Nicotine and the Developing Human

A Neglected Element in the Electronic Cigarette Debate
      The elimination of cigarettes and other combusted tobacco products in the U.S. would prevent tens of millions of tobacco-related deaths. It has been suggested that the introduction of less harmful nicotine delivery devices, such as electronic cigarettes or other electronic nicotine delivery systems, will accelerate progress toward ending combustible cigarette use. However, careful consideration of the potential adverse health effects from nicotine itself is often absent from public health debates. Human and animal data support that nicotine exposure during periods of developmental vulnerability (fetal through adolescent stages) has multiple adverse health consequences, including impaired fetal brain and lung development, and altered development of cerebral cortex and hippocampus in adolescents. Measures to protect the health of pregnant women and children are needed and could include (1) strong prohibitions on marketing that increase youth uptake; (2) youth access laws similar to those in effect for other tobacco products; (3) appropriate health warnings for vulnerable populations; (4) packaging to prevent accidental poisonings; (5) protection of non-users from exposure to secondhand electronic cigarette aerosol; (6) pricing that helps minimize youth initiation and use; (7) regulations to reduce product addiction potential and appeal for youth; and (8) the age of legal sale.
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      1. USDHHS. The Health Consequences of smoking—50 Years of progress: A Report of the Surgeon General. Atlanta, GA: USDHHS, CDC, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health; 2014.

        • IOM.
        Ending the Tobacco Problem: A Blue-Print for the Nation.
        National Academies Press, Washington, DC2007
        • Abrams D.B.
        Promise and peril of e-cigarettes. Can disruptive technology make cigarettes obsolete?.
        JAMA. 2014; 311: 135-136
      2. Abrams D, Axéll T, Bartsch P, Letter: statement from specialists in nicotine science and public health policy.

        • Grana R.
        • Benowitz N.
        • Glantz S.A.
        E-cigarettes: a scientific review.
        Circulation. 2014; 129: 1972-1986
      3. U.S. Food and Drug administration. Deeming—Extending Authorities to Additional Tobacco Products.

      4. USDHHS, Food and Drug Administration 21 CFR Parts 1100, 1140, and 1143 [Docket No. FDA-2014-N-0189] RIN 0910-AG38.

      5. National Conference of State Legislatures. Alternative Nicotine Products/Electronic Cigarettes.

      6. Campaign for Tobacco Free Kids. 7 ways e-cigarette companies are copying big tobacco’s playbook.

      7. Staff of Richard Durbin, Henry Waxman, Tom Harkin, et al. Gateway to addiction? A survey of popular electronic cigarette manufacturers and targeted marketing to youth.

      8. ecigExpress. DIY e-liquid, electronic cigarettes, and wholesale nicotine.

      9. ProVape.

        • Grana R.
        • Glantz S.
        • Ling P.
        Electronic nicotine delivery systems in the hands of Hollywood.
        Tob Control. 2011; 20: 425-426
        • Duke J.C.
        • Lee Y.O.
        • Kim A.E.
        • et al.
        Exposure to electronic cigarette television advertisements among youth and young adults.
        Pediatrics. 2014; 134: e29-e36
      10. Public Law 91-222-APR. 1, 1970.

      11. International Vapor Group. Why E-cigs?

      12. Vapourart. Which are the benefits of electronic cigarettes over tobacco cigarettes?

      13. RJ Reynolds Vapor. Transforming tobacco.

        • Parry L.
        “Nicotine is good for you”: scientist employed by cigarette manufacturers claims highly addictive drug makes your brain work better.
        Mail Online Health. 14 December 2013;
      14. RJ Reynolds. Guiding principles and beliefs.

      15. British American Tobacco. Reducing harm through innovation.

        • Corey C.
        • Wang B.
        • Johnson S.E.
        • et al.
        Notes from the field: electronic cigarette use among middle and high school students—United States, 2011–2012.
        MMWR Morb Mortal Wkly Rep. 2013; 62: 729-730
        • Arrazola R.A.
        • Neff L.J.
        • Kennedy S.M.
        • Holder-Hayes E.
        • Jones C.D.
        Tobacco use among middle and high school students—United States, 2013.
        MMWR Morb Mortal Wkly Rep. 2014; 63: 1021-1026
        • Mangan D.
        E-cigarette sales are smoking hot, set to hit $1.7 billion.
        CNBC Healthcare. August 28, 2013;
        • Brustein J.
        A social networking device for smokers.
        New York Times, May 10, 2011
      16. Blu Premium 100 kit.

