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to users and nonusers of tobacco products.” To get started, the subcommittee reviewed lists of harmful chemicals in tobacco products and smoke compiled by other countries, including Brazil, Canada, Australia, and New Zealand, as well as those listed in the World Health Organization’s Framework Convention on Tobacco Control. Altogether there were 59 chemicals and chemical mixtures included on the lists, 20 of which were common to four or more lists. Patricia Richter, a researcher with the Centers for Disease Control & Prevention’s Office on Smoking & Health, emphasized that “there is limited information on the rationale for the constituents being on the lists.” As a result, CDC looked at potential associations with known tobaccorelated diseases, she noted. SMOKING MACHINE
A CDC scientist loads cigarettes into a machine that condenses and collects chemicals in smoke for analysis.
TOBACCO TURMOIL FDA takes first steps to identify HAZARDS in tobacco products and smoke BRITT E. ERICKSON, C&EN WASHINGTON
WITH EACH PUFF of a cigarette, a smoker
inhales more than 5,000 chemicals. And smokeless tobacco is thought to contain even more compounds. It is now up to the Food & Drug Administration to decide which of those chemicals are unsafe for human health. As part of the Family Smoking Prevention & Tobacco Control Act, which was signed into law last year, FDA is required to develop a list of harmful or potentially harmful constituents in tobacco products and smoke by June 22, 2011. Tobacco manufacturers will then have one year to provide the agency with the quantities of each of those chemicals in their products, including smokeless tobacco, as well as in cigarette smoke. By June 22, 2012, FDA must make the information public so that consumers can compare the quantities of dangerous ingredients in one brand with those in another. To help meet such a daunting task and to get advice from outside experts, FDA recently formed a subcommittee of its Tobacco Products Scientific Advisory Committee (TPSAC). The subcommittee met in Gaithersburg, Md., earlier this month to discuss criteria for selecting the chemicals, to develop a draft list of chemicals that FDA should consider, and to determine
whether analytical methods are currently available for those chemicals. FDA instructed the subcommittee to focus on chemicals that are carcinogenic, those that cause respiratory or cardiovascular problems, and those that promote addiction. But that “does not imply that FDA will not be reviewing other chemicals or chemical compounds for possible inclusion” on the list, Corinne G. Husten, senior medical adviser with FDA’s Center for Tobacco Products, told the panel. Husten also referred to FDA’s draft guidance, published on June 10 in the Federal Register, which clarifies the meaning of harmful and potentially harmful constituents. According to that draft guidance, FDA interprets the phrase to mean “any chemical or chemical compound in a tobacco product or in tobacco smoke that is or potentially is inhaled, ingested, or absorbed into the body and that causes or has the potential to cause direct or indirect harm
AMONG THE 59 chemicals, “32 may play a
role in smoking-related cancers based on classifications by the International Agency for Research on Cancer, the National Toxicology Program, the Environmental Protection Agency, and reports in the peer-reviewed literature,” Richter said. In addition, 24 of the chemicals are associated with respiratory effects, 17 with cardiovascular effects, and six with addiction, she pointed out. Beyond the 59 chemicals, the subcommittee also examined the other carcinogens in tobacco products and smoke listed by the International Agency for Research on Cancer, the National Toxicology Program, and other government agencies. In addition, the panel looked at chemicals in tobacco and smoke that are toxic on the basis of criteria established by the Agency for Toxic Substances & Disease Registry, the National Institute for Occupational Safety & Health, EPA’s Integrated Risk Information System, and the California EPA. After two days of discussion, the subcommittee came up with a list of 108 chemicals that are harmful or potentially harmful in tobacco products and smoke.
