Role of the Laboratory in the Diagnosis

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80: ROLE OF THE LABORATORY IN THE DIAGNOSIS AND MANAGEMENT OF POISONING 337
Tubular reabsorption: See Active tubular reabsorption.
Tubular secretion: See Active tubular transport.
U
Unbound fraction: The unbound or free fraction of drug in the
plasma (fU), which is the ratio of unbound or free concentration
to the total (i.e., unbound plus bound) concentration. For most
drugs, this fraction is constant and independent of plasma drug
concentration.
Unbound intrinsic clearance: See Intrinsic clearance of unbound
drug.
Unbound volume of distribution: The apparent volume of
distribution corrected for plasma protein binding, Vunbound =
V/fU.
V
Volume of distribution (apparent volume of distribution): A
primary pharmacokinetic parameter reflecting the reversible
uptake of drug by tissues from the blood. The fictitious space or
volume that a drug appears to occupy in the body relative to the
concentration of drug in the blood. Volume of distribution is the
imaginary volume the drug occupies if it is present throughout
the body in the same concentration as plasma. Because the refer-
ence fluid is always blood, the larger the volume of distribution,
the more drug is in tissue relative to plasma. Volume of distribu-
tion has units of volume, but is commonly normalized to body
weight, as, for example, liters/kg or V/m2. Volume of distribu-
tion multiplied by plasma concentration equals the amount of
drug in the body (but with some limitations). This parameter may,
therefore, exceed the real volume of the body. There are numerous
apparent volumes used in pharmacokinetics, including Vextrapolated,
Vβ or VAREA, VC or V1, VP or V2, VSS. The apparent volume serves
two purposes: gives an indication of the magnitude of distribu-
tion or movement out of the blood and into tissues (the greater the
apparent volume, the less drug is in the blood and more is in tis-
sues); acts as a proportionality constant between the amount of
drug in the body and the concentration in the blood.
Z
Zero-order: A rate is zero-order when it is constant, indepen-
dent of concentration or amount. See Order.
CHAPTER 80
Role of the Laboratory in the Diagnosis 
and Management of Poisoning
Robert J. Flanagan
Analytical toxicology is concerned with the detection, identifica-
tion, and measurement of drugs and other foreign compounds
(xenobiotics) and their metabolites in biologic and related speci-
mens. The analytical toxicologist can play a useful role in the
diagnosis and management of poisoning, but to do so, he or she
should have a basic knowledge of emergency medicine and inten-
sive care and must be able to communicate effectively with phy-
sicians. In addition, a good understanding of clinical chemistry,
pharmacology, and toxicology is desirable. The analyst’s dealings
with a case of suspected poisoning are usually divided into pre-
analytical, analytical, and post-analytical phases (Table 1).
Many acutely poisoned patients are treated successfully
without any contribution from the laboratory other than routine
clinical laboratory tests. The analytical toxicologist can only con-
tribute to diagnosis and management if a physician, pathologist,
or other person first suspects poisoning. Close collaboration
between the analyst and the physician is then important if any-
thing other than the simplest of analyses is to be useful. Many
requests for emergency analytical toxicologic investigations are,
in fact, requests for advice on the diagnosis or management of
poisoning and are best handled by staff of a poisons information
service, at least in the first instance.
Toxicologic analyses can play a useful role if the diagnosis of
poisoning or the nature of any poison(s) present is in doubt, the
administration of antidotes or protective agents is contem-
plated, or the use of active elimination therapy is being consid-
ered. All relevant information about a particular patient should
be communicated to the analyst and appropriate specimens
must be collected and properly labeled. Information to enable
the analyst to assign the appropriate priority to the analysis in
such cases is especially vital because, in general, specific therapy
is only started when the nature and the amount of the poison(s)
involved are known. At the least, a request form should be com-
pleted to accompany the specimens to the laboratory.
TABLE 1. Steps in undertaking an analytical 
toxicologic investigation
Preanalytical Obtain details of current (suspected) poisoning episode, 
including any circumstantial evidence of poisoning, 
and the results of biochemical and hematologic 
investigations, if any. Also obtain the patient’s medi-
cal and occupational history, if available, and ensure 
access to the appropriate samples. Decide the prior-
ities for the analysis.
Analytical Perform the agreed analysis.
Postanalytical Interpret the results in discussion with the physician look-
ing after the patient. Perform additional analyses, if 
indicated, using either the original samples or further 
samples from the patient. Save any unused or residual 
samples in case they are required for additional tests.
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338 I: GENERAL APPROACH TO THE POISONED PATIENT
SPECIMEN COLLECTION, TRANSPORT, 
AND STORAGE
Sample requirements for general analytical toxicology are sum-
marized in Table 2. If possible, all biologic specimens should be
analyzed immediately or stored at 4°C before analysis. If the
amount of sample that can be collected is limited (e.g., a young
child is under study), then contact the laboratory beforehand.
Special precautions are needed when collecting samples for the
analysis of trace elements and toxic metals (Table 3). In such
cases, it is prudent to send an empty container from the same
batch as that used to collect the sample to test for possible con-
tamination from the container. Contamination with metals can
arise from unusual sources. Contamination of blood with chro-
mium and manganese, for example, can occur from an indwell-
ing stainless steel cannula.
