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  • The role of alternative specimens in toxicological analysis · 2019. 3. 12. · tissues), namely...
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REVIEW Copyright © 2008 John Wiley & Sons, Ltd. BIOMEDICAL CHROMATOGRAPHY Biomed. Chromatogr. 22: 795–821 (2008) Published online 27 May 2008 in Wiley InterScience (www.interscience.wiley.com) DOI: 10.1002/bmc.1009 The role of alternative specimens in toxicological analysis E. Gallardo and J. A. Queiroz* CICS, Centro de Investigação em Ciências da Saúde, Universidade da Beira Interior, 6201-001 Covilhã, Portugal Received 18 January 2008; accepted 22 January 2008 ABSTRACT: The use of alternative specimens in the field of toxicology was first described in 1979, when hair analysis was used to document chronic drug exposure. Since then, the use of these ‘alternative’ samples has gained tremendous importance in foren- sic toxicology, as well as in clinic toxicology, doping control and workplace drug testing. It is not surprising, therefore, that a large number of papers dealing with the determination of several classes of drugs in saliva, sweat, meconium and hair have been published ever since, owing to the fact that chromatographic equipment is becoming more and more sensitive, mass spectrometry (and tandem mass spectrometry) being the most widely used analytical tool, combined with gas or liquid chromatography. ‘Alter- native’ specimens present a number of advantages over the ‘traditional’ samples normally used in toxicology (e.g. blood, urine and tissues), namely the fact that their collection is not invasive, their adulteration is difficult, and they may allow increased windows of detection for certain drugs. The main disadvantage of this kind of samples is that drugs are present in very low concentrations, and therefore high-sensitivity techniques are required to accomplish the analysis. This paper reviews a series of publications on the use of alternative specimens, with special focus on the main analytical and chromatographic problems that these samples present, as well on their advantages and disadvantages over traditional samples in documenting drug exposure. Copyright © 2008 John Wiley & Sons, Ltd. KEYWORDS: unconventional samples; analytical chromatography; therapeutic drug monitoring; toxicological analysis *Correspondence to: J. A. Queiroz, CICS, Centro de Investigação em Ciências da Saúde, Universidade da Beira Interior, 6201-001 Covilhã, Portugal. E-mail: [email protected] INTRODUCTION In the last decade, alternative or unconventional matri- ces have becoming more important in the field of toxicology, owing to the advantages that these speci- mens present when compared with ‘conventional’ samples used in laboratorial routine analysis. In general these samples present the advantage that collection is almost non-invasive and easy to perform. On the other hand, collection can also be achieved under close supervision, which prevents sample adulteration or sub- stitution. Furthermore, some of these samples present larger detection windows, and therefore their range of analytical applications can be very wide. Recent advances in analytical techniques have en- abled the detection of drugs and metabolites at very low concentrations that were unthinkable a few years ago. In fact, LC/MS and LC/MS/MS techniques are increas- ing in popularity as confirmation techniques because of high sensitivity and specificity, and the ability to handle complex matrices. Also, LC/MS techniques do not require the time-consuming derivatization steps needed in GC/MS for a large number of compounds; how- ever, ion suppression or enhancement due to complex matrices is a frequent analytical complication and must be addressed during method development and validation. In fact, despite the analytical problems that liquid chromatography-based techniques can present, these are the state of art concerning analysis of alternative specimens because of their higher sensitivity, which is crucial if one takes into account the low amount of sample usually available in these situations. Therefore, very low amounts of drugs of abuse or pre- scription drugs can be detected, for instance in the low picogram range for carboxy-THC, which is definite proof of cannabis consumption, using hair analysis, and for benzodiazepines, a single exposure to which in a drug- facilitated assault can be detected through hair analysis. The first unconventional sample used was hair in the 1960s and 1970s to evaluate human exposure to toxic heavy metals, namely arsenic, lead and mercury (Ham- mer et al., 1971; Kopito et al., 1967). Since then, numer- ous papers dealing with the determination of various classes of compounds have been published in the scien- tific literature, normally concerning drugs of abuse and therapy. Nowadays other alternative samples such as oral fluid, meconium or sweat are being introduced and present a wide range of applications, e.g. in therapeutic drug monitoring, workplace drug testing and prenatal exposure to drugs of abuse. This review will deal with the most used unconven- tional samples, with special focus on their advantages and disadvantages, collection procedures, classes of drugs that are analyzed and analytical methods.

The role of alternative specimens in toxicological analysis · 2019. 3. 12. · tissues), namely the fact that their collection is not invasive, their adulteration is difficult,

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  • Copyright © 2008 John Wiley & Sons, Ltd. Biomed. Chromatogr. 22: 795– 821 (2008)DOI: 10.1002/bmc

    Alternative specimens in toxicological analysis 795REVIEWREVIEW

    Copyright © 2008 John Wiley & Sons, Ltd.

    BIOMEDICAL CHROMATOGRAPHYBiomed. Chromatogr. 22: 795–821 (2008)Published online 27 May 2008 in Wiley InterScience(www.interscience.wiley.com) DOI: 10.1002/bmc.1009

    The role of alternative specimens in toxicological analysis

    E. Gallardo and J. A. Queiroz*

    CICS, Centro de Investigação em Ciências da Saúde, Universidade da Beira Interior, 6201-001 Covilhã, Portugal

    Received 18 January 2008; accepted 22 January 2008

    ABSTRACT: The use of alternative specimens in the field of toxicology was first described in 1979, when hair analysis was usedto document chronic drug exposure. Since then, the use of these ‘alternative’ samples has gained tremendous importance in foren-sic toxicology, as well as in clinic toxicology, doping control and workplace drug testing. It is not surprising, therefore, that a largenumber of papers dealing with the determination of several classes of drugs in saliva, sweat, meconium and hair have beenpublished ever since, owing to the fact that chromatographic equipment is becoming more and more sensitive, mass spectrometry(and tandem mass spectrometry) being the most widely used analytical tool, combined with gas or liquid chromatography. ‘Alter-native’ specimens present a number of advantages over the ‘traditional’ samples normally used in toxicology (e.g. blood, urine andtissues), namely the fact that their collection is not invasive, their adulteration is difficult, and they may allow increased windowsof detection for certain drugs. The main disadvantage of this kind of samples is that drugs are present in very low concentrations,and therefore high-sensitivity techniques are required to accomplish the analysis. This paper reviews a series of publications onthe use of alternative specimens, with special focus on the main analytical and chromatographic problems that these samplespresent, as well on their advantages and disadvantages over traditional samples in documenting drug exposure. Copyright © 2008John Wiley & Sons, Ltd.

    KEYWORDS: unconventional samples; analytical chromatography; therapeutic drug monitoring; toxicological analysis

    *Correspondence to: J. A. Queiroz, CICS, Centro de Investigação emCiências da Saúde, Universidade da Beira Interior, 6201-001 Covilhã,Portugal.E-mail: [email protected]

    INTRODUCTION

    In the last decade, alternative or unconventional matri-ces have becoming more important in the field oftoxicology, owing to the advantages that these speci-mens present when compared with ‘conventional’samples used in laboratorial routine analysis. In generalthese samples present the advantage that collectionis almost non-invasive and easy to perform. On theother hand, collection can also be achieved under closesupervision, which prevents sample adulteration or sub-stitution. Furthermore, some of these samples presentlarger detection windows, and therefore their range ofanalytical applications can be very wide.

