Forensic Toxicology

Forensic Toxicology

IN THE NAME OF GOD .Seyed Ali Nazeri , Toxicology M.S [email protected] 021-81452381 021-66752515 09121960690

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(Cross-reactivity ) - - ()TLC

- TLC Troubleshooting ( ) RECOMMENDED METHODS FOR THE IDENTIFICATION AND ANALYSIS OF AMPHETAMINE, METHAMPHETAMINE and ... United Nations Office on Drugs and Crime ,Vienna

NATIONS New York, 2006 UNITED Clarck `s Analysis of Drug and Poison Pharmaceutical Press , Third Edition , Published 2004 RAPID ON-SITE SCREENING OF DRUGS OF ABUSE :A summary of commercially available products and their applications guidance for the selection of suitable products United Nations Office on Drugs and Crime

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Specimen (matrix) There are a variety of biological specimens suitable for drug screening, including urine, sweat and saliva, blood and hair/nails. The choice of a specimen for analysis depends on : the purpose of the testing, and may be affected by : concerns about sample collection, transport, handling, and assurance of sample integrity between the collection site and

point of analysis. Most commonly, focus on the detection of illicit drugs in urine. Specimen (matrix) Urine: However,urine samples can be relatively easily substituted, or adulterated. Among the most popular manipulations is dilution of the sample, for example, by excessive drinking or use of diuretics, or simply by adding water. Furthermore, the patterns of drug excretion are dependent on the pH value of the urine and are thus

influenced by diet. Deliberate changes of the pH of the urine can be effected by the addition of pH-modifying agents (e.g.,vinegar,ascorbic acid, lemon juice). Specimen (matrix) Similarly, addition of oxidizing (sodium hypochlorite) and surface-active (e.g.,detergents,soap) agents, certain medicaments , and even sweeteners (saccharin) or table salt (sodium chloride), may also lead to false results.

Therefore, to ensure the integrity of the sample it may be necessary to observe directly the collection of urine, i.e., urine testing can be invasive of privacy. Specimen (matrix) There is no clear relationship between dose and urine concentration. If the purpose of drug testing is to relate concentrations to impairment or other toxicological / pharmacological responses, blood is generally the specimen of choice, as

blood drug concentrations are most closely related to concentrations at receptor sites. Comparison of biological specimens for drug testing Table 1: Comparison of biological specimens for drug testing with on-site screening devices Note that this comparison does not consider applications of the specimen in other than ON-SITE situations. It does, therefore, not consider sweat testing in the form of sweat patches, which )because worn for several days( are a cumulative

measure of drug excretion, thus allowing to monitor drug intake for a period of days to weeks Criteria for Urine Comparison History of use/ Long history of use; experiences Uniform testing criteria

with specimens established Sweat Saliva Relatively new Relatively new

approach; approach; performance testing performance testing under under development; more R&D

development; more R&D required required Easy; Sample acquisition (note: Easy practicalities of sampling

)but less practical, for depend on the facilities at example, at the the sampling sites) roasided( Easy, but sensitivity might be a problem

but existing collection devices may still need improving for practical use in on-site situations Privacy Invasive Non-invasive

Non-invasive Comparison of biological specimens for drug testing Table 1: Comparison of biological specimens for drug testing with on-site screening devices Note that this comparison does not consider applications of the specimen in other than ON-SITE situations. It does, therefore, not consider sweat testing in the form of sweat patches, which )because worn for several days( are a cumulative measure of drug excretion, thus allowing to monitor drug intake for a period of days to weeks

Criteria for Comparison Detection time Urine Relatively long Sweat Saliva

Relatively short Relatively short Adulteration possible Adulteration, Substitution and Contamination Easily adulterated / substituted

but Adulteration possible, difficult; external but contamination difficult possible

Indicates prior Result exposure in past few days Current-status / Current-status / real timeresults

real timeresults DRUG DETECTION TIMES IN URINE DRUG DETECTION TIMES IN URINE DRUG DETECTION TIMES IN URINE Table 2: The following table should be used as a guide only )individual differences in the metabolism and excretion of drugs and their metabolites may affect specific detection times(. DRUG type *