Analytical results concerning any specimen submitted for
toxicologic investigation may end up under scrutiny in court. It
is thus important that all such specimens are clearly labeled with
the patient’s family or last name and any forenames, the date
and time of collection, and the nature of the specimen if this is
not self-evident. Hospital and casualty numbers should also be
recorded. Attention to these details is especially important if
large numbers of patients have been involved in a particular
incident, or if a number of specimens have been obtained from
one patient. Further problems may arise if one or more blood
samples have been centrifuged and the plasma separated in a
local laboratory and the original containers discarded.
Sending Samples by Post
In many countries, strict rules govern the transport and storage
of biologic specimens. Details should be obtainable from a local
hospital laboratory. Specimens should always be stored in
labeled biohazard polythene bags. Letters and request forms
should be placed in a pouch attached to the bag. Specimens sent
by post (first class letter post or Datapost only in the United
Kingdom) or courier should be dispatched in post office–
approved containers. The polythene bags containing the sam-
ples should be sandwiched in the box between absorbent pack-
aging. The lid of the box should be secured with adhesive tape
and the package clearly labeled with its destination, its origin,
and an indication of its contents (e.g., pathologic specimen).
The associated documentation must give full details of any
special risk associated with a specimen (hepatitis B, human
immunodeficiency virus, and so forth). In the case of human
immunodeficiency virus–risk specimens, the specimen con-
tainer and the request form must all be markedwith a danger of
infection sticker and an indication that the specimen carries an
inoculation risk. Before dispatch of the specimen, the receiving
laboratory must be informed by telephone of the risk, the
patient’s name, and the investigation required. Records must be
kept of all specimens sent by post, taxi, or courier. The minimum
information should include type of specimen, destination, and
date sent. Additional information to identify specific specimens
could be patient’s name, laboratory number, name of person
packing the sample, request, taxi firm used, and driver’s name.
Chain-of-Custody Procedures
If it is clear from the outset that the analyses have medicolegal
implications, then strict chain-of-custody procedures should be
TABLE 2. Sample requirements for general analytical toxicology 
Sample Notesa
Whole blood 10 ml (lithium heparin or EDTA tube—use fluoride/
oxalate if ethanol suspected; plastic tube if 
paraquat suspected; glass or plastic tube with 
minimal headspace if carbon monoxide or other 
volatiles suspected).
Plasma/serum 5 ml (send whole blood if volatiles, metals, and 
some other compounds suspected).
Urineb 20–50 ml (plain bottle, no preservativec).
Gastric contentsd 25–50 ml (plain bottle, no preservative).
Scene residuese As appropriate.
Other samples Vitreous humor, bile, or liver (approximately 5 g) can 
substitute for urine in postmortem work. Other tis-
sues (brain, liver, kidney, lung, subcutaneous fat—
5 g) may also be valuable, especially if organic 
solvents or other volatile poisons are suspected.
EDTA, ethylenediaminetetraacetic acid.
aSmaller volumes may often be acceptable; for example, in the case of children.
bAll that is normally required for drugs of abuse screening.
cSodium fluoride (1% w/v) should be added if ethanol is suspected and blood is not 
available.
dIncludes vomit, gastric lavage (stomach washout) (first sample), and so forth.
eTablet bottles, drinks containers, aerosol canisters, and so forth—pack entirely sep-
arately from biologic samples, especially if poisoning with volatiles is a possibility.
TABLE 3. Sample requirements for some
metals/trace elements analysis
Element Sample requirements
Aluminum 10 ml whole blood in plastic (not glass) tube—no antico-
agulant/separating beadsa
20 ml dialysate/supply water in plastic bottle rinsed sev-
eral times with portions of the intended samplea
Antimony 5 ml heparinized whole blood
20 ml urine
Arsenicb 5 ml heparinized whole blood
20 ml urine
Bismuth 5 ml heparinized whole blood
Cadmium 2 ml EDTA whole blooda
10 ml urinea
Chromium 2 ml heparinized whole blooda,c
20 ml urine (hard plastic bottle)a
Copper 2 ml heparinized or clotted whole blood, or 1 ml 
plasma/serum
10 ml urine
Iron 5 ml clotted blood or 2 ml serum (no hemolysis)
10 ml urine
Lead 2 ml EDTA whole blood (no clots)
Lithium 5 ml clotted blood or 2 ml serum (not lithium heparin tube)
Manganese 1 ml heparinized whole blood or 0.5 ml plasmaa,c
Mercury 5 ml heparinized whole bloodd
20 ml urine (hard plastic bottle)d
Selenium 2 ml heparinized whole blood or 1 ml plasma/serum
Silver 2 ml heparinized whole blood or 1 ml plasma
10 ml urine
Strontium 2 ml heparinized whole blood or 1 ml plasma
Thallium 5 ml heparinized whole blood
20 ml urine
Zinc 2 ml whole blood (heparinized or clotted but not EDTA) 
or 1 ml plasma/serum
EDTA, ethylenediaminetetraacetic acid.
aSend unused sample container from the same batch as used for sample collection 
to check for possible contamination.
bTo diagnose chronic poisoning exclude seafood (shell fish and so forth) from diet 
for 15 days before sample collection.
cUse of a plastic cannula to collect blood is advisable.
dSend samples promptly to avoid loss of mercury on storage.
