Tobacco Documents Online

~eis~urger Associates N. White Plains, NY On Friday, August 21, 1987, a meeting was held in Elmsford, NY, from 8:30 am to 6:00 pm between John H. Weisburger and the following key professional staff of RJR: A. Wallace Hayes Johnnie R. Hayes William Y. Rice, Jr. Christopher Coggins John H. Reynolds J. Don deBethizy David J. Doo!ittle Michael F. Borgerding Arnold T. Mosber~ .i; ...... ": Gary T. Burger :~~The ~ge.nda dealt with a presentation by RJR Staff of ~rese~ undertaken on comparative toxicological properties of ~ Produc~ and a reference IRF~. of the problems associated ~ith the use of the stand~ smoking products in relation to risk for coronary heart disease, specific types of cancer, emphysema, and related problems in the respiratory tract, RJR has invented a smoking product with a radically new revolutionary ~esign in order to avoid many of the adverse claims associated with conventional smoking products. The toxicological studies aim to provide the evidence needed to underwrite safety claims associated with Alpha Product. The use of a standard smoking product involves the combustion of tobacco leading to thousands of chemicals in the mainstream and the sidestream. It is thought t~at a number o? the adverse effects claimed stem from complex interactions of some of these key chemical classes.

~eisburger Associates N. White Plains,.NY Adverse effects have been associated with the presence of appreciable amounts of polyoyclic aromatic hydrocarbons, tobacco specific nitrosamines, and other nitrosamines, reactive nitrosating elements, aromatic and heterocyclic amines, and acidic compounds like phenols, catechols, aldehydes, thiocyanate, and HCN. In great part the Presence of these chemicals in the mainstream has been related to adverse effects as regards cancer, emphysema, and respiratory tract Oiseases. Recently emission of some of these products in the sidestream smoke has been of concern in relation to passive smoking. In addition, standard p~oducts emit appreciable amounts of CD, C02, and nicotine. The presence of CO and in part of nicotine has been thought to be related to an increase risk of myocardial infarction, at least in individuals on a Western nutritional tradition. During our review of the comparative properties o~ Alpha Pro~i~!with !RF4, a number of specific approaches were revving. This i~cludes the physical design and combustion p?o~r~es, the aerosol chemistry, the analytical chemistry, ~the~biological a~tivities in relat.~on to gene~ic toxicology ~iin ~0 and in vivo (urinary ~utagens>, any promoting ~ ..-...~ff~F~t.~ detailed inhalation experiments in animals short ~ up to 90 days as well as physiological and pat~'~ogical observations. ~ecently, behavioral smoking pat~, utilizing Alpha Product and a customarily used pro~~.~ were compared. A number of the experiments to delineate the properties of Alpha Product were conducted not only in house at ~DR but also in a select number of highly qualified external contract laboratories. It can ~e noted that the results o~tained in contract laboratories confirmed and extended the results obtained at RJ~ suggesting a high quality design and performance of tests. Exacting chemical analyses demonstrate that alpha product yields smoke that is totally different in relation to many components relevant to toxicology compared to reference smoke. Thus, virtually absent is the large class of polycyclic hydrocarbons, of phenols and catechols, and the presence of only small amounts o~ aldehydes and of the tobacco specific nitrosamines (4 units compared to 130 to bOO). Also absent are HCN and thiocyanate. The levels of CO are Io~er, usually about one half, as are the nicotine levels.

