Table 1
Averages and ranges for the daily consumption of the five nicotine productsa.
| Product | Daily consumption (units/d) | References | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Unit of use | Nb | Mean | SD | Median | Min | Max | 25th Perc. | 75th Perc. | ||
| CC | 1 Cig. | 19 | 15.95 | 1.95 | 16.0 | 12.4 | 18.8 | 14.3 | 16.6 | (Bergen et al., 2015 (161); Czoli et al., 2019 (48); Gale et al., 2019 (33); Haziza et al., 2016 (34);Krautter and Borgerding, 2014 (71); Round et al., 2019 (54); US Department of Health and Human Services, 2014 (2)) |
| HNB | 1 Stick | 4 | 16.83 | 1.26 | 16.9 | 15.5 | 18 | 15.9 | 17.85 | (Gale et al., 2019 (33); Haziza et al., 2016 (34)) |
| EC | 10 Puffs | 11 | 12.59 | 7.38 | 11.6 | 2.2 | 25 | 7.15 | 21.25 | (Etter, 2014 (57); Etter and Bullen, 2011 (58); Farsalinos et al., 2015 (59); Farsalinos et al., 2014 (87); Hammett et al., 2017 (60); Landmesser et al., 2019 (56); Leavens et al., 2019 (61); National Academies of Sciences (NAS), 2018 (63); O’Connell et al., 2016 (53); Round et al., 2019 (54); Wagener et al., 2017 (66)) |
| OT (Snus) | 1 g | 8 | 2.62 | 0.98 | 2.53 | 1.20 | 4.24 | 1.98 | 3.05 | (Jitnarin et al., 2014 (70); Krautter and Borgerding, 2014 (71); Krautter et al., 2014 (72); Ogden et al., 2015 (39); Sarkar et al., 2010 (73); Wang et al., 2016 (162)) |
| NRT (NG) | 1 Piece | 9 | 6.35 | 2.30 | 5.15 | 3.2 | 9.45 | 5.00 | 8.50 | (Etter et al., 2009 (80); Round et al., 2019 (54); Shiffman et al., 2003 (81); Xiao et al., 2014 (82)) |
Table 2
Release of 38 chemicals by the products of interest as well as medians of the estimated daily intakes and corresponding biomarker levels in the 6 user/non-user groups. The bold numbers in parentheses indicate the relative exposure levels (1 to 4). Italic blue numbers in parentheses indicate assumption-based changes (made as described in the text). Crossed out values were found to be implausible, a reasonable exposure level assigned instead. Also these numbers are presented in italic blue.
| Chemical (CAS No) | CC | HNB | EC | OT | NG | NU a | |
|---|---|---|---|---|---|---|---|
| Nicotine-/tobacco-derived chemicals | |||||||
| N (54-11-5) | Content / unit | 0.59–1.67 mg/cig | 0.42–1.19 mg/stick | 0.24–1.38 mg/10 puffs | 10.7–21.0 mg/g | 2.0–4.0 mg/piece | – |
| Intake (mg/d) | 11.7 (4) | 9.01 (4) | 6.99 (3) | 10.58 (4) | 10.35 (4) | 0.05 (1) | |
| Nequ (mg/d) | 14.4 (4) | 7.19 (3) | 9.1 (3) | 11.09 (4) | 7.58 (3) | 0.37 (1) | |
| Cot P (ng/mL) | 215.7 (4) | 161.0 (4) | 187.1 (4) | 143.1 (3) | 137.5 (3) | 0.58 (1) | |
