forensic toxicology - drugs and chemicals_ overview, definitions, scene findings

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3/24/2016 Forensic Toxicology - Drugs and Chemicals: Overview, Definitions, Scene Findings

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Forensic Toxicology - Drugs and Chemicals

Author: Gregory G Davis, MD, MSP H Chief Editor: J S cott Denton, MD more...

Updated: May 01, 2014

Overview

In 2006, deaths caused by poisoning accounted for 20.8% of all deaths caused byinjury in the United States, surpassing the percentage of deaths caused by firearms

(17.3%) and second only to deaths caused by motor vehicle collisions (24.4%).[1]

Given that an element of intoxication is involved in many motor vehicle collisions,

he vital role toxicologic analysis plays in modern death investigation becomes clear.

Deaths related to drug overdoses in celebrities have brought mass media attention

o the drug abuse pandemic. Whereas historically drugs such as heroin and cocainehave been considered the "dangerous" drugs, in recent years, prescription drugabuse has far surpassed "illegal" drugs as agents of lethal drug toxicity. This trend

is expected to continue.

Entire textbooks have been written on forensic toxicology and individual drugs and

chemicals that can cause death. This article highlights aspects not necessarily foundin general textbooks. Discussions of common classes of drugs and other poisonous

substances can be found at Medscape Reference, as listed in the Further Readingsection.

The image below depicts the scene of a death caused by drug overdose.

Kitchen counter with paraphernalia used in intravenous drug abuse. Spoons, syringes, andlighter are present on the counter. The decedent was dead at the kitchen table.

History

Toxicologic analysis is applied analytical chemistry modern toxicologic analysis

depends upon screening and confirmatory tests. Screening tests are typicallyperformed with commercial kits that contain antibodies directed toward commondrugs of abuse. If this screening test is negative, then the decedent is usually

considered negative for an intoxicating substance. If the screening test is positive,hen that positive result must be confirmed, typically with gas chromatography/mass

spectrometry (GC/MS).

GC/MS analysis allows separation of compounds based on their retention time

within a chromatography column and identification of each compound by thecharacteristic fragments into which a given chemical is broken following ionization of

he compound. (A concise account of the technique of GC/MS is available here.)

Over the years, technologic advances in electronics and detectors have allowedGC/MS to detect ever smaller concentrations of compounds, as has the addition of

other analytical techniques, such as liquid chromatography.

In general, screening tests can be performed quickly, but they provide only aqualitative result (eg, a substance is or is not present). Confirmatory testing usually

akes longer, but it provides an actual concentration of the substance in the bodyfluid analyzed.

Epidemiology

As mentioned i n the Introduction section, poisonings account for some 20% of all

deaths caused by injury in the United States these include both intoxication fromabuse of illicit drugs and deaths resulting from a consequence of medication taken

as medical therapy.[1] The 20-21% figure only accounts for deaths caused byintoxication and does not include cases in which an intoxicant was found that did

not cause death. Several medical examiners' offices that routinely test for alcoholand drugs of abuse report finding some substance on toxicologic analysis in at least

50% of their cases.[2]

Overview of the Entity

The Introduction and Epidemiology sections have both mentioned that drugs arefound in 50% of forensic autopsies (when tested) and that drugs or medications are

responsible for causing or contributing to death in over 20% of deaths unrelated tonatural causes in the United States. The prevalence of drug use is reiterated here to
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emphasize the vital role that toxicologic analysis plays in autopsy pathology.

Blood, urine, bile, ocular fluid, gastric contents, liver, and brain tissue can all beuseful specimens. Peripheral blood (femoral or subclavian) specimens are optimalfor postmortem toxicologic quantification urine is the primary body fluid used for

drug screening. Specimens need not necessarily be tested automatically, but thebest practice is to at least collect and hold the specimens until completion of the

autopsy report and death certificate. Sometimes, additional history does notbecome known until after the body is released, which is then too late to collect

samples.

Indications for the Procedure

Based on the prevalence of substances within the population of decedents

examined by forensic pathologists, simply dying in circumstances that would bringone's body to the medical examiner's office for investigation is sufficient indication

o warrant toxicologic analysis.[2] Nevertheless, factors such as cost or a prolonged

lag in receiving toxicologic results can make it impractical to perform a thoroughanalysis on every case. History then becomes the best guide to determining when

and what tests to order.

Cases in which a history or evidence of alcohol or drug abuse exists certainly meritoxicologic analysis, as do cases for which no visible cause of death can be found at

autopsy. Ordering toxicologic analysis in all homicides and accidents is also wise, asquestions concerning the presence or absence of intoxicating substances are likely,

not only from relatives of the decedent but in any legal proceeding that may laterarise. Such questions may arise in suicides as well, and 3 separate studies withinhe United States have reported that 68-73% of suicides have some substance

detected in the body on toxicologic analysis.[3]

The only manner of death not yet discussed is cases in which death appears to bedue to some natural cause. Certainly some of these cases do not seem to need

oxicologic analysis, but even here a pathologist cannot always anticipate questionshat may later arise, particularly when an unexpected civil suit is brought to the

pathologist's attention. One approach is to perform simple screening assays on

apparently natural deaths to quickly rule out the presence of substances that mayhave contributed to death (eg, cocaine may trigger a myocardial infarct orcerebrovascular accident). Pathologists rarely regret ordering toxicologic analysis ona case regret usually comes from cases in which no toxicologic testing was

performed, the specimens have been discarded, and only then do questions come

from family and their attorneys.

