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

Scherer, Gerhard; Pluym, Nikola; Scherer, Max

doi:10.2478/cttr-2021-0014

Figures & Tables

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	N^b	Mean	SD	Median	Min	Max	25^th Perc.	75^th 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	nda^b	–
	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)	104.5^c (2)	26.6 (1)	539.8 (4)	176.7^c (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

	Biomarker^a	Level	Biomarker^a	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
NU	Cotinine (p)	< 21.4 ng/mL

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

Figures & Tables

Figure 1

Averages and ranges for the daily consumption of the five nicotine productsa_

Complete biomarker exposure level-derived patterns for the 6 groups of single product users (or non-users) as well as 3 dual user groups_

Uniqueness of single biomarker levels for particular product users or non-users_

Paradigm

My account