The “Continuum of Risk” Must Include Cardiovascular Disease

This public comment has been submitted to the FDA.
 
The “Continuum of Risk” Must Include Cardiovascular Disease
 
Comment Submitted in Response to FDA Regarding Proposed Rule Deeming Tobacco Products to be Subject to the Federal Food, Drug, and Cosmetic Act, as Amended by the Family Smoking Prevention and Tobacco Control Act; Regulations on the Sale and Distribution of Tobacco Products and Required Warning Statements for Tobacco Products
 
Docket No. FDA-2014-N-0189
 
Suzaynn F. Schick, PhD, Ganna Kostygina, PhD and Carolyn Calfee, MD
University of California, San Francisco
 
June 9, 2014
 
Most of the discussion of “continuum of risk” that the FDA states that it intends to use in its rulemaking (p 23144) has been focused on cancer.  While e-cigarettes deliver lower levels of carcinogens than conventional cigarettes, the ultrafine particles and nicotine that these products deliver have important effects on the development of cardiovascular disease and triggering of cardiac events that are likely to be as large as for inhalation of combusted tobacco products.
 
Cancer is not the only important health risk to consider for tobacco use.  Indeed, cardiovascular disease accounts for 40.50 % of smoking-induced deaths (U.S. Department of Health and Human Services, Centers for Disease Control and Prevention et al. 2014).  Nicotine itself also has important adverse health effects on several other biological systems that the FDA must consider.
 
The idea of a “spectrum of risk” or “continuum of risk” among tobacco and nicotine delivery products is logical.  However at this time it is a hypothesis lacking sufficient empirical evidence to use as a basis for regulatory decisions.  There have been many instances in the history of the tobacco epidemic when similar logical hypotheses have been proven to be wrong.  It was logical to believe that filtered cigarettes would be safer than unfiltered cigarettes.  It was logical to believe that light cigarettes would be safer than full-flavor cigarettes.  It was logical to believe that the risk of cardiovascular disease from exposure to secondhand cigarette smoke would be 10-100 times less than that of active smoking.  Each one of these logical hypotheses has been proven wrong, at an immense cost to the public health (U.S. Department of Health and Human Services, U.S. Public Health Service et al. 2001, Institute of Medicine 2010, U.S. Department of Health and Human Services, Centers for Disease Control and Prevention et al. 2014).  The FDA should not predicate regulatory actions on the assumption that any tobacco or nicotine delivery product is substantially safer than another until the improved safety profile has been demonstrated by a substantial body of peer-reviewed scientific research. 
 
E-cigarette Particles May Cause Substantial Cardiovascular and Pulmonary Disease
 
Like combustible tobacco products, E-cigarettes deliver nicotine in an aerosol of ultrafine respirable particles to the user.  Exposure to respirable particles causes cardiovascular morbidity and mortality (Institute of Medicine 2010).  In both cardiovascular and pulmonary disease, increasing evidence supports a non-linear dose-response relationship between cigarette smoke exposure and toxicity.  For instance, in cardiovascular disease, mortality increases in a logarithmic fashion with increasing exposure to even small amounts of cigarette smoke and airborne fine particulate matter (Pope et al, Circulation 2009).  Likewise, a similar pattern of rapid increases in risk at low levels of exposure has been demonstrated in the association between cigarette smoke exposure and acute lung injury after severe blunt trauma (Calfee, Matthay et al. 2011). Thus, even if e-cigarettes or other tobacco products deliver lower doses of specific toxins compared with traditional cigarettes, they cannot necessarily be presumed to be safer, since substantial risk may be present with even low levels of exposure.
 
The mechanisms by which particle exposure causes a near-immediate increase in the risk of myocardial infarction and the chemical and physical properties of particles that convey this risk are not fully understood.  It is possible that e-cigarette aerosol particles are less harmful to cardiovascular health than combustion particles.  However, until research has shown that e-cigarette particles do not cause the same kinds of acute changes in biomarkers of cardiovascular disease risk or increase the incidence of cardiovascular disease at the population level as exposure to combustion particles does, protection of public health requires treating them as being as dangerous as similar size particles in primary and secondhand smoke. 
 