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80: ROLE OF THE LABORATORY IN THE DIAGNOSIS AND MANAGEMENT OF POISONING 339
implemented. The physician or nurse taking the sample should
seal the sample with a tamper-proof device and sign and date
the seal. A chain-of-custody form should also accompany the
specimen. Each person taking possession of the sample should
sign and date the form when he or she takes possession. The
sample should be secured in a locked container or refrigerator if
left unattended before arrival at the laboratory.
After the Analysis
Residues of samples and any unused samples should be saved at
4°C for 4 to 6 weeks in case further analyses are required. In view
of the medicolegal implications of some cases, then any specimen
remaining should be kept at –20°C or below until investigation of
the incident is concluded. This can take several years.
Urine
Urine is useful for screening because it is sometimes available in
large volumes and usually contains higher concentrations of
drugs and some other poisons than blood. The presence of
metabolites may sometimes assist identification if chromato-
graphic techniques are used. A 50-ml specimen from an adult,
collected into a sealed, sterile container, is sufficient for most
purposes. No preservative should be added (e.g., use of Thi-
omersal (merthiolate) preservative invalidates a urine mercury
measurement). The sample should be obtained as soon as possi-
ble after admission, ideally before any drug therapy is initiated.
Samples taken soon after ingestion, however, may not contain
detectable amounts of poison. A further complication is that
drugs with anticholinergic activity, such as tricyclic antidepres-
sants, cause urinary retention and, thus, there may be delay in
obtaining a specimen, especially if the patient remains conscious
or is in shock. Conversely, little poison may remain in specimens
taken many hours or days later, though the patient may be ill, as
in acute paracetamol (acetaminophen) or paraquat poisoning. If
the specimen is obtained by catheterization, there is a possibility
of contamination with lignocaine (lidocaine) gel.
Stomach Contents
Stomach contents include vomit, gastric aspirate, and gastric
lavage fluid (stomach washings). It is important to obtain the
first sample of lavage fluid because later samples may be dilute.
At least 20 ml (plain bottle, no preservative) should be collected.
This sample can be variable in composition, and additional pro-
cedures, such as homogenization followed by filtration and cen-
trifugation, may be required to produce a fluid amenable to
analysis. It is the best sample on which to perform certain tests,
however, although clearly of little use if the poison has been
inhaled or injected. If obtained soon after ingestion, large
amounts of poison may be present whereas metabolites, which
may complicate some tests, are usually absent. It may be possi-
ble to identify tablets or capsules simply by inspection. Emetine
from syrup of ipecacuanha may be present, although the use of
this mixture is no longer recommended, especially in children.
Scene Residues
It is important that all powders, tablets, bottles, syringes, aero-
sol, or other containers found with or near the patient (scene res-
idues) are retained because they may be related to the poisoning
episode. It is usually best to analyze biologic specimens. An
exception is one in which topical exposure is suspected because
systemic absorption may be undetectable. There is always the
possibility that the original contents of containers such as drink
bottles have been discarded and replaced either with innocuous
material or with more noxious ingredients such as acid, bleach,
or pesticides. Care should be taken to assure that containers of
volatile materials such as aerosols and organic solvents are
packaged entirely separately from biologic specimens to pre-
vent cross-contamination. Indeed, it is best to pack all scene res-
idues entirely separately from biologic samples because the
possibility of contamination could be suggestedin any future
legal proceedings. If police have attended an incident, scene res-
idues may have been removed for forensic analysis.
Blood
Blood plasma or serum is normally used for quantitative assays,
but some poisons are best measured in whole blood. A 10-ml
sample in a glass or clear hard plastic (polycarbonate) tube con-
taining heparin (or heparinized beads) or sodium ethylenedi-
aminetetraacetic acid (EDTA) should be taken. EDTA is
preferred for aminoglycoside antibiotics, carboxyhemoglobin,
and for lead and some other metals (Table 3). A fluoride/oxalate
tube should be used if ethanol, cocaine, nitrazepam, or clon-
azepam are suspected. Note that the tubes of this type available
commercially contain approximately 0.1% (w/v) fluoride,
whereas approximately 1% (w/v) fluoride (40 mg sodium fluo-
ride/2 ml blood) is needed to fully inhibit microbial action in
such specimens (1).
The use of disinfectant swabs containing alcohols (ethanol,
2-propanol) before venipuncture should be avoided, as should
heparin, which contains phenolic preservatives (chlorbutol,
cresol). Use a blood collection site remote from any infusion site.
The sample should be dispensed with care: the vigorous dis-
charge of blood through a syringe needle can cause sufficient
hemolysis to invalidate a serum iron (or potassium) assay. Do
not use a lithium heparin tube if lithium is to be measured. Use
plastic tubes if paraquat is to be measured and, ideally, glass if
volatiles are suspected.