History and scene investigation, powerful as they are, are not infallible guides in

ordering toxicologic analysis in a medical examiner population (see Scene Findings,below). (Scene investigation is discussed in detail in a separate article.) Gruszecki

et al reported that history and scene findings detected only 63% of all cases inwhich intoxicating substances were found hence, the authors' suggestion that dyingin circumstances that bring a body to the medical examiner for investigation is

sufficient in and of itself to warrant toxicologic analysis.[2]

Definitions

Benzodiazepines

These agents are a family (or class) of drugs used as antianxiety agents. Often

abused in conjunction with opiates, benzodiazepines can potentiate the effects ofopiates. Diazepam (Valium) and alprazolam (Xanax) are members of this family.

Cooker spoon

Cooker spoons are spoons used for melting a substance for injecting. The bottom of

he bowl is heated, usually with a lighter, until the substance in the bowl melts as aresult, the bottom of the bowl is usually coated with soot.

Crack pipe

This is a device used for smoking crack cocaine. Crack pipes are generally a short

length of a hollow cylinder, such as a glass or metal tube. The ends are charred,and one end often contains a tuft of copper mesh (See the image below). The endsmay be wrapped in electrical tape to insulate the fingers and lips from the hot pipe.

Photograph of a crack pipe found in the pocket of clothing. Notice that the ends are broken andcould cut an individual carelessly examining the pockets.

Date rape drugs

These drugs include any of several sedative hypnotics, such as gammahydroxybutyrate (GHB) or flunitrazepam Rohypnol), that can induce hypotonia and

amnesia when ingested. GHB is endogenous in mammals at nanomolarconcentrations.

Depressant
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Any substance t hat depresses or suppresses t he normal function of the central

nervous system is a depressant (eg, alcohol, opiates, and benzodiazepines).

Designer drugs

Drugs that have been altered chemically so that the substance falls outside of a listof substances that are legally proscribed are known as designer drugs. The chemical

side groups of amphetamines, for example, can be altered slightly while retaininghe stimulant properties characteristic of amphetamines. Similar chemical changes

can be made to cannabinoids.

Drug screen

This is an initial test on a body fluid that is performed to look for the presence of

classes of commonly abused drugs. Screens often rely upon antibodies directedagainst specific drug classes and some specific drugs. A drug screen is qualitative

only and is subject to false positives.

Excited delirium

Excited delirium refers to an agitated state that may or may not be associated withhe use of stimulant drugs. This condition is typically manifested as rash, abnormal

behavior, often associated with delusion or paranoia and extraordinary strength.Hyperthermia is common.

Huffing

This is the practice of inhaling volatile compounds to experience a "high."

Needle track

A needle track is a line of needle marks or scars lef t on t he skin along the course ofa vein. Such tracks are often on the arms but can also be found in sites generally

hidden from public view, as seen in the images below.

A needle track mark in the arm of an individual who died as a result of intravenous drug abuse.

Needle marks in the left side of the groin of a man who died of intravenous drug abuse. Thearrow points toward a scarred track that formed because of repeated injection in the same site.The decedent's arms were free of needle marks he worked as a salesman.

Opioids

Opioids are also known as narcotics, the family or class of drugs that are narcoticanalgesics, exemplified by the prototype morphine. Natural and synthetic analoguesof morphine exist, and all have the potential for abuse. Heroin, oxycodone,
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methadone, and fentanyl are members of this family.

Sedative

Any drug used t o i nduce relaxation or anesthesia is a sedative these agents

depress the central nervous system. Benzodiazepines, opiates, and alcohol all havesedative properties.

Stimulant

Any substance t hat stimulates or increase the normal f unction of the central nervous

system is a stimulant (eg, cocaine and amphetamines). Caffeine is a mild stimulant.

(See also the Pill Identifier tool.)

Scene Findings

The presence of drugs or drug paraphernalia at a scene alerts the death

investigation team to the possibility of an overdose. Drug evidence may bemarijuana, pills, crack cocaine (as in the image below), or powdery material, or thecontainers these drugs were packaged in, such as plastic baggies, medication

containers, or bottles for liquids.

Crack cocaine found wrapped in a paper towel in the intergluteal cleft.

Paraphernalia includes articles used for selling (eg, pocket scale), injecting (eg,syringes, lighters, cooker spoon with soot on bottom of bowl see the first imagebelow), smoking (eg, roach clips, bong, lighter, crack pipe (as shown in the second

image below), or snorting (eg, razor blade, card, mirror) drugs. Of course, family orfriends may hide or dispose of this evidence before the arrival of the death

investigator. Likewise, the decedent may have hidden his stash -- for example, byplacing a rock of crack cocaine inside a partially empty pack of cigarettes.

