Toxic Tips

CH3

N

N

Nicotine

lion gallons will be used this year to refille-cigarettes.7 Currently, China is one of themajor manufacturers of e-cigarettes with the

rate than the acid salts of nicotine.6 Upon

respiratory system. The area of the skin ex-

cular junction, and in the CNS. The psychoac-tive and addictive properties associated with afeeling of relaxation most likely reside in the

1871-5532

http://dx.doi.org/10.1016/j.jchas.2INTRODUCTION

Chemical and Physical Description

Nicotine, C10H14N2, also known as 1-methyl-2-(3-pyridyl)pyrrolidine, has the chemicalname 3-[(2S)-1-methyl-2-pyrrolidinyl]pyri-dine.1 It is a colorless to pale yellow, oilyhygroscopic liquid. It turns brown on exposureto air or light, has an acrid burning taste, anddevelops the fishy odor of pyridine. It is misci-ble with water below 60 8C, and when mixedwith water, the volume contracts. It is verysoluble in alcohol, chloroform, ether, petro-leum ether, and kerosene. It forms salts withalmost any acid and double salts with manymetals and acids.2 Nicotine is combustiblewhen exposed to an ignition source. It is mod-erately explosive in vapor form, with a lowerexplosive limit of 0.75%, an upper explosivelimit of 4.0%, and a specific gravity of 1.0092 at20 8C.3 The molecular weight of nicotine is162.23. Its CAS number is 54-11-5.2

Uses and Typical Exposure Situations

Nicotine is extracted from the dried leaves ofNicotiana tabacum and N. rustica, where it iscombined with citric and malic acids, andmakes up 28% dry weight of the leaf. It iswidely available in tobacco products and cer-tain pesticides. Tobacco was introduced inEurope from the Americas in 1559, where ithad been cultivated continuously since prior tothis time until present, primarily for smoking.4

Tobacco extracts have been used as an insecti-cide in France since at least 1690, and in theU.S. since the 1860s.5 Very little nicotine iscurrently used as an insecticide in the UnitedStates. The most notorious commercial prod-uct, Black Leaf 40R, was discontinued in 1992.Nicotine is still available as an insecticide inparts of Asia.4 So, absorption through the skinand resulting systemic toxicity can occur fromhandling of uncured tobacco leaves and in themanufacture and use of nicotine insecticides.Nicotine has been used in tranquilizing dartsfor capturing feral or wild animals, and intanning.6 The recent popularity of the e-ciga-rette has also caused an increase in the sale ofnicotine. Fifty-five gallon containers of 10%nicotine are now available on the internet.It is estimated that between one and two mil- Division of Chemi014.05.006posed, concentration of the nicotine and thelength of time of skin contact will determinethe amount absorbed through the skin.

Mechanism of Action

Nicotine binds to the nicotine receptors, asubset of the acetylcholinergic receptors(nAChRs), located in ganglia, at the neuromus-entering the bloodstream, nicotine quicklycrosses the bloodbrain barrier, in as little as10 s. The half-life of nicotine in the body isapproximately two hours. The effects are some-what independent of dose, and may last for upto 24 h.8 Nicotine is metabolized primarily inthe liver by cytochrome P450 enzymes, butalso in the lungs and kidney, producing pri-marily cotinine and nicotine-N-oxide. Theme-tabolites are then excreted by the kidneys. If asmall dose is absorbed, 412% of nicotine isexcreted in the urine unchanged.9 It is alsoeliminated in breast milk.10 Cotinine has alonger half-life that nicotine, and is often usedas a biomarker.8

PATHOPHYSIOLOGY

Determinants of Toxicity

The airborne concentration of nicotine, therespiratory rate of the individual, and the timeexposure to the contaminated air will deter-mine the amount of nicotine absorbed into theconcentrations and purity of nicotine oftenunknown, and the presence of contaminantsundetermined.7 Acute overdose of nicotineoccurs most often in children who accidentallyingest tobacco or nicotine products, especiallywith the increased popularity of e-cigarettesthat come in bright colors and fragrant flavorssuch as cherry, chocolate, and bubble gum.4,7

METABOLISM AND PHARMACOKINETICS

Nicotine, in the free base form, can be easilyabsorbed through the alimentary canal, respi-ratory tract, and intact skin and then enter theblood almost instantly.6 The free alkaloid formof nicotine can penetrate the skin at a fastercal Health and Safety of the American Chemical Society 39Elsevier Inc. All rights reserved.

cular disease, malignancies of the lungs

breath.

