Chapter 12 Drugs and driving

M.J. Bogusz (Ed.), Forensic Science Handbook of Analytical Separations, Vol. 2 9 2000 Elsevier Science B.V. All rights reserved

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Drugs and driving R. Wennig a and A. Verstraete b Laboratoire National de Sante, Division Toxicologie, Centre Universitaire de Luxembourg, L- 1511 Luxembourg b University Hospital Ghent, Laboratory of Toxicology, 185 De Pintelaan, B-9000 Ghent, Belgium a

12.1 I N T R O D U C T I O N Driving while impaired, whether by alcohol, by other drugs, or by a combination of alcohol and one or more other drugs, is a major health and safety problem. Since several years drugs and driving issues have been of great concern for law enforcement agencies, prosecutors, toxicologists and politicians all over the world. As the drug situation is much more complicated than the alcohol situation (which is still sometimes controversial), attempts were made to find solutions at regional, national or supranational levels. Most traffic crashes are the result of human error. No reliable statistics are kept for people injured or killed in accidents involving impaired driving. As an example, Transport Canada has recorded that in 1989 as much as 38.9% of all drivers killed on Canadian roads had been drinking prior to their deaths. A recent study in the UK calculated that 2365 accidents and 165 deaths could be attributed to use of anxiolytic benzodiazepines by drivers aged less than 45 in the UK [ 1]. Ethanol is still the most widely used drug and the one most often linked to motor vehicle accidents. It is known since many years now that other drugs, and especially when they are combined with alcohol, can also interfere with a person's driving ability. While there is a large knowledge on the contribution of alcohol to traffic injuries and deaths, there is less information available about the effects of prescription, over-the-counter, or illicit drug use, especially when these drugs are combined with alcohol. As a result of this situation many countries are encouraging more research in this field of toxicology and are beginning to elaborate or have already elaborated a specific legislation on drugs and traffic safety. Toxicological analysis finds several applications in drugs and driving: (1) studies on the pharmacokinetics of drugs and their metabolites, and their pharmacodynamic relationship to impairing effects; (2) epidemiological and survey studies which require the analysis of physiological specimens collected from either injured or fatally injured drivers; (3) the analysis of specimens for law enforcement purposes [2]. References pp. 453-457

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12.2 L E G A L ISSUES Each country has its specific legislation, but some generalizations can be made. Most countries (e.g. all the countries of the European Union) have a legislation based on the demonstration of impairment, in short 'impairment laws'. Impaired driving must be demonstrated by the prosecution, and the analysis of drugs in body fluids (blood or urine) only provides corroborating evidence as to the cause of the impairment. We give examples of the law in three Scandinavian countries. 9 In Norway, no one must drive or attempt to drive a motor vehicle when he is under the influence of alcohol (not sober) or of other intoxicating or narcotic agents. If the breathalyser test is negative, the police may take him to be examined by a medical practitioner who can take blood (and urine) tests or otherwise seek to ascertain the degree of influence. 9 In Finland, a person who operates a motor vehicle under the influence of an intoxicating substance other than alcohol or under the combined influence of alcohol and another intoxicating substance, so that his ability to perform faultlessly is reduced, shall be sentenced for intoxicated driving to a fine or to imprisonment for at most two years. 9 In Denmark, a power-driven vehicle is not allowed to be driven or attempted to be driven by any person who is, because of illness, debility, strain, too little sleep, influence of drugs or for similar reasons, in such a condition that such person is incapable of driving such vehicle properly. In this case, the police may hold a person in order to have laboratory specimens of such person's blood and urine taken. The degree of enforcement varies greatly among the different countries, with some (like the Scandinavian countries and some states in the US) having a high degree of enforcement, and others like Belgium or Spain where this law is very seldom enforced. Proving impairment remains subjective and requires the assessment of a medical doctor or a specially trained police officer (the well-known Drug Recognition Expert or DRE). Despite standardization efforts, this remains subjective, and many countries experience difficulty in obtaining convictions. For this reason, and in analogy to alcohol, some countries have added new legislation that forbids driving if a drug is present in the body of a driver. These laws are called 'per se laws'. No proof of impairment is required any more. The demonstration of a drug in a body fluid (mostly blood, but sometimes also urine) is sufficient to bring a conviction. With 'per se' laws, the question arises whether, similarly to alcohol, legal limits can be determined. In 1985, a consensus panel concluded that 'per se' levels could not be determined, because the blood concentration-impairment relation is more complex with illicit drugs than it is with ethanol [3]. The presumed Gaussian distribution curve relating impaired driving ability at a given drug concentration against numbers of individuals is probably broad, flat and diffuse for most drugs. For this reason, the cut-offs used are analytical cut-offs, i.e. any detectable concentration of a drug is enough, and these laws are also called 'zero-tolerance laws. In Europe, Germany was the first country to introduce such a law: the w24a of the Road Traffic Act was amended in March 1998. Under this amendment, any person driving a vehicle in road traffic under the influence of cannabis, heroin, morphine, cocaine, amphetamine or designer amphetamines commits