Dual Use Can Increase Cardiovascular Disease Risk
 
If there are differences in the health risks associated with combustible and non-combustible tobacco and nicotine delivery products, it is still unlikely that regulating the products presumed to be least harmful less stringently will result in improvements in the public health.  The FDA is only one contributor to the array of communications on tobacco that is dominated by the tobacco industry.  If the FDA indicates that one tobacco product is safer than another, it is likely to increase dual use by nonusers.  The concomitant use of two or more tobacco products, can exacerbate dependence on nicotine among light-to-medium consumption smokers (Timberlake 2008). The INTERHEART study (Teo, Ounpuu et al. 2006) suggests that dual use may be more dangerous than continued smoking alone.  In this international study of 52 countries, current smoking was associated with a greater risk of non-fatal AMI (odds ratio [OR] 2.95, 95% CI 2.77-3.14, p  
The “Spectrum of Risk” is a Useful Marketing Tool for the Tobacco Industry
 
Tobacco companies have a strong motivation to exploit the market potential of alternative nicotine products to generate new profits, without cannibalizing existing profits from cigarettes, by creating new forms of nicotine and tobacco use (Peeters and Gilmore 2013). For instance, in 2009, Reynolds American acquired the Swedish company Niconovum AB, which makes nicotine replacement therapy (NRT) products, including nicotine gum and oral spray (Craver 2013, CSP News 2013).  In September 2012, Altria announced the launch of Tju “chewing tobacco gum” in Denmark and of Verve tobacco-derived nicotine discs, which are currently being test-marketed in Virginia (Altria Group Inc. 2013). Although not directly promoted as smoking cessation aids, these tobacco products resemble NRT products and so may be perceived as analogous to NRT gums and lozenges in regards to product safety. The resulting effects on the health of the population are unknown.
 
Nicotine Presents Significant Cardiovascular Health Risks
 
E-cigarettes deliver both particles and nicotine.  In addition to being highly addictive, nicotine also has numerous pathological effects (Bruin, Gerstein et al. 2010, Mills, Thorlund et al. 2014, Samet 2014).  A meta-analysis of 63 randomized clinical trials of smoking cessation therapies found that the use of nicotine replacement therapy was associated with an elevated risk of cardiovascular disease events (RR, 2.29%; 95% CI, 1.39-3.82), when compared to the use of buproprion or varenicline (Mills, Thorlund et al. 2014, Samet 2014).   When the studies with only 12 months of follow up were excluded, the increased risk for all cardiovascular disease events increased to 3.03 (95% confidence interval, 2.04-4.67) (Samet 2014).  Nicotine has wide-ranging and potentially persistent effects on cardiovascular disease risk. 
 
Myocardial infarctions are caused by the rupture of atherosclerotic plaques in the coronary arteries. Pathology in the endothelial cells that line arteries and enhanced blood supply to the plaques within arteries contribute to myocardial infarction.  Endothelial cell function can be measured by a technique called flow-mediated dilation of the brachial artery.  Briefly, the diameter of the main artery in the arm is measured by ultrasound before and after a significant increase in blood flow.  When blood flow increases, healthy endothelial cells secrete nitric oxide which relaxes the muscles in the arteries causing dilation.  Unhealthy endothelial cells cannot do this.  The use of smokeless tobacco and nicotine nose spray both decrease endothelial  function as measured by flow-mediated dilation of the brachial artery (Neunteufl, Heher et al. 2002, Granberry, Smith et al. 2003). 
 
Angiogenesis, the growth of new capillaries, is another essential part of the development and rupture of atherosclerotic plaques (Moulton 2006).  Heeschen et al. showed that subcutaneous nicotine doubled the local growth of capillaries in mice (Heeschen, Jang et al. 2001).  At clinically relevant concentrations (similar to those of a light to moderate smoker), nicotine promotes endothelial cell migration, poliferation, survival, tube formation and nitric oxide production in vivo (Heeschen, Jang et al. 2001).  Nicotine also accelerates the growth of lung tumors in a mouse model (Heeschen, Jang et al. 2001), an effect also produced by secondhand smoke exposure (Zhu, Heeschen et al. 2003). Potential mechanisms include the development and mobilization of endothelial progenitor cells (Heeschen, Chang et al. 2006, Yu, Liu et al. 2011).  It is important to note that all the animal studies cited in these comments used nicotine concentrations comparable to those found in the plasma and follicular fluid of light to moderate smokers.
 
