PMI-58 list of harmful and potentially harmful constituents

Cigarette smoke is a very complex mixture in which more than 6000 constituents have been identified. Within this complex mixture, about a 100 constituents have been associated with smoking-related disease in smokers.

The World Health Organization (WHO), the Food and Drug Administration (FDA) and Health Canada (HC) have independent requirements for reporting on some of these constituents.

At PMI, we routinely monitor the levels of these constituents in standardized settings and we aim to reduce and, if possible, completely eliminate their formation in our smoke-free products.

Table 1. Abbreviations and symbols: FDA, Food and Drug Administration; HC, Health Canada; WHO, World Health Organization; ●, listed constituent; ● ⃰, listed constituent subject to reporting; a, combined nitric oxide and nitrogen oxides; b, combined m+p cresols

PMI-58 list		HC (2000)	WHO (2007)	WHO (2008)	FDA (2012)	WHO (2015)
ISO Parameters:
1	Carbon monoxide	●*	●	●*	●*	●*
2	Nicotine	●*	●		●*	●*
3	NFDPM	●*	●
4	Total Particulate Matter
5	Water
Aliphatic dienes:
6	1,3-Butadiene	●*	●	●*	●*	●*
7	Isoprene	●*			●*	●*
Carbonyls:
8	Acetaldehyde	●*	●	●*	●*	●*
9	Acetone	●*			●	●*
10	Acrolein	●*	●	●*	●*	●*
11	Butyraldehyde	●*				●*
12	Crotonaldehyde	●*		●	●*	●*
13	Formaldehyde	●*	●	●*	●*	●*
14	Methyl ethyl ketone	●*			●
15	Propionaldehyde	●*			●	●*
Acid derivatives:
16	Acetamide				●
17	Acrylamide				●
18	Acrylonitrile			●	●*	●*
Epoxides:
19	Ethylene oxide		●		●
20	Propylene oxide				●
Nitro compounds:
21	Nitrobenzene				●
Aromatic amines:
22	1-Aminonaphthalene	●*			●*	●*
23	2-Aminonaphthalene	●*	●	●	●*	●*
24	3-Aminobiphenyl	●*				●*
25	4-Aminobiphenyl	●*	●	●	●*	●*
26	o-Toluidine				●
N-Heterocyclic aromatics:
27	Pyridine	●*				●*
28	Quinoline	●*			●	●*
Halogen compounds:
29	Vinyl chloride				●
Inorganic compounds:
30	Ammonia	●*			●*	●*
31	Hydrogen cyanide	●*	●	●	●	●*
32	Nitric oxide	●*		●^a		●^a,*
33	Nitrogen oxides	●*	●	●^a		●^a,*
Monocyclic aromatic compounds:
34	Benzene	●*	●	●*	●*	●*
35	Styrene	●*			●
36	Toluene	●*			●*	●*
N-nitrosamines:
37	4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone [NNK]	●*	●	●*	●*	●*
38	N-Nitrosoanabasine	●*	●			●*
39	N-Nitrosoanatabine	●*	●			●*
40	N-Nitrosonornicotine [NNN]	●*	●	●*	●*	●*
Phenols:
41	o-Cresol	●*			●	●*
42	m-Cresol	●b,*			●	●*
43	p-Cresol	●b,*			●	●*
44	Catechol	●*		●	●	●*
45	Hydroquinone	●*		●		●*
46	Phenol	●*			●	●*
47	Resorcinol	●*				●*
Polycyclic aromatic hydrocarbons:
48	Benzo[a]pyrene	●*	●	●*	●*	●*
49	Benz[a]anthracene				●
50	Dibenz[a,h]anthracene				●
51	Pyrene
Metals:
52	Arsenic	●*	●		●	●*
53	Cadmium	●*	●	●	●	●*
54	Chromium	●*	●		●
55	Lead	●*	●		●	●*
56	Mercury	●*	●		●	●*
57	Nickel	●*	●		●
58	Selenium	●*	●		●
Product specific:	Glycerol

Cigarette smoke is a complex mixture in which more than 6000 constituents have been identified, representing nearly all known organic chemical classes (Rodgman and Perfetti, 2013). Within this complex mixture, several harmful and potentially harmful constituents (HPHCs) have been associated with the causation of disease in smokers, such as aromatic amines (Bartsch et al., 1993; Vineis and Pirastu, 1997), gas-phase constituents (Costa et al., 1986; Penn and Snyder, 1996; Witschi et al., 1997), oxygen-free radicals (Pryor, 1997; Valavanidis et al., 2009), polycyclic aromatic hydrocarbons (PAHs) (Penn et al., 1981; Smith et al., 2000), and tobacco-specific N-nitrosamines (TSNAs) (Hecht, 1998, 1999). However, a causal link between a specific smoke constituent and disease has not been conclusively established.