INFREQUENT FREQUENT CHRONIC USER USER USER Amphetamine

1-3 days 2-6 days Several weeks Methamphetamine 1-3 days 2-6 days

Several weeks Morphine 12-48 hours 2-6 days Codeine 1-3 days 2-5 days

Cannabis products 2-5 days 4-14 days Cocaine 12-48 hours 1-4 days

Methadone 1-4 days 2-10 days Up to several weeks Up to several weeks Up to 2-3 months Up to several weeks

Up to several weeks Amphetamine Racemic Desoxynorephedrin: After a larg dos in urine for several days. 30% 90% 74% 1-4% dose extracted unchange in urine after 24 h. dose extracted in urine after 3-4 days.

increased in urinary pH acidic (unchange). decreased in urinary pH alkalin. Hypuric acid,Benzoic acid,Hydroxyamphetamin, Benzoylglocoronid, 4- Hydroxyamphetamine,norephedrine,... Half life in plasma : 4-8 h. Metamphetamine Desoxyephedrine,Crank,Crystal,Ice,Meth,Speed, Norodine ,. % 70 dose extracted in urine in 24h. 43 % extracted in urine unchange.

15 % 4- Hydroxymetamphetamine . 5 % Amphetamine. (20-30%) Urinary pH alkalin reduced 2% dose. Half life in plasma : 9 h Amph, Meth, MDMA Morphine Opium: 10-12 % Morphine 0.5 % Codeine 90 % dose extracted in urine in 24h. 10 % Free.

65-70 % Conjogate ; M3G, M6G Normorphine,... increased in urinary pH acidic. (Free) decreased in urinary pH alkalin.(Conjogate) Methadone 2-ethylidene 1,5,dimethyl 3,3 diphenylpyrrolin (EDDP) 2- (ethyl-5-dimethyl-3,3 diphenyl -1-pyrrolin (EMDP) 60% after 24h urine 33% unchange , 43% EDDP , EMDP

Half life: 10-25h (15h) , 13-55h (30h) Tramadol O-monodesmethyltramadol 90% after 3 days Urine 30% Unchange Half life : 6 h (6-7) Buprenorphine

Buprenorphine Norbuprenorphine Half life : 1.2 7.2 h N-O-didesmethyltamadol Cross-reactivity Cross-reactivity

Drugs and drug metabolites with significant structural similarities to the target analyte may crossreact with target analyte-specific antibodies, producing false positive results. It is important to know that some immunoassays are class-specific only. They cannot be used therefore to identify, specifically, individual drugs within a class. Examples are tests for amphetamines, benzodiazepines, barbiturates, and opiates. Cross-reactivity Manufacturers test for cross-reactivity by spiking test

samples and documenting test results. This is the information that is found in package inserts. However, the cross-reactivity lists provided by most manufacturers have been found to be far from cmplete. Moreover, since these data are not obtained from actual ingestion of drug, the reported concentrations are not necessarily physiologic and may not give information about possible interference of drug metabolites. Cross-reactivity It is also highly possible that some crossreacting

compounds may not have been tested, and are therefore not listed. Lists of compounds, which have been tested and found not to cross-react, are therefore equally informative to obtain a more comprehensive picture of possible interferences. Cross-reactivity Aamphetamine-type Stimulants (ATS):

Because of the large number of closely related substances, including ecstasy-type analogues (such as MDMA,MDA,MDE,etc. Although amphetamine class tests(Amphetamine and Metamphetamine ) are usually designed to cross-react with ecstasy and other illicit ATS. Cross-reactivity

degrees of cross-reactivity may vary considerably from one substance to another. Because of direct cross-reactivity of some of their ingredients, or because their main urinary metabolites are the target drugs tested. For amphetamine tests, examples include certain nasal decongestants and anorectics e.g.,ephedrine,phenylpropanolamine, phentermine),and the anti-parkinsonian drug selegiline, which is metabolized to amphetamine. Benzphetamin...

