Tobacco Documents Online

King's College London University of London Chelsea Department of Pharmacy London SW3 6LX. UK "Health Effects of Passive Smoking: Assessment of Lung Cancer in Adults and Respiratory Disease in Children." A commentary on specific issues raised in the EPA May 1990 External Review Draft. Author: Professor J.W. Gorrod Date: September 28, 1990 My comments will relate to ideas, views and interpretations presented in Appendix C pertaining to "Dosimetry of Environmental Tobacco Smoke." C1 Introduction, line 10 refers to an increased cancer risk associated with environmental exposure levels; this is bad science and uses an emotive term unnecessarily. It is also possible that exposure to ETS could lead to a decrease in cancer risk. It is clear that the composition of ETS with regard to the various constituents and the physical chemical characteristics of the particulate matter are very different from that to which the active smoker is exposed. C2 Para. 1, line 3: Whilst it may be true that animal studies have shown that levels of certain constituents may be sufficient to be causative agents in pulmonary cancer, this certainly has not been proven for the levels of exposure found in ETS.

- 2 - C2 Para. 2, line 9: This sentence is difficult to understand: what does "typical exposure levels of ETS can be evaluated under suitable models etc." really mean? It is difficult to envisage an evaluation when "typical levels" of ETS have been determined. It is even more difficult to envisage appropriate "suitable models" with our present state of knowledge. C3 Para. 1, line 3: Why is it assumed that constituents associated with particulate phases have parameter values in common and can be treated collectively? Certain parameters such as radii, weight, moisture content, electric charge will be important to the particle as a whole until the moment of impact with the biological system; after this a completely different set of parameters, related to the physicochemical properties of each individual constituent, will be operative. Indeed it could be argued that material in either phase is irrelevant as it is only when it.interacts with a biological system that it poses any threat of toxicity. (NB This argument would be invalidated if any effects of ETS were due to suffocation; but even at the highest concentrations recorded ETS clearly would not have such effects.) C4 Para. 2, lines 7 & 8): I do not believe the statement that "The total exposure intensity for nicotine would be the sum of CN,0.5 and CN,V" is correct. Aerosol

3 particles vary in their diameter, and therefore the concentration in the particulate fraction will be CNO- which will have to be added to CN,V to give the total concentration. C4 Para. 2, penultimate line: It is interesting that having stated that "the total exposure intensity may act as a poor measure of risk" the situation is compounded by the use of "cumulative exposure" which introduces time in association with total exposure intensity - this cannot improve the measurement of risk as T is yet another unknown factor. - C5 Para. 2, line 7 et seq. The report acknowledges that the value of V may change with age and have introduced into the mathematical model; however the influence of age varies considerably depending upon when the actual time interval occurs. I suggest that the influence of T = 10 between the ages of 1-5- 25 years is very different to that obtained between say 65 - 75 years. C6 Para. 3, line 2: f should read fTB' T C9 Para. 3: at the concentrations etc. found in ETS there is no evidence that "the rate of which damage is produced in a tissue at time is assumed to be proportional to the dose rate etc." Indeed, in very many studies it is known that a virtually nil effect is observed until a critical dose

- 4 - (concentration) is reached. This is because cells have very good protection mechanisms which "mop up" either reactive toxicants or reactive metabolites produced from toxicants and so prevent their reaction with susceptible biological molecules. C11 Para. 3, ultimate line: It is not true to say "An exception is the conversion of nicotine to cotinine." We do not know what fraction of the inhaled dose of nicotine is converted to the biologically active form as we do not know what the biologically active form is; in the case of conversion of nicotine to cotinine we do not know the concentration of the 1 , 5 iminium ion under any in vivo situation in any species let alone that arising from ETS in man. As nicotine can be oxidatively metabolised by three known pathways (one producing two products) the arguments used are irrelevant to the ETS situation. C21, Para. 2, the facts are that the relative concentrations do change. What is more important is that the actual concentrations change such that no one is exposed to "pure" diluted side stream smoke. Thia is now well documented and should be properly referred to. Recognition of this would mean that all the figures for exposure to constituents of ETS are far too high.

5 C26, Para. 2, line 5: Nicotine dosimetry cannot be "particularly relevant because it is the addictive factor in active smoking." This has not been proved and in any case this situation cannot be extrapolated to ETS. While nicotine may be a precursor of carcinogenic nitrosamines, at the concentration of nicotine found in ETS any nitrosamine formed would be rapidly bound and trapped by haemoglobin within the red blood cell. It is very unlikely it would be available to react with any genetic material. C33, Para. 2, line 11: It cannot be assumed that nicotine requires the same time to traverse the alveolar cells in passive and active smokers. Whilst it can be assumed that the absorption by the GI tract does not play a significant role in ETS it is not true to say that data of nicotine absorption is not available. This is in the published scientific literature. C34 Para. 2, The metabolism of nicotine to cotinine has been studied long before Jacob et al. (1988), and the failure of the report to recognize this suggests that the report is unaware of the history, background and complexity of nicotine metabolism. Figure C-3 is a very simplistic picture of the metabolism. Some of the 17% unknowns are probably quaternary glucoronic acid conjugates recently reported.

6 C27, Para. 1, line 1 et seq.: I agree that there is a lack of data for the uptake of vapour phase components by lung tissue from smoke and particularly ETS. This paucity of data is not true for other fields and work on the uptake by the lung of drugs including volative anaesthetics and peptide is widely published in the scientific literature. Much more work is needed on ETS before any sound conclusions can be drawn. C29, Para. 1, I do not believe we have any data on the effect (if any) of ETS on mucus movement; until this is available, assumptions are unwarranted. My general conclusions are that the report is flawed by the lack of meaningful data which can be incorporated into the sophisticated (and presently meaningless) formulae. The report is also flawed by the continual reference to nicotine, as though nicotine was a marker of the passage of ETS through a biological system. Nicotine is a single specific chemical whose physico-chemical pharmacological and metabolic properties are unique. Nicotine is a marker of nicotine only and extrapolation of data to other substances, other systems etc. is totally unwarranted.