    Recent advances in analytical techniques have en-abled the detection of drugs and metabolites at very lowconcentrations that were unthinkable a few years ago.In fact, LC/MS and LC/MS/MS techniques are increas-ing in popularity as confirmation techniques because ofhigh sensitivity and specificity, and the ability to handlecomplex matrices. Also, LC/MS techniques do notrequire the time-consuming derivatization steps neededin GC/MS for a large number of compounds; how-ever, ion suppression or enhancement due to complexmatrices is a frequent analytical complication and

    must be addressed during method development andvalidation.

    In fact, despite the analytical problems that liquidchromatography-based techniques can present, theseare the state of art concerning analysis of alternativespecimens because of their higher sensitivity, which iscrucial if one takes into account the low amount ofsample usually available in these situations.

    Therefore, very low amounts of drugs of abuse or pre-scription drugs can be detected, for instance in the lowpicogram range for carboxy-THC, which is definite proofof cannabis consumption, using hair analysis, and forbenzodiazepines, a single exposure to which in a drug-facilitated assault can be detected through hair analysis.

    The first unconventional sample used was hair in the1960s and 1970s to evaluate human exposure to toxicheavy metals, namely arsenic, lead and mercury (Ham-mer et al., 1971; Kopito et al., 1967). Since then, numer-ous papers dealing with the determination of variousclasses of compounds have been published in the scien-tific literature, normally concerning drugs of abuse andtherapy. Nowadays other alternative samples such asoral fluid, meconium or sweat are being introduced andpresent a wide range of applications, e.g. in therapeuticdrug monitoring, workplace drug testing and prenatalexposure to drugs of abuse.

    This review will deal with the most used unconven-tional samples, with special focus on their advantagesand disadvantages, collection procedures, classes ofdrugs that are analyzed and analytical methods.

    https://www.researchgate.net/publication/17159927_Lead_in_Hair_of_Children_with_Chronic_Lead_Poisoning?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/18067974_Hair_trace_metal_levels_and_environmental_exposure?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/18067974_Hair_trace_metal_levels_and_environmental_exposure?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==

  • Copyright © 2008 John Wiley & Sons, Ltd. Biomed. Chromatogr. 22: 795– 821 (2008)DOI: 10.1002/bmc

    796 E. Gallardo and J. A. QueirozREVIEW

    ALTERNATIVE SPECIMENS

    The most commonly used unconventional samples arehair, oral fluid, sweat and meconium. The physiologicaland analytical properties of these samples, as well ofother (less used) samples, including advantages anddrawbacks of each and the main parameters that canaffect their analysis, will be discussed below, in the lightof existing literature on the topic.

    Hair

    Hair is a product of differentiated organs in the skin ofmammals. It is constituted by proteins, mainly keratin(65–95%), water (15–35%), lipids (1–9%) and miner-als (0.25–0.95%; Harkley and Henderson, 1989). A richcapillary system, which provides the growing hair withthe necessary metabolic material, surrounds the hairfollicle (Pragst and Balikova, 2006). It is estimated thatthe total number of hair follicles in adults is approxi-mately 5 million. Hair grows at a rate of 0.6–1.4 cm permonth, depending on the type of hair and anatomicalsite (Saitoh et al., 1969).

    The hair growth cycle is divided into the anagen (activegrowing), catagen (transition) and telogen (resting) stages.The proportions of anagen/telogen hair vary with ana-tomical site and this feature, together with variablegrowth rate, accounts for the observed differencesin drug concentrations in hair collected from differentregions. In fact, not only scalp hair can be used foranalysis, and pubic hair, arm or leg hair and axillaryhair have been suggested as alternative sources for drugdetection when scalp hair is not available. However,care should be taken when interpreting the concentra-tions of drugs in these specimens, since various studieshave found differences between pubic or axillary hairand scalp hair (Balabanova and Wolf, 1989; Offidaniet al., 1993; Han et al., 2005). Indeed, the latter twostudies have compared methadone and methamphe-tamine concentrations in hair from different anatomicalsites, concluding that the highest values were foundin axillary hair, followed by pubic hair and scalp hair.In contrast, in another study the highest morphine con-centrations were found in pubic hair, followed by headhair and axillary hair (Mangin and Kintz, 1993). Thesignificant differences of the drug concentrations inthese studies can be explained not only by the totallydifferent anagen/telogen ratio or growth rate, but alsoby a better blood circulation and a greater number ofapocrine glands (Pragst et al., 1998).

    Beard hair is also a suitable specimen for analysis.This type of hair grows at about 0.27 mm per day, andtherefore can be collected on a daily basis with an elec-tric shaver.

    Hair analysis is only useful if the measured drugs area result of ingestion, rather than from other sources.

    Therefore, the mechanisms of incorporation of thedrugs into the hair shaft must be addressed. It is gener-ally accepted that drugs can enter the hair from threesources: (1) from the bloodstream during hair growth;(2) following excretion by sweat and sebum bathing thehair, usually after the hair emerges from the skin, and(3) from passive exposure from the hair to the drug,e.g. from smoke or dirty hands, followed by dissolutionof the drug into the drug-free sweat. It is virtuallyimpossible to distinguish between the presence of drugsderived from these two latter mechanisms and that pro-ceeding from actual consumption, which is explainedby the fact that the drugs are in an aqueous moiety,enhancing their incorporation. This is the reason whyenvironmental exposure is sometimes called the ‘stum-bling block of hair testing’ (Kidwell and Blank, 1996).

    Incorporation of drugs is affected by the melanincontent of the hair and by the substances’ lipophilicityand basicity. For instance, the effect of melanin contentof the hair on drug incorporation can be studied inindividuals with gray hair, showing that the concentra-tion of basic drugs in pigmented hair can be about10-fold higher than in non-pigmented hair (Pragst andBalikova, 2006). In fact, it has been suggested thatdrugs bind to melanin, which explains the higher con-centrations normally found in darker hair (Rollinset al., 2003; Mieczkowski and Kruger, 2007).

    Hair samples are best collected from the back of thehead, the so-called vertex posterior. In fact, this is theregion where hair grows with more homogeny, andalso where the anagen/telogen ratio is higher, meaningthat the number of hairs in active growth is larger. Hairshould be cut as close as possible to the scalp with theaid of scissors, and the proximal zone (i.e. the zonewhich is closer to the root) should be clearly indicatedif segmental analysis is to be performed. The samplecan then be stored light and moisture protected at roomtemperature, for instance wrapped in aluminum foil.

    Drugs are usually stable in regularly treated hair(without using aggressive cosmetic agents, such as oxi-dant dyes, bleaching or permanent wave), which makesthem detectable for at least one year after intake(Pragst and Balikova, 2006).