Reproductive and Developmental Effects of Nicotine
 
Exposure to nicotine in utero has significant and life-long effects on the heart, lungs, brain, reproductive systems and metabolism (Maritz 2008, Bruin, Gerstein et al. 2010). Children of women who smoke have hypertension (Beratis, Panagoulias et al. 1996, Blake, Gurrin et al. 2000). Animal studies suggest that nicotine alone can cause hypertension.  Fetal and neonatal nicotine exposure causes increased blood pressure during adulthood in normotensive rats and spontaneously rats (Pausova, Paus et al. 2003, Gao, Holloway et al. 2008). Nicotine exposure changed the composition and quantity of perivascular fat and impaired the ability of the perivascular fat tissue to modulate the contraction of blood vessels (Gao, Holloway et al. 2005, Gao, Lu et al. 2007). 
 
Maternal smoking during pregnancy increases the risk of asthma in childhood, adolescence and adulthood and is associated with diminished lung function (Gilliland, Berhane et al. 2000, Gilliland, Li et al. 2001, Gilliland, Berhane et al. 2003, Li, Langholz et al. 2005, Lannero, Wickman et al. 2006).  Animals studies testing the effects of pure nicotine have shown that it can change airway structure and reduce pulmonary function in fetal monkeys.  Perinatal nicotine exposure impairs alveolarization in rats (Maritz, Scott et al. 1993, Maritz and van Wyk 1997, Maritz and Dennis 1998, Maritz and Windvogel 2003) and accelerates aging of the lungs, resulting in decreased internal surface for gas exchange (Maritz 2002, Maritz and Windvogel 2003). 
 
Epidemiological studies have demonstrated that prenatal tobacco exposure is associated with adverse neurobehavioral outcomes including attention-deficit hyperactivity disorder, learning disabilities, behavioral problems and increased risk of nicotine addiction (reviewed in (Pauly and Slotkin 2008, Winzer-Serhan 2008, Dwyer, McQuown et al. 2009) ).  Prenatal exposure to nicotine alone causes similar problems in rodent models (Pauly and Slotkin 2008, Winzer-Serhan 2008, Dwyer, McQuown et al. 2009). 
 
There is a significant association between smoking and reduced fertility among both women (Hughes and Brennan 1996, Augood, Duckitt et al. 1998, Shiverick and Salafia 1999, Hull, North et al. 2000, Greenlee, Arbuckle et al. 2003) and men (Vine 1996, Kunzle, Mueller et al. 2003, Fuentes, Munoz et al. 2010).  Data from animal studies suggest that nicotine exposure is a critical contributor to the infertility observed in women who smoke.  Female rats exposed to nicotine during fetal and neonatal development had reduced fertility, dysregulation of ovarian steroidogenesis, and altered follicle dynamics.  Developmental nicotine exposure also resulted in reduced granulosa cell proliferation, increased ovarian cell death, and decreased blood vessel development in the ovary during adulthood (Holloway, Kellenberger et al. 2006, Petrik, Gerstein et al. 2009). 
 
Epidemiological studies have shown a strong relationship between maternal smoking and subsequent obesity and metabolic diseases, including hypertension and type-2 diabetes, in children (Montgomery and Ekbom 2002, Power and Jefferis 2002, Toschke, Koletzko et al. 2002, von Kries, Toschke et al. 2002, Bergmann, Bergmann et al. 2003, Wideroe, Vik et al. 2003, Oken, Levitan et al. 2008, Syme, Abrahamowicz et al. 2010).  Of the 6000+ chemicals in cigarette smoke, animal studies suggest that fetal exposure to nicotine alone may result in postnatal metabolic changes associated with obesity, type-2 diabetes and hypertension.  Maternal nicotine exposure during pregnancy and lactation in rats causes increased fat mass and increased body mass, altered perivascular fat composition and function, elevated blood pressure and impaired glucose homeostasis postnatally  (Gao, Holloway et al. 2005, Holloway, Kellenberger et al. 2006, Gao, Lu et al. 2007, Gao, Holloway et al. 2008, Somm, Schwitzgebel et al. 2008). 
 