      17. Supersmoker Bluetooth. The first e-cigarette with Bluetooth phone function.

        • Polosa R.
        • Rodu B.
        • Caponnetto P.
        • Maglia M.
        • Raciti C.
        A fresh look at tobacco harm reduction: the case for electronic cigarettes.
        Harm Reduct J. 2013; 10: 19
        • Fagerström K.O.
        • Bridgman K.
        Tobacco harm reduction: the need for new products that can compete with cigarettes.
        Addict Behav. 2014; 39: 507-511
      18. International Program on Chemistry Safety. Nicotine.

        • Albuquerque E.C.
        • Pereira E.F.R.
        • Alkondon M.
        • Rogers S.W.
        Mammalian nicotinic acetylcholine receptors: From structure to function.
        Physiol Rev. 2009; 89: 73-120
        • Wessler I.
        • Kilpatrick C.J.
        Acetylcholine beyond neurons: the non-neuronal cholinergic systems in humans.
        Br J Pharmacol. 2008; 154: 1558-1571
        • Gahring L.C.
        • Rogers S.W.
        Neuronal nicotinic acetylcholine receptor expression and function on nonneuronal cells.
        AAPS J. 2006; 7 (Article 86)
        • Thompson B.L.
        • Levitt P.
        • Stanwood G.D.
        Prenatal exposure to drugs: effects on brain development and implications for policy and education.
        Nat Rev Neurosci. 2009; 10: 303-312
        • Hellström-Lindahl E.
        • Gorbounova O.
        • Seiger A.
        • Mousavi M.
        • Nordberg A.
        Regional distribution of nicotinic receptors during prenatal development of human brain and spinal cord.
        Brain Res Dev Brain Res. 1998; 108: 147-160
        • Dwyer J.D.
        • McQuown S.C.
        • Leslie F.M.
        The dynamic effects of nicotine on the developing brain.
        Pharmacol Ther. 2009; 122: 125-139
        • Slotkin T.A.
        • Seidler F.J.
        • Qiao D.
        • et al.
        Effects of prenatal nicotine exposure on primate brain development and attempted amelioration with supplemental choline or vitamin C: neurotransmitter receptors, cell signaling and cell development biomarkers in fetal brain regions of Rhesus monkeys.
        Neuropsychopharmacology. 2005; 30: 129-144
        • Slotkin T.A.
        Fetal nicotine or cocaine exposure: which one is worse?.
        J Pharmacol Exp Ther. 1998; 285: 931-945
        • Slotkin T.A.
        • Cho H.
        • Whitmore W.L.
        Effects of prenatal nicotine exposure on neuronal development: selective actions on central and peripheral catecholaminergic pathways.
        Brain Res Bull. 1987; 18: 601-611
        • Dwyer J.B.
        • Broide R.S.
        • Leslie F.M.
        Nicotine and brain development.
        Birth Defects Res C Embryo Today. 2008; 84: 30-44
        • Baba S.
        • Wikstöm A.K.
        • Stephansson O.
        • Cnattingius S.
        Influence of smoking and snuff cessation on preterm birth.
        Eur J Epidemiol. 2012; 27: 297-304
        • Gupta P.C.
        • Sreevidya S.
        Smokeless tobacco use, birth weight, and gestational age: population-based, prospective cohort study of 1217 women in Mumbai, India.
        BMJ. 2004; 328 ( 1538
        • Gupta P.C.
        • Subramoney S.
        Smokeless tobacco use and risk of stillbirth: a cohort study in Mumbai, India.
        Epidemiology. 2006; 17 ( 47-51
        • Steyn K.
        • de Wet T.
        • Saloohee Y.
        • et al.
        The influence of maternal cigarette smoking, snuff use, and passive smoking on pregnancy outcomes: the Birth to Ten Study.
        Paediatr Perinat Epidemiol. 2006; 20: 90-99
        • Wikström A.K.
        • Cnattingius S.
        • Stephansson O.
        Maternal use of Swedish snuff (snus) and risk of stillbirth.
        Epidemiology. 2010; 21: 772-778
        • Gunnerbeck A.
        • Wikström A.K.
        • Bonamy A.K.
        • Wickström R.
        • Cnattingius S.
        Relationship of maternal snuff use and cigarette smoking with neonatal apnea.
        Pediatrics. 2011; 128: 503-509
        • Dietz P.M.
        • England L.J.
        • Sharpiro-Mendoza C.K.
        • et al.
        Infant morbidity and mortality attributable to prenatal smoking in the U.S.
        Am J Prev Med. 2010; 39: 45-52
        • Pauly J.R.
        • Sparks J.A.
        • Hauser K.F.
        • Pauly T.H.
        In utero nicotine exposure causes persistent, gender-dependant changes in locomotor activity and sensitivity to nicotine in C57Bl/6 mice.
        Int J Dev Neurosci. 2004; 22: 329-337
        • Vaglenova J.
        • Birru S.
        • Pandiella N.M.
        • Breese C.R.
        An assessment of the long-term developmental and behavioral teratogenicity of prenatal nicotine exposure.
        Behav Brain Res. 2004; 150: 159-170
        • Levin E.D.
        • Wilkerson A.
        • Jones J.P.
        • Christopher N.C.
        • Briggs S.J.
