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Comments from Michael J. Oldham Ph.D., Associate Principal Scientist, and Willie J. McKinney Jr., Ph.D., D.A.B.T., Director, Product Integrity, Altria Client Services, March 5, 2012, re: Wertz et al. 2011 “The Toxic Effects of Cigarette Additives. Philip Morris’ Project Mix Reconsidered: An Analysis of Documents Released through Litigation”, PLoS Medicine, December 2011, Vol 8(12).
Posted by Michael_Oldham on 08 Mar 2012 at 19:09 GMT
In response to Wertz et al. 2011, we offer the following comments. Our Project Mix studies, like our PM USA cigarette ingredient testing program, were based upon sound toxicological principles and guidelines. We developed our testing program by adapting toxicological evaluation approaches used by the United States Food and Drug Administration for food  and proposed by the Consumer Product Safety Commission for cigarettes . Our program is also consistent with the German Institute of Standardization (Duetsches Institut fur Normung) approach for testing cigarettes [3,4]. We used classical toxicological evaluation assays and internationally recognized methods [5-8] (including group size recommendations) adapted for use with mainstream cigarette smoke. The purpose of our cigarette ingredient testing program is to ensure that any ingredients added to cigarettes do not increase cigarette toxicity.
We conduct our ingredient testing studies in accordance with country specific Good Laboratory Practice guidelines [9, 10] and humane animal care and use guidelines . Additionally, we use analytical chemistry, in-vitro, and in-vivo toxicological endpoints that are validated for mainstream cigarette smoke. We recently published on the power of these assays to discriminate effects of ingredients added to cigarettes . Although we provided data that allow various methods of normalization, we agree with the comment by Philip Morris International’s Dr. Dempsey that total particulate matter (TPM) is the most appropriate metric to normalize constituent data.
The conclusions from our Project Mix studies are consistent with results from other cigarette ingredient studies [e.g. 13-18]. For example, two other studies evaluated mixtures of cigarette ingredients and reached the same conclusions as our Mix studies [19, 20]. In addition, our individual cigarette ingredient testing studies, in which we tested exaggerated levels of individual cigarette ingredients, reached the same conclusion as our MIX studies [21-36]. Most importantly, conclusions from cigarette ingredient studies are consistent with recent human epidemiological evidence which indicates there is no direct evidence suggesting that smoke from cigarettes with ingredients is any more hazardous than smoke from cigarettes without .
1. FDA 1993. Toxicological Principles for the Safety Assessment of Food Additives and Color Additives Use in Food (Redbook II).
2. CPSC 1993. Toxicity testing plan for low ignition-potential cigarettes, Consumer Product Safety Commission.
3. DIN-Fachbericht 133, 2004. Toxicological evaluation of additives for tobacco products – A guide. Bestellnummer:97615. Beuth Verlag GmbH.
4. DIN-Fachbericht 133, 2005. Toxicological evaluation of additives for tobacco products – A guide. Bestellnummer:97615. Beuth Verlag GmbH.
5. OECD. 1981. No. 413. Subchronic inhalation toxicity: 90-day study. In OECD Guideline for the testing of chemicals. Paris, France.
6. OECD. 1997. No. 471. Bacterial reverse mutation test. In OECD guideline for testing of chemicals. Paris, France.
7. ICH. 1995a. Guidance on Specific Aspects of Regulatory Genotoxicity Tests for Pharmaceuticals: S2A. In International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. Geneva, Switzerland.: International Conference on Harmonisation; ICH. 1995b. Guideline on the need for carcinogenicity studies of pharmaceuticals: S1A. In International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. Geneva, Switzerland: International Conference on Harmonisation
8. ICH. 1997. Genotoxicity: a standard battery for genotoxicity testing of pharmaceuticals: S2B. In International Conference on Harmonisation of technical requirements for registration of pharmaceuticals for clinical use. Geneva, Switzerland: International Conference on Harmonisation.
9. Grundsatze der Guten Laborpraxis (GLP) 1994. Anhang 1 (zu §19a Abs. 1) der Neufassung des Chemikaliengesetzes vom 25 Juli 1994:Bundesgesetzblatt I (47):1703-1732.
10. OECD. 1997. The Principles of Good Laboratory Practice, OECD C(97)186/Final.
11. American Association for Laboratory Animal Science Policy on the Humane Care and Use of Laboratory Animals. 1996, Guide for Laboratory Animal Facilities and Care.