    Hair is usually exposed to several agents that mayimpair drug testing, such as shampoos, dust, sunlightand rain. In fact, there are several studies on the effectof cosmetic treatments on drug stability in hair. Forexample, Martins et al. (2007) have found that the con-centrations of amphetamine-type stimulants decreasedin bleached hair when compared with non-bleachedhair, without influencing their enantiomeric ratios.Likewise, it has been shown that this treatment affectsthe stability and decreases hair concentrations of otherdrugs (Pötsch and Skoop, 1996; Yegles et al., 2000).Cosmetic treatments can also produce analytical inter-ferences that may hinder the detection of drugs. This is

    https://www.researchgate.net/publication/null?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/12625136_Influence_of_bleaching_on_stability_of_benzodiazepines_in_hair?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/14366889_Stability_of_opiates_in_hair_fibers_after_exposure_to_cosmetic_treatment?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/null?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/null?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/20426858_Methadone_concentrations_in_human_hair_of_the_head_axillary?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/15061469_Drug_distribution_in_the_head_axillary_and_pubic_hair_of_chronic_addicts?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/15061469_Drug_distribution_in_the_head_axillary_and_pubic_hair_of_chronic_addicts?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/15061491_Variability_of_opiates_concentrations_in_human_hair_according_to_their_anatomical_origin_head_axillary_and_pubic_regions?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/null?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/280909818_Illegal_and_Therapeutic_Drug_Concentrations_in_Hair_Segments_-_A_Timetable_of_Drug_Exposure?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==

  • Copyright © 2008 John Wiley & Sons, Ltd. Biomed. Chromatogr. 22: 795– 821 (2008)DOI: 10.1002/bmc

    Alternative specimens in toxicological analysis 797REVIEW

    the case for minoxidil, whose TMS derivative preventsthe detection of cocaine and metabolites (Zucchelaet al., 2007).

    As stated above, one of the most important pitfallsin hair analysis is environmental contamination. Indeed,if adequate measures are not taken, the risk of report-ing false positive results increases, which is unaccept-able, especially if there are legal implications of drugconsumption. Therefore, to minimize this effect it isstrongly recommended that hair analysis proceduresinclude a washing step. Several decontamination proce-dures are described in the literature, and these includeorganic solvents, aqueous buffers, water, soaps andcombinations of these (Kintz et al., 1995; Eser et al.,1997; Girod and Staub, 2000; Skender et al., 2002;Schaffer et al., 2002; Villamor et al., 2005). There isno general consensus regarding decontamination pro-cedures, and it is assumed that the total eliminationof deposited drug is not achieved even after laboriouswashing procedures. Several researchers propose crite-ria for differentiation between drug use and environ-mental contamination, namely the establishment of aconcentration ratio between the last wash and the hairsample (Schaffer et al., 2005; Tsanaclis and Wicks,2007a).

    Hair decontamination prior to analysis is not theonly way to deal with environmental exposure. There-fore, the Society of Hair Testing also recommends thedetection of drug metabolites and the use of metaboliteto parent drug ratios to report positive results (Societyof Hair Testing, 2004). In fact, as environmental con-tamination is not totally removed even using laboriouswashing techniques, only the detection of drug metabo-lites, i.e. proceeding from endogenous metabolism,guarantees that the drug that is being measured hasbeen actively consumed. This is of particular impor-tance in the case of drugs that are likely to be in theenvironment because of the way they are consumed,such as cannabis (THC-COOH should be detected)and cocaine (where at least one metabolite should bedetected, with a concentration ratio to the parent drugof higher than 0.05).

    The major practical advantage of hair testing com-pared with urine or blood testing for drugs is that ithas a larger detection window (weeks to months,depending on the length of the hair shaft, against 2–4days for most drugs). However, it is not advisable torely only on hair analysis, since there are issues whereit cannot provide adequate results, such as short-terminformation on an individual’s drug use, for which bloodand/or urine are better specimens. On the other hand,long-term histories are only accessible through hairanalysis. Therefore, one can say that these tests com-plement each other.

    The assessment of this ‘chronic exposure’ to drugs isachieved by segmental hair analysis. In fact, hair grows

    at approximately 1 cm per month, and it is possible toassociate the drug distribution pattern in the analyzedsegments with a period in the past, taking into accountboth variable hair growth rates and intra- and inter-individual differences. Furthermore, drugs are very stablewithin the hair matrix for long periods of time, provid-ing that specimens are stored light- and moisture-protected. Another advantage of hair analysis whencompared with blood or urine analysis is the collectionprocedure, because: (1) it is non-invasive and easy toperform; (2) the sample is not easy to adulterate bydiluting with water (as can occur in urinalysis); and (3)in the case that there is a claim (sample switching,break in the chain of custody, etc.), it is possible toget an identical sample from the subject. Obviously,this latter is of great importance in the field of forensictoxicology.

    However, hair analysis has several drawbacks, whichsometimes are very difficult to handle in manageableproportions. The main problem in this type of analysisis the possibility of reporting false positive resultsdue to environmental contamination of the hair, whichcan occur at any level. The fact that a drug is detectedin a hair specimen does not necessarily mean thatit was actively consumed. Therefore, hair specimensshould be decontaminated prior to analysis, and specificmetabolites of the drugs must be searched for. Thismay present a problem, because normally the metabo-lites are more polar drugs, and have less affinity forhair matrix constituents. This is the case, for example,for THC-COOH, the metabolite of THC (cannabismain constituent), which is found in hair in extremelylow concentrations, usually in the low picogram range.To detect these low concentrations, mass spectrometrictechniques are mandatory, using either gas or liquidchromatography.

    In addition, as hair is quite a ‘dirty’ matrix, its con-stituents may interfere with chromatographic analysis,and therefore a sample cleanup step is normally re-quired. In the development of new methods for drugdetection in hair, special attention should be paid to thematrix effect, especially using liquid chromatographicmethods, because they are more sensitive to ion sup-pression/enhancement effects.

    Since the first report in the 1970s, hair analysis hasaided toxicologists in several fields, such as in historyand archaeology (Nakahara et al., 1997; Báez et al., 2000),in assessing consumption profiles of drugs and alcoholby the general (Jurado et al., 1996; Hartwig et al., 2003;Tsanaclis and Wicks, 2007b) or student populations(Kidwell et al., 1997; Quintela et al., 2000), drivinglicence renewals (Ricossa et al., 2000), assessing intra-uterine drug exposure (Chiarotti et al., 1996; Ursitti et al.,1997; Koren et al., 2002; Garcia-Bournissen et al., 2007),evaluating of compliance with drug substitution therapy(Moeller et al., 1993; Kintz et al., 1998; Lucas et al.,