Cross-reactivity

Amphetamin Test: Methylenedioxyamphetamine (MDMA) Phentermine Benzphetamin Ephedrine Pseudoephedrine Selegiline Deprenyl Methamphetamine L-Methamphethamine (Vicks inhaler) Methylphenidate Phenylpropanolamine

Phenylephrine Ranitidine Tyramine , . Metamphetamine Test: Methylenedioxymethamphetamine (MDMA) Amphetamine Ephedrine Phenyletylamine Chloroquine Cross-reactivity

Opiate-type tests: Most opiate assays are designed to detect morphine. Heroin use causes a positive opiate test result because its predominant urinary metabolite is morphine. A number of cough suppressants, such as codeine, some analgesics, and morphine agonists and antagonists cross-react to a high extent with opiatetype tests. Cross-reactivity

False positive results may also be produced from the ingestion of food containing poppy seeds. In contrast, the ability to detect the use of synthetic opioids, such as hydromorphone, hydrocodone, oxycodone and oxymorphone varies among immunoassays from different manufacturers. Cross-reactivity

Opiate,Opioids tests: Morphine Codeine Poppy seed Dextromethorphn

Diphenhidramine Hydrocodone Hydromorphon Nalorphine Procaine Tebaine Naloxane Regulatory Process Evolution of Workplace testing :Mandatory Guideline For Drug Testing

Health and Human Services (HHS) :Which became known as the National Institute For Drug Abuse (NIDA) : Today sa The Substance Abuse and Mental Health Services Administration (SAMHSA) and United Nation on Drug and Crim (UNODC) Cannabioids, 1999 Morphine 1994

Cut-off value / Concentration The cut-off value of an assay is the specific concentration of a drug , or drug metabolite, in the sample that is chosen as a limit to distinguish a presumptive positive from a negative test result. Samples with concentrations at or above the cut-off level are considered presumptive positive and

results below are considered negative. In this connection, it should be remembered that a clear correlation between the cut-off concentration and the level of impairment has not been established for any of the sample specimens. Cut-off value / concentration Moreover, any attempt to correlate test results with impairment has to carefully consider these pharmacokinetic / metabolic aspects for individual drugs and how they are reflected in concentration profiles in different sample specimens. Usually established based on epidemiological

information, i.e., they reflect, to a certain extent, the prevalence of, and the importance attached to the abuse of certain drugs or drug classes in different countries. Workplace drug screening cut-off in urine (ng/ml) Table 3: Workplace drug screening cut-offs in urine (ng/m( Drug type

Cut-off in urine (ng/mL) Amphetamines 500 Metamphetamine *** 500 Opiate 300

Methadone or metabolites 300 Cocaine metabolites 300 Cannabis metabolites 50

Methods Immunochromatography Chromatography Drug Screening Tests - A )(Immonochromatography

)(Immonoassay )(Immonofloresent )(RIA

)(EIA EMIT : , Principles of on-site immunoassay devices

Direct competition technology**** Displacement technology Trapping technology Principles of on-site immunoassay devices Immunochromatographic methods Most of these tests are based on competitive technology. In these assays, drug (or drug metabolite) that may be present in

the test sample competes with a drug conjugate for antibody binding sites. Purpose and intended use of on-site drug screening

Currently, on-site testing for drugs of abuse is being carried out, to varying extents, in the following applications: Workplace surveillance programmes (including preemployment, random /periodic, reasonable suspicion, postaccident, and return-to-duty/follow-up testing), including testing of military and personnel in other safety-sensitive jobs. Roadside drug testing programmes, Crime investigations and legal proceedings, Drug treatment and rehabilitation programmes, Parole/probation programmes (including so-called drug courts), Hospital emergency. Analytical performance characteristics of onsite screening devices The performance of on-site screening devices is usually