Kitchen counter with paraphernalia used in intravenous drug abuse. Spoons, syringes, andlighter are present on the counter. The decedent was dead at the kitchen table.

Photograph of a crack pipe found in the pocket of clothing. Notice that the ends are broken andcould cut an individual carelessly examining the pockets.

Additional history may come f rom examination of writings of the decedent in a diary

or calendar, from examination of websites visited on the decedent's computer, orfrom examination of e-mail messages, text messages, or information within a social
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networking site. When computer evidence is found, it should be recorded in some

way such that if the site is later changed, the information will not be lost to theforensic pathologist.

Given the widespread nature of prescription drug abuse, all medications found on

scene should be carefully documented. [4] Pills should be counted to establish

appropriate usage patterns. Over-the-counter (OTC) medications present at thescene should also be recorded -- some of these medications, such asacetaminophen, can have potentially lethal consequences if taken inappropriately.

Trace Evidence

Trace evidence may be found at the scene or when examining the body in themorgue. Paraphernalia described in the Scene Findings section can be found withinpockets of a decedent's clothing or in belongings. Paraphernalia or drugs are often

hidden, and whoever looks through pockets must be careful to avoid a stab from aneedle on a syringe or a cut from a broken crack pipe. Long forceps or surgical

clamps are useful tools for looking through pockets rather than using a hand toreach into the pocket. Evidence can be hidden in any significant crease in the skin

including under a breast, in the intergluteal cleft (such as in the image below), orsimply within a fold of fat. Evidence may also be found in any body cavity (eg,within the vagina or rectum).

Crack cocaine found wrapped in a paper towel in the intergluteal cleft.

A crack pipe or a syringe l ikely contains residue f rom the drugs used. I f deemednecessary, washings of paraphernalia can be tested for drugs via gaschromatography/mass spectrometry (GC/MS), but it is important to remember that

he amount of drug in such washings may be much greater than the amount of drugextracted from a blood sample. This results in a potential technical hazard for thelaboratory. If enough drug is present, it can overwhelm the binding sites on a

chromatography column, and subsequent slow elution of drug from the column canhen contaminate subsequent samples. The column must be washed until clean

after confirming the presence of any drugs.

Gross Examination and Findings

Gross examination may reveal evidence of drug abuse on either external or internalexamination. Drugs or drug paraphernalia may be found during examination of the

clothing or tucked between clothing and the body, such as in underwear or withinhe cup of a bra. Examination of the body itself may reveal needle marks or scarred

needle tracks, as in the first image below. These marks are often on the arms but

may be found elsewhere. In rare cases, the needle mark is in a specific location,generally hidden from public view, where the decedent habitually injected drugs, as

in the second image below.
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A needle track mark in the arm of an individual who died as a result of intravenous drug abuse.

Needle marks in the left side of the groin of a man who died of intravenous drug abuse. Thearrow points toward a scarred track that formed because of repeated injection in the same site.The decedent's arms were free of needle marks he worked as a salesman.

Internal examination may reveal pills or chalky white material within the stomach,particularly in a suicidal overdose. Usually, however, the pills have dissolvedcompletely and are no longer evident, even when toxicologic analysis reveals a

lethal concentration of some drug taken by mouth. In other words, the absence ofpills in the stomach does not rule out a suicidal drug overdose.

Various organ systems can be affected by drug abuse at the gross level. Forexample, massive hepatic necrosis is commonly seen following acetaminophenoxicity (see the images below), endocarditis may involve cardiac valves if

intravenous drug abusers are not using sterile technique, and cerebrovascularaccidents and myocardial infarcts may be seen in the setting of stimulant use. Other

changes may be seen at the microscopic level in the brain, lungs, heart, kidney,liver, and skin.

Hepatic necrosis that developed following ingestion of an overdose of acetaminophen. Necrosiscan be global or focal. Notice the lack of inflammation, which may be true early in the process ofnecrosis. M agnification 100.


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Hepatic necrosis that developed following ingestion of an overdose of acetaminophen. Necrosiscan be global or focal. Notice the lack of inflammation, which may be true early in the process ofnecrosis. This higher-power view shows microsteatosis of hepatocytes at the edge of necrosis.Magnification 400.

Forensic pathologists are familiar with the practice of smuggling drugs within the

bodies of people entering the United States, a process reported as early as 1975. [5]

Those who smuggle drugs in this way are called body packers or mules, and these

people are at risk for sudden death from a massive overdose if one or more packets

should the drugs leak.[6]

A variant of this sort of death can occur when an individual swallows drugs, packageand all, to try to avoid discovery of the drugs when confronted by the police. Death

can occur from massive intoxication, but it can also occur if the decedent aspirates

he evidence rather than swallowing it (see the image below). The findings in such acase can be subtle if the drug was wrapped in a small portion of plastic wrap, onlya diligent search of gastric contents will reveal the colorless piece of plastic.

A bag of marij uana was aspirated by an individual who tried to swallow his drug evidence whenpulled over by the police. The decedent suddenly became unresponsive while in police custody.