| NN (494-97-3) | Content per unit | 19.98–21.49 μg/cig | 0.02–0.05 μg/stick | 0.55–3.13 μg/10 puffs | 140–173 μg/g | ndab | – |
| Intake (μg/d) | 215.2 (4) | 0.4 (1) | 15.93 (1) | 106.18 (3) | nda (1) | nda (1) | |
| Uptake | No specific biomarker for nornicotine available | ||||||
| AT (581-49-7) | Content per unit | 7.00–13.45 μg/cig | 1.16–1.27 μg/stick | 0.81–34.47 μg/10 puffs | 65.0–84.0 μg/g | nda | – |
| Intake (μg/d) | 105.57 (3) | 13.71 (1) | 152.75 (4) | 50.23 (2) | nda (1) | nda (1) | |
| AT U (μg/d) | 16.28 (3) | nda (1) | 1.01 (1) | 40 (4) | 0.38 (1) | 0.77 (1) | |
| AB (13078-04-1) | Content per unit | 1.12–3.31 μg/cig | 0.21–0.62 μg/stick | 0.0–0.55 μg/10 puffs | 8.50–17.0 μg/g | nda | – |
| Intake (μg/d) | 22.65 (4) | 4.59 (2) | 2.33 (2) | 8.52 (2) | nda (1) | nda (1) | |
| AB U (μg/d) | 15.5 (4) | nda (1) | 1.34 (1) | 20 (4) | 1.12 (1) | 0.76 (1) | |
| NNK (64091-91-4) | Content per unit | 86.9–254 ng/cig | 6.7–7.3 ng/stick | 0.6–1.5 ng/10 puffs | 200–870 ng/g | 0.5–1.5 ng/piece | – |
| Intake (ng/d) | 1740.7 (4) | 79.2 (1) | 9.5 (1) | 352.3 (2) | 3.4 (1) | 10.6 (1) | |
| NNAL U (ng/d) | 347.9 (3) | 104.5c (2) | 26.6 (1) | 539.8 (4) | 176.7c (2) | 2.2 (1) | |
| NNN (16543-55-8) | Content per unit | 96.4–270 ng/cig | 10.5–24.0 ng/stick | 0.4–1.0 ng/10 puffs | 900–2650 ng/g | 1.5–3.0 ng/piece | – |
| Intake (ng/d) | 1876.9 (4) | 194.5 (2) | 6.4 (1) | 1183.2 (3) | 7.7 (1) | nda (1) | |
| NNN U (ng/d) | 17.9 (4) | 3.6 (2) | 2.7 (2) | 8.7 (3) | 2.9 (2) | 2.2 (2) | |
| NAT (71267-22-6) | Content per unit | 141–268 ng/cig | 14.0–20.5 ng/stick | 0.4–1.2 ng/10 puffs | 710–2350 ng/g | 0.5–1.5ng/piece | - |
| Intake (ng/d) | 2111 (4) | 193.2 (1) | 7.1 (1) | 1006 (3) | 3.4 (1) | nda (1) | |
| NAT U (ng/d) | 275.3 (4) | nda (1) | 4.4 (1) | 163.3 (3) | 3.7 (1) | 2.9 (1) | |
| NAB (37620-20-5) | Content per unit | 18–24 ng/cig | 1.9–4.7 ng/stick | 0.1–0.2 ng/10 puffs | 50–180 ng/g | 0.5–0.8 ng/piece | - |
| Intake (ng/d) | 216.8 (4) | 37.2 (2) | 1 (1) | 77.1 (2) | 1.7 (1) | nda (1) | |
| NAB U (ng/d) | 58.8 (4) | nda (1) | 3.8 (1) | 19.9 (2) | 6.1 (2) | 1.3 (1) | |
| PG-/G-derived chemicals | |||||||
| PG (57-55-6) | Content per unit | 0.03–0.60 mg/cig | 0.39–0.63 mg/stick | 49.2–69.9 mg/10 puffs | 5.5–16.5 mg/g | nda | - |
| Intake (mg/d) | 3.2 (1) | 5.8 (1) | 555.3 (4) | 7.3 (1) | nda (1) | 0.005 (1) | |
| PG U (mg/d) | 6.85 (3) | nda (1) | 14.93 (4) | nda (1) | nda (1) | nda (1) | |
| G (56-81-5) | Content per unit | 0.93–2.27 mg/cig | 1.83–3.44 mg/stick | 15.30–67.52 mg/10 puffs | 0.58–8.56 mg/g | nda | - |