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TABLE 12.1 ANALYTICAL CUT-OFF LIMITS IN BLOOD FOR SOME DRUGS AS AGREEDUPON OR PROPOSED IN DIFFERENT COUNTRIES (ALL CONCENTRATIONS IN NG/ML)a

Amphetamine MDEA MDMA MDA MBDB Cocaine Codeine Benzoylecgonine Ecgonine methyl ester Morphine (free) Tetrahydrocannabinol a

Belgium

France

50 50 50

50 50 50

50 50 20 50 50 20 2

50 20 2

From Moniteur belge du 30.03.1999, 10157-10160, pers. commun. Pascal Kintz.

an offence [4,5]. A person is deemed to be under the influence of a drug if the drug is detected in his blood. This does not apply if the substance originates from having taken prescribed medication as intended for a specific illness. In Belgium a similar law was voted in March 1999. A driver can be stopped by the police and asked to perform a standardized test battery to establish the presence of external signs of influence by drugs. If this is positive, a urine sample is taken and an on-site immunoassay is performed. If this is positive, a medical doctor is called to examine the subject and take blood. The blood is than sent to a laboratory for G C MS analysis with deuterated internal standards. If drugs are present in the blood (the analytical cut-offs are mentioned in Table 12.1), the driver can be condemned to fines and/or imprisonment similar to those for driving with a blood alcohol greater than 0.8 g/1. In case of a positive analysis, the driver must also pay for the costs of the analysis. 'Per se' laws also exist in several US states like Arizona, Georgia, Illinois, Indiana, Minnesota, Rhode Island and Utah. It is illegal to drive if there is any amount of a drug, substance, or compound in the person's blood or urine resulting from the unlawful use or consumption of cannabis or a controlled substance [6]. In Germany these analytical cut-off limits [5] have not been included as such in the law, but they are used by the forensic laboratories for implementation. The European Council Directive 91/439/EEC of 29 July 1991 on driving licences states that "Driving licences shall not be issued to or renewed for applicants or drivers who are dependent on psychotropic substances or who are not dependent on such substances but regularly abuse them, whatever category of licence is requested". With regard to regular use, the directive states that for group 1 (motorcycles with or without side-car and motor vehicles with a maximum authorized mass not exceeding 3500 kg and having not more than eight seats in addition to the driver's seat) driving licences shall not be issued to, or renewed for, applicants or drivers who regularly use psychotropic substances, in whatever form, which can hamper the ability to drive safely where the quantities absorbed are such as to have an adverse effect on driving. References pp. 453-457

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This shall apply to all other medicinal products or combinations of medicinal products which affect the ability to drive. For group 2 (trucks and buses) the competent medical authority shall give due consideration to the additional risks and dangers involved in the driving of vehicles covered by the definitions of this group. In some countries like Germany, Italy and Spain, hair analysis for drugs of abuse has become a routine test to demonstrate that a driver who had his driving licence suspended is no more dependent.

12.3 SURVEYS THAT SCREENED FOR SEVERAL COMPOUNDS In this category, we place the epidemiological surveys which have estimated the prevalence of drugs in different groups of drivers: roadside surveys (involving a representative sample of the whole driving population), surveys of injured drivers, surveys of killed drivers, re-analysis of blood samples taken for blood alcohol analysis and surveys of impaired drivers. Another type of study is mentioned here for completeness: the pharmaco-epidemiological studies where the incidence of traffic accidents in people who take drugs is compared to a control population. These studies do not use analysis of body fluids, but data from medical records and provide very interesting information on the accident risk associated with the use of medication. Examples are the studies by Ray et al. [7] and Barbone et al. [1]. This last study involved some 19 386 drivers of which 235 were using benzodiazepines and 17,312 were users of any drug. The authors recommended to users of anxiolytic benzodiazepines and zopiclone not to drive. For practical reasons, many of these studies have analysed urine, while only a minority have analysed blood or saliva. In many of these studies, the description of the analytical method used is rather limited or absent [8-15]. In some studies only immunoassays were used [16,17], and in some others only a subset of the immunoassay positives are confirmed by GC-MS [ 18]. While some older studies used TLC and GC, more recent studies used GC-MS with deuterated internal standards [ 19]. The importance of the sensitivity and specificity of the analytical method is illustrated by the following example. In a large multicentre study in France [20] the prevalence of benzodiazepines in blood of drivers who were responsible for the accident was not significantly higher than in those who were not considered responsible for the accident. The poison control centre in Marseille [21], which analysed a subset of samples and used EMIT and HPLC-DAD, found respectively 6.8 and 12.8% of positives in 234 drivers. With the HPLC method, a significant difference was found between the two groups of drivers, while there was no difference if the EMIT results were used. In a series of 72000 arrests for impaired driving in California between 1973 and 1978, the following procedure was followed. If BAC was negative, blood (10 mL collected in tubes containing 200 mg sodium fluoride and 20 mg potassium oxalate) was screened for other drugs: barbiturates by UV spectrophotometry and paper chromatography, benzodiazepines, methaqualone, carbamates and ethchlorvynol by TLC. The results were confirmed on a second sampling of the blood by UV, GC,