Vomiting and aspirating gastric contents into the airways or lungs is not uncommonfor persons dying of drug toxicity. Remember that although terminal aspiration may

have occurred, the underlying cause of death is drug toxicity and, in most cases,his will be an accidental manner of death. Similarly, pulmonary edema and anoxic

encephalopathy are commonly seen following drug intoxication. These findings are

not the underlying cause of death and do not result in a natural manner of death.

Special Dissections

If the pathologist wishes to document a needle track mark microscopically as well asgrossly, then an incision is made immediately to one side of the vein with the track

mark. Extravasated blood from the venipuncture may be visible in the soft tissueadjacent to the vein. A portion of the vein may then be dissected out of the body,

fixed, and submitted for histologic examination. The best view comes from a sectionaken perpendicular to the long axis of the vein. Microscopic examination typically

shows scarring around the vein, foreign body giant cells, and, upon polarization,

birefringent material such as crystals or fibers (see the image below).
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Cross-polarization of the wall of a vein from the antecubital fossa in an individual with a historyof intravenous drug abuse. Notice the birefringent crystalline material within foreign body giantcells. Original magnifications 100 and 400.

Special Autopsy Procedures

From a medical point of view, collecting and retaining specimens for potential

oxicologic analysis is always appropriate in every autopsy that is undertaken todetermine the cause of a person's death. Thorough specimen collection is possiblein examinations mandated by law, but hospital autopsies are authorized by the

permission of the decedent's next-of-kin. Therefore, the discussion below must beempered, in hospital practice, by abiding by the restrictions stated in the autopsy

permit.

Blood obtained from a peripheral vessel is the preferred blood specimen foroxicologic analysis, as the concentration of compounds in blood from the heart may

be altered after death by redistribution of blood from the lungs or liver. [7] Some

authors claim that blood from a femoral or iliac vein is least susceptible to

contamination from the liver when the vein is first occluded by a tie or clamp, [7] but

others report that ligation of the vein has no significant effect on the blood sample.[8] Even authors who advocate ligation of the peripheral vein before obtaining blood

acknowledge that such procedures are sometimes impractical. [7] The worst mistake,

of course, is to have no sample at all. At least some of the collected blood shouldbe stored in a gray-top tube containing sodium fluoride.

hen available, urine should be obtained from every autopsy, because it is ideallysuited for rapid screening assays. Vitreous fluid can be screened for drugs andethanol as can cerebrospinal fluid and bile. Depending on the case, vitreous fluid

may be stored in a red-top tube (if analysis for electrolytes is being considered) or agray-top tube (if drug screening may be performed) (forensic vitreous analysis is

discussed in detail in a separate article.) Many medical examiner offices also

routinely retain liver, brain, bile, and gastric contents for toxicologic analysis ifneeded. Splenic tissue and skeletal muscle may be used in decomposed bodies.Subdural hematomas should be sampled if present they may contain drugs oralcohols that have since been metabolized in the peripheral blood.

If an individual was evaluated at a hospital before death, then they likely had blooddrawn for tests. This perimortem blood is a precious, irreplaceable resource for

oxicologic analysis and should be routinely obtained as part of the death

investigation.[4] Blood obtained at the hospital would not be subject to postmortem

redistribution the way that blood obtained at autopsy is. Hospital pathologylaboratories hold blood only for several days, so requesting that the laboratory hold

he sample as soon as investigation of the death begins is important. A sample ofblood may be retained in the blood bank longer than elsewhere in the laboratory.

The brain can be an especially useful matrix for toxicologic analysis this organ is

little affected by postmortem redistribution of drugs. [7] Furthermore, the brain, which

is fatty and sequestered both by its anatomic location and by the blood-brain barrier,

can harbor a drug longer than other matrices. [9] Thus, the brain may be the only

matrix positive for cocaine in a case in which a pathologist suspects a drug ofabuse, such as cocaine in a young person who has died from a hypertensive bleed

in the basal ganglia. Hair analysis can be used in the same sort of way.[10] The

brain can also be used for molecular analysis in cases of excited delirium. [11]

Special Handling

Some substances, such as ethanol, are stable after death and require no specialhandling. Cocaine, on the other hand, is notoriously unstable, undergoing both

enzyme-mediated and spontaneous hydrolysis even after death. The enzyme-

mediated hydrolysis of cocaine is inhibited by fluoride and by cold. [12] Given the

frequent presence of cocaine in forensic practice, forensic pathologists use fluorideas an anticoagulant and refrigerate toxicologic samples. (Sodium fluoride is in gray-

op tubes it also inhibits in vitro glycolysis in blood samples.) Refrigeration retardsother unwanted chemical reactions as well. Although ethanol is stable after death,

one does not want samples to putrefy, allowing bacteria to produce additionalethanol.