12. Oldham MJ, Haussmann Hans-Juergen, Gomm W, Rimmer LT, Morton MJ, McKinney Jr. WJ, 2012. Discriminatory power of standard toxicity assays used to evaluate ingredients added to cigarettes, Regulatory Toxicology Pharmacology. 62:49-61.
13. Roemer E, Hackenberg U. 1990. Mouse skin bioassay of smoke condensates from cigarettes containing different levels of cocoa. Food Additives and Contaminants, 7, 563-9.
14. Gaworski CL, Dozier MM, Heck JD, Gerhart JM, Rajendran N, David RM, Brennecke LH, Morrissey R. 1998. Toxicologic evaluation of flavor ingredients added to cigarette tobacco: 13-week inhalation exposures in rats. Inhal Toxicol, 10, 357-81.
15. Gaworski CL, Heck JD, Bennett MB, Wenk ML. 1999. Toxicologic evaluation of flavor ingredients added to cigarette tobacco: skin painting bioassay of cigarette smoke condensate in SENCAR mice. Toxicology, 139, 1-17.
16. Stavanja MS, Ayres PH, Meckley DR, Bombick BR, Pence DH, Borgerding MF, Morton M, Mosberg AT, Swauger JE. 2003. Toxicological evaluation of honey as an ingredient added to tobacco. Journal Toxicology Environmental Health, 66, 1453-73.
17. Stavanja MS, Ayres PH, Meckley DR, Bombick ER, Borgerding MF, Morton MJ, Garner CD, Pence DH, Swauger JE. 2006. Safety assessment of high fructose corn syrup (HFCS) as an ingredient added to cigarette tobacco. Experimental Toxicology Pathology. 57, 267-81.
18. Stavanja MS, Curtin GM, Ayres PH, Bombick ER, Borgerding MF, Morgan WT, Garner CD, Pence DH, Swauger JE. 2008. Safety assessment of diammonium phosphate and urea used in the manufacture of cigarettes. Experimental Toxicology Pathology. 59:339-353.
19. Baker RR, Massey ED, Smith G. 2004. An overview of the effects of tobacco ingredients on smoke chemistry and toxicity. Food Chemical Toxicology, 42S:S53-S83.
20. Renne, R. A., Yoshimura, H., Yoshino, K., Lulham, G., Minamisawa, S., Tribukait, A., Dietz, D. D., Lee, K. M., and Westerberg, R. B. 2006. Effects of flavoring and casing ingredients on the toxicity of mainstream cigarette smoke in rats. Inhalation Toxicology. 18:685-706.
21. Carmines EL, Lemus R, and Gaworski CL. 2005. Toxicologic evaluation of licorice extract as a cigarette ingredient. Food and Chemical Toxicology. 43:1303-1322.
22. Carmines EL, and Gaworski CL. 2005. Toxicological evaluation of glycerin as a cigarette ingredient. Food and Chemical Toxicology. 43:1521-1539.
23. Lemus R, Carmines EL, Van Miert E, Coggins CRE, Anskeit E, Gerstenberg B, Meisgen T J, Schramke H, Stabbert R, Völkel H, Terpstra PM. 2007. Toxicological comparisons of cigarettes containing different amounts of vanillin. Inhalation Toxicology. 19:683 - 699.
24. Gaworski C L, Lemus-Olalde R, and Carmines EL. 2008. Toxicological evaluation of potassium sorbate added to cigarette tobacco. Food and Chemical Toxicology. 46:339-351.
25. Gaworski CL, Oldham M J, and Coggins CRE. 2010. Toxicological considerations on the use of propylene glycol as a humectant in cigarettes. Toxicology. 269:54-66.
26. Gaworski CL, Oldham MJ, Wagner KA, Coggins CRE, Patskan G.J. 2011. An evaluation of the toxicity of 95 ingredients added individually to experimental cigarettes: approach and methods, Inhalation Toxicology. 23 (S1):1-12.
27. Gaworski CL, Wagner KA, Morton MJ, Oldham MJ. 2011. Insights from a multi-year program designed to test the impact of ingredients on mainstream cigarette smoke toxicity, Inhalation Toxicology. 23(S1):172-183.
28. Coggins CRE, Wagner KA, Werley MS, Oldham MJ. 2011. A comprehensive evaluation of the toxicology of cigarette ingredients: carbohydrates and natural products, Inhalation Toxicology. 23(S1):13-40.