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paper chromatography, GC or GC-MS. Drugs were found in 60-70% of those blood samples in which alcohol was absent [22]. In a study of 242 drivers detained for driving while impaired in the city and county of Denver from 1988 to June 1990, a screening was performed for 44 drugs: illicit drugs were screened by EMIT and confirmed by GC-MS, stimulants (ephedrine and phenylpropanolamine), depressants and some other drugs by TLC (detection limit 0.5 ~g/ml), fentanyl and LSD by RIA (confirmed by a reference laboratory) and toluene by GC-FID [23]. In a study of injured drivers in France, psychotropic medicines (benzodiazepines and other sedatives or hypnotics) were detected by HPLC [24]. In another French study on the same topic, urine screening by FPIA was followed by confirmation by GC-MS [25]. In a more recent study, blood samples of 94 drivers whose abnormal behaviour (not explainable by alcohol) provoked an accident as well as samples from 164 drivers involved in an accident with severely or fatally wounded were analysed [19]. Fifty-six samples (19%) were positive, in decreasing frequency, for cannabis, opiates and amphetamines. In a Belgian toxicology and trauma study (BTTS) 2053 injured drivers were screened. Urine was screened by FPIA, followed by confirmation by GC-MS, except for barbiturates where HPLC on plasma was used [26-30]. In a spin-off study, blood levels of amphetamines, cannabinoids, cocaine, methadone, opiates and propoxyphene were determined by GC-MS [28]. From the end of the 70's until today many surveys have been made in different countries or regions, where not always all the emphasis was made on analytical aspects; some investigated accidents, some considered only fatal outcomes, some injured drivers, etc. [31-40] [41-50] [51-58]. All are sufficiently interesting to be at least referenced here. One survey has considered the special situation of railroad accidents [59].

12.4 SURVEYS CONSIDERING ONLY ONE OR TWO COMPOUNDS

Many studies have surveyed only one or two compounds or drug families. For instance, Hingson et al. [60] investigated the effects of legal BAL lowered to 0.5 g/kg for drivers in Maine/USA involved in fatal accidents. They found a decline of 25%. Phebo et al. [61] studied the risk behaviour among young drivers and recommended implementation and evaluation of complete graduated driver licence systems. DeJong et al. [62] investigated the usefulness of the use of designated drivers by US college students (37% reported having used alcohol in the past 30 days), and Roeper et al. [63] examined the alcohol consumption by measuring ethanol at the roadside in 33 614 persons in California during the last 4 years. The incidence of cannabis and ethanol on driving performance in Canada was studied by Cimbura et al. [64] in 1169 drivers and 225 pedestrians. THC levels (in 10.9% of drivers) ranging from 0.2 to 37 ng/ml: mean 3.1 • 5.9 ng/ml and EtOH levels (in 57% of drivers) ranging from 0.09 g/1 to 4.0 g/1. A very comprehensive study was made by Daldrup [65] on cannabis and driving in Nordrhein-Westphalen/Germany, including detailed analytical methods, and recommends the use of a so-called 'Cannabis Influence References pp. 453-457

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TABLE 12.2 MEAN SERUM CONCENTRATIONS OF CANNABINOIDS AMONGCANNABIS-POSITIVEDRIVERS (FROM REF. [65]) Substance

Mean concentration (ng/ml)

Standard deviation (ng/ml)

THC 11-OH-THC THC-COOH

5.5 1.95 37.5

7.01 1.82 31.16

Factor' (CIF) for the evaluation of the impairment. Mean concentrations of cannabinoids are summarized in Table 12.2. Marzuk et al. [66] studied the prevalence of recent cocaine use (18.2%) and ethanol use (46%) (10% use of both cocaine and EtOH) in 643 motor vehicle fatalities in New York City. An other similar comprehensive study was made by Daldrup [67] on heroin and driving. A free morphine level range of 0.4-530 ng/ml with a mean of 31.7 ng/ml and an SD of 35.4 were found. In a pilot study Bogusz et al. [68] investigated heroin, its metabolites and other drugs in two groups: road traffic offenders (n = 14) and other offenders (n = 26). Blood concentrations of morphine, M3G, M6G, 6-MAM, codeine and C6G were monitored by L C - A P C I - M S . The concentration range in the group of road traffic offenders was for morphine 3 to 80 txg/1 and for its active metabolite M6G 8 to 248 txg/1. In the group of other offenders the concentration range for morphine was 1 to 95 txg/1 and for M6G 15 to 278 gg/1. In almost each case, several non-opiate drugs were detected. Kunsman et al. described phencyclidine concentrations in drug recognition expert (DRE) cases [69]. The mean concentration was 51 ng/ml, with a range of 12 to 118 ng/ml. An interesting study on the influence of benzodiazepines on driving was undertaken by Ulrich [70] in Bern/Switzerland (42 positive benzodiazepines in 1000 drivers). In Florida the increasing use of flunitrazepam (Rohypnol | in drugs and driving cases was investigated by Raymon et al. [71]. The use of tramadol in impaired drivers was investigated by Goeringer et al. [72] in 12 fatalities. Gjerde et al. [73] have investigated the driving under the influence of toluene (mean 109 ~mol/1) in Norway in 114 arrested drivers. The fenproporex abuse by truck drivers (n = 3538 urine specimens with 1.58% positive rate) in Brazil was surveyed using GC-NPD and GC/MS by Silva et al. [74].