Some individuals enjoy the intoxication brought on by inhaling volatile fumes, suchas gasoline, toluene, or halogenated hydrocarbons, a process commonly calledhuffing. When confronted with such a case, the pathologist must make certain to

obtain and save specimens in a way that minimizes loss of these volatilecompounds to evaporation before analysis. Samples of the usual matrices (blood,

urine, vitreous humor, bile, liver, and brain, if available) should be saved, and, ifdesired, samples of lung tissue or gas aspirated from the trachea can also be savedand analyzed.
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The solid and liquid samples should be placed in airtight, nonreactive containers,

and the containers should be as full as possible to reduce the head space availablewithin the specimen container, thus minimizing loss of the volatile compound when

he container is opened for analysis.[13] Glass specimen tubes are nonreactive andreadily available, but toluene can be absorbed by rubber so, if possible, insert a

sheet of aluminum foil between the specimen and the stopper before stopping the

ube, especially for samples of solid tissue that require removal of the stopper. [14]

(This is easier than it might seem first, fit the foil tightly around the base of thestopper, and then insert the stopper into the tube.)

Volatile compounds are less volatile at lower temperatures thus, the specimens

should be refrigerated promptly and kept cool until analysis. [13] For any case in

which unusual steps are necessary, personal communication with the toxicologylaboratory that will perform the analysis will help assure that the specimens are

collected, stored, transferred, and analyzed correctly. [15]

Actual drugs found at postmortem examination, whether in property or during

internal examination, require special handling. With illicit drugs, the handling maybe to transfer the evidence to a police officer or to a police drug laboratory, with an

appropriate form documenting transfer of this evidence. Some drugs, such asopioids, have potential for abuse even though they may be licit. If such drugs are

held at the coroner's or medical examiner's office, they should be held as securelyas any other evidence, such that tampering would be evident. When the time comeso dispose of such drugs, disposal is best done in some way that is above reproach -

- for example, in the presence of witnesses in the office -- and the disposal shouldbe documented in the office records.

If the examination and analysis of drugs or other evidence may have eventualimportance in a legal proceeding, then the transfer of items from the custody of oneperson to another must be documented in a way that is acceptable in court. This

documentation is called the chain of evidence or chain of custody. A chain ofevidence is used in court to show who had control of the item or specimen in

question at all times. This is necessary, because United States law states thatanyone on trial has the constitutional right to question his or her accusers about the

circumstances of the trial.

If no chain of custody is documented, or if a link in the chain is missing, then it maynot be possible to satisfy a jury that the specimen was handled properly, and thus

he item may be excluded as evidence in a trial. The chain of custody paper traildescribes the item and lists the names (with signatures), dates, times, and places

when the item changed hands. A fuller discussion is available in the book Pathology

and Law.[16]

Histology and Microscopic Examination andFindings

In addition to the findings seen in association with needle track marks, as discussed

in the Special Dissections section, microscopic examination can show features ofintravenous drug abuse in internal organs. The lungs are particularly apt to contain

birefringent crystalline material, as drugs and insoluble material injectedintravenously must pass first through the pulmonary circuit, where the pulmonarycapillaries act as a filter for debris (see the first image below). In some cases,

crystals may be seen in the liver in addition to the lungs. When present, crystals inhe liver are in the connective tissue of the triads (see the second image below). Not

everyone who abuses drugs intravenously, however, has birefringent material in

either of these organs.

Cross-polarization of a section of lung in an individual with a history of intravenous drug abuse.Notice the birefringent crys talline material within foreign body giant cells . Ori ginalmagnifications 100 and 200.
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Cross-polarization of a section of liver in an individual with a history of intravenous drug abuse.Notice the birefringent crystalline material within triads, as well as evidence of hepatitis. Originalmagnifications 100 and 400.

Alcoholics sometimes consume ethylene glycol, which produces an anion gap.

Ethylene glycol is converted to oxalic acid in the body, and with time, this acid isdeposited as birefringent oxalate crystals in the renal tubules (see the image below).

A forensic pathologist should routinely screen for these crystals when examining

histologic sections of a kidney, especially if no vitreous chemistry has beenperformed. The yield is low, but when present, these oxalate crystals may be the

only sign alerting the pathologist to tell the toxicology laboratory to test specificallyfor ethylene glycol. Ethylene glycol is not very volatile, hence its usefulness as

antifreeze, but as a consequence of its low volatility, ethylene glycol is not found inroutine toxicologic screens for volatile compounds, such as ethanol or acetone.

Ethylene glycol must be specifically sought.

Cross-polarization of a section of a kidney in an alcoholic found dead on a stoop. Calciumoxalate crystals in tubules led to analysis for ethylene glycol and determination of the cause ofdeath. Original magnifications 100 and 200.

Other histologic findings seen in drug abusers includes aggregates of hemosiderinaround cerebral vessels and fibrointimal hyperplasia of coronary arterioles in chronic

stimulant users, bacterial endocarditis in intravenous drug abusers, hepatic necrosisand steatosis following toxicity with acetaminophen and other substances (see theimages below), and deep tissue abscess formation at injection sites.

Hepatic necrosis that developed following ingestion of an overdose of acetaminophen. Necrosiscan be global or focal. Notice the lack of inflammation, which may be true early in the process ofnecrosis. M agnification 100.
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Hepatic necrosis that developed following ingestion of an overdose of acetaminophen. Necrosiscan be global or focal. Notice the lack of inflammation, which may be true early in the process ofnecrosis. This higher-power view shows microsteatosis of hepatocytes at the edge of necrosis.Magnification 400.