    https://www.researchgate.net/publication/null?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/12625152_Evaluation_of_cocaine_amphetamines_and_cannabis_use_in_university_students_through_hair_analysis_Preliminary_results?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/null?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/12579718_Drugs_in_prehistory_chemical_analysis_of_ancient_human_hair_Forensic_Sci_Int?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/13681157_Dose--Concentration_Relationships_in_Hair_from_Subjects_in_a_Controlled_Heroin-Maintenance_Program?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/11552907_Estimation_of_Fetal_Exposure_to_Drugs_of_Abuse_Environmental_Tobacco_Smoke_and_Ethanol?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/12625155_Hair_analysis_for_driving_licence_in_cocaine_and_heroin_users_An_epidemiological_study?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/14339196_Hair_Testing_for_Cannabis_in_Spain_and_France_Is_There_a_Difference_in_Consumption?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/15061475_Simultaneous_determination_of_drugs_of_abuse_opiates_cocaine_and_amphetamine_in_human_hair_by_GC_MS_and_its_application_to_a_methadone_treatment_program?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/null?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/null?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/14167751_Influence_of_sample_preparation_on_analytical_results_Drug_analysis_GCMS_on_hair_snippets_versus_hair_powder_using_various_extraction_methods?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/14167751_Influence_of_sample_preparation_on_analytical_results_Drug_analysis_GCMS_on_hair_snippets_versus_hair_powder_using_various_extraction_methods?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/null?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/13801420_Clinical_Utilization_of_the_Neonatal_Hair_Test_for_Cocaine_A_Four-Year_Experience_in_Toronto?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/13801420_Clinical_Utilization_of_the_Neonatal_Hair_Test_for_Cocaine_A_Four-Year_Experience_in_Toronto?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/227151946_Treatments_against_hair_loss_may_hinder_cocaine_and_metabolites_detection?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/227151946_Treatments_against_hair_loss_may_hinder_cocaine_and_metabolites_detection?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/14167731_Cocaine_detection_in_a_university_population_by_hair_analysis_and_skin_swab_testing?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1M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  • Copyright © 2008 John Wiley & Sons, Ltd. Biomed. Chromatogr. 22: 795– 821 (2008)DOI: 10.1002/bmc

    798 E. Gallardo and J. A. QueirozREVIEW

    2000; Sabzevari et al., 2004), in the workplace and pre-employment (Cairns et al., 2004) and in post-mortemtoxicology (Kintz, 2004). Another important applicationof hair analysis is in drug-facilitated crimes, in whichthe analytes must be detected after a single exposure,which is achieved due to the high sensitivity of LC/MS/MS (Negrusz and Gaensslen, 2003; Kintz, 2007).

    Several classes of drugs can be detected in hair, suchas biomarkers of alcohol consumption, cocaine and meta-bolites, opiates, cannabinoids, amphetamines and otherdesigner drugs, GHB, benzodiazepines and hypnotics,antipsychotics, antidepressants, steroids, anaesthetics,antiparkinsonics and alkaloids (Table 1).

    Hair analysis usually begins with a general screeningby immunoassays, followed by a confirmation usingchromatographic techniques. Gas chromatographycoupled to mass spectrometry is by far the most widelyused analytical tool for drug determination in hairspecimens. Nevertheless, liquid chromatography–massspectrometry (or tandem mass spectrometry) basedmethods are becoming more and more important inthis field, owing to their better sensitivity for termo-labile compounds, yielding lower limits of detectionand quantitation, and the fact that time-consumingderivatization steps are not necessary to accomplish theanalysis. However, before chromatographic analysis,the analytes must be (1) extracted from within thematrix (where they are bound to hair constituents)and (2) concentrated in a solvent which is compatiblewith the analytical instruments. There is no universalmethod to extract the analytes from the hair matrix,and it depends on the nature and chemical stabilityof the particular compound. Therefore, opioids andcocaine are best extracted using mild acidic hydrolysis(e.g. 0.05–0.5 M hydrochloric acid), to avoid conversionof heroin or 6-acetylmorphine to morphine and ofcocaine to benzoylecgonine (Girod and Staub, 2000;Romano et al., 2003; Cognard et al., 2005; Corderoet al., 2007; Tsanaclis and Wicks, 2007a). On the otherhand, stable compounds like cannabinoids and amphe-tamines can be extracted using strong alkaline con-ditions (e.g. 1 M sodium hydroxide; Quintela et al., 2000;Stanaszek and Piekoszewski, 2004; Villamor et al., 2005;Martins et al., 2005, 2006; Tsanaclis and Wicks, 2007a).Other extraction methods include buffer or solventextraction (with, or without sonication; Paterson et al.,2001; Scheidweiler and Huestis, 2004) and enzymatichydrolysis (Vincent et al. 1999; Quintela et al., 2000;Míguez-Framil et al., 2007).

    Following this extraction step, which is normally themost time-consuming step in hair analysis, a samplecleanup step is often required, to minimize any interfer-ence caused by endogenous compounds, which is particu-larly important in the case of liquid chromatography-based methods because of ion suppression/enhancementeffects. This sample cleanup procedure is usually per-

    formed using liquid–liquid extraction (Sachs and Dressler,2000; Stanaszek and Piekoszewski, 2004; Villamor et al.,2005; Nakamura et al., 2007) or solid-phase extraction(Girod and Staub, 2000; Scheidweiler and Huestis,2004; Cognard et al., 2005; Martins et al., 2006; Mooreet al., 2006a,b; Lachenmeier et al., 2006; Cordero andPaterson, 2007). However, solid-phase microextrac-tion (Sporkert and Pragst, 2000; Lucas et al., 2000;Musshoff et al., 2002; Nadulski and Pragst, 2007), solid-phase dynamic extraction (Musshoff et al., 2003) andsupercritical fluid extraction (Cirimele et al., 1995;Allen and Oliver, 2000; Brewer et al., 2001) have alsobeen described.

    Saliva/oral fluid

    Saliva is the excretion product originated from threepairs of major salivary glands (parotid, submandibularand sublingual), a great number of minor salivary glands,the oral mucosa and gingival crevices. As this excretionproduct is actually a fluid mixture, the term ‘oral fluid’seems more appropriate to designate it, instead of ‘saliva’or ‘whole saliva’ (Malamud, 1993). Water (99%) is themajor oral fluid constituent, and other componentssuch as proteins (mucins and digestion enzymes) andmineral salts are also present. Its pH is 6.8 in restingsituations, but an increase in the salivary flow turnsit more basic (approaching the plasma’s pH) as a resultof higher osmolarity (Kintz and Samyn, 2000). All thesecharacteristics are influenced by a variety of factors,as the circadian rhythm, the type of the salivation stimu-lus, hormonal changes, stress, and therapeutic drugs(Aps and Martens, 2005). The total volume of oral fluidproduced by an adult may be 1000 mL/day with typicalflows of 0.05 mL/min while sleeping, 0.5 mL/min whilespitting and 1–3 mL/min or more while chewing (Crouch,2005).

    Different mechanisms of drug transport are thoughtto occur, such as passive diffusion through the membrane,active processes against a concentration gradient, filtra-tion through pores in the membrane and pinocytosis(Spihler, 2004). Most of the drugs enter oral fluid by amechanism of passive diffusion, which is dependent onthe particular physicochemical properties of the com-pound or class of compounds, such as molecular weight(a molecular weight of less than 500 Da favors dif-fusion), liposolubility, pH and pKa, protein binding andionization state (Paxton, 1979; Aps and Martens, 2005).Therefore, the concentrations of drugs in oral fluidrepresent the free non-ionized fraction in the bloodplasma. In fact, the fraction of drug bound to saliva andplasma protein as a function of pKa and pH can be pre-dicted by the Henderson–Hasselbach equation (Spihler,2004).