| Intake (mg/d) | 16.42 (1) | 29.55 (1) | 360.75 (4) | 3 (1) | nda (1) | 0.003 (1) | |
| Uptake | No suitable biomarker for PG available | ||||||
| Gly (556-52-5) | Content per unit | 3.0–6.0 μg/cig | 22–66 μg/stick | 37.6–59.9 μg/10 puffs | - | - | - |
| Intake (μg/d) | 46.26 (1) | 492.61 (4) | 454.91 (4) | nda (1) | nda (1) | 0.005 (1) | |
| Uptake | No sufficient biomarker data for Gly available | ||||||
| EO (75-21-8) | Content per unit | 14.5–21.8 μg/cig | 0.02–0.20 μg/stick | nda | nda | nda | - |
| Intake (μg/d) | 186.6 (4) | 1.23 (1) | nda (1) | nda (1) | nda (1) | nda (1) | |
| HEMA (μg/d) | 5.23 (4) | 2.53 (3) | 1.8 (2) | 7.19 (2) | 7.9 (2) | 1.194 (2) | |
| PO (75-56-9) | Content per unit | 1.22–2.14 μg/cig | 0.008–0.148 μg/stick | 0.622–0.992 μg/10 puffs | nda | nda | - |
| Intake (μg/d) | 17.27 (4) | 0.88 (1) | 7.53 (3) | nda (1) | nda (1) | nda (1) | |
| 2-HPMA (μg/d) | 72.69 (4) | nda (1) | 33.31 (2) | 164.61 (2) | 46.75 (2) | 37.99 (2) | |
| FA (50-00-0) | Content per unit | 40.5–74.0 μg/cig | 4.35–16.5 μg/stick | 1.60–2.02 μg/10 puffs | 0.32–4.5 μg/g | nda | - |
| Intake (μg/d) | 588.93 (4) | 89.35 (2) | 16.86 (1) | 1.02 (1) | nda (1) | 0.08 (1) | |
| Uptake | No biomarker data for FA available | ||||||
| AA (75-07-0) | Content per unit | 1044–1766 μg/cig | 168–212 μg/stick | 0.77–2.30 μg/10 puffs | 1.40–27.4 μg/g | nda | - |
| Intake (μg/d) | 14470 (4) | 2141 (2) | 16.5 (1) | 9.6 (1) | nda (1) | 0.2 (1) | |
| Uptake | No biomarker data for AA available | ||||||
| ACR (107-02-8) | Content per unit | 75–155 μg/cig | 5.3–10.3 μg/stick | 0.5–2.1 μg/10 puffs | nda | nda | - |
| Intake (μg/d) | 1176.4 (4) | 87.6 (1) | 11 (1) | nda (1) | nda (1) | 0.007 (1) | |
| 3-HPMA (μg/d) | 1604.3 (4) | 603.9 (2) | 555.4 (2) | 466.5 (2) | 512.5 (2) | 340.5 (2) | |
| CRO (4170-30-3) | Content per unit | 33.7–48.7 μg/cig | 1.1–2.9 μg/stick | 0.5–1.5 μg/10 puffs | 0.2–2.4 μg/g | nda | - |
| Intake (μg/d) | 424.3 (4) | 22.4 (1) | 8.4 (1) | 0.9 (1) | nda (1) | 0.07 (1) | |
| HMPMA (μg/d) | 708.5 (4) | 76.7 (2) | 251.1 (2) | 130.6 (2) | 128.9 (2) | 227.5 (2) | |
| PA (123-38-6) | Content per unit | 111–125 μg/cig | 8.8–13.3 μg/stick | 0.2–0.5 μg/10 puffs | nda | nda | - |
| Intake (μg/d) | 1217.8 (4) | 124.3 (2) | 3.0 (1) | nda (1) | nda (1) | 1.9 (1) | |
| Uptake | No biomarker data for PA available | ||||||
| AC (513-86-0) | Content per unit | 2.8–6.2 μg/cig | 2.9–8.7 μg/stick | 0.008–0.023 μg/10 puffs | nda | nda | - |