        Prenatal nicotine effects on memory in rats: pharmacological and behavioral challenges.
        Dev Brain Res. 1999; 97: 207-215
        • Huang L.Z.
        • Liu X.
        • Griffith W.H.
        • Winzer-Serhan U.H.
        Chronic neonatal nicotine increases anxiety but does not impair cognition in adult rats.
        Behav Neurosci. 2007; 121: 1342-1352
        • Abdel-Rahman A.
        • Dechkovskaia A.M.
        • Sutton J.M.
        • et al.
        Maternal exposure of rats to nicotine via infusion during gestation produces neurobehavioral deficits and elevated expression of glial fibrillary acidic protein in the cerebellum and CA1 subfield in the offspring at puberty.
        Toxicology. 2005; 209: 245-261
        • Slotkin T.A.
        If nicotine is a developmental neurotoxicant in animal studies, dare we recommend nicotine replacement therapy in pregnant women and adolescents?.
        Neurotoxicol Teratol. 2008; 30: 1-19
        • Hanrahan J.P.
        • Tager I.B.
        • Segal M.R.
        • et al.
        The effect of maternal smoking during pregnancy on early infant lung function.
        Am Rev Respir Dis. 1992; 145: 1129-1135
        • Lødrup Carlsen K.C.
        • Jaakkola J.J.
        • Nafstad P.
        • Carlsen K.H.
        In utero exposure to cigarette smoking influences lung function at birth.
        Eur Respir J. 1997; 10: 1774-1779
        • Stocks J.
        • Dezateux C.
        The effect of parental smoking on lung function and development during infancy.
        Respirology. 2003; 8: 266-285
        • Tager I.B.
        • Ngo L.
        • Hanrahan J.P.
        Maternal smoking during pregnancy. Effects on lung function during the first 18 months of life.
        Am J Respir Crit Care Med. 1995; 152 (997–983)
        • Maritz G.S.
        • Harding R.
        Life-long programming implications of exposure to tobacco smoking and nicotine before and soon after birth: evidence for altered lung development.
        Int J Environ Res Public Health. 2011; 8: 875-898
        • Sekhon H.S.
        • Jia Y.
        • Raab R.
        • et al.
        Prenatal nicotine increases pulmonary alpha 7 nicotinic receptor expression and alters fetal development in monkeys.
        J Clin Invest. 1999; 103: 637-647
        • Sekhon H.S.
        • Keller J.A.
        • Benowitz N.L.
        • Spindel E.R.
        Prenatal nicotine exposure alters pulmonary function in newborn rhesus monkeys.
        Am J Respir Crit Care Med. 2001; 164: 989-994
        • Sekhon H.S.
        • Keller J.A.
        • Proskocil B.J.
        • Martin E.L.
        • Spindel E.R.
        Maternal nicotine exposure upregulates collagen gene expression in fetal monkey lung: association with alpha7 nicotinic acetylcholine receptors.
        Am J Respir Cell Mol Biol. 2002; 26: 31-41
        • Li Y.F.
        • Langholz B.
        • Salam M.T.
        • Gilliland F.D.
        Maternal and grandmaternal smoking patterns are associated with early childhood asthma.
        Chest. 2005; 127: 1232-1241
        • Rehan V.K.
        • Liu J.
        • Naeem E.
        • et al.
        Perinatal nicotine exposure induces asthma in second generation offspring.
        BMC Med. 2012; 10: 129
        • Leslie F.M.
        Multigenerational epigenetic effects of nicotine on lung function.
        BMC Med. 2013; 11: 27
        • Tong V.T.
        • Dietz P.M.
        • Farr S.L.
        • D’Angelo D.V.
        • England L.J.
        Estimates of smoking before and during pregnancy: comparing two population-based data sources.
        Public Health Rep. 2013; 128: 179-188
        • Finer L.B.
        • Zolna M.R.
        Shifts in intended and unintended pregnancies in the United States, 2001–2008.
        Am J Public Health. 2014; 104: S44-S48
        • Tong V.T.
        • England L.J.
        • Dietz P.M.
        • Asare L.A.
        Smoking patterns and use of cessation interventions during pregnancy.
        Am J Prev Med. 2008; 35: 327-333
        • Zhu S.
        • Gamst A.
        • Lee M.
        • Cummins S.
        • Yin L.
        • Zoref L.
        The use and perception of electronic cigarettes and snus among the U.S. population.
        PLoS One. 2013; 8: e79332
        • King B.A.
        • Patel R.
        • Nguyen K.H.
        • Dube S.R.
        Trends in awareness and use of electronic cigarettes among U.S. adults, 2010-2013.
        Nicotine Tob Res. 2014;
        • CDC.
        Notes from the field: electronic cigarette use among middle and high school students—United States, 2011–2012.
        MMWR Morb Mortal Wkly Rep. 2013; 62: 729-730
        • Arrazola R.A.
        • Neff L.J.
        • Kennedy S.M.
        • Holder-Hayes E.
        • Jones C.D.
        Tobacco use among middle and high school students—United States 2013.
        MMWR Morb Mortal Wkly Rep. 2014; 63: 1021-1026
      19. Consumer Updates: Smoking cessation products.