    A variety of methods are available for oral fluidcollection (Navazesh, 1993), including spitting, draining,

    https://www.researchgate.net/publication/null?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/null?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/null?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/null?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/null?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/12625140_Use_of_headspace_solid-phase_microextraction_HS-SPME_in_hair_analysis_for_organic_compounds?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/12625152_Evaluation_of_cocaine_amphetamines_and_cannabis_use_in_university_students_through_hair_analysis_Preliminary_results?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/12625152_Evaluation_of_cocaine_amphetamines_and_cannabis_use_in_university_students_through_hair_analysis_Preliminary_results?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/12625152_Evaluation_of_cocaine_amphetamines_and_cannabis_use_in_university_students_through_hair_analysis_Preliminary_results?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/null?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/14588507_Supercritical_fluid_extraction_of_drugs_in_drug_addict_hair?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/12625145_The_use_of_supercritical_fluid_extraction_for_the_determination_of_amphetamines_in_hair?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/12625149_Detection_of_THCCOOH_in_hair_by_MSD-NCI_after_HPLC_clean-up?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/12625149_Detection_of_THCCOOH_in_hair_by_MSD-NCI_after_HPLC_clean-up?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/null?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/null?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/null?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/12853313_Determination_of_Buprenorphine_and_Norbuprenorphine_in_Urine_and_Hair_by_Gas_Chromatography-Mass_Spectrometry?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/14984367_Methods_for_Collecting_Saliva?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/null?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/null?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/null?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/null?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/11937002_Analysis_of_Cocaine_Benzoylecgonine_Codeine_and_Morphine_in_Hair_by_Supercritical_Fluid_Extraction_with_Carbon_Dioxide_Modified_with_Methanol?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/null?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/null?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/null?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/null?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/12009656_Qualitative_Screening_for_Drugs_of_Abuse_in_Hair_Using_GC-MS?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/12009656_Qualitative_Screening_for_Drugs_of_Abuse_in_Hair_Using_GC-MS?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/null?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/null?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/null?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/null?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/null?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/null?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/null?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/null?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/251466528_Chapter_13_Unconventional_samples_and_alternative_matrices?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==https://www.researchgate.net/publication/null?el=1_x_8&enrichId=rgreq-9b191a59-1579-4e24-86de-ecff0a87eb3c&enrichSource=Y292ZXJQYWdlOzUzNDM2MTU7QVM6OTg1MDI5NzM1OTE1NjZAMTQwMDQ5NjM0Nzc3NA==

  • Copyright © 2008 John Wiley & Sons, Ltd. Biomed. Chromatogr. 22: 795– 821 (2008)DOI: 10.1002/bmc

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  • Copyright © 2008 John Wiley & Sons, Ltd. Biomed. Chromatogr. 22: 795– 821 (2008)DOI: 10.1002/bmc

    800 E. Gallardo and J. A. QueirozREVIEWT

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    roin

    , 0.0

    2ng

    /mg;

    0.15

    ng/m

    g fo

    r M

    AM

    ,0.

    03ng

    /mg;

    0.1

    1ng

    /mg

    for

    MO

    R, 0

    .02

    ng/m

    g;0.

    04ng

    /mg

    for

    CO

    D,

    0.01

    ng/m

    g; 0

    .11

    ng/m

    gfo

    r C

    OC

    , 0.0

    3ng

    /mg;

    0.26

    ng/m

    g fo

    r B

    E,

    0.05

    ng/m

    g; 0

    .21

    ng/m

    gfo

    r C

    OE

    T50

    pg/m

    g fo

    r al

    l ana

    lyte

    s

    0.1

    ng/m

    g fo

    r am

    phet

    amin

    esan

    d 0.

    2ng

    /mg

    for

    rem

    aini

    ngdr

    ugs

    1.6

    pg/m

    g; 5

    .6pg

    /mg

    for

    bupr

    enor

    phin

    e,12

    .7pg

    /mg;

    50.

    8pg

    /mg

    for

    CO

    D,

    0.8

    pg/m

    g; 2

    .6pg

    /mg

    for

    fent

    anyl

    ,2.

    0pg

    /mg;

    6.6

    pg/m

    gfo

    r hy

    drom

    orph

    one,

    8.9

    pg/m

    g; 3

    0.0

    pg/m

    gfo

    r m

    etha

    done

    ,6.

    1pg

    /mg;

    29.

    9pg

    /mg

    for

    MO

    R,

    12.0

    pg/m

    g; 4

    2.7

    pg/m

    gfo

    r ox

    ycod

    one,

    1.2

    pg/m

    g; 4

    .7pg

    /mg

    for

    oxym

    orph

    one,

    2.2

    pg/m

    g; 9

    .1pg

    /mg

    for

    piri

    tram

    ide,

    2.4

    pg/m

    g; 8

    .7pg

    /mg

    for

    tilid

    ine,

    15.2

    pg/m

    g; 5

    7.8

    pg/m

    gfo

    r tr

    amad

    ol,

    17.4

    pg/m

    g; 5

    9.1

    pg/m

    gfo

    r B

    NT

    I, 9

    .3pg

    /mg;

    32.2

    pg/m

    g fo

    r N

    TI,

    0.9

    pg/m

    g; 3

    .5pg

    /mg

    for

    NF

    E, a

    nd 3

    .4pg

    /mg;

    9.5

    pg/m

    g fo

    r N

    OM

    O0.

    09; 0

    .44

    ng/m

    g fo

    r T

    HC

    ,0.

    09; 0

    .44

    ng/m

    g fo

    r C

    BD

    ,0.

    12; 0

    .44

    ng/m

    g fo

    r C

    BN

    Ref

    eren

    ces

    Lac

    henm

    eier

    et

    al. (

    2006

    )

    Moo

    re e

    t al

    . (20

    06a)

    Cor

    dero

    and

    Pat

    erso

    n (2

    007)

    Mus

    shof

    f et

    al.

    (200

    7)

    Mus

    shof

    f et

    al.