assessed in terms of sensitivity, which is the percentage of true positive, and specificity or percentage of true negative results. These analytical measures therefore indicate the ability of the on-site device to identify, at a given cut-off concentration, those samples that truly contain the target analyte (sensitivity) or are truly drug-free (specificity ) Analytical performance characteristics of onsite screening devices In analytical performance studies, sensitivity and specificity are expressed as percentage of results confirmed by another method such as gas

chromatography-mass spectrometry (GC/MS). The specimens identified as positive by the on-site screening device but later confirmed as negative are called false positive. And specimens identified as negative by the device but confirmed positive are called false negative. Analytical performance characteristics of on-site screening devices The overall performance of a test is often expressed by the term efficiency (sometimes called accuracy), which is defined as the percentage of all true (correct) results, whether positive or negative (equation 3).

High efficiency is desired when both false positives and false negatives can have equally serious consequences for the tested individual. Analytical performance characteristics of onsite screening devices Sensitivity = TP (TP + FN )x 100 Specificity = TN (TN + FP)x 100 Efficiency = (TP + TN) N x 100 The following analytical criteria are . recommended for a good screening test

Sensitivity 90% Specificity 90% Efficiency 95% Other considerations

Temperature / Humidity (Stability) Shelf life (length of storage) Range of drugs /classes Time requirements to perform a test Documentation / storage of results Costs & Time Validation protocol Sensitivity 90% Specificity 90% Efficiency 95% Accuracy (Control-Comparison method- Recovery- St.add.)

Precision Intera assay ) ( Inter assay )) Cross - reactivity Cut - off Stability (Accel, Real, in use) Precision Precision is a measure of the reproducibility of the whole analytical method (including sampling, sample preparation

and analysis) under normal operating circumstances. Precision is determined by using the method to assay a sample for a sufficient number of times to obtain statistically valid results .The precision is then expressed as the relative standard deviation. mean / %RSD = std dev x 100% Accuracy Accuracy is a measure of the closeness of test results obtained by a method to the true value.

Re-Co-Comp... (Chromatography Methods) Confirmatoryt Tests -B Paper Chromatography :

): Thin layer Chromatography (TLC Gas Chromatography (GC) ,GC/MS :

. MS/MS, LC/MS, HPLC Chromatography Methods : )Exteraction(

) )Mobile Phas )Stationary Phase( )Detecore( Liquid liquid extraction (LLE) Solid phase Extraction (SPE)

Introduction Thin layer chromatography (TLC) has become one of the most commonly used techniques for the separation and identification of illicitly manufactured drugs . TLC is a widely-used chromatography technique used to separate chemical compounds.

It is a technique used to separate and identify individual components in a mixture. It can be used to determine the pigments a plant contains, to detect drugs , pesticides or insecticides in food , in forensics to analyze or to identify compounds present in a given substance. .... Introduction

TLC is rapid, sensitive (sub-milligram quantities of analyte required), enormously flexible in both the stationary and the mobile phase, and thus amenable to a wide variety of substances, in base and salt form, ranging from the most polar to the most non-polar materials. It is also amenable to a variety of visualization techniques. TLC is one of the easiest of the many chromatographic techniques, and it is inexpensive. TLC Theory It involves : A stationary phase consisting of a thin layer of adsorbent material, usually silicagel, alumina, cellulose immobilised

onto a flat, inert carrier sheet. A mobile Phase (solvent )(eluent) travels up the matrix by capillarity, moving the components of the samples at various rates because of their different degrees of interaction with the matrix (stationary phase) and solubility in the developing solvent. TLC Theory Non-polar solvents will force non-polar compounds to the top of the plate, because the compounds dissolve well and do not interact with the polar stationary phase.