        • American College of Obstetricians and Gynecologists. Tobacco use and women׳s health.
        Committee Opinion No. 503.
        Obstet Gynecol. 2011; 118: 746-750
      20. King BA, Patel R, Babb SD. Prevalence of smokefree home rules—United States, 1992-1993 and 2010-2011. MMWR Morb Mortal Wkly Rep. 2014;63(35):765–769.

        • King B.A.
        • Dube S.R.
        • Homa D.M.
        Smoke-free rules and secondhand smoke exposure in homes and vehicles among U.S. adults, 2009-2010.
        Prev Chronic Dis. 2013; 10: 120218
        • Schober W.
        • Szendrei K.
        • Matzen W.
        • et al.
        Use of electronic cigarettes (e-cigarettes) impairs indoor air quality and increases FeNo levels of e-cigarette users.
        Int J Hyg Environ Health. 2014; 217: 628-637
        • Matt G.E.
        • Quintana P.J.E.
        • Destaillats H.
        • et al.
        Thirdhand tobacco smoke: emerging evidence and arguments for a multidisciplinary research agenda.
        Environ Health Perspect. 2011; 119: 1218-1226
        • Singer B.C.
        • Hodgson A.T.
        • Nazaroff W.W.
        Gas-phase organics in environmental tobacco smoke: exposure-relevant emission factors and indirect exposures from habitual smoking.
        Atmos Environ. 2003; 37: 5551-5561
        • Goniewicz M.L.
        • Lee L.
        Electronic cigarettes are a source of thirdhand exposure to nicotine.
        Nicotine Tob Res. 2015; 17: 256-268
        • Ballbè M.
        • Martínez-Sánchez J.M.
        • Sureda X.
        • et al.
        Cigarettes vs. e-cigarettes: passive exposure at home measured by means of airborne marker and biomarkers.
        Environ Res. 2014; 135C: 76-80
        • Flouris A.D.
        • Chorti M.S.
        • Poulianiti K.P.
        • et al.
        Acute impact of active and passive electronic cigarette smoking on serum cotinine and lung function.
        Inhal Toxicol. 2013; 25: 91-101
        • Yolton K.
        • Dietrich K.
        • Auinger P.
        • Lanphear B.P.
        • Hornung R.
        Exposure to environmental tobacco smoke and cognitive abilities among U.S. children and adolescents.
        Environ Health Perspect. 2005; 113: 98-103
      21. National Scientific Council on the Developing Child. Early exposure to toxic substances damages brain architecture. 2006. Working Paper No. 4.