Reactivities and Incompatibilitiesand upper airways and other cancers,and chronic pulmonary disease. Anincreased likelihood for platelet aggre-gation is seen in smokers, at a levelthat correlates to nicotine level. TheCNS receptors. Upon interaction withnicotine, the nAChRs are initiallystimulated, followed by a protracteddepolarization, resulting in receptorparalysis.4

CLINICAL PRESENTATION

Effects Following Acute Exposure

Inhalation of nicotine from smokingtobacco, or pharmacological doses,increases heart rate, elevates bloodpressure, and constricts blood vesselswithin the skin.4 Nicotine is primarilyresponsible for many of the acute psy-chological and physiological effects ofsmoking or chewing tobacco.6 In termsof acute toxicity risk, e-liquids are farmore dangerous than tobacco, becauseliquid nicotine is absorbedmore quick-ly, even in diluted concentrations.7

Effects Following Over-Exposure

Overexposure to nicotine, nicotin-ism, is characterized by stimulationand subsequent depression or evenparalysis of the central and autonomicnervous systems.3 Symptoms of over-exposure may include nausea, saliva-tion, abdominal pain, vomiting,diarrhea, headache, dizziness, auditoryand visual disturbances, confusion,weakness, incoordination, paroxysmalatrial fibrillation, convulsion, and dys-pnea. Death may result from paralysisof the respiratory muscles.5 The fataldose for a healthy adult is approxi-mately 60 mg. Recovery of the victimusually occurs, if surviving for one tofour hours.5

Effects of Long-Term Exposure

Exposure to low levels of nicotine isvery common, and the health effects ofthis exposure are a source of greatconcern. Adverse health effects mayoccur at some time after exposure,andmay last for years. Due to the othercomponents of cigarette smoke, it isdifficult to directly study the effectsof nicotine in humans.4 Complicationsof smoking tobacco include cardiovas-40Carcinogenicity

Although there is no evidence thatnicotine alone directly causes cancerin animals,1 it has been shown to in-hibit apoptosis.11 Cell death throughapoptosis may be an important mech-anism used by the immune system toprevent tumor development. If nico-tine inhibits apoptosis, it may functionas a tumor promotor.11 Also, nicotinehas been found to be co-carcinogenicwith benzo(a)pyrene in causing skincancer in mice.12

Reproductive and DevelopmentalToxicity

Children of women who smoke duringpregnancy show higher levels of atten-tion deficit disorders.4 Mutagenic andteratogenic effects have beenreported.3 There is limited evidencethat nicotine may decrease fertility inmales.1

FIRST AID

If a person has been exposed to nico-tine, remove the victim to fresh air. If aperson has stopped breathing, beginartificial respiration, and CPR if neces-sary. Transport to a hospital or othermedical facility. Remove contaminatedclothing, to reduce absorption throughthe skin. Wash the contaminated areaswith soap and water. Seek medicalattention. If nicotine has been splashedinto the eyes, wash with large amountsof water for at least 15 min, removingcontact lenses, if they are worn. Seekmedical attention.1accelerated heart rate and increasedblood pressure caused by nicotineplaces an increased burden on theheart, which may play a role in theonset of myocardial ischemia.8

Effects Following Skin or Eye Exposure

Contact with liquid nicotine can irri-tate the skin causing a rash and burn-ing sensation. It can also causeirritation of the eyes.1

Effects Following Inhalation

Inhaling nicotine mist can irritate thenose, throat, and lungs, causing cough-ing, wheezing and/or shortness of