The cost of analyzing a particular tobacco product for the chemicals on the draft list will likely be tens of thousands of dollars. WWW.CEN-ONLINE.ORG
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THE COST of analyzing a particular tobac-
co product for the chemicals on the draft list will likely be tens of thousands of dollars, noted Richard G. Higby, president of Arista Laboratories, a commercial lab specializing in tobacco and smoke analysis. But the cost will depend on many factors, including how quickly the data are needed and how many replicates are required, he said. Replicate analyses will be very important, Higby stressed. “Natural products are inherently variable despite mass production under seemingly uniform conditions. The variability arising from the products combined with the variability of machine smoking prior to analytical methods makes it imperative that a sufficient number of replicate analyses are made to give statistical significance to the data,” he explained. Higby also warned the panel that only six methods for tobacco and smoke constituents exist today that have been validated by the International Organization for Standardization (ISO). Those methods cover a narrow range of analytes—tar, nicotine, carbon monoxide, water, alkaloids, and benzo(a)pyrene. “Establishment of methods suitable to address all of the
constituents of likely interest to FDA will require many more years if not decades to complete,” he pointed out. But other sources of analytical methods are available for quantifying harmful chemicals in tobacco and smoke, noted Clifford Watson, a research chemist at CDC’s National Center for Environmental Health. For example, methods have been recommended by the Cooperation Centre for Scientific Research Relative to Tobacco (CORESTA), an organization that promotes international cooperation in tobacco research. In addition, methods have been developed by Health Canada, CDC, commercial labs, and the tobacco industry, he said. “There are many examples of methods in the peer-reviewed literature— too many to mention,” Watson added. Most of those methods, however, have not been validated by a collaborative approach such as the one used by ISO, which typically involves a minimum of 10 labs, Higby cautioned. One ends up with methods from single perspectives, he said. “It is not unusual for these published methods to contain conflicting detail, insufficient descriptions, or just fully erroneous information from typographical errors that prevents verbatim execution of the method.” Assuming that analytical methods can be developed and validated for all of the tobacco and smoke constituents on the list, the question then becomes: What will FDA do with the data? Representatives from both small and large tobacco companies asked FDA several times about the purpose of generating a list of harmful constituents in tobacco products. If FDA decides to then establish threshold limits for each of the chemicals, it should do so only if such reductions lead to improvements in public health, they maintained. But it is difficult to prove that removing a particular chemical or decreasing the amount of it in tobacco products will make the products safer, pointed out Jane Y. Lewis, a senior executive with Altria, the parent company of tobacco giant Philip Morris and U.S. Smokeless Tobacco Co. Michael W. Ogden, senior director with R. J. Reynolds Tobacco Co., agreed. He argued that it may not be worth the resources to try to decrease levels of some constituents. For example, when the company
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decreased the amount of carcinogenic nitrosamines in flue-cured tobacco, it didn’t decrease the risk to consumers, he noted. Subcommittee member Jack E. Henningfield, vice president of research and health policy at the Bethesda, Md.-based consulting firm Pinney Associates and an expert on addiction, objected to that argument. “Risk is a function of how the product is made and what is in it. Some companies have shown that decreasing the constituents leads to a decrease in disease,” he contended. IT REMAINS to be seen whether FDA will
set threshold levels for the chemicals that make the final list, but the agency is under a great deal of pressure from public health activists to do so, particularly for chemicals such as nicotine that promote addiction. As the agency finalizes the list, it should be cognizant of the natural variability of SHUTTERSTOCK
A pdf of the draft list is available on C&EN Online, www.cen-online.org. The subcommittee will meet again next month to finalize the proposed list of chemicals and the criteria used for including each chemical on the list. It will also provide references to validated analytical methods and standards for quantifying the chemicals. The list will then be presented to the full TPSAC for consideration at a future meeting. Although the total number of chemicals that tobacco manufacturers will need to test in their products and smoke has yet to be finalized, laboratories that specialize in tobacco analysis are gearing up for the increased demand from small tobacco companies that don’t have their own scientists and laboratories. Small tobacco companies, which make up only about 4% of the tobacco market in the U.S., are very concerned about the idea of testing for more than 100 chemicals in their products and smoke. “Small tobacco product manufacturers will be limited in their ability to stay in business if the cost of analysis becomes excessive,” emphasized David M. Johnson, who spoke on behalf of the Council of Independent Tobacco Manufacturers of America, a trade association representing small tobacco manufacturers.
tobacco, several industry representatives argued. Such variability brings up questions about how to obtain representative samples—a topic the subcommittee will discuss when it meets next month. The panel will also provide FDA with advice on the format for reporting the levels of the chemicals in tobacco and smoke. Various options include the amount of a chemical per cigarette or can of smokeless tobacco, the amount of a chemical per volume of smoke or per grams of smokeless tobacco, or the amount of a chemical per milligrams of nicotine or per milligrams of tar. “For smokeless tobacco, the portion size issue is really important,” Henningfield noted. He recommended that FDA learn from its experiences with food and make sure that communications to consumers are based on realistic portion sizes. “It can be assumed that the industry will manipulate its products and its packaging to beat the system,” he warned. ■
