Fundamentals of Analytical Toxicology. Robin Whelpton

sample collection, the parent compound may not be detectable. Sometimes, however, metabolite identification can be used to demonstrate systemic exposure to a particular drug. 2-Ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) is monitored to demonstrate systemic exposure to methadone, for example. Other samples, such as oral fluid, exhaled air, sweat, and meconium can also provide useful samples for specific purposes (Pleil, 2016; Chapter 18).

      Analysis of hair, long advocated as a way to assess exposure to toxic metals, can also provide a history of exposure to illicit drugs and other organic poisons, but care is needed in the interpretation of results. Analytes including metabolites can arise in or on hair in many ways, and indeed attempts to remove external contamination may move analytes from the hair surface into the medulla, giving the impression that the analyte was present in the body when the hair was formed in the hair follicle (Cuypers & Flanagan, 2018).

Testing for substance misuse may also be valuable in the psychiatric assessment of patients presenting with no overt history of drug misuse. In addition, the diagnosis of maternal drug use, either during pregnancy or post-partum, can be important in the management of the neonate. The need for substance misuse screening of personnel in sensitive positions (armed forces, security services, pilots, drivers) or those applying for such positions (‘employment’ and ‘pre-employment’ screening, respectively), has become accepted in recent years. The detection of illicit or performance-enhancing drug use in sport has also assumed importance. In animal sports the definition of an illicit compound is much easier than in man and can include any substance not normally derived from feedstuffs.

      The illicit drugs encountered most commonly in the UK are opioids, mainly heroin (Box 1.1), cocaine, amfetamines including amfetamine, metamfetamine and methylenedioxymetamfetamine (MDMA, ‘ecstasy’), and cannabis. In the US, misuse of cocaine either as the hydrochloride, or as the free base (‘crack’) is relatively common, and a range of additional compounds may also be encountered, including dextropropoxyphene (propoxyphene), fentanyl and its analogues, and phencyclidine (PCP, ‘angel dust’).

      Worldwide, whilst traditional drugs such as alcohol, cocaine, heroin, and metamfetamine, continue to dominate, the last few years have seen the emergence of so-called ‘legal highs’ (new or novel pharmaceutical substances, NPS), which can be divided broadly into novel stimulants, synthetic cannabinoids, and analogues of fentanyl and other synthetic opioids such as carfentanil. Increasingly these compounds are mentioned on death certificates in England and Wales. The synthetic opioids and cannabinoids are particularly potent and thus dangerous (Handley et al., 2018).

      The purity of ‘street’ drugs varies widely – heroin may be between 2 and 95 % pure, for example. Overdosage, either with excessively pure ‘street’ drug, or with drug ‘cut’ with a particularly toxic compound such as strychnine, is a further cause of acute poisoning ‘epidemics’. Compounds such as atropine, barbiturates, chloroquine, ephedrine, levamisole, lidocaine, methaqualone, phenacetin, phentermine, quinine, and strychnine may be used to ‘cut’ street drugs. Serious acute poisoning may occur if tolerance to heroin or methadone has been reduced through abstinence. Methadone is widely used in the management opioid addiction, although buprenorphine is also employed in this role. Misuse of other opioids such as codeine, dihydrocodeine, oxycodone, and pethidine (meperidine) may also be encountered.

      The availability of a variety of immunoassay kits has proved invaluable, especially in employment and pre-employment screening when large numbers of negative results are to be expected and high sensitivity is required. However, confirmation of positive results with MS linked either to capillary GC or LC is essential. In clinical samples TLC can be used to resolve drugs such as morphine from compounds such as codeine and pholcodine that are available in over-the-counter preparations. TLC requires a minimum of apparatus and is generally cost effective. It is also amenable to batch sample processing, but is labour intensive, analyte capacity is low, and interpretation of results can be anything but straightforward. Capillary GC, GC-MS, or LC-MS is used to detect and identify amfetamines, and increasingly to confirm immunoassay results.

      Ingestion of diuretics and/or laxatives either to produce weight loss, or to provoke covert alterations in body biochemistry (Munchausen syndrome, factitious illness) is uncommon and can be difficult to diagnose. Collection of serial urine samples over several days is advisable (Section 22.4.12). Detection of the misuse of osmotic laxatives such as lactulose and bulk-formers such as bran is not possible analytically. The covert ingestion or administration of anticoagulants and antidiabetic drugs is also well documented, but can be difficult to diagnose.

       1.4.4 Therapeutic drug monitoring

The measurement of plasma concentrations of drugs given in therapy is useful in assessing adherence and for compounds for which pharmacological effects cannot be assessed easily and for which the margin between adequate dosage and overdosage is small, as discussed in Chapter 20. The availability of a variety of immunoassay and other kits means that many TDM assays can be performed more conveniently by such means than by chromatographic methods. However, chromatographic assays are still important in the case of antiepileptic, antimicrobial, antipsychotic, and immunosuppressant drugs, for amiodarone, where it has proved impossible to produce an antibody that does not cross-react significantly with thyroxine and tri-iodothyronine, and in general where active metabolites need to be measured as well as the parent compound. Examples include carbamazepine/carbamazepine-10,11-epoxide, clozapine/norclozapine, procainamide/N-acetylprocainamide, and amitriptyline/nortriptyline.

       1.4.5 Occupational and environmental toxicology

      The monitoring of occupational or environmental exposure to toxic substances is an important area. Metal ions such as lead and also some organochlorine pesticides such as chlordane and dieldrin have long half-lives in the body and thus accumulation can occur with prolonged exposure to relatively low concentrations. The manufacture of drugs can also present a hazard to those involved via either dermal, or inhalational absorption. The misuse of alcohol and of controlled drugs is of concern in occupational medicine, especially as regards screening for substance misuse amongst potential employees and amongst, for example, operators of heavy machinery and pilots, as discussed above.

      Control of occupational exposure to toxic metals, volatile solvents, and of some other substances is an integral part of industrial hygiene and has been achieved, in part, by monitoring ambient air concentrations of the compound(s) under investigation. However, an individual's work pattern and attention to safety procedures may greatly influence exposure and ‘biological effect’ monitoring, where clinical chemical parameters such as blood zinc protoporphyrin are measured as an indicator of lead exposure, is required practice in certain occupations.

      Not all poisons are amenable to effect monitoring and so ‘biological’ monitoring is performed widely. This involves measuring blood, urinary, or breath concentrations of a compound, and possibly of its metabolites. The ACGIH (2018) recommends Threshold Limit Values (TLVs) for more than 700 chemical substances and physical agents. There are also more than 50 Biological Exposure Indices (BEIs) that cover more than 80 chemical substances. The DFG (2018) ‘MAK List’ (maximum allowable concentration in workplace air) classifies more than 1000 compounds according to their toxicological profile and gives threshold values for their use.

      The investigation of the accidental release of chemicals into the workplace or into the environment (so-called chemical incidents) is an important area. Examples include the Bhopal disaster in India when methyl isocyanate was released into the atmosphere and the Camelford incident in the UK, in which aluminium sulfate was accidentally added to the local drinking water supply. Toxicological analyses can be valuable not only in providing evidence of the nature and magnitude of an exposure, but also in demonstrating that no significant exposure has occurred, thereby allaying public apprehension. Clearly, the early collection of appropriate biological samples is essential.

      In the absence of information