29. Coggins CRE, Edmiston JS, Jerome AM, Langston TB, Sena EJ, Smith DC, Oldham MJ. 2011. A comprehensive evaluation of the toxicology of cigarette ingredients: essential oils and resins, Inhalation Toxicology. 23(S1):41-69, 2011.
30. Coggins CRE, Fisher MT, Smith DC, Oldham MJ. 2011. A comprehensive evaluation of the toxicology of cigarette ingredients: cocoa derived ingredients, Inhalation Toxicology. 23(S1):70-83.
31. Coggins CRE, Merski JA, Oldham MJ. 2011. A comprehensive evaluation of the toxicology of cigarette ingredients: heterocyclic nitrogen compounds, Inhalation Toxicology. 23(S1):84-89.
32. Coggins CRE, Sena EJ, Langston TB, Oldham MJ. 2011. A comprehensive evaluation of the toxicology of cigarette ingredients: aromatic carbonyl compounds, Inhalation Toxicology. 23(S1):90-101.
33. Coggins CRE, Jerome AM, Edmiston JS, Oldham MJ. 2011. A comprehensive evaluation of the toxicology of cigarette ingredients: aliphatic carbonyl compounds, Inhalation Toxicology. 23(S1):102-118.
34. Coggins CRE, Liu J, Merski JA, Werley MS, Oldham MJ. 2011. A comprehensive evaluation of the toxicology of cigarette ingredients: aliphatic and aromatic carboxylic acids, Inhalation Toxicology. 23(S1):119-140.
35. Coggins CRE, Frost-Pineda K, Smith DC, Oldham MJ. 2011. A comprehensive evaluation of the toxicology of cigarette ingredients: aromatic and aliphatic alcohols compounds, Inhalation Toxicology. 23(S1):141-156.
36. Coggins CRE, Sena EJ, Oldham MJ. 2011. A comprehensive evaluation of the toxicology of cigarette ingredients: inorganic compounds, Inhalation Toxicology. 23(S1):157-171.
37. Lee PN, Forey BA, Fry JS, Hamling JS, Hamling JF, Sanders EB, and Carchman RA. 2009. Does use of flue-cured rather than blended cigarettes affect international variation in mortality from lung cancer and COPD? Inhalation Toxicology. 21:404-430.
Philip Morris USA's letter (also) continues business as usual
glantz replied to Michael_Oldham on 28 Mar 2012 at 04:17 GMT
Like Philip Morris International’s response to our paper on Project Mix, Philip Morris’ USA’s response sidesteps the two most important findings in our paper: (1) After it found that the levels of many toxins in the smoke from cigarettes with additives increased (and TPM, generally by even more), Philip Morris changed the Project MIX protocol to normalize by total particulate matter (TPM), thereby obscuring the absolute increases; and (2) The animal toxicology studies were seriously underpowered, making it unlikely that it would detect statistically significant changes in biological effects due to the additives.
Philip Morris USA simply ignores the first finding, that the use of a post-hoc normalization by TPM obscures the absolute increases in many toxins associated with putting the additives in the cigarettes.
In response to the fact that the Project Mix studies were seriously underpowered, Philip Morris USA says that “We used classical toxicological evaluation assays and internationally recognized methods (including group size recommendations) [emphasis added].” They go on to state that “we recently published on the power of these assays [used in Project Mix] to discriminate effects of ingredients added to cigarettes.” As Philip Morris notes in reference 12 (a paper by Oldham himself) in its comment, the power of a study depends on the size of the effect one seeks to detect, the confidence with which one wishes to be able to detect that effect, and the underlying variation in the response. These are all factors which depend on the specific situation, so one cannot rely on “group size recommendations” developed in general. Indeed, the power calculations presented in reference 12 demonstrate a very wide range of minimum detectable effects (reflecting corresponding wide variations in power) for the Project Mix assays. More important, reference 12 shows that many of the assays had very low power to detect the kind of small changes in toxicity that would be important when exposing tens of millions of people to a toxin. The minimum detectable differences (with 80% power) for many of the endpoints reported in reference 12 exceeded 20%, with many exceeding 50% or even 100%. Even a 5% increase in toxicity would have devastating population impacts on the 40 million smokers in the United States.
