Scientific assessment of the use of sugars as cigarette tobacco ingredients: A review of published and other publicly available studies

Figures & data

Figure 1.  Chemical structures demonstrating the inversion of sucrose to glucose and fructose.

Table 1.  Estimate of ingredient sugar uptake (worst case assumptions) by smoking American-blend cigarettes.

Parameter	Estimate
Number of cigarettes per day^§	40 cig.
Maximum use level for all sugar sources	5%
Tobacco weight	0.8 g/cig.
Transfer of unchanged sugars	0.5%
Bioavailability (deposition)	100%
Dose per cigarette	0.2 mg
Daily dose	8 mg

For risk extrapolations, worst case assumptions were made: sucrose, glucose, or fructose, respectively, used as if representing total sugar doses; local deposition on tongue or in lungs as if total dose would be deposed at either site.

^§95 percentile (Waingrow et al., 1968).

Table 2.  Compounds qualitatively identified in a sucrose pyrolysis experiment according to Figure 2.

Peak number	Compound
1	Air
2	Carbon dioxide
3	Formaldehyde
4	Water
5	Acetaldehyde
6	Furan
7a	Mixture of acrolein and
7b	2-propanol
8	Acetone
9	Pyruvaldehyde
10	2-methylfuran
11	2-butanone
12	3-buten-2-one
13	Diacetyl
14	Glycolaldehyde
15	2,5-dimethylfuran
16	Formic acid
17	Acetic acid
18	1-hydroxy-2-propanone
19	3-furanone
20	Furfural
21	2-furanmethanol
22	2-acetylfuran
23	2(3H)-dihydro-4-hydroxy-2-3(H)furanone
24	2-hydroxycyclopent-2-en-1-one
25	5-methyl-2-furfural
26	1,3-dihydroxy-2-propanone
27a	Mixture of 2-hydroxy-3-methyl-2-cyclopenten-1-one and
27b	furanone
28a	Mixture of 2,5-dimethyl-4-hydroxy-3-(2H)furanone and
28b	2,4-hexanedione
29	Methylfuroate
30	5-methyl-1,3-benzenediol
31	2,3-dihydro-3,5-dihydroxy-4H-pyran-4-one
32	3,5-dihydroxy-2-methyl-4H-pyran-4-one
33	1,4:3,6-dianhydro-α-d-glucopyranose
34	5-(hydroxymethyl)-2-furfural
35	1,5-anhydro-4-deoxy-d-glycero-hex-1-en-3-ulose
36	An anhydro-sugar
37	Levoglucosan
38	1,6-anhydro-β-d-glucofuranose

Figure 2.  Total GC-MS ion current finger-print chromatogram obtained from the pyrolysis of sucrose in air. For compound identifications, see Table 2. The pyrolysis unit was programmed to 1000°C with a three-step temperature program (400, 700, and 1000°C) with a 10-s hold time at each temperature. Comparison to data published elsewhere (Baker et al., 2005) suggest that yields of pyrolysis products are in the order of 1 µg per mg sugar pyrolyzed in this type of experiment.

Table 3.  Regression analyses of individual and pooled chemical-analytical data on the relationship of mainstream smoke constituent yields (nicotine-based) and sugar addition levels in research cigarettes.