Since it is not possible to quantify all constituents present in cigarette smoke, various priority lists of smoke toxicants in mainstream cigarette smoke have been proposed for the evaluation of commercial market cigarettes based mainly on risk assessments (Cunningham et al., 2011; Fowles and Dybing, 2003; Haussmann, 2012; Hecht, 2006; Hoffmann et al., 1997; Pankow et al., 2007; Rodgman and Green, 2003; Smith and Hansch, 2000; Talhout et al., 2011; Vorhees and Dodson, 1982; Xie et al., 2012).

Smoke Constituent Reporting

Smoke constituent reporting and brand-by-brand disclosure is required by different regulatory authorities, either on an annual basis (Health Canada, British Columbia, Brazil, and Taiwan) or as a one-off disclosure (Massachusetts Department of Health, UK, and Australia) (Wright, 2015). The lists of smoke constituents to be reported show a great deal of similarity between different regulatory authorities (Table 1); however, with the exception of Health Canada (Health Canada, 2000), specific test methods have not been defined or validated.

Philip Morris International’s Aerosol Chemistry List of 58

The list of constituents measured in the evaluation of the mainstream aerosol composition of PMI's Tobacco Heating System (THS) 2.2 is presented in Table 1 and compared to lists of priority smoke constituents proposed by TobReg (WHO, 2007; WHO, 2008; WHO, 2015), Health Canada (Health Canada, 2000), and the FDA (FDA, 2012). The list of 58 constituents (‘PMI-58 list’) covers both smoke constituents and analytes determined by ISO standard methods (CO, nicotine, NFDPM, total particulate matter [TPM], and water) and chemical constituent representatives of all major toxicologically relevant chemical classes of compounds present in both the particulate-phase and gas/vapor-phase of cigarette smoke and was originally based on recommendations by the U.S. Consumer Product Safety Commission on smoke constituents presenting toxicological concerns in low ignition-potential cigarettes (US CPSC, 1993) and compounds reported in cigarette smoke which have been classified as either known or probable human carcinogens by the International Agency for Research on Cancer (IARC, 1985). Further additional HPHCs identified in mainstream cigarette smoke were considered and, if deemed relevant, included in the PMI-58 list of constituents requiring measurement for product evaluation. The PMI-58 list contains all constituents required for reporting by different regulatory authorities including the 18 HPHCs which are subject to reporting on the FDA’s abbreviated list (FDA, 2012b), Health Canada (Health Canada, 2000), all smoke constituents identified as priority toxicants and proposed for reporting by TobReg (WHO, 2007; WHO 2008; WHO, 2015).

All machine-smoking methods have their limitations (Borgerding and Klus, 2005; Dixon and Borgerding, 2006; Roemer and Carchman, 2011), particularly the inability to reflect the variation in human puffing patterns and exposure to smoke constituents (Hammond et al., 2007; Stratton et al., 2001). Compared to the ISO 3308 machine-smoking regimen (ISO, 1991), the more intense machine-smoking regimen proposed by Health Canada (2000) results in much higher aerosol constituent yields which are thought to more closely represent smoker exposure to smoke constituents (Hammond et al., 2007; Hammond and O’Conner, 2008). No single machine-smoking regimen can represent all human smoking behavior (Stratton et al., 2001); however, machine-smoking testing is useful for characterizing tobacco product emissions for design and regulatory purposes. Data on emissions from machine measurements may also be useful as inputs for product hazard assessment, but smoking machine-derived data are not intended to be, nor are they valid as, measures of human exposure or risks (Hatsukami et al., 2012; WHO, 2012).

