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Comments on: ENVIRONMENTAL TOBACCO SMOKE: A GUIDE TO WORKPLACE SMOKING POLICIES [Dratl] EPA 40016-901004 Response Addressing: Chapter 1: What Is ETS? Section: Toxins and Irritants Topic: HCN Prepared by: Patricia Martin, Ph.D. R&D Chemist R.J. Reynolds Tobacco Company October 1990

SUMMARY: The statements in the EPA Public Review draft document, "Environmental Tobacco Smoke: A Guide to Workplace Smoking Policies", concerning toxic effects of hydrogen cyanide (HCN) are misleading and inappropriate. Although HCN is toxic at elevated exposure levels, the physiological responses have been shown to be insignificant at concentrations found in environmental tobacco smoke. Consequently, the statement that HCN is "more potent than carbon monoxide in its ability to starve one of oxygen" is deceptive and inappropriate. Claims regarding the relative concentration of HCN in sidestream-versus-mainstream smoke are incorrect. COMMENTARY: Statements concerning HCN toxicity in the EPA Public Review draft document, "Environmental Tobacco Smoke: A Guide to Workplace Smoking Policies" ('The Guide"), although true, are misleading and inappropriate in a document on environmental tobacco smoke (ETS). The physiological responses listed on page 9 have not been demonstrated at concentrations of HCN measured in ETS. In fact, an EPA document published in 1981, "Health Effects of Hydrogen Cyanide" [1], claimed a "no effect" response at HCN levels far above those reported in the majority of the ETS scientific literature [2,3]. Only one paper reported an ETS HCN concentration within the "no effect" range [4]. In addition, we emphasize that the "no effect" range is far below the threshold limit value (TLV) and permissible exposure limit (PEL) set by the American Conference of Governmental Industrial Hygienists (ACGIH) or OSHA [5]. Specific critique is presented below.

Chapter 2: WHAT IS ETS?: Toxins and Irritants: "Sidestream smoke has been documented to contain more of each of these compounds than mainstream smoke u" This statement is not true in the case of HCN. Mainstream deliveries of HCN are higher per cigarette than sidestream values. This fact is clearly documented not only in general tobacco technical literature [6], but also in the reference cited by the EPA [7]. The accompanying "support" document "Health Effects of Passive Smoking: Assessment of Lung Cancer in Adults and Respiratory Disorders in Children" (EPA 600/6-90/006A, External Review Draft), also contains an error in the Sidestream/Mainstream (SS/MS) value for HCN. Specifically, Table C-2 (page C-19) of this document incorrectly reports SS/MS ratios of three compounds: 3-methylpyridine, 3-vinylpyridine and hydrogen cyanide. Either the authors have inaccurately transcribed entries from the original source [81 or miscalculated "averages." Following the authors' technique of averaging the high and low values of a reported range (in itself a questionable practice) to achieve a "representative value," the proper ratios for these substances should be 8, 30 and 0.18, respectively (as opposed to the reported 13, 10 and 30). The ratio reported for HCN is two orders of magnitude greater than the properly calculated value. OD ~ ~ In addition to these SS/MS relative concentration errors, the Guide fails to put ETS HCN 6D. ~ r+ 2

concentrations in perspective, either with respect to standard threshold levels or to other ETS components. This makes assessment of exposure significance impossible. The following discussion provides some of the important background information which is indispensable if the HCN section is to be retained. IndustriaUOccupational Sources of HCN Annual cyanide production in the United States has been documented at approximately 700 million pounds [9]. It is used for industrial production of acrylonitrile, methyl methacrylate, adiponitrile, and sodium cyanide. Inorganic cyanides have many uses - the two major uses being electroplating and metal treatments. Other industries using cyanide are the steel and chemical industries. Organic cyanides are used in the production of acrylic and methacrylic fibers, nitrile elastomers, and plastics. Cyanide is an intermediate in the manufacture of synthetic fibers, inorganic salts, and nitriles as well as a reagent used in the photographic development process [9]. Ttte industrial applications listed above are potential sources of environmental HCN. Pollutant sources include atmospheric emissions from petrochemical industries and automobiles with improperly functioning catalytic converters. In addition, HCN is a frequent product of combustion processes. A well-known example is a house fire in which plastic materials are burned. Combustion of wool, silk, nylon, polyurethane, and melami.ne resins 3