Other Direct Adverse Effects of Nicotine
 
Nicotine causes macular degeneration.  Growth of blood vessels into the choroid of the eye causes retinal edema, hemorrhage and fibrosis which lead to loss of central vision.  Mice that received nicotine orally had greater growth of blood vessels in the choroid after an experimental injury to Bruch’s membrane (Kiuchi, Matsuoka et al. 2008).  Nicotine also increases cerebrovascular permeability and this effect can be blocked by an antagonist to the nicotinic acetylcholine receptors (nAChR)  (Suner, Espinosa-Heidmann et al. 2004).
 
Indeed, the FDA has categorized NRT as a category D drug during pregnancy because of the nicotine.  The FDA recognizes that “There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks” (Briggs, Freeman et al. 2011).  While this risk is tolerable for people using therapeutic nicotine, it is not acceptable for recreational nicotine.
 
The FDA should also develop its regulations in full cognizance of the conclusions in the 2104 Surgeon General’s report (U.S. Department of Health and Human Services, Centers for Disease Control and Prevention et al. 2014) regarding nicotine:
 
1. The evidence is sufficient to infer that at high-enough doses nicotine has acute toxicity.
2. The evidence is sufficient to infer that nicotine activates multiple biological pathways through which smoking increases risk for disease.
3. The evidence is sufficient to infer that nicotine exposure during fetal development, a critical window for brain development, has lasting adverse consequences for brain development.
4. The evidence is sufficient to infer that nicotine adversely affects maternal and fetal health during pregnancy, contributing to multiple adverse outcomes such as preterm delivery and stillbirth.
5. The evidence is suggestive that nicotine exposure during adolescence, a critical window for brain development, may have lasting adverse consequences for brain development.
6. The evidence is inadequate to infer the presence or absence of a causal relationship between exposure to nicotine and risk for cancer.
 
Taken together, these studies demonstrate unequivocally that products and devices that deliver respirable particles and nicotine are inherently dangerous.  The “Spectrum of Risk” is an unproven hypothesis with potentially deadly effects on the public health.  FDA should not deem any tobacco or nicotine product to be safer than another, until it is proven to be safer through a substantial and consistent body of peer-reviewed scientific research. 
 