Constituent	Statistical significance of slopes and change at 5% application level based on linear regression
	ISO data												HCI data
	Individual studies&								Pooled studies				Individual		Pooled
	1	2	3	4	5	6	7	8	Slope	p value	R2	Change§	7–HCI	8–HCI	Slope
Tar	=	=	=	=	=	=	=	=	=	0.9491	–	–	=	=	=
Carbon monoxide	=	=	=	=	=		=	=	=	0.1804	–	–	=	=	=
Formaldehyde	=	↑	=	↑	↑	↑	=	=	↑	0.0005	0.24	25%	=	=	↑
Acetaldehyde	=	↑	↑	=	=	=	=	↑	=	0.3826	–	–	=	=	=
Acrolein	=	↑	=	↑	=	↑	=	=	↑	0.0009	0.22	10%	↑	=	=
Propionaldehyde	=	=	↑	↑	=	↑	=	↑	=	0.6376	–	–	↑	=	↑
n-Butyraldehyde	–	–	–	–	=	=	=	↑	=	0.5435	–	–	=	=	=
Crotonaldehyde	–	–	–	–	=	=	=	↑	=	0.1022	–	–	=	=	=
Acetone	–	–	–	–	↑	=	=	↑	=	0.1234	–	–	=	=	=
2-Butanone	–	–	–	–	=	↑	=	↑	↑	0.0045	0.29	9%	=	=	=
1,3-Butadiene	=	=	=	↑	–	–	=	↑	=	0.6112	–	–	=	=	=
Isoprene	=	=	=	=	–	–	=	↑	↑	0.0065	0.25	12%	=	=	=
Acrylonitrile	↑	=	=	↑	–	–	=	=	=	0.2444	–	–	=	=	=
Hydrogen cyanide	=	=	↑	↑	–	–	=	=	=	0.6849	–	–	=	=	=
2-Nitropropane	=	=	=	=	–	–	–	–	=	0.6466	–	–	–	–	–
4-Aminobiphenyl	=	=	=	=	–	–	=	=	↓	0.0124	0.22	–21%	=	=	=
o-Toluidine	↓	↓	=	=	–	–	–	–	=	0.5124	–	–	–	–	–
2-Naphthylamine	=	=	=	=	–	–	–	–	=	0.8311	–	–	–	–	–
o-Anisidine	–	–	=	=	–	–	–	–	=	0.2250	–	–	–	–	–
Nitrogen oxides	=	=	=	=	–	–	↓	=	=	0.5313	–	–	=	=	=
Benzene	=	↑	↑	↑	–	–	=	↑	↑	0.0011	0.34	9%	=	=	=
Toluene	↑	↑	↑	↑	–	–	=	↑	↑	<0.0001	0.51	9%	=	=	=
Styrene	–	–	–	↑	–	–	=	=	=	0.0039*	–	–	=	=	↑
N-Nitrosodimethylamine	–	–	=	↑	–	–	–	–	↓	0.0003	0.74	–12%	–	–	–
N-Nitrosopyrrolidine	=	=	=	↓	–	–	–	–	=	0.0902	–	–	–	–	–
N-Nitrosonornicotine	=	=	=	↓	–	–	↓	=	↓	<0.0001*	0.69	–12%	=	=	=
NNK	=	=	=	=	–	–	=	=	=	0.4278*	–	–	=	=	=
Phenol	=	=		↓	–	–	=	=	=	0.4072	–	–	=	=	=
Catechol	=	=	=	=	–	–	=	=	=	0.1749	–	–	=	=	=
Benzo[a]anthracene	=	=	=	=	–	–	–	–	=	0.9136	–	–	–	–	–
Benzo[b]fluoranthene	=	=	=	↑	–	–	–	–	=	0.6700	–	–	–	–	–
Benzo[j]fluoranthene	–	–	=	↑	–	–	–	–	=	0.8542	–	–	–	–	–
Benzol[a]fluoranthene	–	–	=	↑	–	–	–	–	↑	0.0044	0.57	7%	–	–	–
Benzo[a]pyrene	=	=	=	↑	–	–	=	=	=	0.2168	–	–	=	=	=
Indeno[1,2,3-cd] pyrene	↑	=	=	↑	–	–	–	–	=	0.2400	–	–	–	–	–

Sugars used as ingredients in individual studies:

1: Sucrose (Coggins et al., 2011).

2: Invert sugar (Coggins et al., 2011).

3: Honey (Coggins et al., 2011).

4: High fructose corn syrup (Coggins et al., 2011).

5: White and brown sugar, invert sugar (Baker, 2006; test cigarettes D2 to D5, D8, and D10 vs. control cigarette D1).