Photography and Documentation

Needle marks, track marks, and illicit substances found during examination all

deserve photographs. Weighing illicit drugs is also wise, as this weight bothquantifies the amount of drug and records how much drug was present shouldquestions later arise about the amount of drug remaining. In cases of ingested drug

overdoses, the gastric contents should be measured and collected to facilitatecalculation of the amount of drugs swallowed.

Ancillary and Adjunctive Studies

Toxicologic tests for substances commonly found are easily performed, as suchests are routine. Sometimes, however, an unusual substance requires unusual

measures. Sending samples of a substance rarely abused in a given region to a

reference laboratory twice a year may be more economical than for a localoxicology laboratory to buy a machine dedicated solely to a test that is seldom

needed.

More rarely still, the pathologist and toxicologist may need to create a new meanso test for a substance that is suspected in a given case. For example, the book

Final Exitoffers techniques for committing suicide, one of which is to place one'shead into an airtight bag filled with helium from a hose connected to a helium

canister.[17] Recognition of the cause of death in such a case is simple enough, ifhe bag, hose, and canister remain in place, but toxicologic analysis for helium

requires alteration of the normal procedure for gas chromatography, because heliumis typically used as the carrier gas. Auwaerter et al have reported a procedure for

detecting helium in such a case by using nitrogen as the carrier gas.[18]

Other cases have been reported regarding the development of a new analytical

procedure to assess a given case.[19] When faced with a unique compound,

communication between the pathologist and the toxicologist is critically important sohat both parties know what is possible and can plan how to proceed to best

evaluate a given case.

See alsoAdjuncts t o the Forensic Autopsy.

Diagnostic Criteria

Interpretation of concentrations of drugs, whether licit or illicit, is properly madefrom blood or solid organ concentrations determined and confirmed by gas

chromatography/mass spectrometry (GC/MS) within the context of the

circumstances that surrounded death.[4] By itself, a positive screening test of urine,

or any other matrix for that matter, is insufficient to conclusively prove use of a drug

by the decedent, although it may strongly suggest recent use and can providevaluable information when taken in concert with the circumstances of death.

Further, screening tests (such as immunoassays) do not provide concentrations for

any class of compounds they detect -- they are purely qualitative. Sometimes,however, no specimen is available for confirmation of screening results, andquantification of drug concentrations in the blood at the time that an injury or

overdose happened is not possible. An example of such a scenario occurs when anindividual with a positive drug screen upon admission lingers in a coma for over 1

week in a hospital or extended care facility before dying. In these cases, although adrug screen performed on urine detected some intoxicating substance, no blood

remains from the time of admission for quantification and, of course, the substancewas metabolized and excreted by the body long before death.

In such a case, the results of a screening test must be accepted for what they are --

a screen and no more. Coupled with additional evidence, however, such as a crackpipe in a pocket and witness reports that the decedent had been smoking crack

cocaine before suddenly collapsing, then a screening test that detected cocainemetabolites in the urine is probably accurate, and it would be appropriate to opine

hat evidence exists that cocaine was in the decedent's system at the time ofadmission.

Note that some screening tests are subject to false-positive results, sometimes by

cross-reactivity of the antibodies with prescribed medications. [20] Quite commonly,

decomposed bodies test positive on amphetamine screens, because the productionof phenylethylamine is part of the putrefaction process. Good medical practicealways calls for correlation of the history with the physical findings. If a screening
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est result cannot be validated by some other means, then it must be considered

possible that the screening test result is a false positive.

The determination that death was caused by intoxication with a single substance orwith a mixture of substances is the business of forensic pathology, sometimes a

fiendishly tricky business. Finding a range of concentrations of a given substancehat have been reported as the cause of death in the medical literature is usually

possible. Biologic systems know nothing of cutoffs, however, and studies aboundhat show that a drug concentration that caused death in one case was an incidental

finding in another.

For example, Darke et al reported no significant difference in morphineconcentrations in individuals dying of a drug overdose when compared with

individuals killed by homicidal violence, such as shooting or stabbing.[21] Such a

finding should come as no surprise when one remembers the pharmacologicconcept of the LD50, the dose of a given drug that will kill 50% of the rats exposed

o that dose. If a given dose kills 50% of the rats, then a smaller dose presumablywould kill 10% of the rats or a larger dose 90% of the rats. The variability in biologic

systems means that the same concentration of drug may kill one individual butleave another unscathed, even if one ignores the effect of drug tolerance.

How, then, does a pathologist make a determination of the role a drug plays in

causing death based on reproducible criteria and not intuition? Irey suggested a

useful scheme in the book Pathology of Drug Induced and Toxic Diseases.[22] Inbrief, Irey provided several categories of significance that any substance found in a

decedent may have, including the following[22] :

Causative: The substance is unequivocally responsible for illness or death.

Probable cause of death: Death is a known complication of that substanceand the clinical picture is in keeping with previous experience and reports,

provided other causes of death have been reasonably eliminated.Possible cause of death: The clinicopathologic picture could be caused by

the drug in question, but it could just as easily be caused by some otherprocess found in the decedent assigning the drug in question as the causeof death would be unique and warrant publication in the medical literature.