References

1. Altria Group Inc. (2013). Investor day June 2013 presentation, Altria Group Inc.,.
2. Augood, C., K. Duckitt and A. A. Templeton (1998). "Smoking and female infertility: a systematic review and meta-analysis." Hum Reprod 13(6): 1532-1539.
3. Beratis, N. G., D. Panagoulias and A. Varvarigou (1996). "Increased blood pressure in neonates and infants whose mothers smoked during pregnancy." J Pediatr 128(6): 806-812.
4. Bergmann, K. E., R. L. Bergmann, R. Von Kries, O. Bohm, R. Richter, J. W. Dudenhausen and U. Wahn (2003). "Early determinants of childhood overweight and adiposity in a birth cohort study: role of breast-feeding." Int J Obes Relat Metab Disord 27(2): 162-172.
5. Blake, K. V., L. C. Gurrin, S. F. Evans, L. J. Beilin, L. I. Landau, F. J. Stanley and J. P. Newnham (2000). "Maternal cigarette smoking during pregnancy, low birth weight and subsequent blood pressure in early childhood." Early Hum Dev 57(2): 137-147.
6. Briggs, G. G., R. K. Freeman and S. Yaffe (2011). Drugs in Pregnancy and Lactation: a reference guide to fetal and neonatal risk. Philadelphia, PA, Lippincott Williams & Wilkins.
7. Bruin, J. E., H. C. Gerstein and A. C. Holloway (2010). "Long-term consequences of fetal and neonatal nicotine exposure: a critical review." Toxicol Sci 116(2): 364-374.
8. Calfee, C. S., M. A. Matthay, M. D. Eisner, N. Benowitz, M. Call, J. F. Pittet and M. J. Cohen (2011). "Active and passive cigarette smoking and acute lung injury after severe blunt trauma." Am J Respir Crit Care Med 183(12): 1660-1665.
9. Craver, R. (2013) "Reynolds subsidiary selling smoking-cessation gum." Winston-Salem Journal.
10. CSP News (2013) "Reynolds Readies Nicotine-Replacement Therapy Products. Will launch Zonnic in Iowa in September; also testing e-cigs, pouches, pellets, extracts." CSP News.
11. Dwyer, J. B., S. C. McQuown and F. M. Leslie (2009). "The dynamic effects of nicotine on the developing brain." Pharmacol Ther 122(2): 125-139.
12. Fuentes, A., A. Munoz, K. Barnhart, B. Arguello, M. Diaz and R. Pommer (2010). "Recent cigarette smoking and assisted reproductive technologies outcome." Fertil Steril 93(1): 89-95.
13. Gao, Y. J., A. C. Holloway, L. Y. Su, K. Takemori, C. Lu and R. M. Lee (2008). "Effects of fetal and neonatal exposure to nicotine on blood pressure and perivascular adipose tissue function in adult life." Eur J Pharmacol 590(1-3): 264-268.
14. Gao, Y. J., A. C. Holloway, Z. H. Zeng, G. E. Lim, J. J. Petrik, W. G. Foster and R. M. Lee (2005). "Prenatal exposure to nicotine causes postnatal obesity and altered perivascular adipose tissue function." Obes Res 13(4): 687-692.
15. Gao, Y. J., C. Lu, L. Y. Su, A. M. Sharma and R. M. Lee (2007). "Modulation of vascular function by perivascular adipose tissue: the role of endothelium and hydrogen peroxide." Br J Pharmacol 151(3): 323-331.
16. Gilliland, F. D., K. Berhane, Y. F. Li, E. B. Rappaport and J. M. Peters (2003). "Effects of early onset asthma and in utero exposure to maternal smoking on childhood lung function." Am J Respir Crit Care Med 167(6): 917-924.
17. Gilliland, F. D., K. Berhane, R. McConnell, W. J. Gauderman, H. Vora, E. B. Rappaport, E. Avol and J. M. Peters (2000). "Maternal smoking during pregnancy, environmental tobacco smoke exposure and childhood lung function." Thorax 55(4): 271-276.
18. Gilliland, F. D., Y. F. Li and J. M. Peters (2001). "Effects of maternal smoking during pregnancy and environmental tobacco smoke on asthma and wheezing in children." Am J Respir Crit Care Med 163(2): 429-436.
19. Granberry, M. C., E. S. Smith, 3rd, R. D. Troillett and J. F. Eidt (2003). "Forearm endothelial response in smokeless tobacco users compared with cigarette smokers and nonusers of tobacco." Pharmacotherapy 23(8): 974-978.
20. Greenlee, A. R., T. E. Arbuckle and P. H. Chyou (2003). "Risk factors for female infertility in an agricultural region." Epidemiology 14(4): 429-436.
21. Heeschen, C., E. Chang, A. Aicher and J. P. Cooke (2006). "Endothelial progenitor cells participate in nicotine-mediated angiogenesis." J Am Coll Cardiol 48(12): 2553-2560.