Use of evacuated blood collection tubes and tubes containing
gel separators or soft rubber stoppers are not recommended if a
toxicologic analysis is to be performed on the specimen. These
tubes may contain phosphate and phthalate plasticizers, which
not only interfere in chromatographic methods, but tris(2-butox-
yethyl)phosphate can also cause release of many basic drugs
from binding sites on α1-acid glycoprotein. The released drug is
then free to diffuse into red blood cells, thereby lowering the
plasma concentration (2). Some other compounds present in gel
separators dissolve in blood and can thereby affect the solvent
extraction characteristics of certain drugs (3). Relatively high
concentrations (20 mg/L or more) of ethylbenzene and the
xylenes have been detected in blood collected into Sarstedt
Monovette serum gel tubes (4).
In general, no significant differences exist in the concentra-
tions of poisons between plasma and serum. However, if a com-
pound is not present to any extent within erythrocytes, then
using lysed whole blood results in considerable dilution of the
specimen. On the other hand, some poisons such as carbon mon-
oxide, cyanide, and lead are found primarily in erythrocytes and
thus whole blood is needed for such measurements. A heparin-
ized or EDTA whole blood sample gives either whole blood or
plasma as appropriate. The space above the blood in the tube
(headspace) should be minimized if carbon monoxide or other
volatile poisons are suspected.
Hair
In some circumstances the analysis of hair can provide a record
of exposure to a poison and confirm poisoning. However, hair
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340 I: GENERAL APPROACH TO THE POISONED PATIENT
analysis and its interpretation are difficult. For a poison to
appear in hair closest to the scalp takes 4 to 7 days. Hair grows
at a rate of approximately 1 cm/month. Hair treatment such as
bleaching may destroy adsorbed drug, whereas hair-coloring
agents may add toxic metals such as lead. A chemical or drug in
the air can contaminate hair. Aspects of the collection and anal-
ysis of hair specimens from the point of view of testing for drugs
of abuse have been reviewed (5).
Breath
Provided absorption is complete, the exhaled air concentration
of a volatile compound such as ethanol is related to its blood
concentration. Simple electrochemical devices to measure
breath ethanol have been available for many years and have
proved useful in assessing ethanol intoxication in trauma vic-
tims (6). A further simple device is available to measure breath
carbon monoxide (hence carboxyhemoglobin) to rapidly diag-
nose carbon monoxide poisoning and monitor treatment. Etha-
nol interference can be eliminated by use of a carbon filter (7).
Respiratory mass spectrometry has also been developed to
assess exposure to other volatiles such as organic solvents but
currently is impractical for clinical use.
Other Biologic Specimens
A simple dipstick test for salivary ethanol based on alcohol dehy-
drogenase has been used but has been largely superseded by
breath measuring devices. Apart from this, there has been some
interest in measuring salivary concentrations of drugs given in
therapy, particularly in children, but in practice such analyses are
rare, a major problem being the lack of homogeneity of the sam-
ple. Other specimens (sweat, tears, nasal secretions, breast milk,
cord blood, meconium, fat biopsy, tissue biopsy, and so forth)
may be useful in the context of a particular case.
Postmortem Tissue
Tissue samples may be valuable in the investigation of poison-
ing fatalities. Vitreous humor is a useful substitute for urine if
the bladder is empty and can be used to measure potassium and
glucose. Tissue specimens may be especially valuable if death
was due to the inhalation of lipophilic compounds, such as
many organic solvents, because blood concentrations may be
low. Liver, kidney, lung, brain, and subcutaneous fat are the
most useful specimens.
PHYSICAL EXAMINATION OF THE SPECIMEN
Physical examination of the specimen may yield valuable diag-
nostic information. However, appropriate toxicologic investiga-
tions are usually needed to confirm such findings.
Urine
High concentrations of some drugs or metabolites can impart
characteristic colors to urine (Table 4). Strong-smelling poisons
such as camphor, ethchlorvynol, and methyl salicylate (oil of
wintergreen) can sometimes be recognized in urine because they
are excreted in part unchanged. Acetone may arise from metab-
olism of 2-propanol (isopropanol), as well as from ingestion/
inhalation of acetone or from disordered carbohydrate metabo-
lism. Turbid urine may be due to underlying pathology (blood
microorganisms, casts, epithelial cells), or to carbonates, phos-
phates, or urates in amorphous or microcrystalline forms. Such
findings should not be ignored though they may not be related
to a poisoning episode. Chronic therapy with sulfonamides may
give rise to yellow or green/brown crystals in neutral or alkaline
urine. Primidone, sulthiame, and, possibly, phenytoin may form
crystals in urine after overdosage, whereas calcium oxalate
forms characteristic colorless crystals at neutral pH after inges-
tion of ethylene glycol (Chapter 192) or of soluble oxalates.
Stomach Contents and Scene Residues
Characteristic smells may indicate a variety of substances (Table
5). Many other compounds (e.g., ethchlorvynol, methyl salicyl-
ate, paraldehyde, phenelzine) also have distinctive smells.