Coincidental: The substance happens to be present but has no bearing onillness or death.

Negative: The substance is not detected.

Application of Irey's criteria is reproducible, as properly applied science should be.

The decision of whether death was caused by a given drug or combination of drugsin a given case remains difficult sometimes, but Irey's criteria provide a usefulconceptual framework for making accurate, defendable diagnoses.

Common Misconceptions

Misconceptions concerning drugs are held by those who abuse drugs and health

practitioners. Due to the popularity of forensic-themed television series, manylaypeople assume that thorough toxicologic analysis takes as long as a commercial

break. Even under the best of circumstances, conducting toxicologic analyses

correctly may take days to weeks, and it may take much longer than that in somebusy jurisdictions. People also tend to think that laboratories are interchangeable,which is a credit to the uniformity of good practice followed by accreditedlaboratories. Not all laboratories are accredited, however, as pointed out in the

National Academy of Sciences 2009 report on forensic science in the United States.[23] Variation in quality of work is but one reason that laboratory results are subjecto challenge in court, a point discussed in more detail below in Issues Arising in

Court.

Drug users also fall victim to fallacies pertaining to their drug of choice. They oftenhink of the drugs that they choose to use as safe, ignoring the overlap that exists

between the therapeutic and lethal ranges for controlled substances and illicit drugs.Further, drug users who have been incarcerated for a time often resume drug use

again upon release from prison but fail to take into account the loss of tolerancehat occurred during their internment. Therefore, they are at risk of dying when they

use the same amount of drug that they had been using before their imprisonment.

Moreover, no agency oversees drug purity for street drugs, and the purity of thesubstance being abused may have changed while an individual was in jail.

Misinterpretation of public health advisories has also resulted in fatalities. In theinterest of promoting public health, officials have occasionally issued warnings tohe public to avoid certain neighborhoods because a drug being sold there was

unusually powerful and likely to cause death. Paradoxically, these warnings have ledo increased traffic and deaths in the area, because some drug users took the

information as an advertisement rather than as a warning.

Practitioners may also be duped by drug users by failing to acknowledge that

addicts are distributed across every socioeconomic cohort. As described earlier inhe section Indications for the Procedure, some drug users take great care not to be

detected. Assuming that a specific person could not possibly abuse drugs is nave.

Blindly sticking to a published "lethal" range for a drug, as described above in thesection Diagnostic Criteria, is also nave. Certainly a published lethal range is useful

and must be considered, but to dismiss some drug as causing death because itsconcentration is 0.01 mg/L below the reported lethal range is to ignore the truth, if

he circumstances indicate that the death is caused by a drug overdose. Suffice it tosay that if a person died due to the effects of a drug on that person, the level islethal regardless of where the blood concentration falls on a table.

Finally, overdose as a concept may be misunderstood by both drug users and healthpractitioners. Some deaths certainly occur because a lethal concentration of drug is

in the body, but, in other cases, drugs can lead to death by alternate mechanismsirrespective of the concentration of the drug in the body. Cocaine, for example, can

cause death at any concentration. [9] Mechanisms by which a drug can cause deathat low concentration are being elucidated, as described below in Future
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Developments.

Issues Arising in Court

Forensic pathologists most often testify in murder trials, and those trials often

include discussion of the degree to which the decedent's behavior was altered by

intoxicating compounds found in the body. For alcohol, data exist that provide somedegree of confidence in answering a question about the decedent's behavior ingeneral terms based on a given blood ethanol concentration.

For other drugs, such as cocaine, no such data exist. Furthermore, for cocaine and

other drugs, the behavior of the individual depends not only on the concentration ofhe drug in the blood but also on whether the concentration is increasing or

decreasing.[9] The honest forensic expert limits speculation concerning the behaviorof an individual based on drugs found in the system to generalities, for example,

saying that cocaine does alter behavior, that it has stimulant properties, but thatpredicting from the blood concentration alone what a given person's behavior would

have been is not possible.

Part of preparing for court is anticipating questions that may arise. This process

begins at the autopsy and includes preservation of evidence. For example, savingfentanyl patches in bottle labeled with the appropriate case number is prudent

practice in cases of unexpected death.[15] In the event that a legal suit later allegeshat the patch was defective, the patch is available for examination and testing.

Remember that the purpose of court is to resolve disputes, so whenever apathologist is able to produce evidence that settles a dispute, then the pathologisthas served the court well.

The wise pathologist acts to resolve disputes about a finding or diagnosis before thedisputes reach court. As an example, the following scenario recurs periodically:

Toxicologic analysis detects an illicit substance in an individual who, the decedent'sfamily adamantly maintains, never used drugs. Once the pathologist realizes that

he family doubts the results of the initial toxicology test, sending a sample foroxicologic analysis to a second toxicology laboratory other than the initial facility

may head off litigation.

The pathologist tells the family it is only proper to double check in cases of suchvehement disagreement, because mistakes do sometimes occur, but makes no

promise of what the second laboratory will find. If the toxicology results from thesecond facility disagree with those of the first -- that is, if the offending substance is

not found in a repeat test -- then evaluation of what went wrong in the firstlaboratory test is appropriate, as is an apology to the family for any distress caused.If, however, the second laboratory confirms the presence of the offending

substance, then the pathologist has already taken the step that any court will firstorder if the family sues.

