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Discussion on Cardiovascular Disease • 163 jvith Pu- or It's ous did m- ~me ~ore 6ng. 'e ber om I use ac- ~nst hly. ting - ~ius- 're ta ch his luy kak lom k is pnt bre gin t uly eo- kial ou rst I I place, and the rationality in which we place them comes after the initiating discovery.. This is certainly true for most new rypes of drugs that are discovered. It's interesting to note that carbonic anhydrase had been demonstrated in the stomach many years ago, and was only then discovered in the kidney when they first used sulfonamides and obtained a diuretic response. The only way you could explain this diuretic response was by actually postulating that this enzyme was there and sulfonamides inhibited it. So quite often you get some- thing amazing, biologically implausible and that then promotes discoveries that result in a rational background being discovered. I think a more economical phrase that we ought to try an& use, if we have to be stuck with this notion ofbiological plausibiliry,, is "freedom, from biological implausibility." That's putting the boot on the other foot and ask- ing people to do a little bit of thinking rather than just justifying their orignal thoughts. Joseph Wu: We'1li have the comments ftom Dr. Philip Witorsch. Philip Witorsch: Like Max Weetman, I've spent most of' my, life being at the end ofl the list. I therefore decided: to comment briefly on an aspect that none of the other speakers has addressed, namely the acute effects of' ETS exposure on, individuals with pre-existing coronary artery disease. Dr. Wexler very eloquently critiqued~ the Aronow study but there is another, very goo& study that was published in 1987 by Sheps et al. from the University of North Carolina. The Sheps study raises the issue of the biological implausibility of the acute effects postulated by Xronow. Aronow and others have suggested that the acute effects of'ETS exposure with regard to exacerbation of angina in individuals with pre-existing coro- nary artery disease relate, at least partially,,to elevation of carboxyhaemoglo- bin from ETS exposure. Superficially, this sounds like it might make sense, until' you think about the amount of carbon monoxide actually generated from ETS. Studies have shown only a slight difference in the levels of carbox- yhaemoglobin in nonsmokers exposed to ETS as compared'to those imnon- smokers not exposed. This result causes the hypothesi's to lose its plausibility. The Sheps study examined thirty individuals with welk documented cor- onary artery disease and symptomatic angina who had documentation of electrocardiographic changes on exercise typical of angina. Thty exposed these individuals in~an exposure chamber to carbon monoxide, using an end- point of approximately four percent carboxyhaemoglobin: That compares to levels usually found in nonsmokers and in their controls of about 1.5°fe carboxyhaemoglobin. Interestingly, to achieve the 4% carboxyhaemoglobin they had to expose their subjects to one hundred' parts per million of carbon monoxide in air for a period of an hour or more. This is probably three to five times the level of

! 164 • Environmental Tobacco Smoke carbon monoxide that has beemmeasured in very smoke-polluted areas. Theyy exercised these individuals and measured a variety of cardiovascular param- eters, including electrocardiographic evidence of angina, ST-T wave changes, radionuclide imaging of the heart, ejection fraction, and a number of other cardiovascular indices. They found absolutely no effect on the duration to onset of angina, or any of the objective cardiovascular parameters, despite the subjects' exposure to a hundred parts per million of carbommonoxide and a carboxyhaemoglo• bin level approaching four percent. The Sheps study, when added to all the deficiencies cited relative to the Aronow study,, should lay this issue to rest. It's very clear that in a real-life situation it is biologically implausible for the degree of carbon monoxide exposure related to ETS to have any effect as far as exacerbation of angina, I think this might have implications for studies of ETS and reproductive effects as well. Frank Sullivan mentioned earlier that carboxyhaemoglobin is thought possibly to play a role relative to reproductive effects. But it appears implausible that the degree of real-life exposure to ETS results in any signif- icant changes in carboxyhaemoglobin.. Josepb Wu: We have time for a couple of additional' comments or ques- tions from the flbor. Dr. R'oe. Francis Roe: If I could just address a question to the panel imgeneral. 1 have the impression that coronary heart disease is not a single disease but at least two. Coronary heart disease in mem under the age of fifty seems to be related' to different factors tham CHD occurring from age sixty onwards. These seem to be two different diseases, but maybe there are many others. I wonder what the implications of this are in relation to studies of ETS.. Secondly, from a causative point of view, one would be concerned with two things. The first is the set of factors that cause arteriosclerosis, and the second is the set of factors that make a fatal coronary occlusion more likely in a person with arteriosclerosis. They seem to be two different things. Aronow obviously was ]boking at the second of these. The first shoul& not be overlookedi in examining carcinogenesis, I earlier stressed the point that you need to know what an individual has been exposed to from childhood in order to get any reliable feeling of what happens in lung cancer risk. I suggested that this has not been done so far. Now, isn't this also true of cardiovascular disease? I mean, the idea of' Aronow collecting a lot of old gentlemen and sticking them all on exercise bicycles, to me, is horrific. Would' we not be better off if we really started such studies with younger people? Peter Lee: I would comment on the second of Dr. Roe's points. I suspect lifetime exposure isn't so important in heart disease as it is in respiratory disease. If one takes the analog of active smoking, the evidence seems to

} Discussion on Cardiovascular Disease • 165 ey suggest that current smoking is important and ex-smoking is not really im- m- portant because if you give up smoking, your risk reverts fairly quickly. Yet, es, there may still be something in it even so. er Ross Lorimer: A similar problem arises in studies of women. Coronary artery disease in women expresses itself differently than in men insofar as or pre-menopausali women are concerned. From a clinical point of view, the re coronary heatro disease occurring in women also is usually associated with, ~1o much smaller diameter of coronary vessels with more diffuse disease than in, young men with myocardiall infarction, in whom it is not unusual to find~ The single vessel disease, especialliy involving the left anterior descending and hav- Ilife ing an acute thrombotic episode. So I'm, sure you're absolutely right. tide Philip Witorsch: If I can just add a brief comment. I agree that there are a. different diseases involved. I think lifetime factors are important, but not tive necessarily lifetime ETS exposure or lifetime cigarette smoking. In many of n is these studies, people tend to forget that perhaps the most important deter- tars minant of, coronary artery disease is the choice of parents that one makes. nif- Added to that are diet, lifestyle, exercise and a whole host of other factors, all of which have been very poorly controlled~ for in the studies to date and es- I are, frankly, very difficult to control for. Assessing cholesterol levels is not an adequate control of many of these factors and'that's, perhaps, thcmost that's been done. It's very analogous to the token control for socio-economic status at that has been done in a lot of studies. be Jarnail Singh: I have been doing research on the effect of carbon mon- ds. oxide levels in animals since 1972. 1 have a series of papers and a series of s. I experiments where I expose mice from when they are newly born, three, four days old, until they are about eight weeks old. The mice are constantly ex- ith posed, except during cleaning and watering, to three levels of CO, 25 PPM, the 50 PPM and 100 PPM. At the end of eight weeks, we sacrifice the animals, eiy take all the tissues, lungs, hearts,spleen and kidney, and send them to a pa- ~gs. thologist to determine whether there is any dose-dependent effect on these not organs. The conclusion is that at these levels, 25, 50 and 100' PPM, there is no dose-dependent effect on the heart or on the lungs. p to get this I of icise rced ~ect ory ~ to