately aa:o=odated the time factor in any case. Armitage et al., in 1974, rreported that four human subjects who inhaled habitually, achieved arterial kapod nicotine levels of 30-~0 ng.,/ml (0.03-Q.04 ncg./ral) when smoki.:g, as nurma)ly as possible, one radiolabelled cigarette, at one puff per ninute for 9-11 total puffs. (They were estiaated to have absoroed 1Yom 1.s3 to 2.62 a.g. of total nicotine from the eiCarette, or loJ, of that originally presPnt.)