The family may or may not accept the truth of their loved one's intoxication, butothers without the blinders of vested interest will be convinced, and the pathologist'spart in the dispute is essentially done. The family may not be done, however, and

may demand DNA testing to prove the blood is from their loved one. The

pathologist may perform such testing, but telling the family that the pathologist issatisfied is also possible, and any further testing will be done at the family'sexpense. If the family chooses a laboratory for DNA analysis, then the pathologist

ransmits the blood sample for DNA testing directly to the laboratory withappropriate chain of custody. The sample must not be given to the family unless soordered by a court.

On June 25, 2009, the US Supreme Court ruled that pathology laboratories are notexempt from US laws that require that evidence against a person accused in court

is subject to challenge in the form of cross-examination. This means that alaboratory report alone may no longer be sufficient as evidence in a trial the analyst

who performed the test may also be subpoenaed and may have to testify in court.

The Supreme Court ruling runs counter to the experience of pathology laboratories,which are accustomed to dispensing many reports a day that are almost always

accepted as true and accurate without question. Someone calling and questioninghe results of a laboratory test is not unheard of medical practitioners call to double

check and challenge unexpected results daily.

hat makes the Supreme Court's ruling different is that routine laboratory resultshat are seldom questioned in clinical practice will require the presence of a

pathologist or technician in court to explain and justify the results concerning anygiven laboratory test relevant to a criminal trial. Pathology laboratories are not

staffed to provide such service to courts, and how this matter will impact uponlaboratories when all is settled remains to be seen. Despite the inconvenience of

he Supreme Court's ruling to pathology laboratories, this does afford pathologistsan opportunity to get out of the laboratory, place themselves in the public eye, anddemonstrate the importance and worth of pathology testing and pathologists to the

community.

Future Developments

Enterprising individuals with sophisticated knowledge of chemistry have synthesizedchemical analogs of common drugs of abuse, such as amphetamines, opiates, and

marijuana. These chemical analogs are pharmacologically active, but because ofheir novel structure they technically escape legal restrictions on their sale and use.

[24] These substances are marketed and sold under many names, such as bath

salts, K2, or spice.[25] They can be bought at stores or over the Internet. Often, thesubstances bear a label stating that they are not intended for human consumption,

another ploy to avoid legal repercussions for selling the material. Other new drugsavailable for purchase are the opiate agonists Salvia and Kratom, both derived from

plants.[24] The sale and use of Salvia and Kratom are also largely unrestricted bylaw.

The compounds and laws continue to change in a never-ending game of cat-and-
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mouse faster than publications can keep up with the latest fad. Internet postings arehe best source of information on this rapidly changing process. Perhaps most

important is to remember that these substances are likely to be missed by a

standard toxicological screen directed against the usual drugs of abuse. Therefore,if reason exists to have a high index of suspicion for drug use or intoxication, but no

substance is detected on standard screens, one of these chemical analogs may bepresent. Testing for the chemical could be expensive, however.

Research in basic sciences will improve the understanding and practice of forensic

pathology in the years ahead regarding deaths caused by intoxication. For example,cocaine and methadone can cause death at concentrations often perceived as too

low to be "overdoses." Research indicates that cocaine[26] and methadone[27] bothalter proper repolarization of the heart, helping to explain how death can occur at

low concentrations of these drugs. Others are working in pharmacogenomics, which

has the potential to help forensic pathologists understand the mechanism of deathfor certain individuals who may metabolize a drug more slowly than others, thus

overdosing more easily.[28] These fields are interrelated, as the absence of a gene

or gene copy necessary for proper repolarization of the heart can cause death justas surely as the absence of a gene or gene copy for proper metabolism of a drug.

Contributor Information and Disclosures

Author

Gregory G Davis, MD, MSPHProfessor of Pathology, Director, Forensic Division, Department of Pathology,University of Alabama at Birmingham School of Medicine Chief Coroner/Medical Examiner, Jefferson County,

Alabama

Gregory G Davis, MD, MSPH is a member of the following medical societies: American M edical A ssociation,American Society f or Clinical Pathology, College of American Pathologists, National Association of MedicalExaminers, United States and Canadian Academy of Pathology,American Academy of Forensic Sciences

Disclosure: Nothing to disclose.

Chief EditorJ Scott Denton, MDClinical Assistant Professor of Pathology, University of Illinois College of Medicine at

Peoria Forensic Pathologist and Illinois Coroners Physician

J Scott Denton, MD is a member of the following medical societies: Alpha Omega Alpha,American Medical

Association,American M edical A ssociation,American S ociety for Clinical P athology, College of AmericanPathologists, Illinois State Medical Society, National Association of Medical Examiners,American A cademy of

Forensic Sciences, Illinois Society of Pathology, Peoria Medical Society

Disclosure: Nothing to disclose.

AcknowledgementsThanks to Gene P. Siegal for his time and help with photomicrographs and to Stephen J. Cina for supplying

photographs and cogent editorial suggestions.

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