6: Brown sugar, invert sugar, honey, glucose, fructose (Baker, 2006; test cigarettes E2 to E9, E11, and E13 vs. control cigarette E1).

7: Sucrose, research cigarettes yielding 6 mg ISO tar/cig., machine-smoked under ISO and HCI conditions (Roemer et al., 2010).

8: Sucrose, as in 7 but with research cigarettes yielding 10 mg ISO tar/cig. (Roemer et al., 2010).

↑, ↓: Slopes of regression analysis (GraphPad software) statistically significantly different from zero (increase, decrease); = : slopes of regression analysis not statistically significantly different from zero; -: not done/not applicable; R²: regression coefficient.

^§: Change at a usual maximum use level of 5% sugar addition relative to control without sugar use.

*: Two different pools of data from different laboratories, lowest p value given.

ISO smoking conditions: puff volume, duration, and frequency of 35 ml, 2 s, and 1 min⁻¹, respectively (International Organization for Standardization, 2000).

HCI (Health Canada intense) smoking conditions: puff volume, duration, and frequency of 55 ml, 2 s, and 2 min⁻¹, respectively, and blocked filter ventilation holes (Health Canada, 2000).

Figure 3.  Yields (nicotine-based) of formaldehyde (A), acetaldehyde (B), acrolein (C), benzene (D), N-nitrosonornicotine (E), and 4-aminobiphenyl (F) in the mainstream smoke of research cigarettes of pooled studies with research cigarettes with varying sugar application levels. Linear regression (solid lines) with 95% confidence limits was performed on yield data obtained with ISO machine-smoking. For formaldehyde, an additional linear regression (dashed line) was derived for yield data obtained under HCI smoking conditions. The HCI data for the other constituents fit well to the set of ISO data. M ± SD for individual data points (SDs by non-weighted error propagation). The legend in graph C applies to all graphs in Figure 3; for study references, see Table 3.

Figure 4.  Cytotoxicity (EC₅₀, TPM-based) of the mainstream smoke particulate and gas/vapor phases of research cigarettes with varying sugar application levels relative to the respective control. Linear regression with 95% confidence limits was performed. The legend in graph A also applies to graph B; for study references, see Table 3.

Figure 5.  Bacterial mutagenicity (TPM-based) of the mainstream smoke particulate phase of research cigarettes with varying sugar application levels relative to the respective control. Selected conditions are tester strains TA98 and TA100 with metabolic activation (+S9) (A, B) and TA1537 and TA100 without metabolic activation (–S9) (C, D). Linear regression with 95% confidence limits was performed. The legend in graph A also applies to graphs B to D; for study references, see Table 3.

Table 4.  Histopathological findings (mean severity scores) with significant differences between rats exposed to the smoke of research cigarettes with and without sugars applied as tobacco ingredients at the end of at least one subchronic rat inhalation study on mainstream smoke from research cigarettes with various application levels of sugars: sucrose and invert sugar (Coggins et al., 2011).

Finding	Gender	Control	Sucrose			Invert sugar
		0%	3.6%	7.2%	10%	2.5%	5%	10%
Nose level 1,	M	2.3	2.0	1.9	2.6	2.3	2.8	2.8
goblet cell hyperplasia	F	1.0	0.8	0.5	1.3	1.1	1.6	0.7
Nose level 2,	M	0.7	0.8	1.0	1.7	1.3	1.1	1.6
respiratory epithelium hyperplasia	F	1.2	0.8	0.7	1.2	0.9	0.9	0.9
Nose level 2,	M	0.0	0.1	0.0	0.5	0.0	0.0	0.0
olfactory epithelium atrophy	F	0.7	0.8	0.4	1.6	0.3	0.6	1.0
Nose level 3,	M	0.0	0.0	0.0	0.0	0.0	0.0	0.0
olfactory epithelium atrophy	F	0.2	0.6	0.3	0.9	0.0	0.3	0.7
Larynx, arytenoid projections	M	2.3	1.8	1.9	2.2	2.1	2.1	2.2
squamous metaplasia	F	3.0	2.1	1.4	2.2	1.8	2.5	2.6

Severity scores on a scale of 0 to 4.