Extremes of pH may indicate ingestion of acids or alkali,
whereas a green-blue color suggests the presence of iron or cop-
per salts. Examination using a polarizing microscope may reveal
tablet or capsule debris. Starch granules used as filler in some
tablets or capsules may be identified by microscopy using
crossed polarizing filters. They appear as bright grains marked
with a dark Maltese cross. Undegraded tablets or capsules, and
any plant remains or specimens of plants thought to have been
ingested, should be examined separately. The local poison cen-
ter or pharmacy normally has access to publications or other
aids for identification.
Blood
Chocolate-brown venous blood suggests methemoglobinemia
from exposure to strong oxidizing agents such as nitrites. Cherry-
pink blood suggests carbon monoxide poisoning. Pink-brown
colored plasma froma carefully collected sample suggests hemol-
TABLE 4. Some possible causes of colored urine
Color Possible cause
Yellow/brown Bilirubin, hemoglobin, myoglobin, porphyrins, urobilin
Anthrone derivatives (e.g., from aloin, aloe, cascara, 
senna, rhubarb, and so forth),a bromsulphthalein,a 
carotenes, chloroquine, congo red,a cresol, flavins 
(yellow/green fluorescence), fluorescein, mepacrine, 
methocarbamol (on standing), methyldopa (on 
standing), nitrobenzene, nitrofurantoin, pamaquine, 
phenolphthaleina, primaquine, quinine, santonina
Red/brown Bilirubin, hemoglobin, myoglobin, porphyrins, urobilin
Aminophenazone, anisindione,a anthrone derivatives,a 
bromsulphthalein,a cinchophen, congo red,a cresol, 
deferoxamine,b ethoxazene, furazolidone, furazo-
lium, levodopa (black on standing), methocarbamol, 
methyldopa, niridazole, nitrobenzene, nitrofuran-
toin, phenacetin, phenazopyridine, phenindione,a 
phenolphthalein,a phenothiazines, phensuximide, 
phenytoin, pyrogallol, rifampicin, salazosulphapyri-
dine, santonin,a sulphamethoxazole, warfarin
Blue/green Bile, biliverdin, indican (on standing)
Acriflavine (green fluorescence), amitriptyline, azuresin, 
copper salts, indigo carmine, indomethacin, methy-
lene blue (methylthioinium chloride),b nitrofural, 
phenylsalicylate, resorcinol, toluidine blue,b triam-
terene (blue fluorescence)
Black Blood (on standing), homogentisic acid, indican (on 
standing), porphobilin
Cascara (on standing), levodopa (on standing), phenols, 
pyrogallol, resorcinol, thymol
apH dependent.
bUsually used to treat poisoning.
From Lentner C, ed. Geigy scientific tables. Vol. 1. Units of measurement, body fluids, 
composition of the body, nutrition. Basle: Ciba-Geigy, 1981:54, with permission.
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80: ROLE OF THE LABORATORY IN THE DIAGNOSIS AND MANAGEMENT OF POISONING 341
ysis and, thus, possible poisoning with compounds such as ars-
ine, chlorates, or dapsone. Orange plasma has been described
after ingestion of canthaxanthin as a sun-tanning aid (8,9).
CLINICAL LABORATORY TESTS AND 
THE POISONED PATIENT
Many routine clinical laboratory tests are helpful in the diagnosis
of poisoning and in assessing prognosis. Still more specialized
tests may be appropriate depending on the patient’s clinical con-
dition, the circumstantial evidence of poisoning and the past med-
ical history, although only larger laboratories may be able to offer
all of the tests discussed later on an emergency basis. Tests used in
monitoring supportive treatment are not considered here. For fur-
ther information, see Watson and Proudfoot (10).
Blood Glucose
Marked hypoglycemia often results from overdosage with insu-
lin, sulfonylureas such as tolbutamide, or other antidiabetic
drugs. Hypoglycemia may also follow ingestion of salicylates
such as aspirin, ethanol (especially in children or fasting adults),
and beta-receptor blocking drugs and may also complicate
severe poisoning due to a number of hepatotoxic agents, includ-
ing acetaminophen, chlorinated hydrocarbons such as carbon
tetrachloride, isoniazid, phenylbutazone, iron salts, and certain
fungi. Hypoglycin is a potent hypoglycemic agent found in
unripe akee fruit and is responsible for Jamaican vomiting sick-
ness. Hyperglycemia is a less common complication of poison-
ing than hypoglycemia but has been reported after poisoning
with a variety of compounds (Table 6).
Plasma Electrolytes
Electrolyte disturbances may be simple to monitor and to inter-
pret but are often complex. The correct interpretation of serial
measurements requires a detailed knowledge of the therapy
administered. Poisons associated with abnormal potassium
concentration are shown in Table 7. Hyperkalemia is addressed
in Chapter 35. Hypokalemia and metabolic acidosis are features
of theophylline and salbutamol overdose. Hypokalemia and
metabolic alkalosis can be caused by chronic abuse of laxatives
or sodium bicarbonate (12). Hyponatremia can result from
many causes, including water intoxication (11), inappropriate
loss of sodium, or impaired excretion of water by the kidney.
Hypocalcemia can occur after ingestion of ethylene glycol or
oxalates, such as oxalic acid, due to sequestration of calcium.