12.5 CASE REPORTS It may also be interesting to report some isolated case reports where one or two substances were found responsible for the cause of accident and where some analytical methods have been discussed. Such a case was discussed by Kintz et al. [75,76] where methaqualone at a concentration of 355 ng/ml was found to be the causal agent of an aircraft crash. It was also possible to prove chronic use of methaqualone by segmental hair analysis.

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The use and influence of methamphetamine in 28 cases (range 0.09-9.46 mg/1) of arrested drivers was studied by Logan [77]. Hooft and van de Voorde [78] found an MDMA level of 0.63 mg/1 and an EtOH concentration of 1.23 g/1 in one case of a fatal accident. Crifasi and Long [79] studied a traffic fatality due to the use of ecstasy-type amphetamines and found levels of MDMA 2.32 mg/1 and as metabolite MDA of 0.25 mg/1. Famprofazone which undergoes metabolic conversion to amphetamine and methamphetamine, was identified in a traffic accident case by Musshoff and Krfimer [80]. A case of driving under the influence of gamma-hydroxybutyrate (GHB) was reported by Stephens and Baselt [81]. Analysis of a urine specimen collected 1 h after the traffic stop revealed a GHB level of 1975 mg/1. Sticht et al. [82] examined the case of two road accidents after heroin consumption. In one case a free morphine level of 0.96 rag/1 was found in blood. Augsburger et al. [83] discovered in the biological specimens of a driver in a car crash that he had ingested digoxin and midazolam. The digoxin in blood was 12.9 ng/mL and the midazolam level was 7 ng/ml 6 h after the crash. Two cases of driving under the influence of atropine-adulterated cocaine were described by Schmid and Iten [84]. Atropine concentrations in whole blood were 3 and 9 ~g/1, respectively, and in urine 6.6 and 27 mg/1.

12.6 PERFORMANCE TESTING

Although out of the scope of the analytical aspects, some interesting studies that feature the different performance testings in laboratories or at the road side have been undertaken by e.g. Hobi who was a pioneer in this field in the beginning of the 80's [85]. Irving and Jones [86] in the UK and Alvarez and Del Rio [87] studied for different psychological laboratory tests the influence of several drugs on the driving ability and recommended to better inform the drivers. Mechanisms of drug-induced driving impairment were investigated by Riedel et al. [88]. For many colleagues a controversial study was performed by Robbe [89] in Maastricht/Netherlands on the influence of cannabis on driving performance. He demonstrated that THC applied in a dose of 0.3 mg/kg body weight produced a slight impairment of the ability to maintain a constant headway while following another car. This impairment was considered as less than that associated with a blood alcohol level of 0.8 g/kg in previous studies employing the same test methods. Pharmacodynamic effects of antihistamines mizolastine and cetirizine as well as of EtOH (0.7 g/l) on psychomotor and driving performance were studied by Patat et al. [90]. No significant reduction of driving skills in cancer patients receiving morphine was demonstrated by Vainio et al. [91]. In a recent review on the effects of opioids on psychomotor and cognitive functioning in humans Zacny [92] came to the conclusion that impairment, if any, may only be transient in chronic-pain patients. A comprehensive literature survey was used by a group of toxicologists from Belgium and Luxembourg [93] to make an attempt to categorise 179 legal drugs from 9 therapeutic classes, in order to provide physicians and pharmacists with a scientific base for guiding their patients on the effects of drugs on driving performance. Analysis of drug concentrations in body fluids is only rarely performed in this type References pp. 453-457

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of study, although that was recommended by Ferrara et al. [42]. These analyses could provide some insight into the relationship between blood (or saliva) levels and driving behaviour, and thus allow a better interpretation of drug levels found in impaired drivers.

12.7 ANALYTICAL TOXICOLOGY The methods used will be dependent on the aims of the analysis. In case of a medicolegal analysis in a country where an impairment law is in effect, a large-scale screening analysis will be needed. If a per se law is in effect, an analysis of the compounds specifically mentioned in the law will be needed. This will also be the case in surveys where only a number of compounds are analysed. Finally, in some specific cases, like experimentally controlled studies or case reports, only one compound and its metabolites will be analysed.