Thin Layer Chromatography Technique (Operation involved)

Choice of adsorbent (stationary phase,plate) Preparation of plate Preparation & application of sample (spotting) Choice of solvent (mobile phase) Development of chromatogram Drying of chromatogram Location of spot (visualization) Quantitative estimation. Choice of adsorbent

Two general properties decides the selection are Particle size and homogeniscity. Factor affecting selection: There should not be any reaction with substance to be separated. It should be insoluble with mobile phase and solvent used for elution. It should not catalyses or decompose off substance. It should be colour less. Classification of adsorbents used Classification according to bonding strength: Weak adsorbent; eg. Sucrose, starch, talc ,cellulose. Intermediate adsorbent eg. Silica gel, calcium

carbonate, calcium phosphate, magnesia Strong adsorbent: alumina ,charcoals Stationary Phase (adsorbents) A special finely, ground matrix (silicagel,alumina,or similar material) is coated on a glass plate,a metal or a plastic film as a thin layer (~0.25 mm). In addition a binder like gypsum is mixed into the stationary phase to make it stick better to the slide. In many cases, a fluorescent powder is mixed into the

stationary phase to simplify the visualization later on (e.g. bright green when you expose it to 254 nm UV light). Sample Application (spotting) Dissolve solid sample in MeOH. Use TLC capillary to transfer and spot dissolved sample. Plate preparation (spotting)

The plate is dried and activated by heating in an oven for thirty minutes at 80-110 C. (90)(120) Spotting must be done carefully, without damaging the plates surface. The starting point of the run, i.e., the spotting line, should be 1-2 cm from the bottom of the plate. The solvent level has to be below the starting line of the TLC, otherwise the spots will dissolve away. Plate preparation (spotting)

The spacing between applications of sample (spotting points) should be at least 1 cm, and spots should not be placed closer than 1.5 cm to the side edge of the plate. To avoid diffuse spots during development, the size of the sample spot should be as small as possible ( 2 mm). Spotting and developing

Remove plate from the development tank as soon as the solvent reaches the development line marked beforehand; until ~1 cm from the top. otherwise, diffuse spots will occur. Do not allow the solvent to run over the edge of the plate. Next, let the solvent evaporate completely . Choice of solvent

Selection of M.P. depends on: nature of substance to be separated ,Viscosity & Polarity of S.P. The solvent used may be a single or double phase system. N-hexane, cyclohexane, carbon tetra chloride, benzene, toluene, trichloro ethylene, chloroform, diethyl ether, ethyl acetate, n-butanol, acetone, ethanol, methanol and water. Choice of solvent Solvent systems (mobile phases) System A:

Methanol 100 : Concentrated ammonia 1.5 System B: Ethyl acetate 85: Methanol 10 : Concentrated ammonia 5 System C: Cyclohexane 75: Toluene 15: Diethylamine 10 Visualization/detection

Plates must be dried prior to visualization: The solvent can be allowed to evaporate at room temperature, or removed with a hot air blower. If hot air is used,care must be taken because of the volatility of the ATS free bases. It is important for proper colour development that all traces of ammonia be removed from the plate. Visualization of TLC Results There are various techniques to visualize the compounds.

Iodine , Sulforic ,., RF, UV, long wavelength (background green, spots dark), short wavelength (plate dark, compounds glow) Be sure not to use the UV lamp outside of the cabinet and wear the safety glasses at all times while viewing.

Using Silica plates impregnated with methanolic KOH (0.1 mol/l). Detection time ( 1-1.5 h) Dark Temperature Moisture Experienced & Expert person Interpretation After visualization, mark spots (e.g., by pencil), and calculate retardation factor (Rf) values: Rf = Migration distance: from origin to centre of analyte zone (spot)/

Development distance: from origin to solvent front It is very common to express retention factors as Rf x 100, Thin Layer Chromatography (TLC) Thin Layer Chromatography (TLC) Troubleshooting TLC About the first time you run a TLC, and see spots everywhere and blurred , streaked spots?