~eis~urger Associates N. White Plains, NY Detailed studies in cell systems, including those to reveal genetic and promoting effects confirm the absence of significant amounts of chemicals that would be expected to affect such cell systems. Thus the biological effects observed extend the chemical findings. Inhalation tests in rats on Battelle smoking machines for R weeks and for 90 days also gave very little evidence of any physiological and pathological effects of alpha product, whereas such effects were observed with the reference material. Enlargement of the heart was seen in some tests. The use of Alpha Product by humans provided information about achieved nicotine titers in blood and also showed that use~-s did not excrete any additional mutagens whereas with reference material mu~agens were noted in urine. The ~C.~S idera~ ions outlined above deal mainly ~i~ o v e ~:~ ..... proOlem of risk for n~op lastic diseases and em~h:~sema as studied by chemical and biologic ao~roaches. ~~:~App~:~es ~o evaluate any risk fhr myocardial infarction ~a r e ~m~ more difficult to de~i ne mainly because the ~ ~mec~m whereby smoking of co~entional p~oducts may lead to ~s condition has not ~een defined precisely. Hypo ~es suggest that inhaled CO and nicotine meta:~:~"[~es are involved. ~ is ou~ view that these agents, in td~n, exacerbate p:e-exist ing conditions like at~erosclerosis in individuals on a typical Western nutritional tradition. Perhaps this is the reason why has not been possible to design appropriate animal models to mimic ~his particular effect and approach an understanding of the underlying mechanisms. I am aware of alternative explanations like the singular vascular damage by unknowns in tobacco smoke as a first step in athe~osclerosis. I am, however, not impressed wit~ the evidence produced thus far. Thus, the only current element on which to base a possible risk situation "as regards heart disease is the presence of CO measured through carboxyhemoglobin titers, and nicotine levels measured as such or as metabolites.

WeisPurger Associates N. White Plains, NY Alpha Product appears to yield about 50% of the CO and carboxyhemoglobin levels compared to the reference material. If the preceding discussion is relevant, one would conclude that alpha product is of lower risk. The nicotine levels in Alpha Product are also somewhat lower than in many standard produots. However, it has been shown with standard cigarettes of varying nicotine outDut that smokers tend to compensate use pattern in order to ensure a certain specific blooO level. Your group has performed detailed studies in this area including mechanism studies on bharmacokinetics of infused nicotine. It appears clear that Alpha Product offers the user nicotine in a manner that will be not too dissimilar from that of other cigarettes but at a lower level t yet sufficiently high that the alleged pharmacological requirement is met. Sugg~:~!on for Additional Experiments RJR i~sta~f has noted a number of spontaneous suggestions that ~ e r e made during their pr es.entat ions and ensuing ~sc~ons. I will list here a( few that are oonsidere~ ~ ~rel~ that might not have been emphasized during our F i r ~.~ would like to reiterate the essence of our conc~'t~sions on the desirability of select experimentation on the skin of Swiss mice or other a~propriate strain (not Sencar } on the question of initiation and promoting potential of smoke condensates. I should be glad to help design such experiments. We also noted the desirability in human users to test for the presence of reactive nitrosation potential by giving subjects a pulse of praline and analyzing urine for nitrosopraline. • With standard cigarettes, a positive finding has been made. It will be useful to evaluate this particular question ~ith Alpha Product. ' 14042

Weisburger Associates N. White Plains, NY It has been shown that standard cigarettes lead to hi~ner levels of certain of the cyto~hrome metabolic enzymes in appropriate test systems and would be useful to evaluate Alpha Product in such tests. Because of the absence of polycyclics, I guess Alpha Product would be negative. Along these lines, certain endocrine levels are also different in users of conventional cigarettes, a finding a~counting perhaps for a lower risk far certain of the endocrine-related cancers. It might be useful, although not essential, to explore t~is area. Summary risk for conditions that ~gative elements in us emp h~s~a, respiratory tra~t ~"~ ~n e o ~i a, and cancee in s~l e~t o~ Alpha ~oduct ~s a ma;o~ The data presented on a comparison of the toxicological p~oper ties of Alpha Product compa~e~ to convent ional ma~.erials lead to the concluSiOn tha~ this ne'a product does not ~ many of the components of the conv-=ntional product t~a~e been associated with disease risk. Thus, ev~n~. ~hat t~e user of Alpha P~oduct will ~e at lo~, preyiously ~ere one of the user s ~" especially ~:oblems of .' aDno~mal it ies including other o~gans. In my technological advance, base~.~ an intimate understanding what kind of potentially har~ elements haO to ~e eliminated. Alpha p~oduct successful, in my opinion, in meeting this goal. , 14.043