      22. WHO. Childhood lead poisoning.

        • Chen R.
        • Clifford A.
        • Lang L.
        • Anstey K.J.
        Is exposure to secondhand smoke associated with cognitive parameters of children and adolescents? A systematic literature review.
        Ann Epidemiol. 2013; 23: 652-661
        • Ginzel K.H.
        • Maritz G.S.
        • Marks D.F.
        • et al.
        Critical review: nicotine for the fetus, the infant, and the adolescent?.
        J Health Psychol. 2007; 12: 215-224
        • Gould T.J.
        • Leach P.T.
        Cellular, molecular, and genetic substrates underlying the impact of nicotine on learning.
        Neurobiol Learn Mem. 2014; 107: 108-132
      23. WHO. Tobacco Free Initiative (TFI): Electronic cigarettes (e-cigarettes) or electronic nicotine delivery systems.

        • Chatham-Stephens K.
        • Law R.
        • Taylor E.
        • et al.
        Notes from the field: calls to poison centers for exposures to electronic cigarettes—United States, September 2010–February 2014.
        MMWR Morb Mortal Wkly Rep. 2014; 63: 292-293
        • Bunnell R.E.
        • Agaka I.T.
        • Arrazola R.A.
        • et al.
        Intentions to smoke cigarettes among never-smoking U.S. middle and high school electronic cigarette users, National Youth Tobacco Survey 2011-2013.
        Nicotine Tob Res. 2014;
        • Poorthuis R.B.
        • Goriounova N.A.
        • Couey J.J.
        • Mansvelder H.D.
        Nicotinic actions on neuronal networks for cognition: general principles and long-term consequences.
        Biochem Pharmacol. 2009; 78: 668-676
        • Goriounova N.A.
        • Mansvelder H.D.
        Short- and long-term exposure of nicotine exposure during adolescence for prefrontal cortex neuronal network function.
        Cold Spring Harb Perspect Med. 2012; 2: a012120
        • Giedd J.N.
        Structural magnetic resonance imaging of the adolescent brain.
        Ann N Y Acad Sci. 2004; 1021: 77-85
        • Durston S.
        • Hulshoff Pol H.E.
        • Casey B.J.
        • Giedd J.N.
        • Buitelaar J.K.
        • van Engeland H.
        Anatomical MRI of the developing human brain: what have we learned?.
        J Am Acad Child Adolesc Psychiatry. 2001; 40: 1012-1020
        • Ernst M.
        • Fudge J.
        A developmental neurobiological model of motivated behavior: anatomy, connectivity and ontogeny of the triadic nodes.
        Neurosci Biobehav Rev. 2009; 33: 367-382
        • Jacobsen L.K.
        • Krystal J.H.
        • Mencl W.E.
        • Westerveld M.
        • Frost S.J.
        • Pugh K.R.
        Effects of smoking and smoking abstinence on cognition in adolescent tobacco smokers.
        Biol Psychiatry. 2005; 57: 56-66
        • Musso F.
        • Bettermann F.
        • Vucurevic G.
        • Stoeter P.
        • Konrad A.
        • Winterer G.
        Smoking impacts on prefrontal attentional network function in young adult brains.
        Psychopharmacology (Berl). 2007; 191: 159-169
        • Trauth J.A.
        • Seidler F.J.
        • Slotkin T.A.
        Persistent and delayed behavioral changes after nicotine treatment in adolescent rats.
        Brain Res. 2000; 880: 167-172
        • Brown R.W.
        • Kolb B.
        Nicotine sensitization increases dendritic length and spine density in the nucleus accumbens and cingulate cortex.
        Brain Res. 2001; 899: 94-100
        • Goniewicz M.L.
        • Gawron M.
        • Nodolska J.
        • Balwicki L.
        • Sobczak J.
        Rise in electronic cigarette use among adolescents in Poland.
        J Adolesc Health. 2014; 55: 713-715
        • USDHHS.
        Preventing tobacco use among youth and young adults: a report of the Surgeon General.
        USDHHS, CDC, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, Atlanta, GA2012
        • O’Dell L.E.
        A psychological framework of the substrates that mediate nicotine addiction use during adolescence.
        Neuropharmacology. 2009; 56: 263-278
        • O’Dell L.E.
        NICO-TEEN: neural substrates that mediate adolescent tobacco abuse.
        Neuropharmacol Rev. 2011; 36: 356-357
        • Kandel E.R.
        • Kandel D.B.
        A molecular basis for nicotine as a gateway drug.
        N Engl J Med. 2014; 317 ( 932-943