Additional groups not shown here: Air-exposed sham group as negative control, groups exposed to mainstream smoke of 1R4F standard reference cigarettes as quality control.

Bold print: significant effect compared to control (ANOVA followed by Dunnett’s test, or if there was an increase of >1.0 in the severity score).

Table 5.  Histopathological findings (mean severity scores) with significant differences between rats exposed to the smoke of research cigarettes with and without sugars applied as tobacco ingredients at the end of at least one subchronic rat inhalation study on mainstream smoke from research cigarettes with various application levels of sugars: high fructose corn syrup (HFCS), single (Coggins et al., 2011) and in combinations with sucrose and invert sugar.

Finding	Gender	Control	HFCS			HFCS + Sucrose 3.3 + 3.3%	HFCS + Invert Sugar 3.3 + 3.3%	Sucrose + Invert Sugar 3.3 + 3.3%	HFCS + Sucro + Invert Sugar 3.3 + 3.3 + 3.3%
		0%	3.3%	6.6%	10%
Nose level 1,	M	2.2	1.2	1.9	2.2	1.6	1.4	1.8	1.6
goblet cell hyperplasia	F	1.4	0.9	0.8	1.5	0.7	0.8	1.0	0.2
Nose level 2,	M	2.1	1.7	2.4	2.2	1.6	1.8	2.0	1.8
respiratory epithelium hyperplasia	F	1.8	1.2	1.2	2.0	1.6	1.0	1.4	1.0
Nose level 2,	M	0.4	0.2	0.6	0.1	0.8	0.2	0.4	0.5
olfactory epithelium atrophy	F	1.0	0.3	1.6	1.2	1.7	0.4	0.9	1.1
Nose level 3,	M	0.0	0.0	0.0	0.0	0.5	0.2	0.5	0.0
olfactory epithelium atrophy	F	0.5	0.0	1.0	0.4	0.9	0.0	0.9	0.4
Larynx, arytenoid projections	M	3.8	3.5	3.8	3.7	3.7	3.9	3.7	3.7
squamous hyperplasia − metaplasia	F	3.7	3.9	3.6	3.6	3.7	3.7	3.8	3.9
Trachea,	M	2.6	2.1	2.8	1.9	3.2	2.7	3.3	3.3
goblet cell number/hyperplasia	F	2.3	2.6	3.1	2.6	3.7	3.7	3.4	1.7
Left lung,	M	3.2	2.5	3.3	2.6	3.4	3.2	3.3	3.5
goblet cell number/hyperplasia	F	3.5	3.0	3.2	3.6	3.9	3.6	4.0	2.4
Right lung,	M	2.2	2.0	1.8	1.6	2.7	2.0	2.3	2.3
goblet cell number/hyperplasia	F	2.7	3.0	2.3	3.1	3.4	2.6	3.3	1.9

Conditions as in Table 4, except of 2R4F as quality control.

Table 6.  Histopathological findings (mean severity scores) with significant differences between rats exposed to the smoke of research cigarettes with and without honey applied as tobacco ingredient at the end of at least one subchronic rat inhalation study on mainstream smoke from research cigarettes with various application levels of sugars (Coggins et al., 2011).

Finding	Gender	Control	Honey
		0%	3.3%	4.8%	6.6%
Nose level 1,	M	2.1	1.8	2.6	1.8
goblet cell hyperplasia	F	1.5	1.3	1.7	1.5
Nose level 2,	M	2.3	1.8	2.4	2.2
respiratory epithelium hyperplasia	F	2.3	2.3	2.2	2.4
Nose level 2,	M	0.2	1.0	0.5	1.9
olfactory epithelium atrophy	F	1.0	1.3	1.0	1.7
Nose level 3,	M	0.0	0.5	0.2	1.1
olfactory epithelium atrophy	F	0.5	0.6	0.1	1.0
Larynx, arytenoid projections	M	3.6	3.7	3.6	3.3
squamous hyperplasia − metaplasia	F	3.5	3.1	3.1	3.6
Trachea,	M	2.0	1.3	2.9	2.4
goblet cell number/hyperplasia	F	1.3	1.6	1.1	1.2
Left lung,	M	2.2	1.9	3.0	2.8
goblet cell number/hyperplasia	F	2.6	2.3	2.6	2.8
Right lung,	M	1.5	1.6	2.0	2.5
goblet cell number/hyperplasia	F	1.4	1.7	1.7	2.4