22. Heeschen, C., J. J. Jang, M. Weis, A. Pathak, S. Kaji, R. S. Hu, P. S. Tsao, F. L. Johnson and J. P. Cooke (2001). "Nicotine stimulates angiogenesis and promotes tumor growth and atherosclerosis." Nat Med 7(7): 833-839.
23. Holloway, A. C., L. D. Kellenberger and J. J. Petrik (2006). "Fetal and neonatal exposure to nicotine disrupts ovarian function and fertility in adult female rats." Endocrine 30(2): 213-216.
24. Hughes, E. G. and B. G. Brennan (1996). "Does cigarette smoking impair natural or assisted fecundity?" Fertil Steril 66(5): 679-689.
25. Hull, M. G., K. North, H. Taylor, A. Farrow and W. C. Ford (2000). "Delayed conception and active and passive smoking. The Avon Longitudinal Study of Pregnancy and Childhood Study Team." Fertil Steril 74(4): 725-733.
26. Institute of Medicine (2010). Secondhand smoke exposure and cardiovascular effects: Making sense of the evidence. Washington, DC, The National Academies Press.
27. Kiuchi, K., M. Matsuoka, J. C. Wu, R. Lima e Silva, M. Kengatharan, M. Verghese, S. Ueno, K. Yokoi, N. H. Khu, J. P. Cooke and P. A. Campochiaro (2008). "Mecamylamine suppresses Basal and nicotine-stimulated choroidal neovascularization." Invest Ophthalmol Vis Sci 49(4): 1705-1711.
28. Kunzle, R., M. D. Mueller, W. Hanggi, M. H. Birkhauser, H. Drescher and N. A. Bersinger (2003). "Semen quality of male smokers and nonsmokers in infertile couples." Fertil Steril 79(2): 287-291.
29. Lannero, E., M. Wickman, G. Pershagen and L. Nordvall (2006). "Maternal smoking during pregnancy increases the risk of recurrent wheezing during the first years of life (BAMSE)." Respir Res 7: 3.
30. Li, Y. F., B. Langholz, M. T. Salam and F. D. Gilliland (2005). "Maternal and grandmaternal smoking patterns are associated with early childhood asthma." Chest 127(4): 1232-1241.
31. Maritz, G. S. (2002). "Maternal nicotine exposure during gestation and lactation of rats induce microscopic emphysema in the offspring." Exp Lung Res 28(5): 391-403.
32. Maritz, G. S. (2008). "Nicotine and lung development." Birth Defects Res C Embryo Today 84(1): 45-53.
33. Maritz, G. S. and H. Dennis (1998). "Maternal nicotine exposure during gestation and lactation interferes with alveolar development in the neonatal lung." Reprod Fertil Dev 10(3): 255-261.
34. Maritz, G. S., L. Scott and R. A. Thomas (1993). "The influence of maternal nicotine exposure on neonatal lung alveolar epithelial status: an electron microscope study." Cell Biol Int 17(12): 1085-1089.
35. Maritz, G. S. and G. van Wyk (1997). "Influence of maternal nicotine exposure on neonatal rat lung structure: protective effect of ascorbic acid." Comp Biochem Physiol C Pharmacol Toxicol Endocrinol 117(2): 159-165.
36. Maritz, G. S. and S. Windvogel (2003). "Chronic maternal nicotine exposure during gestation and lactation and the development of the lung parenchyma in the offspring. Response to nicotine withdrawal." Pathophysiology 10(1): 69-75.
37. Mejia, A. B., P. M. Ling and S. A. Glantz (2010). "Quantifying the effects of promoting smokeless tobacco as a harm reduction strategy in the USA." Tob Control 19(4): 297-305.
38. Mills, E. J., K. Thorlund, S. Eapen, P. Wu and J. J. Prochaska (2014). "Cardiovascular events associated with smoking cessation pharmacotherapies: a network meta-analysis." Circulation 129(1): 28-41.
39. Montgomery, S. M. and A. Ekbom (2002). "Smoking during pregnancy and diabetes mellitus in a British longitudinal birth cohort." BMJ 324(7328): 26-27.
40. Moulton, K. S. (2006). "Angiogenesis in atherosclerosis: gathering evidence beyond speculation." Curr Opin Lipidol 17(5): 548-555.
41. Neunteufl, T., S. Heher, K. Kostner, G. Mitulovic, S. Lehr, G. Khoschsorur, R. W. Schmid, G. Maurer and T. Stefenelli (2002). "Contribution of nicotine to acute endothelial dysfunction in long-term smokers." J Am Coll Cardiol 39(2): 251-256.
42. Oken, E., E. B. Levitan and M. W. Gillman (2008). "Maternal smoking during pregnancy and child overweight: systematic review and meta-analysis." Int J Obes (Lond) 32(2): 201-210.
43. Pauly, J. R. and T. A. Slotkin (2008). "Maternal tobacco smoking, nicotine replacement and neurobehavioural development." Acta Paediatr 97(10): 1331-1337.