    (200

    3)

    Sam

    ple

    prep

    arat

    ion

    50m

    g of

    hai

    r; S

    PE

    10m

    g of

    hai

    r; S

    PE

    10–5

    0m

    g of

    hai

    r; S

    PE

    50m

    g of

    hai

    r; m

    etha

    nol

    10m

    g of

    hai

    r; S

    PD

    E

  • Copyright © 2008 John Wiley & Sons, Ltd. Biomed. Chromatogr. 22: 795– 821 (2008)DOI: 10.1002/bmc

    Alternative specimens in toxicological analysis 801REVIEW

    Tab

    le 1

    . (C

    onti

    nued

    )

    Com

    poun

    d(s)

    11-n

    or-Δ

    9 -te

    trah

    ydro

    cann

    abin

    ol-9

    -car

    boxy

    licac

    id (

    TH

    C-C

    OO

    H),

    TH

    C, C

    BN

    TH

    C, C

    BD

    , CB

    NT

    HC

    , CB

    D, C

    BN

    , TH

    C-C

    OO

    H

    TH

    C-C

    OO

    HT

    HC

    -CO

    OH

    , TH

    C

    TH

    C, C

    BD

    , CB

    N

    TH

    C, C

    BD

    , CB

    N

    TH

    C, C

    BD

    , CB

    N

    TH

    C-C

    OO

    HA

    mph

    etam

    ine

    (AP

    ), m

    etha

    mph

    etam

    ine

    (MA

    ),3,

    4-m

    ethy

    lene

    diox

    yam

    phet

    amin

    e (M

    DA

    ),3,

    4-m

    ethy

    lene

    diox

    ymet

    ham

    phet

    amin

    e (M

    DM

    A),

    3,4-

    met

    hyle

    nedi

    oxye

    tham

    phet

    amin

    e (M

    DE

    A)

    MA

    , MD

    MA

    , AP

    , MD

    AM

    A, A

    P

    MD

    MA

    , MD

    A, M

    A, A

    P

    MD

    MA

    , MD

    AM

    A, M

    DM

    A, A

    P, M

    DA

    , MD

    EA

    ,N

    -met

    hyl-1

    -(3,

    4-m

    ethy

    lene

    diox

    yphe

    nyl)

    -2-

    buta

    nam

    ine

    (MB

    DB

    )

    Det

    ectio

    n m

    ode

    GC

    /MS/

    MS;

    GC

    /MS;

    EL

    ISA

    GC

    /MS

    GC

    /MS

    GC

    /MS;

    EL

    ISA

    GC

    /MS

    GC

    /MS

    GC

    /MS

    GC

    /MS/

    MS

    GC

    /MS

    GC

    /MS

    GC

    /MS

    HP

    LC

    -flu

    ores

    cenc

    ede

    tect

    ion

    GC

    /MS

    LC

    -MS/

    MS

    LO

    D; L

    OQ

    0.1

    pg/m

    g fo

    r T

    HC

    -CO

    OH

    0.04

    ng/m

    g fo

    r T

    HC

    and

    CB

    N

    0.00

    5ng

    /mg

    for

    CB

    D,

    0.00

    2ng

    /mg

    for

    CB

    N0.

    006

    ng/m

    g fo

    r T

    HC

    revi

    ew0.

    05pg

    /mg

    1.0

    pg/m

    g fo

    r T

    HC

    and

    0.1

    pg/m

    g fo

    r T

    HC

    -CO

    OH

    0.01

    2; 0

    .037

    ng/m

    g fo

    r T

    HC

    ,0.

    013;

    0.0

    38ng

    /mg

    for

    CB

    D,

    0.01

    6; 0

    .048

    ng/m

    g fo

    r C

    BN

    0.02

    5ng

    /mg;

    0.0

    6ng

    /mg

    for

    CB

    N a

    nd C

    BD

    0.07

    ng/m

    g; 0

    .12

    ng/m

    gfo

    r T

    HC

    , CB

    D, C

    BN

    0.02

    pg/m

    g; 0

    .05

    pg/m

    g0.

    045

    ng/m

    g; 0

    .151

    ng/m

    g fo

    rA

    P, 0

    .014

    ng/m

    g; 0

    .048

    ng/m

    gfo

    r M

    A, 0

    .013

    ng/m

    g;0.

    043

    ng/m

    g fo

    r M

    DA

    ,0.

    017

    ng/m

    g; 0

    .057

    ng/m

    gfo

    r M

    DM

    A, 0

    .007

    ng/m

    g;0.

    023

    ng/m

    g fo

    r M

    DE

    A0.

    125

    ng/m

    g; 0

    .5ng

    /mg

    0.02

    ng/0

    .08

    mg/

    vial

    ; 0.0

    5ng

    /0.

    08m

    g/vi

    al f

    or M

    A0.

    05ng

    /0.0

    8m

    g/vi

    al;

    0.10

    ng/0

    .08

    mg/

    vial

    for

    AP

    0.25

    ng/m

    g fo

    r M

    DM

    A,

    0.15

    ng/m

    g fo

    r M

    DA

    ,0.

    25ng

    /mg

    for

    MA

    ,0.

    19ng

    /mg

    for

    AP

    — 1.1

    pg/m

    g; 2

    .4pg

    /mg

    for

    MA

    , 2.1

    pg/m

    g; 4

    .8pg

    /mg

    for

    MD

    MA

    , 6.1

    pg/m

    g;14

    .7pg

    /mg

    for

    AP

    ,6.

    3pg

    /mg;

    15.

    7pg

    /mg

    for

    MD

    A, 1

    .4pg

    /mg;

    3.2

    pg/m

    g fo

    r M

    DE

    A,

    0.3

    pg/m

    g; 0

    .7pg

    /mg

    for

    MB

    DB

    Ref

    eren

    ces

    Uhl

    and

    Sac

    hs (

    2004

    )

    Kim

    et

    al. (

    2005

    )M

    ussh

    off

    and

    Mad

    ea (

    2006

    )

    Moo

    re e

    t al

    . (20

    06b)

    Hue

    stis

    et

    al. (

    2007

    )

    Nad

    ulsk

    i an

    d P

    rags

    t (2

    007)

    Skop

    p et

    al.

    (200

    7)

    Diz

    ioli

    Rod

    rigu

    es d

    eO

    livei

    ra e

    t al

    . (20

    07)

    Kim

    and

    In

    (200

    7)V

    illam

    or e

    t al

    . (20

    05)

    Han

    et

    al. (

    2006

    )N

    ishi

    da e

    t al

    . (20

    06b)

    Nak

    amur

    a et

    al.

    (200

    6)

    Liu

    et

    al. (

    2006

    )C

    hèze

    et

    al. (

    2007

    a)

    Sam

    ple

    prep

    arat

    ion

    15m

    g of

    hai

    r; S

    PE

    50–1

    00m

    g of

    hair

    ; met

    hano

    l50

    mg

    of h

    air;

    LL

    E

    20m

    g of

    hai

    r; S

    PE

    20m

    g of

    hai

    r; S

    PE

    100

    mg

    of h

    air;

    HS-

    SPM

    E

    50m

    g of

    hai

    r; L

    LE

    10m

    g of

    hai

    r; H

    S-SP

    ME

    25m

    g of

    hai

    r; L

    LE

    50m

    g of

    hai

    r; L

    LE

    5–19

    mg

    of h

    air;

    met

    hano

    l1

    piec

    e of

    hai

    r; S

    PM

    E

    met

    hano

    l

    50m

    g of

    hai

    r; L

    LE

    20m

    g of

    hai

    r; L

    LE

  • Copyright © 2008 John Wiley & Sons, Ltd. Biomed. Chromatogr. 22: 795– 821 (2008)DOI: 10.1002/bmc