Hypocalcemia may also occur as a result of acute poisoning
with fluorides.
Plasma Osmolality
Plasma osmolality and the concept of osmolal gap are addressed
in Chapter 25. Although the measurement of plasma osmolality
and calculation of the osmolal gap (measured osmolality–calcu-
lated osmolality) may give useful information, interpretation can
be difficult. It is vital, therefore, that toxicologic analyses are per-
formed to confirm any provisional diagnosis. For example, there
may be secondary dehydration, as in salicylate poisoning; ethanol
may have been taken together with a more toxic, osmotically
active substance; or enteral or parenteral therapy may have
involved the administration of large amounts of sugar alcohols
(mannitol, sorbitol) or formulations containing glycerol or
1,2-propanediol. Note also that a normal plasma osmolality does
not exclude severe poisoning with ethylene glycol or methanol.
Plasma Enzyme Activity
Shock, coma, or convulsions are often associated with nonspe-
cific increases in the plasma or serum activities of aspartate ami-
notransferase and alanine aminotransferase, primarily of
hepatic origin, and of lactate dehydrogenase, primarily from
heart muscle. Usually the activities increase over a period of a
few days and slowly return to normal. Not surprisingly, changes
TABLE 5. Smells associated with particular poisonsa
Smell Possible cause
Almonds Cyanide
Cloves Oil of cloves
Fruity Alcohols (including ethanol), esters
Garlic Arsenic, phosphine
Mothballs Camphor
Nail polish remover Acetone, butanone
Pears Chloral
Petrol Petroleum distillates (may be vehicle in pesticide 
formulation)
Phenolic Disinfectants, cresols, phenols
Shoe polish Nitrobenzene
Stale tobacco Nicotine
Sweet Chloroform and other halogenated hydrocarbons
aCARE, specimens containing cyanides may give off hydrogen cyanide gas (prussic 
acid), especially if acidified—stomach contents are often acidic. Not everyone can 
detect hydrogen cyanide by smell. Similarly, phosphides evolve phosphine, and sul-
fides evolve hydrogen sulfide—the ability to detect hydrogen sulfide (rotten egg 
smell) is lost at higher concentrations.
TABLE 6. Poisons reported to cause hyperglycemia
Acetone Nalidixic acid
Adrenaline Nifedipine
Aspirin and other salicylates Phenylbutazone
Cadmium chloride Phenylpropanolamine
Caffeine 2-Propanol
Clonidine Salbutamol
Cyanide ion Sodium azide
Hemlock water dropwort 
(Oenanthe crocata)
Terbutaline
Theophylline
Iron salts Verapamil
Isoniazid Yew (Taxus baccata) leaves
Methanol Zinc chloride
TABLE 7. Poisons reported to alter 
plasma potassium concentrations
Hyperkalemia Hypokalemia
Atenolol Barium salts Oxpentifylline
Cardiac glycosides Caffeine Quinine
Disopyramide Chloroquine Salbutamol
Fluoride ion Disopyramide Sodium bicarbonate
Ibuprofen Diuretics Sotalol
Opioids Insulin Terbutaline
Oxprenolol Laxatives Theophylline
Potassium chloride Magnesium sulfate Toluene
Potassium-sparing 
diuretics
Nalidixic acid Yew (Taxus baccata) 
leavesNifedipine
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342 I: GENERAL APPROACH TO THE POISONED PATIENT
of this nature are of little diagnostic or prognostic value except
in the context of poisoning with specific hepato- or myotoxins.
Plasma aspartate aminotransferase and alanine aminotransfer-
ase activities, for example, may increase rapidly after absorption
of toxic doses of hepatotoxins such as paracetamol, carbon tetra-
chloride, 1,2-dichloropropane (propylene dichloride), and cop-
per salts. It may takeseveral weeks for values to return to
normal. Plasma aspartate aminotransferase and alanine amino-
transferase activities may also be raised in patients on chronic
therapy with drugs such as sodium valproate. Chronic ethanol
abuse is usually associated with increased plasma carbohy-
drate-deficient transferrin and γ-glutamyltransferase activity.
In severe poisoning, especially if a prolonged period of coma,
convulsions, hypothermia, or shock has occurred, there is likely
to be clinical or subclinical muscle injury associated with rhab-
domyolysis and disseminated intravascular coagulation (DIC).
Such damage may also occur as a result of chronic parenteral
abuse of psychotropic drugs. Frank rhabdomyolysis is charac-
terized by high serum aldolase or creatine phosphokinase activ-
ities together with myoglobinuria. This can be detected by test
strips, provided there is no hematuria. In serious poisoning, for
example with theophylline or with strychnine, or after a pro-
longed period of convulsions, high serum or plasma potassium,
uric acid, and phosphate concentrations may indicate the onset
of myoglobinuria and of acute renal failure.
Cholinesterase Activity
Systemic toxicity from carbamate and organophosphorus insec-
ticides is due largely to inhibition of acetylcholinesterase (acetyl-
choline acetylhydrolase, EC 3.1.1.7) in nerve synapses.