may also produce HCN. Finally, HCN is used as a rodenticide and an insecticide. All are common sources; and all afford possibilities for airborne exposure [9]. Government Regulations and Standards In 1977 the American Conference of Governmental Industrial Hygienists (ACGIH) adopted a TLV for HCN on a time weighted average of 10 ppm (11 mgim) [9]. The ACGIH asserted this concentration represents a "two-fold safety margin" against mild symptoms and a "7-to-8-fold safety margin" against lethal effects of cyanide. Five other countries have set a more conservative standard of 0.3 mg/m3 (0.27 ppm); most countries have set levels comparable to that of the United States [9]. The ACGIH has summarized the adverse effects in humans resulting from exposure to HCN. Specifically, exposure to concentrations of 45 to 54 ppm can be tolerated for 1 hour with no immediate or delayed effects; concentrations of 18 to 36 ppm produce "slight" symptoms after several hours of exposure [5]. Although the ACGIH considered in 1979 a recommendation to set a 3 ppm TLV-ceiling for HCN, a majority of members favored retention of the 10 ppm ceiling. The 10 ppm TLV is based on studies indicating some health (physiological) effects at 18 to 36 ppm levels, and no observed effects at 10 ppm. More recent epidemiologic data indicate that a variety of symptoms may be associated with exposure to HCN at levels less than 10 ppm [5]. As a result, on January 19, 1989 OSHA ~ ~ ~ G'1 GD W 4

set a transitional limit of 10 ppm to be in effect until December 31, 1992, at which time a new short term exposure limit (STEL) of 4.7 ppm goes into effect [10]. The lowest exposure limits on human dose-response to HCN inhalation found in the literature are as follows [1]: Threshold limit value (TLV) = 11 mg/m3 (10 ppm), Odor detection threshold = 0.2-5.5 mglm3 (0.2-5.0 ppm). No effect was found at concentrations of 0.11-0.99 mglm3 (0.1-0.9 ppm) [1]. Food and Other Sources HCN occurs chemically bound in a number of glycosides found in food [11]. Examples include: oil of bitter almonds, apricot or peach kernels, cashew nuts, some brandies, cassava (a dietary staple in Africa), lima beans, sorghum, linseed, sweet potatoes, maize, millet, bamboo shoots, cabbage, broccoli, cauliflower, turnips, radishes, garlic, horse-radish, and mustard [11). The Food and Agricultural Association/World Health Organization has set an acceptable daily intake (ADI) of cyanide from food at 0.05 mglkg-body-weight. This is about 3.5 mg/day for a 70-kg adult male [1]. [Because of the contribution from food, 5

about 3.5 mg/day for a 70-kg adult male [1]. [Because of the contribution from food, thiocyanate determination (quantification) is unsuitable as a measure of ETS exposure. This point is discussed in more detail in the "Metabolism of HCN(Exposure Due to E'TS" section below.] Sources of exposure other than food include tobacco smoke, urinary infection with cyanogenic bacteria (Pseudomonas pyocyanea), and several pharmaceuticals. Pharmaceuticals giving rise to cyanide are Laetrile (a disputed cancer treatment), sodium nitroprusside (used to treat severe hypertension and minimize bleeding during surgery) and succinonitrile, a widely used antidepressant [12]. Tobacco Smoke Hydrogen cyanide is a component of tobacco smoke. Numerous references exist in the literature in which mainstream smoke (MS) and sidestream (SS) smoke HCN concentrations are reported (as well as SS/MS ratios) [see, e.g. 61. All references report higher concentrations of HCN in mainstream smoke than in sidestream smoke. One of the most frequently quoted studies of MS and SS concentrations (of various smoke components) is the review of Klus and Kuhn [6]. These investigators reported HCN levels as follows: Mainstream HCN = 302 - 551 µgfcig, 6