44. Pausova, Z., T. Paus, L. Sedova and J. Berube (2003). "Prenatal exposure to nicotine modifies kidney weight and blood pressure in genetically susceptible rats: a case of gene-environment interaction." Kidney Int 64(3): 829-835.
45. Peeters, S. and A. B. Gilmore (2013). "Transnational tobacco company interests in smokeless tobacco in Europe: analysis of internal industry documents and contemporary industry materials." PLoS Med 10(9): e1001506.
46. Petrik, J. J., H. C. Gerstein, C. E. Cesta, L. D. Kellenberger, N. Alfaidy and A. C. Holloway (2009). "Effects of rosiglitazone on ovarian function and fertility in animals with reduced fertility following fetal and neonatal exposure to nicotine." Endocrine 36(2): 281-290.
47. Power, C. and B. J. Jefferis (2002). "Fetal environment and subsequent obesity: a study of maternal smoking." Int J Epidemiol 31(2): 413-419.
48. Samet, J. M. (2014). "Smoking cessation: benefits versus risks of using pharmacotherapy to quit." Circulation 129(1): 8-10.
49. Shiverick, K. T. and C. Salafia (1999). "Cigarette smoking and pregnancy I: ovarian, uterine and placental effects." Placenta 20(4): 265-272.
50. Somm, E., V. M. Schwitzgebel, D. M. Vauthay, E. J. Camm, C. Y. Chen, J. P. Giacobino, S. V. Sizonenko, M. L. Aubert and P. S. Huppi (2008). "Prenatal nicotine exposure alters early pancreatic islet and adipose tissue development with consequences on the control of body weight and glucose metabolism later in life." Endocrinology 149(12): 6289-6299.
51. Suner, I. J., D. G. Espinosa-Heidmann, M. E. Marin-Castano, E. P. Hernandez, S. Pereira-Simon and S. W. Cousins (2004). "Nicotine increases size and severity of experimental choroidal neovascularization." Invest Ophthalmol Vis Sci 45(1): 311-317.
52. Syme, C., M. Abrahamowicz, A. Mahboubi, G. T. Leonard, M. Perron, L. Richer, S. Veillette, D. Gaudet, T. Paus and Z. Pausova (2010). "Prenatal exposure to maternal cigarette smoking and accumulation of intra-abdominal fat during adolescence." Obesity (Silver Spring) 18(5): 1021-1025.
53. Teo, K. K., S. Ounpuu, S. Hawken, M. R. Pandey, V. Valentin, D. Hunt, R. Diaz, W. Rashed, R. Freeman, L. Jiang, X. Zhang, S. Yusuf and I. S. Investigators (2006). "Tobacco use and risk of myocardial infarction in 52 countries in the INTERHEART study: a case-control study." Lancet 368(9536): 647-658.
54. Timberlake, D. S. (2008). "A latent class analysis of nicotine-dependence criteria and use of alternate tobacco." J Stud Alcohol Drugs 69(5): 709-717.
55. Toschke, A. M., B. Koletzko, W. Slikker, Jr., M. Hermann and R. von Kries (2002). "Childhood obesity is associated with maternal smoking in pregnancy." Eur J Pediatr 161(8): 445-448.
56. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion and O. o. S. a. Health (2014). The health consequences of smoking -- 50 years of progres: a report of the Surgeon General. Atlanta GA: 944.
57. U.S. Department of Health and Human Services, U.S. Public Health Service, National Institutes of Health and National Cancer Institute (2001). Risks Associated With Smoking Cigarettes With Low Machine-Measured Yields of Tar and Nicotine. Smoking and tobacco control monographs. National Cancer Institute. Bethesda, MD. 1.
58. Vine, M. F. (1996). "Smoking and male reproduction: a review." Int J Androl 19(6): 323-337.
59. von Kries, R., A. M. Toschke, B. Koletzko and W. Slikker, Jr. (2002). "Maternal smoking during pregnancy and childhood obesity." Am J Epidemiol 156(10): 954-961.
60. Wideroe, M., T. Vik, G. Jacobsen and L. S. Bakketeig (2003). "Does maternal smoking during pregnancy cause childhood overweight?" Paediatr Perinat Epidemiol 17(2): 171-179.
61. Winzer-Serhan, U. H. (2008). "Long-term consequences of maternal smoking and developmental chronic nicotine exposure." Front Biosci 13: 636-649.
62. Yu, M., Q. Liu, J. Sun, K. Yi, L. Wu and X. Tan (2011). "Nicotine improves the functional activity of late endothelial progenitor cells via nicotinic acetylcholine receptors." Biochem Cell Biol 89(4): 405-410.
63. Zhu, B. Q., C. Heeschen, R. E. Sievers, J. S. Karliner, W. W. Parmley, S. A. Glantz and J. P. Cooke (2003). "Second hand smoke stimulates tumor angiogenesis and growth." Cancer Cell 4(3): 191-196.

 
 
 
The comment number is 1jy-8clb-hgy6.