12.7.1 Screening techniques In principle many analytical methods can be used, provided that they have suitable analytical cut-off limits, LODs and LOQs and have been validated for the purpose of drugs and driving testing in biological specimens. No single technique is capable of detecting all substances that impair driving, and a combination of techniques will have to be used. Up until now many analytical methods have been published and some recent comprehensive reviews in a special issue of Journal of Chromatography edited by Maurer [94] on many drugs of clinical and forensic interest may be considered to be useful for DUI testing purposes. Working groups of the United Nations (UNDCP, Vienna) have elaborated several comprehensive overviews on drugs-of-abuse testing like amphetamines and ring substituted derivatives, cannabinoids, cocaine, heroin, benzodiazepines, barbiturates, methaqualone, LSD, phencyclidine and psilocybin, which may also be of interest for drugs and driving cases [95-97]. Other basic reference articles or books including methods that can be used for DUI testing purposes were prepared or edited by Wennig [98], Wong and Sunshine [99], Brandenberger and Maes [100], Kintz [101], Moeller et al. [102] and Korte et al. [103]. In 1983, Crouch et al. [104] proposed a comprehensive drug screening and quantitation method requiting as little as 6 ml of blood. They used radioimmunoassay (RIA) for screening for cocaine and benzoylecgonine, barbiturates, phencyclidine, opiates and tetrahydrocannabinol. GC with selective detectors was used to screen for amphetamines, benzodiazepines, tricyclic antidepressants, antihistamines and other basic drugs. Anticonvulsants and non-barbiturate sedative-hypnotics were detected by HPLC and TLC. All presumptive positive results were confirmed and quantitated by other analytical techniques, particularly GC-MS with chemical ionization. Peat and Finkle [2] have summarized the recommendations of a working group on analytical procedures for studies in drugs and driving. For epidemiological surveys, they recommend the use of blood (10 ml,

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collected in tubes containing fluoride/oxalate as preservative), but they add that it may not be practical in all cases. For studies of fatally injured drivers they recommend that blood should be collected from the femoral vein at the autopsy. The delay between accident or death and sampling should be less than 4 h. In addition, urine (at least 20 ml) should be collected. Urine is useful for identifying drug-free cases. If a drug or metabolite is detected in urine, its presence should be confirmed in blood if available. This is because a number of drugs and/or metabolites are excreted for several days in urine but are not detectable in blood specimens. For screening, the working group recommended immunoassays for cannabinoids, cocaine, opiates and opioids, benzodiazepines, barbiturates and sympathomimetic amines. Thin layer chromatography was acceptable for screening in urine only. Gas chromatography with nitrogen-phosphorus detection (GC-NPD) could be used for all groups except cannabinoids, gas chromatography with electron capture detection (GC-ECD) for benzodiazepines in blood, and HPLC with UV detection for benzodiazepines and barbiturates. For confirmation, GC-MS was the preferred technique, with the exception of barbiturates, where HPLC was recommended, and benzodiazepines in blood, where GC-ECD was recommended. For some drugs and metabolites, for example the benzodiazepines in blood or urine, high-performance liquid chromatography (HPLC) with diode array UV detection was appropriate. For areas where sophisticated chromatographic techniques are unavailable, TLC can be used to confirm the presence of drugs and/or metabolites in urine. This can lead to erroneous results, particularly false negative reports, but the data produced may still serve as a baseline for future research [2]. Ferrara et al. [42] also made recommendations for the analytical toxicology of drugs, and driving studies (both experimentally controlled studies and epidemiological studies): samples should be 10 ml blood (and 10 ml plasma in experimental studies) and 20 ml urine. In fatal cases, 2 ml of vitreous humour should be included. All samples should be stored at 4~ in tubes containing a preservative. The analytical protocol should include screening (by immunoassay, TLC, GC/NPD or HPLC/UV) and confirmation and quantitation by GC-MS or HPLC. The laboratory should participate in a quality control program and validate the method as to specificity, detection limit (LOD) and for quantitation (LOQ): the linearity over the concentration range, precision at concentrations over the linear range, replication of analyses, use of deuterated internal standards and the assay batch should include matrix-matched controls (blank/positive). The Scandinavian countries have a lot of experience in enforcing impairment laws. Lillsunde et al. [105] described the methods that are in use for screening for drugs in the blood of car drivers suspected of driving under the influence of drugs in Finland. Amphetamines, cannabinoids, opioids, cocaine and benzodiazepines were screened by EMIT after acetone precipitation. GC-NPD and GC-ECD were used to screen for neutral and basic drugs after derivatization with HFBA. Acidic molecules were analysed by GC-NPD after methylation. GC-MS was used as a common confirmation method, except for the benzodiazepines, which were confirmed by GC-ECD. Alcohols were quantitated in triplicate by GC using three different kinds of columns. The use of GC-NPD and GC-ECD as screening methods was motivated by the authors because of their better sensitivity compared to full-scan GC-MS. A similar screening protocol is used in Norway [52]. The blood samples are analysed for alcohol and routinely screened for the most commonly abused drugs by EMIT: References pp. 453-457