1Journal of ChemNicotine is not compatible with strongoxidizers, such as perchlorates, perox-ides, chlorates, or chlorine; and strongacids, such as hydrochloric, sulfuric, ornitric acids.1

EXPOSURE CONTROLS

Sampling and Analysis

The National Institute for Occupa-tional Safety and Health (NIOSH)Manual for Analytical Methodscalls for the collection of an air sampleusing a commercially availableXAD-4 sampling tube, 7 cm long,7 mm OD, with two sections of sor-bent (front = 80 mg, back = 40 mg).Analysis is carried out by drawing ameasured 0.5600 L volume of airthrough the tube using a calibratedsampling pump. The sample is thendesorbed with ethyl acetate. Determi-nation is accomplished using a gaschromatograph (GC) with a capillarycolumn, 30 m 0.32 mm ID, 1.0 mmfilm, Crossbond1 5% diphenyl 95%dimethyl polysiloxane, Rtx-51 orequivalent, with a nitrogen-phospho-rus detector (NPD). For specificinstructions, consult NIOSH Method2551 (or Method 2544 using XAD-2HANDLING AND STORAGE

Accidental Release Measures

In the event of an accidental release ofnicotine, evacuate personnel, securethe entrances to the area, and eliminateall ignition sources. Absorb spilled liq-uid in vermiculite, dry sand, earth, orsimilar material, and then place insealed containers for disposal as a haz-ardous waste. Contact a governmentagency, such as the Department of En-vironmental Protection (DEP) or theregional office of the EnvironmentalProtection Agency (EPA), for specificdirections. Do not wash the spilled liq-uid into a sewer.1

Storage Guidelines

Nicotine should be stored in tightlyclosed containers, in a cool, well-ven-tilated place, separated from oxidizingagents and strong acids. Do not store,handle, or use nicotine in locationswhere there are sources of ignition.1ical Health & Safety, July/August 2014

sorbent and a packed column for theGC-NPD).13

Exposure Guidelines

The NIOSH recommended exposurelimit (REL) TWA is 0.5 mg/m3, aver-aged over a 10-h workshift. The OSHApermissible exposure limit (PEL) is0.5 mg/m3, averaged over an 8-hwork-shift. The ACGIH threshold limit value(TLV) is 0.5 mg/m3, averaged over an8-h workshift. ACGIH also gives askin notation for nicotine since ab-sorption through the skin of workersis well-documented and can lead tosystemic toxicity.14 Since nicotinemay be a teratogen in humans, allcontact should be minimized. These

0.5 mg/m , use a NIOSH approvedsupplied-air respirator operated in

concentration exists, use a NIOSH ap-proved self-contained breathing appa-ratus (SCBA) with a full-facepiece,operated in positive-pressure demandmode, with an emergency escapecylinder.1

REFERENCES1. New Jersey Department of Health and

Senior Services. [16_TD$DIFF]Hazardous SubstanceFact Sheet for Nicotine[17_TD$DIFF]. http://nj.gov/health/eoh/rtkweb/documents/fs/1349.pdf[18_TD$DIFF], accessed 3/21/2014.

2. ONeil, M. J.; Heckelman, P. E.; Koch,C. B.; Roman, C. M. (Eds.). [19_TD$DIFF]The MerckIndex, 14th ed. Merck & Co., Inc.:Whitehouse Station, NJ, 2006, pp.11281129.

3. Lewis, R. J. Sr. Saxs Dangerous Proper-

8. Benowitz, N. L. Clinical pharmacologyof nicotine. Annu Rev Med, 1986, 37,2132.

9. Haag, H. B.; Larson, P. S. Studieson the fate of nicotine in the body[30_TD$DIFF]. I.The effect of pH on the urinary excre-tion of nicotine by tobacco smokers.J Pharmacol Exp Ther, 1942, 76,235239.

10. Periman, H. H.; Dannenberg, A. M.Excretion of nicotine in breast milkand urine from cigarette smoking: Itseffect on lactation and nursing. JAMA,1942, 120, 10031008.