    802 E. Gallardo and J. A. QueirozREVIEW

    Tab

    le 1

    . (C

    onti

    nued

    )

    Com

    poun

    d(s)

    MA

    , MO

    R, C

    OD

    , Ket

    amin

    e

    MD

    MA

    , AP

    , MD

    A

    GH

    B

    GH

    BG

    HB

    Dia

    zepa

    m, n

    ordi

    azep

    am, o

    xaze

    pam

    , alp

    razo

    lam

    ,O

    H-a

    lpra

    zola

    m, n

    itraz

    epam

    , 7-a

    min

    onitr

    azep

    am,

    fluni

    traz

    epam

    , 7-a

    min

    oflun

    itraz

    epam

    , clo

    naze

    pam

    ,an

    d 7-

    amin

    oclo

    naze

    pam

    Bro

    maz

    epam

    , clo

    naze

    pam

    , 7-a

    min

    oclo

    naze

    pam

    ,hy

    drox

    y br

    omaz

    epam

    Zop

    iclo

    neA

    lpra

    zola

    m, 7

    -am

    inoc

    lona

    zepa

    m,

    7-am

    inofl

    unitr

    azep

    am, b

    rom

    azep

    am,

    clob

    azam

    , dia

    zepa

    m, l

    oraz

    epam

    ,lo

    rmet

    azep

    am, m

    idaz

    olam

    , nor

    diaz

    epam

    ,ox

    azep

    am, t

    emaz

    epam

    , tet

    raze

    pam

    ,tr

    iazo

    lam

    , zal

    eplo

    n an

    d zo

    lpid

    emT

    etra

    zepa

    m26

    ben

    zodi

    azep

    ines

    and

    met

    abol

    ites,

    zolp

    idem

    and

    zop

    iclo

    ne7-

    Am

    inofl

    unitr

    azep

    am, fl

    unitr

    azep

    am, o

    xaze

    pam

    ,lo

    raze

    pam

    , chl

    ordi

    azep

    oxid

    e, t

    emaz

    epam

    ,di

    azep

    am, n

    ordi

    azep

    am, n

    itraz

    epam

    Dia

    zepa

    m a

    nd o

    ther

    s be

    nzod

    iaze

    pine

    s

    Alp

    razo

    lam

    α-h

    ydro

    xyal

    praz

    olam

    Car

    bam

    azep

    ine,

    am

    itrip

    tylin

    e, d

    oxep

    in,

    trih

    exyp

    heni

    dyl,

    chlo

    rpro

    maz

    ine,

    chlo

    rpro

    thix

    ene,

    tri

    fluop

    eraz

    ine,

    cloz

    apin

    e an

    d ha

    lope

    rido

    l

    Det

    ectio

    n m

    ode

    CSE

    I-Sw

    eep-

    ME

    KC

    and

    LC

    -MS

    LC

    -MS/

    MS

    GC

    /MS

    and

    LC

    /MS

    GC

    /MS/

    MS

    GC

    /MS

    LC

    -MS/

    MS

    LC

    -MS/

    MS

    LC

    -MS/

    MS

    LC

    -MS/

    MS

    LC

    -MS/

    MS

    LC

    -MS/

    MS

    EL

    ISA

    /L

    C/M

    S/M

    S

    MIS

    PE

    and

    LC

    /MS/

    MS

    GC

    /MS

    GC

    -MS

    LO

    D; L

    OQ

    50pg

    /mg

    for

    MA

    and

    keta

    min

    e, 1

    00pg

    /mg

    hair

    for

    CO

    D a

    nd20

    0pg

    /mg

    hair

    for

    MO

    R0.

    1ng

    /mg;

    0.2

    ng/m

    g fo

    rM

    DM

    A, A

    P, M

    DA

    — — 0.1

    pg/m

    g0.

    025

    –0.

    125

    ng/m

    g

    1–2

    pg/m

    g; 5

    pg/m

    gfo

    r br

    omaz

    epam

    ,0.

    5pg

    /mg;

    2pg

    /mg

    for

    clon

    azep

    am,

    2pg

    /mg;

    <10

    pg/m

    gfo

    r 7-

    amin

    oclo

    naze

    pam

    0.3

    pg/m

    g0.

    5–2

    pg/m

    g

    1.5

    pg/m

    g; 5

    pg/m

    g0.

    5–10

    pg/m

    g

    2ng

    /mg

    for

    EL

    ISA

    0.03

    –0.6

    2ng

    /30

    mg;

    0.05

    –1.0

    2ng

    /30

    mg

    for

    LC

    /MS/

    MS

    0.09

    ng/m

    g; 0

    .14

    ng/m

    gfo

    r di

    azep

    am0.

    03–0

    .78

    ng/m

    g;0.

    06–1

    .32

    ng/m

    gfo

    r ot

    hers

    ben

    zodi

    azep

    ines

    7ng

    /mg;

    20

    ng/m

    g0.

    1–0.

    5ng

    /mg

    Ref

    eren

    ces

    Lin

    et

    al. (

    2007

    )

    Kly

    s et

    al.

    (200

    7)

    Kal

    asin

    sky

    et a

    l. (2

    001)

    Gou

    llé e

    t al

    . (20

    03)

    Kin

    tz e

    t al

    . (20

    05d)

    Kro

    nstr

    and

    et a

    l. (2

    002)

    Chè

    ze e

    t al

    . (20

    04)

    Vill

    ain

    et a

    l. (2

    004)

    Vill

    ain

    et a

    l. (2

    005)

    Con

    chei

    ro e

    t al

    . (20

    05b)

    Lal

    oup

    et a

    l. (2

    005a

    )

    Mill

    er e

    t al

    . (20

    06)

    Ari

    ffin

    et a

    l. (2

    007)

    Gar

    cía-

    Alg

    ar e

    t al

    . (20

    07)

    Shen

    et

    al. (

    2002

    )

    Sam

    ple

    prep

    arat

    ion

    10m

    g of

    hai

    r; L

    LE

    20m

    g of

    hai

    r; m

    etha

    nol

    10m

    g of

    hai

    r; b

    uffe

    rso

    lutio

    n an

    d SP

    E5

    mg

    of h

    air;

    LL

    E5

    mg

    of h

    air;

    LL

    E10

    –30

    mg

    of h

    air;

    LL

    E

    20m

    g of

    hai

    r; L

    LE

    20m

    g of

    hai

    r; L

    LE

    20m

    g of

    hai

    r; L

    LE

    20m

    g of

    hai

    r; L

    LE

    20m

    g of

    hai

    r; L

    LE

    30m

    g of

    hai

    r; m

    onob

    asic

    phos

    phat

    e bu

    ffer

    /SP

    E

    30m

    g of

    hai

    r;M

    IP/M

    ISP

    E a

    nd S

    PE

    10m

    g of

    hai

    r10

    –20

    mg

    of h

    air;

    met

    hano

    l

  • Copyright © 2008 John Wiley & Sons, Ltd. Biomed. Chromatogr. 22: 795– 821 (2008)DOI: 10.1002/bmc