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amphetamines, cannabinoids, opiates, high-dose benzodiazepines (e.g. diazepam, nitrazepam, oxazepam), barbiturates and cocaine. Confirmation and quantitation analysis of positive screening results are performed by GC-MS or GC. Further screening analyses for drugs not included in the standard screening are performed if the police suspect certain drugs or if possible impairment is concluded from the clinical examination and no drugs have been found by the standard analytical program. The most common drugs looked for in this extended screening are low-dose benzodiazepines (flunitrazepam, clonazepam, alprazolam) and muscle relaxants. Samples with BAC's above 0.15% are not regularly analysed for drugs as the driver is likely to be sentenced to unconditional imprisonment because of the alcohol result. In a reanalysis study in Germany in 1989-1990 [44] the specimens were screened by radioimmunoassay for amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine and opiates. Moreover, FPIA was performed for antiepileptics and antidepressants, but all samples were negative. All confirmations were performed by GC-MS with deuterated internal standards, except for benzodiazepines (GC-ECD). Many other surveys with more or less comprehensively described classical screening methods have been made so far: e.g. Christophersen et al. in Norway [106], Lillsunde and Korte [107] in Finland, Tomaszewski et al. [23] and Heishman et al. [108] in the United States.

12.7.2 Use of specific analytical techniques Like Peat and Finkle [2], the authors believe that TLC has in general an LOD which is not suitable for most applications for blood testing in drugs and driving cases, so they will not be considered here. There may be some cases where TLC could be used for screening urine specimens like for instance in the survey of Lillsunde et al. [107]. The use of different SPE procedures in the case of systematic toxicological analysis has been recently reviewed and critical steps outlined by Franke and de Zeeuw [109]. Segura et al. [110] have recently reviewed the different derivatization techniques for GC/MS including silylation, acylation, alkylation, formation of cyclic derivatives and chiral derivatization. A review of the determination of drugs of abuse in blood by non-chromatographic methods like immunoassays and by chromatographic methods like GC, LC and GC/MS was recently made by Moeller et al. [102] and by Polettini et al. [111] who studied the possibility of fully automated systematic toxicological analysis by GC/MS. Some methods have been validated specifically for drugs and driving cases by the Soci6te Fran~aise de Toxicologie Analytique (SFTA). They include methods for opiates and cocaine [112], tetrahydrocannabinol [113] and amphetamines [114]. They were used for a survey of blood of drivers involved in accidents [26]. Maurer made recently a review of the application of LC/MS techniques in forensic cases which could also be useful for DUI cases [ 115]. An LC-MS method for the detection of more than 16 drugs in body fluids using one isolation procedure, was published by Bogusz et al. [ 116]. Several papers on capillary electrophoresis (CE) have been recently published by Tagliaro et al. [117], Thormann and Caslavska [118] Hudson et al. [119] and Brunner and DiPiro [120].

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12.8 ANALYTICAL T O X I C O L O G Y OF M E T H O D S S P E C I F I C F O R ONE OR SEVERAL DRUGS Some authors published methods suitable only for the detection and quantification of a few drugs within one drug family or for a specific drug only, like Worm et al. [ 121 ] in 877 ethanol-negative specimens, or like Drummer [122] who reviewed some 72 chromatographic methods for benzodiazepines, or like Bogusz et al. [123] for flunitrazepam and its metabolites with an adequate LOD and LOQ by LC-APCI-MS. Other articles were published as original works or as reviews on cannabinoids by Moeller et al. [124] and Daldrup [125], on antihistamines like loratadine (0.1-30 ng/ml) by Johnson et al. [126], on amphetamines by Kauert et al. [127], or by Kraemer and Maurer [128] including achiral and chiral procedures, on opiates by Sticht and Kfiferstein [129], on cocaine and metabolites by Moeller et al. [130], or on LSD and phencyclidine by Schneider et al. [ 131 ]. Many articles are available on alcohol or ethanol and driving, which is still the major problem in DUI cases. Only a short summary could be presented within this chapter. Reviews on this issue were made by Tagliaro et al. [132] and Deveaux [133]. Charlebois et al. [134] made a comparison for forensic applications of EtOH concentrations in different tissues. Head-space GC methods have been outlined for blood and urine, respectively, by McCarver-May and Durisin [135] and Correa and Pedroso [136]. A new method for ethanol determination by LC with a biosensor detection was proposed by Liden et al. [137]. The use of t-BuOH and methyl ethyl ketone as internal standards was discussed by O'Neal et al. [138]. A great interest was aroused by a rather newly discovered minor metabolite of EtOH, the ethyl glucuronide by Schmitt et al. [139,140]. This issue might have some consequences for the interpretation of negative EtOH results in blood and/or in quality assurance items like the chain of custody. The problem of congeners of EtOH in alcoholic beverages in the DUI field is most popular in Germany. It has been extensively studied by Bonte [141], Felby and Nielsen [142] in Denmark studied the congener production in blood specimens during storage, and Schmitt et al. [143] investigated modelling and congener analysis in case of unusually high-dose alcohol consumption in a drinking trial. The variability of blood/breath alcohol ratio stimulated vivid discussion, as demonstrated for instance in the articles of Jones et al. [144,145]. Wilson and Barnett [146] have discussed the very important problem of quality assurance related to serum ethanol determination within 200 participating laboratories in the UK. There is a growing interest for chronic alcohol abuse markers like several enzymes as shown by Musshoff and Daldrup in a recent review [147]