11. Wright, S. C.; Zhong, J.; Zheng, H.;Larrick, J. W. Nicotine inhibition ofapoptosis suggests a role in tumorpromotion. FASEB J, 1993, 7(11),10451051.

12. Bock, F. G. Cocarcinogenic propertiesof nicotine, In Gori, G. B.; Bock, F. G.positive-pressure demand mode. Air-borne concentrations exceeding 5 mg/m3 are immediately dangerous to lifeand health. If potential for exposureto concentrations exceeding thissure only.6 Skin contact or ingestionmay cause overexposure, even whenairborne levels are within these lim-its.1 The odor threshold for nicotineis 0.066 mg/m3.15

PERSONAL PROTECTION

Avoid skin contact with nicotine.Wear gloves made of Butyl or SilverShield1/41, or another material thatis impervious to nicotine. If potentialfor airborne concentration exceeds

3Journal of Chemical Health & Safety, July/Aties of Industrial Materials, 8[21_TD$DIFF]th ed. VanNostrand Reinhold: New York, NY,1992, p. 2536.

4. Klaassen, C. D. (Ed.). Casarett andDoulls Toxicology: The Basic Scienceof Poisons, [23_TD$DIFF]7th ed. McGraw Hill: NewYork, NY, 2008 [24_TD$DIFF]pp. 651, 907.

5. Zenz, C.; Dickerson, O. B.; Horvath, E.P., Jr. Occupational Medicine, 3[25_TD$DIFF]rd ed.Mosby: St. Louis, MO, 1994, pp. 668669.

6. American Conference of Governmen-tal Industrial Hygienists (ACGIH).Documentation of the Threshold LimitValues for Chemical Substances, 7[26_TD$DIFF]thed. ACGIH: Cincinnati, OH, [27_TD$DIFF]2012.Supplement. Documentation for Nico-tine [28_TD$DIFF]. http://www.acgih.org, accessed 5/3/2014.

7. Richtel, M. Selling a Poison by theBarrel: LiquidNicotine for E-Cigarettes.The New York Times, March 27, [29_TD$DIFF]2014,pp. A1, A8.ugust 2014(Eds.), [31_TD$DIFF]Banbury ReportA Safe Cigar-ette?, Cold Harbor Spring Laboratory:NY, 1980, pp. 129139.

13. National Institute for OccupationalSafety and Health (NIOSH). NIOSHManual of Analytical Methods(NMAM), 4th [32_TD$DIFF]ed. Sampling Methodsfor Nicotine (Methods 2551 and 2544)[33_TD$DIFF].http://www.cdc.gov/niosh/docs/2003-154/pdfs/2551.pdf, accessed on 3/21/2014.

14. American Conference of Governmen-tal Industrial Hygienists (ACGIH).2014 TLVs and BEIs Based on theDocumentation of the Threshold LimitValues for Chemical Substances andPhysical Agents & Biological ExposureIndices; Value for Nicotine[36_TD$DIFF][37_TD$DIFF], ACGIH:Cincinnati, OH, 2014, p. 44.

15. Walker, J. C.; Kendal-Reed, M.; Keiger,C. J.; Bencherif, M.; Silver, W. L. Olfac-tory and trigominal responses to nico-tine. Drug Dev Res, 1996, 38, 160168.exposure limits are for airborne expo-41

Nicotine IntroductionChemical and Physical DescriptionUses and Typical Exposure Situations

Metabolism and PharmacokineticsPathophysiologyDeterminants of ToxicityMechanism of Action

Clinical PresentationEffects Following Acute ExposureEffects Following Over-ExposureEffects of Long-Term ExposureEffects Following Skin or Eye ExposureEffects Following InhalationCarcinogenicityReproductive and Developmental Toxicity

First AidHandling and StorageAccidental Release MeasuresStorage GuidelinesReactivities and Incompatibilities

Exposure ControlsSampling and AnalysisExposure Guidelines

Personal Protection