Conditions as in Table 4, but with 1R4F and 2R4F as quality controls.

Table 7.  Dermal tumorigenicity of mainstream smoke condensate generated from research cigarettes with and without invert sugar as tobacco ingredient.

Research cigarette type	Condensate dose group	Estimated probability of tumor avoidance (M ± SE)		Estimated number of days until 75% of mice remained free of tumors
		No invert sugar	With invert sugar	No invert sugar	With invert sugar
Standard experimental blend III	12.5 mg	0.715 ± 0.053	0.711 ± 0.026	529	515
	25 mg	0.432 ± 0.060	0.449 ± 0.028	376	414
Burley blend*	12.5 mg	0.508 ± 0.059	0.586 ± 0.056	420	452
	12.5 mg	0.532	0.509	417	372

Life-table-corrected data (US Department of Health Education and Welfare, 1977) (no sugar-dependent differences for formaldehyde, acetaldehyde, acrolein, and tar yields).

*Two times low dose; Burley blend and standard experimental blend III tumor probability data (low dose) were statistically significantly different.

Table 8.  Selected mainstream smoke constituent yields (per mg nicotine) for marketed American–blend and Virginia–type cigarettes (Counts et al., 2005; Gregg et al., 2004; Hammond and O’Connor, 2008).

Constituent	Yields (M ± SD) (mg nicotine)^−1						Reference
	ISO smoking conditions			HCI smoking conditions
	American–blend	Virginia–type	Difference^§ (%)	American–blend	Virginia–type	Difference^§ (%)
Formaldehyde (µg)	45	81	– 44	46	76	– 39	Hammond
	31 ± 12	40 ± 14	– 21	39 ± 13	68 ± 23	– 42	Counts
	28 ± 12	34 ± 16	– 18				Gregg
Acetaldehyde (µg)	641	656	– 2	615	513	+ 20	Hammond
	578 ± 122	589 ± 111	– 2	686 ± 163	652 ± 159	+ 5	Counts
	673 ± 123	820 ± 123	– 18				Gregg
Acrolein (µg)	63	80	– 21	65	67	– 3	Hammond
	52 ± 12	53 ± 5	– 2	68 ± 16	67 ± 18	+ 0	Counts
	58 ± 11	68 ± 16	– 15				Gregg
2–Butanone (µg)	68 ± 15	74 ± 17	– 8	92 ± 21	93 ± 19	– 1	Counts
	74 ± 14	95 ± 14	– 22				Gregg
Benzene (µg)	47	51	– 8	41	37	+ 11	Hammond
	51 ± 10	51 ± 17	+ 0	39 ± 8	39 ± 5	+ 0	Counts
	52 ± 9	58 ± 8	– 10				Gregg
Toluene (µg)	76	78	– 3	74	65	+ 14	Hammond
	74 ± 14	71 ± 18	+ 4	72 ± 15	65 ± 9	+ 10	Counts
	85 ± 14	92 ± 16	– 7				Gregg
Benzo[a]pyrene (ng)	7.9	13.1	– 40	7.3	10.0	– 27	Hammond
	11.5 ± 3.0	10.8 ± 1.2	+ 6	8.8 ± 2.2	10.3 ± 2.7	– 15	Counts
	12.0 ± 1.0	15.8 ± 1.8	– 24				Gregg
N–Nitrosonornicotine (ng)	187	28	+567	161	22	+632	Hammond
	149 ± 78	25 ± 6	+496	108 ± 47	17 ± 0	+538	Counts
	94 ± 16	53 ± 34	+ 76				Gregg
4–Aminobiphenyl (ng)	2.4	1.9	+ 26	2.1	1.5	+ 40	Hammond
	3.1 ± 0.8	2.1 ± 0.9	+ 50	2.2 ± 0.5	1.3 ± 0.1	+ 73	Counts
	1.4 ± 0.3	1.2 ± 0.4	+ 17				Gregg

Smoking conditions: ISO: International Standardization Organization; HCI: Health Canada Intense.

