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Comparison of Nicotine and Toxicant Exposure in Users of Electronic Cigarettes and Combustible Cigarettes

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Comparison of Nicotine and Toxicant Exposure in Users of Electronic Cigarettes and Combustible Cigarettes Supplementary Online Content Goniewicz ML, Smith DM, Edwards KC, et al. Comparison of nicotine and toxicant exposure in users of electronic cigarettes and combustible cigarettes. JAMA Netw Open. 2018;1(8):e185937. doi:10.1001/jamanetworkopen.2018.5937 eFigure. Study Inclusion/Exclusion eTable 1. Analytical Limits of Detection (LOD), Biological Half-lives, and Assay Methods for Nicotine and Toxicants Assessed at Wave 1, PATH Study, 2013-2014 eTable 2. Biomarkers of Exposure to Tobacco-Related Compounds and Other Chemicals, Among Current Never Users, e-Cigarette Only-Users, Dual Users, and Cigarette-Only Smokers (Normalized for Creatinine, Geometric Means, 95% Confidence Intervals), PATH Wave 1 (2013-2014) (n=5,105) eMethods. Details on Model Building Procedures for Dual User Analysis and Sample Weighting eTable 3. Biomarkers of Exposure to Tobacco-Related Compounds and Other Chemicals, Among Everyday and Someday Users of e-Cigarettes and Cigarettes (Normalized for Creatinine, Geometric Means, 95% Confidence Intervals), PATH Wave 1 (2013-2014) (n=2,658) eTable 4. Biomarkers of Exposure to Tobacco-Related Compounds and Other Chemicals, Among Dual Users (Normalized for Creatinine, Geometric Means, 95% Confidence Intervals), PATH Wave 1 (2013-2014) (n=792) eReferences This supplementary material has been provided by the authors to give readers additional information about their work. © 2018 Goniewicz ML et al. JAMA Network Open. Downloaded From: https://jamanetwork.com/ on 09/29/2021 eFigure. Study Inclusion/Exclusion Wave 1 (W1) Adults, Population Assessment of Tobacco and Health (PATH) Study: N=32,320 EXCLUDE: N=10,519 N=21,801 W1 adult W1 adult participants participants who who did not provide provided urine samples urine samples EXCLUDE: N=10,279 N=11,522 W1 adult W1 adult participants participants who who provided urine provided urine samples samples but were not and were selected for selected for biomarker biomarker analysis analysis N=5,197 W1 EXCLUDE: N=6,325 who participants from did not meet product biomarker sample who use inclusion criteria met inclusion criteria for product use FINAL SAMPLE n=5,105 EXCLUDE: N=92 due to creatinine levels ≤10 Including: mg/dL or >370 mg/dL ‐ Never users (n=1,655) ‐ E‐cigarette‐only users (n=247) ‐ Dual users (n=792) ‐ Cigarette‐only smokers (n=2,411) © 2018 Goniewicz ML et al. JAMA Network Open. Downloaded From: https://jamanetwork.com/ on 09/29/2021 eTable 1. Analytical Limits of Detection (LOD), Biological Half-lives, and Assay Methods for Nicotine and Toxicants Assessed at Wave 1, PATH Study, 2013-2014 Limit of Biomarker Biological Half‐lifves Analytical Assay Method Detection Urinary Nicotine Metabolites^1 (ng/mL) trans‐3’‐Hydroxycotinine (HCTT) 0.030 6.4 hrs All nicotine metabolites were assessed Cotinine (COTT) 0.030 16‐18 hrs using two separate isotope dilution Nicotine (NICT) 10.5 1‐2 hrs high performance liquid chromatography/ tandem mass Cotinine N‐oxide (COXT) 2.02 N/A spectrometric (HPLC‐MS/MS) methods. Nicotine 1’‐oxide (NOXT) 2.50 N/A 2,3 Norcotinine (NCCT) 1.11 N/A Nornicotine (NNCT) 2.50 N/A Minor Tobacco Alkaloids (ng/mL) Anabasine (ANBT) 0.51 16 hrs All minor tobacco alkaloids were Anatabine (ANTT) 0.39 10 hrs assessed using two separate isotope dilution high performance liquid chromatography/tandem mass spectrometric (HPLC‐MS/MS) methods. 