    Alternative specimens in toxicological analysis 803REVIEW

    Tab

    le 1

    . (C

    onti

    nued

    )

    Com

    poun

    d(s)

    Clo

    zapi

    ne, fl

    upen

    tixol

    , hal

    oper

    idol

    ,pe

    nflur

    idol

    , thi

    orid

    azin

    e, z

    uclo

    pent

    hixo

    l

    Tri

    mep

    razi

    neC

    loza

    pine

    Ris

    peri

    done

    , ser

    tral

    ine,

    par

    oxet

    ine,

    trim

    ipra

    min

    e, m

    irta

    zapi

    ne, a

    nd t

    heir

    met

    abol

    ites

    Clo

    zapi

    neA

    mitr

    ipty

    line,

    nor

    trip

    tylin

    e, d

    othi

    epin

    , dox

    epin

    ,im

    ipra

    min

    e, t

    rim

    ipra

    min

    e, d

    esip

    ram

    ine,

    mia

    nser

    in,

    halo

    peri

    dol,

    chlo

    rpro

    maz

    ine,

    dia

    zepa

    m,

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  • Copyright © 2008 John Wiley & Sons, Ltd. Biomed. Chromatogr. 22: 795– 821 (2008)DOI: 10.1002/bmc

    804 E. Gallardo and J. A. QueirozREVIEW

    suction and collection on various types of absorbentswabs.

    Several techniques may be used to collect stimulatedsaliva. The simplest involves tongue, cheek or lip move-ments without any external stimulus (Mucklow et al.,1978). Chewing paraffin wax, Parafilm, teflon, rubberbands, gum base and chewing gum are usually referredto as mechanical methods of stimulating saliva pro-duction. Likewise, a lemon juice drop or citric acid canbe placed in the mouth to provide a gustatory stimulusfor saliva production (Crouch et al., 2004). However, thestimulation of saliva production may present severalproblems which can compromise drug-testing accuracy.For instance, some drugs and/or metabolites have beenshown to be absorbed by Parafilm, and citric acidstimulation changes saliva pH and may alter drug con-centrations. On the other hand, citric acid and cottonhave also been shown to alter immunoassay drug testresults (Crouch, 2005).

    A variety of commercial collection devices that pro-mote easy, quick and reproducible collection are available.In general, these devices consist of a sorbent materialthat becomes saturated in the mouth of the donor, andafter removal the oral fluid is recovered by applyingpressure or by centrifugation. Examples of commer-cially available devices include Orasure® (Epitope, Inc.,Beaverton, OR, USA), Omni-SAL® (Cozart Biosciences Ltd,Abington, UK), Salivette® (Sarstedt AG, Rommelsdorf,Germany), Drugwipe® (Securetec, Ottobrunn, Germany),Intercept® ORALscreen™ and Quantisal™ (ImmunalysisCorp., Pomona, USA; Spihler, 2004; Samyn et al., 2007).Care should be taken when using these collectiondevices, because deficient recovery of drugs from oral fluidin the absorbent and adsorption of the drug on devicecomponents are likely to occur (Lenander-Lumikariet al., 1995; O’Neal et al., 2000; Samyn et al., 2007).

    One of the advantages of saliva testing is that the sampleis collected under direct supervision without loss of pri-vacy. In consequence, the risk of an invalid specimenbeing provided or sample adulteration and/or substitu-tion (which are likely to occur in urine analysis) is reduced.In addition, monitoring of oral fluid may be especiallyadvantageous and important when multiple serial samplesare needed or when drug concentrations in children arerequired (Kim et al., 2002). Other advantages are that,in principle, saliva drug concentrations can be relatedto plasma free-drug concentrations and to the pharma-cological effects of drugs.

    On the other hand, drugs that are ingested orally aswell as those that can be smoked may be detectedin high concentrations in oral fluid following recent use,due to residual amounts of drug remaining in the oralcavity. Therefore, and for these substances, resultsmay not be accurate because the drug concentrationfound in the oral fluid may not reflect the blood-drugconcentration.

    Another disadvantage of studying oral fluid is thatpeople are sometimes unable to produce sufficientamounts of material for analysis. Moreover, an impor-tant feature of urine testing is the accuracy of theon-site tests to detect drugs of abuse in fresh samples.Unfortunately, this is not the current situation fororal fluid testing (Grönholm and Lillsunde, 2001; Kintzet al., 2005a). In addition, oral fluid contains severalmacromolecules (mucopolysaccharides and mucoproteins),which make it less easily pipetted than for instanceurine, and may not be available from all individualsat all times, since there are drugs that can inhibitsaliva secretion and cause dry mouth. Furthermore,and because drug concentration on this sample dependson plasma drug concentrations, drugs that have a shortplasma half-life and are cleared rapidly from the bodyare detectable in saliva for a short time only, whichrepresents a potential disadvantage over hair, sweat orurine. In fact, saliva and blood have the shortest detec-tion windows (Spihler, 2004).

    Because of the above-mentioned advantages, oralfluid testing is an analytical tool used in therapeuticdrug monitoring of various drugs (Horning et al. 1977;Bennett et al., 2003; Quintela et al. 2005; Dams et al.,2007), pharmacokinetic studies (Schepers et al., 2003;Huestis and Cone, 2004; Huestis, 2005; Drummer, 2005;Kauert et al., 2007), and detection of illicit drugs inimpaired driving (Samyn et al., 2002b; Kintz et al.,2005a; Toennes et al., 2005; Wylie et al., 2005a,b;Laloup et al., 2006; Concheiro et al., 2007; Drummeret al., 2007; Pehrsson et al., 2007).

    There is no doubt that one of the most impactingapplications of oral fluid testing is in the assessmentof drug-impaired driving, enabled not only by thedevelopment of several on-site collection devices, butalso its easy and non-invasive sample collection pro-cedure. In addition, the premise of a good correlationbetween oral fluid levels and blood levels means thatoral fluid levels may be used to assess the degree ofimpairment of a driver.

    Drugs of abuse are by far the most frequentlydetected substances in oral fluid specimens, becauseof their implications in workplace medicine and motorvehicle driving. Therefore, methods are described todetect opiates, cannabinoids, amphetamines, cocaine,benzodiazepines and other substances such as ketamine,GHB, antibiotics, analgesics, cyanides and other tobaccocompounds, and sildenafil (Table 2).

    One issue that is gaining popularity within law en-forcement and traffic regulation agencies is that theinitial testing of oral fluid for drugs can be made in thefield, by means of on-site collecting devices. Severaldevices are commercially available for this purpose,including instruments that provide an electronic readout(e.g. Dräger DrugTest® and Orasure Uplink®, CozartRapiscan® and Drugread® hand photometer) and

    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  • Copyright © 2008 John Wiley & Sons, Ltd. Biomed. Chromatogr. 22: 795– 821 (2008)DOI: 10.1002/bmc

    Alternative specimens in toxicological analysis 805REVIEW

    Tab

    le 2

    . Cla

    sses

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    10ng

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    ; 2ng

    /mL

    for

    MO

    R a

    nd C

    OD


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