| Intake (μg/d) | 46.42 (4) | 65.19 (4) | 0.13 (1) | nda (1) | nda (1) | 0.0002 (1) | |
| Uptake | No biomarker data for AC available | ||||||
| GO (107-22-2) | Content per unit | 8.8–12.3 μg/cig | 0.03–0.1 μg/stick | 0.24–0.72 μg/10 puffs | nda | nda | - |
| Intake (μg/d) | 108.86 (4) | 0.71 (1) | 4.24 (1) | nda (1) | nda (1) | 0.02 (1) | |
| Uptake | No biomarker data for GO available | ||||||
| MGO (78-98-8) | Content per unit | 24.2–31.2 μg/cig | 13.2–39.6 μg/stick | 0.8–1.2 μg/10 puffs | nda | nda | - |
| Intake (μg/d) | 285.4 (4) | 297.3 (4) | 9.2 (1) | nda (1) | nda (1) | nda (1) | |
| Uptake | No biomarker data for MGO available | ||||||
| Combustion-derived chemicals | |||||||
| CO (630-08-0) | Content per unit | 22.7–32.0 mg/cig | 0.30–0.53 mg/stick | 0.25–0.75 mg/10 puffs | nda | nda | - |
| Intake (mg/d) | 281.7 (4) | 4.66 (1) | 4.42 (1) | nda (1) | nda (1) | nda (1) | |
| COHb (%) | 5.62 (4) | 1.62 (2) | 1.52 (2) | 1.05 (2) | 1.35 (2) | 1.35 (2) | |
| BD (106-99-0) | Content per unit | 67–100 μg/cig | 0.21–0.40 μg/stick | 0.25–0.75 μg/10 puffs | nda | nda | - |
| Intake (μg/d) | 863.24 (4) | 3.43 (1) | 4.48 (1) | nda (1) | nda (1) | nda (1) | |
| MHBMA (μg/d) | 3.54 (4) | 0.108 (1) | 0.381 (2) | 0.707 (2) | 2.25 (2) | 0.438 (2) | |
| Iso (78-79-5) | Content per unit | 794.9–869.0 μg/cig | 1.96–2.69 μg/stick | 1.25–3.75 μg/10 puffs | nda | nda | - |
| Intake (μg/d) | 8607 (4) | 26.91 (1) | 22.1 (1) | nda (1) | nda (1) | 0.29 (1) | |
| IPMA3 (μg/d) | 43.94 (4) | nda (1) | 4.684 (2) | nda (1) | nda (1) | 3.555 (1) | |
| Fu (110-00-9) | Content per unit | 49.3–56.3 μg/cig | 0.58–1.74 μg/stick | - | nda | nda | - |
| Intake (μg/d) | 565.12 (4) | 12.94 (1) | nda (1) | nda (1) | nda (1) | 0.002 (1) | |
| Fu B (ng/mL) | 0.06 (4) | nda (1) | nda (1) | nda (1) | nda (1) | 0.013 (2) | |
| Be (71-43-2) | Content per unit | 62.6–85.2 μg/cig | 0.54–0.63 μg/stick | 0.25–0.75 μg/10 puffs | nda | nda | - |
| Intake (μg/d) | 762.57 (4) | 6.82 (1) | 4.45 (1) | nda (1) | nda (1) | 0.52 (1) | |
| SPMA (μg/d) | 1.36 (4) | 0.195 (2) | 0.375 (2) | 0.523 (2) | 0.5 (2) | 0.4 (2) | |
| Sty (100-42-5) | Content per unit | 13.7–24.4 μg/cig | 0.47–1.05 μg/stick | nda | nda | nda | - |
| Intake (μg/d) | 195.6 (4) | 8.52 (1) | nda (1) | nda (1) | nda (1) | 6.6 (1) | |
| PHEMA (μg/d) | 1.22 (4) | nda (2) | 0.6 (2) | nda (2) | 0.94 (2) | 0.656 (2) | |
| AN (107-13-1) | Content per unit | 15.8–24.5 μg/cig | 0.16–0.26 μg/stick | 0.131–0.38 μg/10 puffs | nda | nda | - |
| Intake (μg/d) | 208.5 (4) | 2.4 (1) | 2.2 (1) | nda (1) | nda (1) | 0.17 (1) | |