12.9 ALTERNATIVE MATRICES Depending on the aim of the analysis and the existing legislation, different body fluids can be used: blood, serum, plasma, urine, sweat and/or saliva. In a large-scale roadside survey made in Germany saliva was used as a substrate for analysis by immunoassay in References pp. 453-457

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drivers [47]. A study in Belgium [148] evaluated the use of a roadside screening device (Drugwipe | for the analysis of saliva and sweat in people showing external signs of being under the influence of drugs. Results were confirmed by GC-MS. Sometimes very high concentrations of drugs were found in saliva, much higher than in the experimental studies, where lower doses are administered. Recent critical reviews on testing for drugs in hair were published since 1992 by Sachs and Kintz [149], Moeller [150] and Tagliaro et al. [151-153], including analytical strategies and application of capillary electrophoresis in hair analysis. The chronic use of lorazepam and hair analysis in relation with a traffic accident was discussed by Cirimele et al. [154]. Some experiences with hair testing and immunoassays were published by Cassani and Spiehler [155] and Cassani et al. [156]. Analysis of hair for drugs may be useful as a control before regranting driving licenses, and is applied intensively by Sachs and Kintz in Germany [149], and by Cassani et al. [156] and Tagliaro et al. [152] in Italy. Recent guidelines for testing drugs in hair, sweat and saliva were elaborated by an international working party of the United Nations, UNDCP [ 157]. Peel et al. already in 1984 mentioned the possibility of testing saliva of impaired drivers for drugs of abuse [158]. Testing for drugs in saliva and sweat was investigated by Kidwell et al. [159,160] and included specimen collection, comparison to levels found in urine, window of detection, determination of impairment and interpretation.

12.10 QUALITY ASSURANCE For the time being several external QA schemes for proficiency testing in analytical toxicology exist, but not many are really dedicated to the field of DUI cases. A first step in improving the quality assurance issue in Europe was made by starting with an European Consensus on analytical cut-off limits in at least the workplace testing (WPT) by an international working group in Barcelona. These recommendations were published several times [ 161 ]. A general review of the quality control in toxicological analysis was made by Ferrara et al. [162], including an overview on internal and external quality control systems, types of proficiency testing, feedback to the participants, etc. Existing schemes more or less dedicated to the DUI testing problems are working in France, e.g. the service offered by the French Society for Analytical Toxicology = Soci6t6 Fran~aise de Toxicologie Analytique (SFTA), who published recommended GC-MS methods for the determination of illicit drugs in blood [163] and is going forward to a formal accreditation system. In Germany the 'Gesellschaft fur toxikologische und forensische Chemie' (GTFCh) under the chairmanship of Aderjan [164] offers similar services also available for members from other countries outside Germany. Another scheme, organized by the Norwegian National Institute of Forensic Toxicology (NIFT), exists in the Scandinavian countries since more than 10 years. The samples (spiked whole blood) are sent two times/year and contain the following compounds: amitriptyline, amphetamine, tetrahydrocannabinol, morphine, codeine, diazepam, fluni-

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trazepam, nitrazepam, clonazepam, benzoylecgonine, methadone, propoxyphene, phenobarbital and levomepromazine. Fourteen laboratories participate, including all Nordic forensic institutes and several other European forensic institutes. A proposal for quality criteria for quantitative GC-MS measurements has been recently made by Herbold and Schmitt [165] in view of DUI cases. Evaluation systems for chromatographic methods except for ethyl alcohol [ 146] are not yet widely available. Some validation testing for more recently introduced immunoassays in comparison to other already established systems has been performed [ 166-169].