^§Difference of nicotine–based yields of American–blend vs. Virginia–type cigarettes;

Bold print: statistically significant difference between both types of cigarettes (not available for Hammond dataset for nicotine–based yields).

Figure 6.  Monte Carlo simulation of the nicotine uptake distribution based on nicotine equivalents from a population-based biomonitoring study with smokers of American-blend cigarettes. Data from (Scherer et al., 2007), corrected for 85% recovery of nicotine and its metabolites; log-normal Monte Carlo simulation; blue line: forecast values; magenta line: fitted line (mode: 0.52 mg/cig.; median: 1.03 mg/cig.).

Figure 7.  Simulation of acrolein uptake distributions for research cigarettes with 0 and 5% sugar application and American-blend and Virginia-type market cigarettes (right panel) in comparison to acrolein yields obtained by three machine-smoking conditions (left panel, reproduced with permission; Counts et al., 2005). Machine-smoking data compared to the fitted log-normal Monte Carlo simulation of acrolein uptake using Crystal Ball; left panel: ○: ISO smoking conditions (International Organization for Standardization, 1991), ▴: Massachusetts smoking conditions (Massachusetts General Laws Annotated, 1997), □: Health Canada smoking conditions (Health Canada, 2000); right panel: blue line: research cigarettes with 0% sugar addition; red line: research cigarettes with 5% sugar application; green line: American-blend market cigarettes, violet line: Virginia-type market cigarettes.

Figure 8.  Simulation of benzene (A), formaldehyde (B), and 4-aminobiphenyl (C) uptake distributions for research cigarettes with 0 and 5% sugar application and American-blend and Virginia-type market cigarettes. For color legend, see explanations for the right panel in Figure 7.

Figure 9.  Survey of nicotine uptake estimates per cigarette in smokers (mg/cig.). A: Estimated nicotine uptake from plasma, urine (based on nicotine equivalents for plasma and urine), or cigarette filter analyses (mouth level exposure). Cigarettes of American-blend (Byrd et al., 1998; Gori and Lynch, 1985; Mendes et al., 2009; Scherer et al., 2007; Shepperd et al., 2009; St Charles et al., 2010), Virginia-type (Jarvis et al., 2001), or unknown nature (Ueda et al., 2002) were smoked in these studies. B: Estimated nicotine uptake determined as “mouth level exposure” based on cigarette filter analyses in eight different countries with varying blend preferences (reproduced with permission; Mariner et al., 2011).

Figure 10.  Smoking prevalences in American-blend and Virginia-type cigarette markets. Data from American-blend (United States, Germany, and France) and Virginia-type markets (United Kingdom, Australia, and Canada) (MacKay and Eriksen, 2002; World Health Organization, 2008: data from approximately 2005).

Figure 11.  Daily cigarette consumption in predominantly American-blend (United States) and Virginia-type (United Kingdom/England, Canada, Australia) markets for male (hatched bars) and female (dotted bars) smokers. Data of the years 2000–2002 taken from International Tobacco Control Policy Evaluation Survey (Hammond et al., 2004): ITCPES: International Tobacco Control Policy Evaluation Survey; NHIS: National Health Interview Survey; GHS: General Household Survey; HSE: Health Survey for England; CTUMS: Canadian Tobacco Use Monitoring Survey; CCHS: Canadian Community Health Survey; NTCES: National Tobacco Survey Evaluation Campaign; NDDS: National Drug Strategy Household Survey.

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