The World Health Organization (WHO) Study Group on Tobacco Product Regulation (TobReg), composed of leading public health experts and scientists, has proposed a scientific basis for tobacco product regulation (WHO, 2007). As part of their recommendation, this group concluded that chemical measurements of smoke constituents determined by a smoking machine is probably the most effective approach currently available for scientifically assessing differences between products for regulatory assessment of product toxicity (Burns et al., 2008). However, evaluating tobacco products using machine-measured “tar” (or using ISO 4387 terminology, Nicotine Free Dry Particulate Matter, NFDPM), nicotine, and carbon monoxide (CO) yields may be misleading to smokers and most regulators. It was concluded that the Health Canada intense (HCI) machine-smoking protocol (55 mL puff volume, 30 seconds puff interval, 2 seconds puff, 100% vent blocking, butt length 23 mm for non-filter cigarettes or the length of filter overwrap plus 3 mm for filter brands) (Health Canada, 2000) offered significant advantages over both the International Organization for Standardization (ISO)/Federal Trade Commission (FTC) standard machine-smoking regimen (35 mL puff volume, 60 second puff interval, 2 second puff, no vent blocking) (ISO: ISO, 1991; FTC: Federal Trade Commission, 1967) and the Massachusetts Department of Public Health machine-smoking regimen (45 mL puff volume, 30 seconds puff interval, 2 seconds puff, 50% vent blocking, butt length 23 mm for non-filter cigarettes or the length of filter overwrap plus 3 mm for filter brands). Cigarettes should be collected and sampled according to ISO 8243 (ISO, 2006) and conditioned prior to machine-smoking for at least 48 hours at 22 ± 1ᵒC and a relative humidity of 60 ± 3% according to ISO 3402 (ISO, 1999). Using the HCI machine-smoking protocol, it was recommended that manufacturers of tobacco products report to the Member States of the WHO Framework Convention on Tobacco Control (FCTC) the yields of a priority list of 25 smoke constituents in mainstream smoke (Table 1) expressed on a per milligram (mg) NFDPM basis. Furthermore, it was proposed to regulate the presence of two TSNAs, namely N-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) based on ceilings of 114 and 72 ng normalized per mg nicotine in smoke, respectively. Normalizing the levels of NNK and NNN per mg nicotine was considered to reduce the misleading differences between the levels of both toxicants when expressed on a per cigarette basis (Hammond et al., 2007).

In 2008, TobReg (WHO, 2008) reduced the previous priority list from 25 to 18 toxicants in mainstream smoke and proposed that 9 priority toxicants (1,3-butadiene, acetaldehyde, acrolein, benzene, benzo[a]pyrene, CO, formaldehyde, NNK, and NNN) should be mandated for lowering and regulation (Table 1). The most important criterion for the selection of priority compounds for regulation was evidence of toxicity (Fowles and Dybing, 2003). It was proposed that cigarette samples should be obtained as part of a series of at least five sub-periods from either manufacturers/importers or from retail locations according to the ISO standard method 8243 for sampling of cigarettes (ISO, 2006). The ISO standard method 3402 for conditioning of cigarettes prior to smoking (ISO, 1999) and the HCI machine-smoking regimen (Health Canada, 2000) were proposed. It was also proposed that nicotine and CO yields should be determined by ISO standard methods 10315 and 8454, respectively (ISO, 2000, ISO 2007), while other toxicants should be determined by official methods recommended by Health Canada (2000) and expressed on a per mg nicotine basis.

The U.S. FDA has established a list of 93 HPHCs in tobacco products and tobacco smoke (FDA, 2012a) and issued draft guidance on the reporting of an abbreviated list of 18 HPHCs in mainstream cigarette smoke and 9 HPHCs in smokeless tobacco products for which analytical protocols are well established and widely available (FDA, 2012b). The protocols recommend machine-smoking of cigarettes to be performed using both the ISO and HCI regimens (ISO, 1991; Health Canada, 2000) and seven replicates used for the determination of all HPHCs, except nicotine and CO where 20 replicates are recommended. HPHC quantities should be expressed on a per cigarette basis and reported by tobacco product manufacturers to the FDA. In addition, the FDA has encouraged tobacco product manufacturers to include HPHC data in new product applications.

In 2015, TobReg identified 39 priority toxicants in mainstream cigarette smoke (WHO, 2015). The list of 39 priority toxicants was based primarily on lists of toxicants previously identified by Health Canada (Health Canada, 2000), the National Institute for Public Health and the Environment in the Netherlands (Talhout et al., 2011), and the U.S. Food and Drug Administration (FDA, 2012). Previous recommendations for standard cigarettes were extended to cover other smoked tobacco products, such as non-standard cigarettes (e.g., ‘slims’), cigars, water pipes, roll-your-own and low ignition-propensity cigarettes. However, specific recommendations on machine-smoking regimens for these products were not detailed. It was, however, recommended that standardized testing methods validated by the WHO Tobacco Laboratory Network (TobLabNet), a global network of government, academic and independent laboratories should be used. At present, TobLabNet has validated methods for the determination of B[a]P, CO, humectants, nicotine, “tar”, and TSNAs [N-nitrosoanabasine, N-nitrosoanatabine, NNK, and NNN] in mainstream smoke, while methods for the determination of ammonia, volatile organic compounds and aldehydes are in progress. TobReg also concluded that the same principles used to set upper limits of emissions to toxicants in foods and other consumer products should be applied to tobacco products and that “tar” need not be determined as it is not a sound basis for regulation.

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The PMI-58 list of Harmful and Potentially Harmful Constituents

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Philip Morris International’s Aerosol Chemistry List of 58

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