Run the TLC again after diluting your sample. Or, your sample might just contain many components, creating many spots which run together and appear as a streak. Troubleshooting TLC The sample runs as a downward crescent. The adsorbent was disturbed during the spotting, causing the crescent shape. Troubleshooting TLC

The plate solvent front runs crookedly. Either the adsorbent has flaked off the sides of the plate Or ; the sides of the plate are touching the sides of the container as the plate develops. (Or ; the paper used to saturate the container 30-45 min) Crookedly run plates make it harder to measure Rf values accurately. Interpretation of Results Interpretation of Opiate Positive Results

.Confirmation of Codein and Morphine by GC/MS Use of 300ng/ml criterion resulted in a large number of positive results that drived from ether poppy- seed .ingestion or therapeutic doses for codeine Where there was a prescription for codeine or .morphine However,in the absence of a prescription for codeine or morphine , clinical signs of opiate use befor reporting . verified opiatepositive result back to the employer Interpretation of Amphetamine & Metamphetamine Positive Results

A laboratory report Metamphetamine as positive only if : its concentration is 500 ng\ml or greater, and if that of amphetamine is 200 ng\ml or greater by GC\MS. This reporting criterion was introduced hn 1991 after several specimens were reported as positive for methamphetamine when the specimen contained larg amounts of Pseudoephedrine or Ephedrine . It was discovered (Hornbeck et al. 1993) that hydroxylated sympathomimetics (Pseudoephedrine or Ephedrine) could convert to metamphetamine in either the extraction or chromatographic stage of analysis. None of these specimens contained amphetamine when tested. and

therfor; falsepositive. It was discovered (Hornbeck et al. 1993) that hydroxylated sympathomimetics (Pseudoephedrine or Ephedrine) could convert to metamphetamine in either the extraction or chromatographic stage of analysis. None of these specimens contained amphetamine when tested. and therfor; false positive. Pre oxidation step with preiodate to prevent the possibility of this happening. Interpretation of Amphetamine Positive Results

If both amines are present in concentration greater than 500 ng\ml by GC\MS, both are reported as positive and threre is no confusion. Dificalty araises when the amphetamine between 200 and 500ng\ml , (Less than the amphethamine confirmation cut-off). Interpretation of Amphetamine Positive Results

Some drugs can metabolise to metamphetamine and amphetamine ( benzphetamine and selegeline). Interpretation of Amphetamine Positive Results The Confusion in differentiation of , D - and L-Metamphetamine: Vicks Inhaler (decongestant product); Its use can result (false positive) in the detection of amphetamine and metamphetamine in urine. (low concentration and crossreactivity to the L- isomer of metamphetamine and

amphetamine; a unlikely positive (False Positive) , following normal use. In such case can request a GC/MS separation and isomers. These are usualy analysis and reported as X% disomer and %Y L-isomer. Where the L-Isomer is greater than 80% , the result as negative. L-methamphetamine isnt really anything like the D-methamphetamine isomer that is found in street drugs. D-methamphetamine is psychoactive, while L-methamphetamine isnt very psychoactive at all Thin Layer Chromatography

Thin Layer Chromatography Thin Layer Layer Chromatography Chromatography Thin Thin Layer Chromatography Thin Layer Layer Chromatography Chromatography Thin

Thin Layer Layer Chromatography Chromatography Thin TLC, Multi Drug Thin Layer Chromatography Thin Layer Layer Chromatography

Chromatography Thin TLC, Amphetamine TLC, Amphetamine Thin Layer Layer Chromatography Chromatography Thin Thin Layer Chromatography

Thin Layer Chromatography Thin Layer Chromatography Paper chromatography Paper chromatography HPTLC analysis HPTLC analysis is particularly appreciated in the : following fields

chemical / medical: detection of illicit substances,quality controls and pharmaceutical and cosmetic purity Human and animal nutrition: additives; monitoringcomposition and stability; quality control Environment: pesticides, water and soil pollution,plant extracts, etc HPTLC analysis Thanks for your attention

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()Chlorine : ... ( )Nitrite Whizziez , Klear (Chromat ,)Pyridinium chromat ()Peroxid , Peroxidas Clean choce ()Glutaric aldehyde Instant clean Golden seal,Guick caps ,Test clean... Urine Lock . Mixed reagent : Lock Lab .

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