Indeed, given the need to demonstrate a negative result (i.e., no increase in toxicity due to the additives), one could argue that studies should be large enough to achieve 95% power to detect modest effects (similar to the 95% confidence often used when drawing positive conclusions).
Philip Morris USA cites several studies that “reached the same conclusions” (references 13-32 in their comment) as Project Mix. Every one of these studies was conducted by people working for a tobacco company (Philip Morris/Altria: references 13, 21-37; Lorillard Tobacco: 14, 15; RJ Reynolds: 16-18; British American Tobacco: 19; Japan Tobacco International: 20).
Philip Morris USA cites a paper by long-time industry consultant Peter Lee (reference 37) and coauthored with EB Sanders from Philip Morris and RA Carchmann, Vice President, Scientific Affairs at Philip Morris Incorporated from 1997-1999, as evidence that “recent human epidemiological evidence … indicates there is no direct evidence suggesting that smoke from cigarettes with ingredients is any more hazardous than smoke from cigarettes without.” (This paper did not indicate any funding source.) The first problem with this statement is that reference 37 is not a study of additives, but rather a study of flue-cured versus blended cigarettes on chronic obstructive pulmonary disease. While reference 37 states that flue-cured cigarettes use fewer additives than blended cigarettes (page 405, the flue-cured cigarettes are not additive free. In addition, there are many other differences between these two types of cigarettes than just the additives that are used. Moreover, as demonstrated by our analysis of the Project Mix toxicological studies shows, the additives as associated with many toxicological changes beyond those that lead to chronic obstructive pulmonary disease.
It is also important to consider the source of reference 37. Peter Lee has an established history of reaching conclusions that tobacco products and secondhand smoke do not increase disease risk. In one particularly well-documented case, he worked under the direction of industry lawyers and executives to publish a paper designed to contest the first large Japanese prospective epidemiological study (Hirayama, 1981) linking secondhand smoke with lung cancer (Hong and Bero, 2002; Yano, 2005). The tobacco companies, working with the Covington and Burling law firm, wanted to contest the accuracy of the measure of exposure to secondhand smoke in the Hirayama study as a way to undermine its conclusion that secondhand smoke caused lung cancer in nonsmoking women married to smokers. In the original plan, the paper was to be authored by Japanese investigators, Eiji Yano and Jun Kagawa, with Lee serving as a consultant rather than an author. When the Japanese investigators refused to put their names on the paper the tobacco industry drafted, they were replaced by Lee. Later, when learning that Lee had published the results, Yano (2005) published an analysis showing that the measures of exposure to secondhand smoke were accurate. Given this history, one cannot rely on reference 37 as independent evidence that additives do not increase the toxicity of cigarettes.
Philip Morris USA noted that the experiments were conducted in accordance with good laboratory practices. We did not identify any problems with the actual conduct of the experiments. Quite the contrary, we assumed that their measurements were unbiased when we concluded in our paper that the appropriate interpretation of the Project MIX results is that “many of the toxins in cigarette smoke increase substantially when additives are put in cigarettes, including the level of TPM, and that, assuming that the toxicological results from Project MIX represent unbiased estimates of the true biological effects, these data show many adverse biological consequences (and that the failure to reach statistical significance was the result of underpowered studies rather than lack of an effect).”
Nothing in Philip Morris’ USA’s letter changes our conclusion that, “In particular, regulatory authorities, including the FDA and similar agencies elsewhere who are implementing FCTC articles 9–11, could use the Project MIX data to eliminate the use of these 333 additives (including menthol, which is the major component of ingredient group 3) in cigarettes.”
Indeed, like the exchange with Philip Morris International, Philip Morris’ USA’s refusal to forthrightly engage the substantive issues raised in our paper reinforces our recommendation that scientists and regulators cannot take at face value statements regarding the safety of its products offered by Philip Morris (or other tobacco companies).
Marcia Wertz, PhD RN
Thomas Kyriss, MD
Suman Paranjape, PhD
Stanton A. Glantz, PhD
Hirayama T (1981) Non-smoking wives of heavy smokers have a higher risk of lung cancer: A study from Japan. BMJ 282:183-5.
Hong MK, Bero LA (2002) How the tobacco industry responded to an influential study of the health effects of secondhand smoke. BMJ 325: 1413-1416.
Yano E (2005) Japanese spousal smoking study revisited: how a tobacco industry funded paper reached erroneous conclusions. Tob Control 14: 227-233; discussion 233-225.