Cholinesterase (acylcholine acylhydrolase, EC 3.1.1.8), derived
initially from the liver, is also present in plasma, but inhibition
of plasma cholinesterase is not thought to be physiologically
important. Cholinesterase and acetylcholinesterase are different
enzymes: Plasma cholinesterase may be almost completely
inhibited, whereas acetylcholinesterase itself may still possess
50% activity. This relative inhibition varies between different
compounds and with the route of absorption; with interindivid-
ual differences; as well as whether exposure has been acute,
chronic, or acute-on-chronic. In addition, individual carbamates
and organophosphates differ in the rate at which (acetyl)cholin-
esterase inhibition is reversed after acute exposure.
In practice, plasma cholinesterase is a useful indicator of expo-
sure to organophosphorus compounds or carbamates, and a nor-
mal plasma cholinesterase activity effectively excludes serious
poisoning by these compounds. The difficulty lies in deciding
whether a low activity is indeed due to poisoning or to some other
physiologic, pharmacologic, or genetic cause. The diagnosis can
sometimes be assisted by detecting a poison or metabolite in a
body fluid. Alternatively, pralidoxime, used as an antidote in poi-
soning with organophosphorus insecticides, may be added to a
second portion of the sample at an appropriate concentration and the
cholinesterase assay repeated. If the inhibition of cholinesterase
activity is reversed by pralidoxime, this obviously suggests the
presence of a cholinesterase inhibitor in the sample.
Red blood cell acetylcholinesterase activity can be measured,
but this enzyme is membrane-bound, and the apparent activity
depends on the methods used in solubilization and separation
from residual plasma cholinesterase. Alternatively, quinidine
sulfate can be added to inhibit plasma cholinesterase while red
blood cell acetylcholinesterase is being measured (13). Red
blood cell acetylcholinesterase activity also depends on the rate
of erythropoiesis. Newly formed erythrocytes have a high activ-
ity, which diminishes with time. Hence, red blood cell acetylcho-
linesterase activity is a function of the number and age of the cell
population. However, if the activities of plasma cholinesterase
and red blood cell acetylcholinesterase are low, the likelihood of
poisoning due to either organophosphorus compounds or car-
bamates is strong.
Zinc Protoporphyrin
Lead inhibits ferrochelatase, the enzyme that catalyzes the
incorporation of ferrous iron into protoporphyrin IX to form
heme. Excessive exposure to lead thus results in an increase in
the concentration of protoporphyrin (which is complexed with
zinc) in newly formed erythrocytes. Blood zinc protoporphyrin
(ZPP) concentrations in unexposed individuals are usually less
than 2 µg/g hemoglobin. In the absence of iron-deficiency ane-
mia, which also increases ZPP, blood lead concentrations in the
range 350 to 450 µg/L in males (250 to 350 µg/L in females) are
associated with increased ZPP concentrations. A blood ZPP con-
centration of 7 µg/g hemoglobin equates to a blood lead concen-
tration of approximately 500 µg/L if lead exposure is constant.
The increase in ZPP is not immediate in newly exposed individ-
uals because it depends on the rate of formation of erythrocytes;
the lag period may be up to 2 months in duration. On the other
hand, if exposure ceases, blood ZPP may remain elevated for a
year or more. This test is used in conjunction with measurement
of blood lead concentrations (14).
Ceruloplasmin
Ceruloplasmin is a blue glycoprotein that contains 6 to 8 copper
atoms per molecule. Plasma ceruloplasmin normally carries
some 95% of the copper in the blood. Normal plasma ceruloplas-
min concentrations are 0.2 to 0.4 g/L. In Wilson’s disease,
plasma ceruloplasmin is less than 0.25 g/L; patients with this
disease may have plasma copper concentrations that are 50% of
normal, but liver and urine copper concentrations may be
greatly elevated.
Blood Clotting
Prolongation of the prothrombin time (normally expressed as a
ratio to a control) is a valuable early indicator of hepatic damage
in poisoning with compounds such as acetaminophen; chlori-
nated hydrocarbons (e.g., carbon tetrachloride); isoniazid; iron
salts; phenylbutazone and certain fungi, notably Amanita phal-
loides. The prothrombin time and other measures of blood clot-
ting are likely to be abnormal in acute poisoning with
rodenticides such as warfarin and related compounds, and after
overdosage with heparin or other anticoagulants. Coagu-
lopathies may also occur as a side effect of antibiotic therapy.
The occurrence of DIC together with rhabdomyolysis in severe
poisoning (prolonged coma, convulsions, shock) has been dis-
cussed. DIC occurs commonly after bites from poisonous snakes
and has been reported in severe poisoning with monoamine oxi-
dase inhibitors, phencyclidine, and amphetamines and related
stimulants.
Carboxyhemoglobin and Methemoglobin
Blood carboxyhemoglobin measurements can be used to assess
the severity of acute carbon monoxide poisoning and to monitor
exposure to this compound. Blood carboxyhemoglobin mea-
surements are also useful in monitoring methylene chloride
exposure because it is metabolized to carbon monoxide (15).