12.11 PHARMACOLOGY, PHARMACOKINETICS, INTERPRETATION One of the most difficult tasks in the DUI issues is of course the interpretation of the results obtained in the toxicological laboratory. There is a wide range of feelings among the experts. It goes from the Consensus Report [3] in 1985 where practically no correlation could be retained between concentrations in blood and driving impairment for most drugs, to the more optimistic approach by Daldrup [65,67] based on experience in limited but carefully designed epidemiological studies. As there is a great lack of information, the toxicologist can start her/his interpretation on some collections with blood concentrations already available in the literature, e.g. Uges [170], Wennig [98], Schulz and Schmoldt [171]. Druid and Holmgren [172] compared blood concentrations in Sweden by standardized analytical methodology in 15 800 postmortem femoral blood specimens coming from suspected drugged drivers. A very comprehensive and well documented book on the interpretation of results in case of drugs and driving was published by Iten [173]. This is a very important source of information. It must also be kept in mind that not only the toxicologists alone can take the final decision on driving impairment The complete expertise must be based on witness testimony, police officers' evidence, general practitioners' reports, psychiatrists examinations, etc. Walter and Soice [174] in Canada have suggested some impairment serum levels for triazolam (4.3-8.3 ng/ml). Christophersen and MCrland [52] published a table of blood drug concentrations for some commonly detected drugs in relation to impairment. The list includes amphetamine, THC, codeine and four benzodiazepines. The pharmacological effects related to the blood concentrations of tetrahydrocannabinol THC (7-29 ng/ml) and metabolites observed in users of cannabis in controlled studies were described by Cone and Huestis [175]. These results could be beneficial for the assessment of traffic violation cases. A study on the relation of blood concentrations vs clinical signs of intoxication was carried out on 1073 drivers by Tedeschi et al. [176] (Table 12.3). This study included clinical observations, sampling of biological specimens, and toxicological and forensic assessment. Some serum levels of XTC and related compounds in 30 drivers have been published by Moeller and Hartung [177] (Table 12.4). The morphine and codeine blood concentrations (0.03-0.21 mg/1) observed in opiate addicts while driving in traffic were reported by Schmidt [178] and Hodda [179]. A recent study on morphine metabolites References pp. 453-457

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TABLE 12.3 BLOOD CONCENTRATIONS OF DRUG OF ABUSE (FROM REF. [176]) Substance

N

Range (ng/ml)

THC-COOH Benzoylecgonine MDMA Total morphine

39 30 9 6

0.3-125 18-890 21-266 20-621

TABLE 12.4 SERUM LEVELS OF XTC AND RELATED COMPOUNDS (FROM REF. [177]) Substance

Median concentration (ng/ml)

Range (ng/ml)

MDMA MDEA MDA

76 87 13

1-514 1-777 1-67

clearance performed by Aderjan and Skopp [180] is of major interest to evaluate the disposition of opiates in individuals participating in road traffic under the influence of drugs.

12.12 CONCLUDING REMARKS The DUI issue is not at all easy and it still needs many years of efforts, surveys, studies and basic research to come to a complete toxicological assessment. The analytical techniques will vary according to the aims of the determinations. In enforcing impairment laws and in epidemiological surveys, they will involve narrow or broad screening. These screening protocols involve the use of different analytical methods, that nearly always include quantitation by GC-MS or LC-MS, although GC-ECD or LC-DAD are sometimes used for benzodiazepines. For per se laws, in controlled studies and in case reports, the analysis will focus on specific compounds. The sensitivity and specificity of GC-MS and LC-MS explains the important place these methods have reached in all applications. Only a few CE methods have been described for use in drugs and driving cases, and its place is not yet clear. If for the moment there is obviously not enough evidence for a well established relation between the blood concentration of a drug or several drugs and the behavioural situation of drivers, it is quite obvious that without a clear legal threshold level like in the case of ethyl alcohol, it will always be difficult to come to fair decisions. But absence of evidence is not evidence of absence. In waiting for an internationally accepted consensus, it can be recommended to use carefully the available concentration relations, taking into account also the interindi-

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v i d u a l differences, all r e c o r d e d i n f o r m a t i o n like v i d e o t a p e d b e h a v i o u r of the driver by p o l i c e officers, any e v i d e n c e by w i t n e s s testimony, the m e d i c a l e x a m i n a t i o n results, if any, and to b e a r in m i n d that at least in the case of m a n y drugs of abuse one n e v e r k n o w s at w h a t m o m e n t the driver is m o r e d a n g e r o u s : u n d e r the direct influence or in a w i t h d r a w a l state. M u c h r e s e a r c h is still n e c e s s a r y to e l u c i d a t e the e x a c t p h a r m a c o d y n a m i c m e c h a n i s m s i n v o l v e d o r / a n d to identify the real r e s p o n s i b l e analytes, like e.g. a p a r t i c u l a r e n a n t i o m e r or u n k n o w n m e t a b o l i t e that c o u l d allow a m o n i t o r i n g w h i c h c o r r e l a t e s b e s t with impairment.

12.13 REFERENCES 1 2

3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

20 21 22 23 24

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106 107 108 109 110 lll 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153

Drugs and driving 154 155 156 157 158 159 160 161 162 163 164

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