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Intake and Uptake of Chemicals Upon Use of Various Tobacco/Nicotine Products: Can Users be Differentiated by Single or Combinations of Biomarkers?

Gerhard Scherer
Gerhard Scherer
, 
Nikola Pluym
Nikola Pluym
 y 
Max Scherer
Max Scherer
   | 02 ene 2022
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Publicado en línea: 02 ene 2022
Páginas: 167 - 198
Recibido: 16 abr 2021
Aceptado: 15 sept 2021
DOI: https://doi.org/10.2478/cttr-2021-0014
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© 2021 Gerhard Scherer et al., published by Sciendo
This work is licensed under the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.

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.
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.

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))

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)

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

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
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