| CEMA (μg/d) | 162.6 (4) | 17.2 (2) | 36.6 (2) | 37.7 (2) | 29 (2) | 1.8 (1) | |
| AM (79-06-1) | Content per unit | 4.4–4.8 μg/cig | 1.04–1.73 μg/stick | nda | nda | nda | - |
| Intake (μg/d) | 47.4 (4) | 15.6 (2) | nda (1) | nda (1) | nda (1) | 0.002 (1) | |
| AAMA (μg/d) | 164.9 (4) | 88.8 (3) | 53.3 (2) | 146.8 (2) | 42 (2) | 66.1 (3) | |
| HCN (74-90-8) | Content per unit | 327–356 μg/cig | 1.7–3.5 μg/stick | nda | nda | nda | - |
| Intake (μg/d) | 3529 (4) | 29.5 (1) | nda (1) | nda (1) | nda (1) | nda (1) | |
| SCN P (μg/d) | 123.8 (4) | nda (3) | nda (3) | 80.6 (3) | nda (3) | 75 (3) | |
| o-Tol (95-53-4) | Content per unit | 62–84 ng/cig | 0.5–1.0 ng/stick | nda | nda | nda | - |
| Intake (ng/d) | 750.8 (4) | 8.0 (1) | nda (1) | nda (1) | nda (1) | 280 (2) | |
| o-Tol U (ng/d) | 201 (4) | 56.7 (2) | 100.1(3) | 114 (3) | 96.9 (3) | 63.5 (2) | |
| 2-NA (91-59-8) | Content per unit | 10–14 ng/cig | 0.02–0.05 ng/stick | 0.25–0.75 ng/10 puffs | nda | nda | - |
| Intake (ng/d) | 121.7 (4) | 0.4 (1) | 4.4 (1) | nda (1) | nda (1) | 116.5 (1) | |
| 2-NA U (ng/d) | 27.6 (4) | 1.8 (1) | 2.5 (1) | 3.3 (2) | 2.6 (1) | 3.5 (2) | |
| 4-ABP (92-67-1) | Content per unit | 2.0–2.8 ng/cig | 0.003–0.02 ng/stick | 0.01–0.04 ng/10 puffs | nda | nda | - |
| Intake (ng/d) | 25.1 (4) | 0.1 (1) | 0.2 (1) | nda (1) | nda (1) | 117.75 (1) | |
| 4-ABP U (ng/d) | 20.9 (4) | 2.3 (2) | 7 (2) | 3.8 (2) | 6.9 (2) | 2.4 (2) | |
| Nap (91-20-3) | Content per unit | 0.9–1.2 μg/cig | 0.002–0.004 μg/stick | nda | nda | nda | - |
| Intake (μg/d) | 10.86 (4) | 0.03 (1) | nda (1) | nda (1) | nda (1) | 4.33 (2) | |
| 1-OH-Nap (μg/d) | 13.28 (4) | nda (1) | 1.94 (2) | 2.59 (2) | nda (1) | 1.98 (2) | |
| Combustion-derived chemicals | |||||||
| Flu (86-73-7) | Content per unit | 237–337 ng/cig | 1.5–5.4 ng/stick | nda | nda | nda | - |
| Intake (μg/d) | 2.91 (4) | 0.04 (1) | nda (1) | nda (1) | nda (1) | 0.006 (1) | |
| 2-OH-Flu (μg/d) | 1.94 (4) | nda (1) | 1.05 (3) | 0.61 (2) | 1.05 (3) | 0.58 (2) | |
| Phe (85-01-8) | Content per unit | 159–292 ng/cig | 1.0–2.0 ng/stick | nda | nda | nda | - |
| Intake (ng/d) | 2323 (4) | 16.7 (1) | nda (1) | nda (1) | nda (1) | 76.5 (1) | |
| 1-OH-Phe (ng/d) | 221.9 (4) | nda (1) | 133.8 (3) | 152.2 (3) | nda (1) | 122.9 (3) | |
| Pyr (129-00-0) | Content per unit | 79–89 ng/cig | 2–7 ng/stick | nda | nda | nda | - |
| Intake (ng/d) | 871.7 (4) | 51.1 (1) | nda (1) | nda (1) | nda (1) | 114.8 (2) | |
| 1-OH-Pyr (ng/d) | 305 (4) | 70 (1) | 185 (2) | 360 (2) | 268 (2) | 139 (2) | |