2,3 Arsenic and Arsenic Compounds (ug/L)^ Arsenous Acid 0.12 10 hrs All arsenic compounds were assessed Arsenic Acid 0.79 10 hrs using high performance liquid chromatography/inductively coupled Dimethylarsinic acid 1.19 10 hrs plasma dynamic reaction cell mass Monomethylarsonic acid 0.20 10 hrs spectrometry (HPLC‐ICP‐DRC‐MS). 4,5 Tobacco Specific Nitrosamines (TSNAs) (ng/L) 4‐methylnitrosamino)‐4‐(3‐pyridyl)‐1‐butanol (NNAL) 0.6 10.3 days6 All TSNAs were assessed using isotope N’‐nitrosonornicotine (NNN) 2.8 N/A dilution high performance liquid N’‐nitrosoanatabine (NAT) 4.2 N/A chromatography/atmospheric pressure N’‐nitrosoanabasine (NAB) 1.6 N/A chemical ionization tandem mass spectrometry (HPLC‐MS/MS). 7 © 2018 Goniewicz ML et al. JAMA Network Open. Downloaded From: https://jamanetwork.com/ on 09/29/2021 Limit of Biomarker Biological Half‐lifves Analytical Assay Method Detection Metals (µg/L) Beryllium (UBE) 0.016 Several years All metals were assessed using Cadmium (UCD) 0.036 13.6 years inductively coupled plasma mass 8,9 Cobalt (UCO) 0.023 Several days spectrometry (ICP‐MS). Manganese (UMN) 0.13 39 days 1‐2 months in blood & Lead (UPB) 0.03 soft tissues, years to decades in bone Strontium (USR) 2.34 47.3 hrs Thallium (UTL) 0.018 1‐3 days Uranium (UUR) 0.002 24 hrs Polycyclic Aromatic Hydrocarbons10 (ng/L) 1‐Naphthol or 1‐hydroxynaphthalene (1‐NAP) 60 4.3 hrs All PAHs were assessed using 2‐Naphthol or 2‐hydroxynaphthalene (2‐NAP) 90 9.4 hrs enzymatic hydrolysis, on‐line solid 3‐Hydroxyfluorene (3‐FLU) 8 8.2 hrs phase extraction, and isotope dilution liquid chromatography tandem mass 2‐Hydroxyfluorene (2‐FLU) 8 2.1 hrs spectrometry.11 1‐Hydroxyphenanthrene (1‐PHE) 9 5.1 hrs 1‐Hydroxypyrene (1‐PYR) 70 6.0 hrs 2‐Hydroxyphenanthrene and 3‐Hydroxyphenanthrene (2‐3PHE) 10 4.1 hrs Volatile Organic Compounds (VOCs) (ng/mL) 2‐Methylhippuric acid (2MHA) (Xylene) 5.00 34 hrs All VOCs were assessed using isotope 3, 4‐Methylhippuric acid (34MH) (Xylene) 8.00 34 hrs dilution UPLC‐MS/MS.12,13 N‐Acetyl‐S‐(2‐carbamoylethyl)‐L‐cysteine (AAMA) (Acrylamide) 2.20 11 or 17.4 hrs N‐Acetyl‐S‐(N‐methylcarbamoyl)‐L‐cysteine (AMCA) (N,N‐ 6.26 23 hrs Dimethylformamide/isocyanates) N‐Acetyl‐S‐(benzyl)‐L‐cysteine (BMA) (Toluene) 0.50 <10 hrs N‐Acetyl‐S‐(2‐carboxyethyl)‐L‐cysteine (CEMA) (Acrolein) 6.96 N/A N‐Acetyl‐S‐(1‐cyano‐2‐hydroxyethyl)‐L‐cysteine (CYHA) (Acrylonitrile) 2.60 N/A N‐Acetyl‐S‐(2‐cyanoethyl)‐L‐cysteine (CYMA) (Acrylonitrile) 0.50 8 hrs N‐Acetyl‐S‐(3,4‐dihydroxybutyl)‐L‐cysteine (DHBM) (1,3‐Butadiene) 5.25 N/A N‐Acetyl‐S‐(2‐carbamoyl‐2‐hydroxyethyl)‐L‐cysteine (GAMA) (Acrylamide) 9.40 19 or 25.1 hrs N‐Acetyl‐S‐(2‐hydroxyethyl)‐L‐cysteine (HEMA) (Acrylonitrile, vinyl 0.79 >5 hrs © 2018 Goniewicz ML et al. JAMA Network Open. Downloaded From: https://jamanetwork.com/ on 09/29/2021 Limit of Biomarker Biological Half‐lifves Analytical Assay Method Detection chloride, ethylene oxide) N‐Acetyl‐S‐(2‐hydroxypropyl)‐L‐cysteine (HPM2) (Propylene