SS/MS ratio = 0.17 - 0.37. These ranges are in agreement with more recently reported values [13,14]. Few measurements of environmental HCN concentrations have been reported - either in "the field" or in laboratory chamber studies. Average reported concentrations of HCN have ranged from the low value of 10-35 µg/m3 (0.009-0.0317 ppm) [2], to 56 µg/m3 (0.0507 ppm) [3], to a high value of 122 µg/m3 (0.11 ppm) [4]. All of these values faU below (or barely within) the lowest "no effect" category found in the literature. This point has been suspiciously ignored by the authors of the EPA policy guide. It is equally disturbing that the authors have chosen to juxtapose a toxicologically accurate characterization of HCN (as "more potent than carbon monoxide in its ability to starve one of oxygen") next to scientifically unsubstantiated and inflammatory statements about ETS CO exposure. [See comments by Oldaker in this appendix.] At elevated exposure levels, HCN is indeed to)dc; however, the authors' comments indicating extrapolation from elevated levels to those in ETS are obviously misleading. Metabolism of HCN/Exposure Due to ETS Hydrogen cyanide is indeed a component of tobacco smoke. However, when HCN (at the OD concentrations found in ETS) is absorbed into the body it is rapidly detoxified by the liver CA ~ 7

to thiocyanate (SCN) [13]. Since exposure is substantially influenced by diet, the use of HCN (or SCN) as a biomarker for ETS exposure is limited. In fact, not only is the specificity of SCN to tobacco smoke inhalation problematic, but also experimental differentiation of light smokers from nonsmokers is extremely difficult on the basis of SCN measurements. Finally, because sidestream smoke from a cigarette contains less HCN than mainstream smoke, the specificity problem is compounded by questions of instrumental and methodological sensitivity (13j. Recommendation If the Policy Guide includes a discussion of hydrogen cyanide (HCN) as a component of ETS, then the guide should accurately describe the properties of HCN at the concentrations found in ETS. 8

REFERENCES 1) Carson, B. L; Herndon, B. L.; Baker, L H.; Ellis III, H.V.; Horn, E.M., dro en Cyanide Health Effects, EPA-460/3-81-026, Sept. 1981. 2) Klus, H.; Begutter, H.; Nowak, A.; Pinterits, G.; Ultsch, I.; Wihlidal, H., "Analysis of Environmental Tobacco Smoke (ETS) Constituents in Indoor Air Under Controlled Conditions", Proceedings of CORESTA Symposium, Vo1.II, Oct. 27, 1986, Taormina, Italy. 3) Hoffmann, D.; Brunnemann, K. D.; Adams, J. D.; Haley, N. J.,'Tobacco Sidestream Smoke: Uptake by Nonsmokers", Preventative Medicine, 13, 608-617 (1984). 4) Ball, M.; Intorp, M.; Schilling, B., "Analysis of Environmental Tobacco Smoke (ETS) Constituents in Indoor Air Under Real Life Conditions", Paper presented at the International Experimental Toxicology Symposium on Passive Smoking, Essen University, Essen, Federal Republic Of Germany, October 23-25,1986. ) Federal Register, Vol. 53, No. 109, June 7, 1988, p. 21101. 6) Klus, H.; Kuhn, H.; Verteilung verschiedener Tabakrauchbestandteile auf Haupt- und Nebenstromrauch (Eine Ubersicht)., Beitr. Tabakforsch. Internat. 11, 229-265 (1982). 7) U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES, The Health Consequences of Involuntary Smoking, a report of the Surgeon General op.cit. p. 128, (1986). NATIONAL RESEARCH COUNCIL "Environmental Tobacco Smoke: Measuring Exposures and Assessing Health Effects," National Academy Press, Washington, D.C. (1988). 9) Towill, L E.; Drury, J.S.; Whitfield, B. L; Lewis, E. B.; Gaylan, E. L; Hammons, A. S., Reviews of the Environmental Effects of Pollutants: V. Cyanide. EPA - 600/1-78- 027, Oct. 1978. 10) Federal Register, Vol. 54, FR-2920, January 19, 1989. 11) Shephard, R. J., The Risks Of Passive Smoking, p. 50, Croom Helm Ltd, copyright 1982. 12) Vennesland, B.; Conn, E. E.; Knowles, C. J.; Westley, J.; Wissing, F., eds.; nide m Biolo¢v. Academic Press, Copyright 1981, Chapters 1-2. 13) Haley, N. J.; Sepkoric, D. W.; Brunnemann, K. D.; Hoffmann, D., "Biomarkers For 9