| BaP (50-32-8) | Content per unit | 13–16 ng/cig | 0.2–0.8 ng/stick | 0.25–0.75 ng/10 puffs | 1.4–60.4 ng/g | nda | - |
| Intake (ng/d) | 149.1 (4) | 5.5 (1) | 4.4 (1) | 20.4 (2) | nda (1) | 76.5 (3) | |
| 3-OH-BaP (ng/d) | 203.1 (4) | 36.9 (2) | 87.4 (2) | 78.9 (2) | 119 (2) | 61.9 (2) | |
Figure 1
Box plots for the estimated daily nicotine intake (mg/d) (whiskers represent the 10th–90th percentiles) in users of CC, HNB, EC, OT and NG products. The filled blue circles represent medians of the urinary nicotine equivalents, while the green triangles show the plasma cotinine levels in users of these products and non-users (NU). Note that the right y-axis has two different scales.
Table 3
Uniqueness of single biomarker levels for particular product users or non-users.
| Users | “Unique” (at least 2 classes or ~4-fold difference expected to all other groups and either highest or lowest rank among the 6 groups) | “Possibly unique” (at least 1 class or 2-fold difference expected and either highest or lowest rank among the 6 groups | ||
|---|---|---|---|---|
| Biomarkera | Level | Biomarkera | Level | |
| CC | NAB (u) | > 41 ng/d | NNN (u) | > 12.5 ng/d |
| 3-HPMA (u) | > 1123 μg/d | NAT (u) | > 193 ng/d | |
| HMPMA (u) | > 496 μg/d | MHBMA (u) | > 2.5 μg/d | |
| COHb (b) | > 3.9% | SCN (p, u, sa) | > 87 μM | |
| IPMA3 (u) | > 30.8 μg/d | o-Tol (u) | > 141 ng/d | |
| Fu (b) | > 0.04 ng/d | 2-OH-Flu (u) | > 1.36 μg/d | |
| SPMA (u) | > 0.95 μg/d | 1-OH-Phe | > 155 ng/d | |
| CEMA (u) | > 113.8 μg/d | 3-OH-BaP | > 142 pg/d | |
| 2-NA (u) | > 19.3 ng/d | |||
| 4-ABP (u) | > 14.6 ng/d | |||
| 1-OH-Nap (u) | > 9.3 μg/d | |||
| HNB | none | none | ||
| EC | PG (u) | > 4.4 mg/d | ||
| OT | none | NNAL (u) | > 378 ng/d | |
| NG | none | none | ||
| NU | Nequ (u) | < 0.037 mg/d | CEMA (u) | < 16.1 μg/d |
| Cotinine (p) | < 21.4 ng/mL | |||
Table 4
Complete biomarker exposure level-derived patterns for the 6 groups of single product users (or non-users) as well as 3 dual user groups.
| Group | Pattern (based on 30 biomarker levels in the order as presented in Table 2), pattern for dual users calculated as described in the text |
|---|---|
| CC | 443434443344444444444444444444 |
| HNB | 341122121212221112223321211122 |
| EC | 341112114222222212222322222222 |
| OT | 434443321222222112222322222222 |
| NG | 331122121222222112222321212122 |
| NU | 111112111222222122213322222222 |
| CC/HNB | 442333332333333333334433333333 |
| CC/EC | 442323334333333333333433333333 |
| CC/OT | 444444432333333333333433333333 |