Oxide) 5.30 N/A N‐Acetyl‐S‐(3‐hydroxypropyl)‐L‐cysteine (HPMA) (Acrolein) 13.0 N/A N‐Acetyl‐S‐(3‐hydroxypropyl‐1‐methyl)‐L‐cysteine (HPMM) 3.00 N/A (Crotonaldehyde) N‐Acetyl‐S‐(4‐hydroxy‐2‐methyl‐2‐buten‐1‐yl)‐L‐cysteine (IPM3) 0.74 N/A (Isoprene) Mandelic acid (MADA) 12.0 2.1,3.6, or 3.9 hrs N‐Acetyl‐S‐(4‐hydroxy‐2‐buten‐1‐yl)‐L‐cysteine (MHB3) (1,3 Butadiene) 0.60 >9 or <6 hrs* Phenylglyoxylic acid (PGHA) (Ethylbenzene, styrene) 12.0 8.1,8.8 or 10.5 hrs N‐Acetyl‐S‐(phenyl)‐L‐cysteine (PMA) (Benzene) 0.60 9.1 hrs 2‐Thioxothiazolidine‐4‐carboxylic acid (TTCA) (Carbon Disulfide) 11.2 8 hrs Footnotes: * Estimated from animal study. Multiple values indicate areas in which the literature lists multiple half-life values. N/A = “Not Available” ^ Assays were conducted for each of the seven major nicotine metabolites listed in eTable 1. In addition to the nicotine metabolites listed above, “Total Nicotine Equivalents” (TNE-2) was computed and included in statistical analyses as a reflection of systemic nicotine levels for participants. TNE-2 was calculated as the molar sum of cotinine and trans-3’-Hydroxycotinine. For arsenic and arsenic compounds, individual assays were conducted for each of the four listed compounds in eTable 1. The analysis used a summary variable, “Total Inorganic Arsenic”, representing the sum of the arsenous acid, arsenic acid, dimethylarsinic acid, and monomethylarsonic acid levels in each urine sample. As these are summary variables, TNE-2 and Total Inorganic Arsenic do not have listings for limits of detection. © 2018 Goniewicz ML et al. JAMA Network Open. Downloaded From: https://jamanetwork.com/ on 09/29/2021 eTable 2: Biomarkers of Exposure to Tobacco-Related Compounds and Other Chemicals, Among Current Never Users, e-Cigarette Only-Users, Dual Users, and Cigarette-Only Smokers (Normalized for Creatinine, Geometric Means, 95% Confidence Intervals), PATH Wave 1 (2013-2014) (n=5,105) Never users (1,655) (a) Current e‐cigarette‐only users (n=247) (b) 95% CI 95% CI % N Above 95% CI 95% CI % N Above Biomarker N Geo Mean N Geo Mean Lower Upper LOD Lower Upper LOD Urinary Nicotine Metabolites (ng/mg creatinine) Nicotine Equivalence (TNE2) (nmol/mg) 1,652 0.006b 0.005 0.007 99% 247 2.000acd 1.1 3.5 100% trans‐3’‐Hydroxycotinine (HCTT) 1,641 6.9E‐01b 6.00E‐01 8.00E‐01 98% 247 227.4acd 128.9 401.1 100% Cotinine (COTT) 1,644 4.2E‐01b 3.60E‐01 4.90E‐01 99% 247 124.3acd 68.9 224.4 100% Nicotine (NICT)^ 88 3.1E+01b 1.20E+01 8.00E+01 64% 179 423.6acd 306.7 584.9 93% Cotinine N‐oxide (COXT)^ 88 1.4E+01b 6.80E+00 2.80E+01 99% 179 117.5acd 88.2 156.5 98% Nicotine 1’‐oxide (NOXT)^ 88 1.1E+01b 4.20E+00 3.10E+01 76% 179 143.3acd 105.3 194.9 95% Norcotinine (NCCT)^ 88 4.3E+00b 2.30E+00 8.00E+00 95% 179 31.93acd 24.35 41.87 96% Nornicotine (NNCT)^ 88 3.4E+00b 1.80E+00 6.20E+00 35% 179 18.83acd 14.72 24.11 86% Minor Tobacco Alkaloids (ng/mg creatinine) Anabasine (ANBT)^ 88 0.605 0.347 1.053 29% 179 1.144cd 0.876 1.492 56% Anatabine (ANTT)^ 88 0.615 0.306 1.234 37% 179 0.886cd 0.658 1.192 46% Arsenic and Arsenic Compounds (ug/g creatinine) Total Inorganic Arsenic 1,653 0.054 0.05 0.057 92% 247 0.053d 0.048 0.058 87% Tobacco Specific Nitrosamines (TSNAs) (pg/mg creatinine) 4‐methylnitrosamino)‐4‐(3‐pyridyl)‐1‐butanol
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