However, carboxyhemoglobin is dissociated rapidly once the
patient is removed from the contaminated atmosphere, and, thus,
the sample should be obtained as soon as possible after admis-
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80: ROLE OF THE LABORATORY IN THE DIAGNOSIS AND MANAGEMENT OF POISONING 343
sion. Even then, blood carboxyhemoglobin correlates poorly
with clinical features of toxicity (Table 8).
Methemoglobin (oxidized hemoglobin) may be formed after
ingestion of dapsone, phenacetin, and strong oxidizing agents
such as chlorates, nitrates, and nitrites [including aliphatic
nitrites such as isobutyl and isopentyl (amyl) nitrites (16)].
Methemoglobinemia can also be induced by exposure to aniline
and to aromatic nitro-compounds such as nitrobenzene and
some of its derivatives. Methemoglobinemia may be indicated
by the presence of dark chocolate–colored blood. Blood met-
hemoglobin can be measured but is unstable, and the use of
stored samples is thus unreliable.
Hematocrit
Acute or acute-on-chronic poisoning with ethanol, iron salts,
indomethacin, salicylates, and other nonsteroidal anti-inflam-
matory drugs can cause gastrointestinal bleeding leading to ane-
mia.Anemia may also result from chronic exposure to
compounds that interfere with heme synthesis, such as lead, or
that induce hemolysis either directly (arsine, stibine, mercurials)
or indirectly because of glucose 6 phosphate dehydrogenase
deficiency (chloroquine, primaquine, chloramphenicol, nirida-
zole, nitrofurantoin). Hemolysis has also been reported in severe
poisoning with 1,2-propanediol (17).
Leukocyte Count and Platelet Count
Increases in the leukocyte (white blood cell) count often occur in
acute poisoning. This may be in response to metabolic acidosis
due to ingestion of, for example, ethylene glycol, methanol, or
theophylline, or may be secondary to hypostatic pneumonia
after prolonged coma or another source of sepsis such as snake-
bite. Leukocytopenia and thrombocytopenia may complicate
overdosage with colchicine and cytotoxic drugs. Thrombocyto-
penia may also result from DIC.
ANALYTICAL TOXICOLOGY
A range of powerful chromatographic methods, ligand immu-
noassays, and other techniques (Tables 9 and 10) are available to
the analytical toxicologist. However, it remains impossible to look
for all poisons in all samples at the sensitivity required. It is there-
fore vital that the reason for any analysis is kept clearly in view.
Although the underlying principles remain the same in the differ-
ent branches of analytical toxicology, the nature and amount of
specimen available can vary widely, as may the time-scale over
which the result is required and the purpose for which the result
is to be used. All these factors may in turn influence the choice of
methods for a particular analysis. Cases in which toxicologic anal-
yses are requested tend to fall into (a) emergency and general hos-
pital toxicology, including poisons screening and (b) more
specialized categories, such as forensic toxicology, screening for
drugs of abuse, therapeutic drug monitoring (TDM), and occupa-
tional/environmental toxicology. There is, however, considerable
overlap amongst all of these areas.
TABLE 8. Blood carboxyhemoglobin saturation 
and clinical features of toxicity
Carboxyhemoglobin 
saturation (%) Clinical features
<1 Endogenous carbon monoxide production
3–8 Cigarette smokers
<15 Heavy (30–50 cigarettes/d) smokers
>20 Headache, weakness, dizziness, impaired vision, 
syncope, nausea, vomiting, diarrhea (patients 
with heart disease are at special risk)
>50 Coma, convulsions, bradycardia, hypotension, 
respiratory depression, death
TABLE 9. Some methods for the analysis of drugs and 
other organic poisons in biologic samples
Principle Technique
Chemical Color test
Electrochemical Biosensors
Differential pulse polarography
Spectrometric Mass spectrometry, also known as mass frag-
mentography
Nuclear magnetic resonance
Spectrophotofluorimetry
Ultraviolet/visible absorption spectrophotometry
Chromatographic Gas (liquid) chromatography
(High-performance) liquid chromatography
(High-performance) thin-layer chromatography 
Super-critical fluid chromatography 
Electrophoretic Capillary (zone) electrophoresis
Immunoassay Agglutination inhibition
Apoenzyme reactivation immunoassay system 
Cloned enzyme donor immunoassay
Enzyme-linked immunosorbent assay
Enzyme-multiplied immunoassay technique 
Fluorescence polarization immunoassay 
Hemagglutination inhibition 
Particle concentration fluoroimmunoassay
Radioimmunoassay 
Substrate-labeled fluoroimmunoassay
Enzyme-based assay —
Receptor-based assay —
TABLE 10. Some methods for the analysis of toxic 
metals in biologic materials
Technique Mode Variant
Electrochemical Potentiometric Ion selective electrodes
Coulometric (Differential pulse) polarog-
raphy
Anodic/cathodic stripping 
voltametrya
Spectrophotometric Atomic emission Flame photometryb
Flame
Spark-arc
Direct current plasma
Inductively coupled plasma
Atomic absorption Flame
Hydride
Furnace
Cold vapor
X-ray Fluorescence
Nuclear Neutron activation
Proton activation
Mass spectrometry — Spark source (includes iso-
tope dilution)
Inductively coupled plasma
aAlso known as potentiometric stripping analysis.
bNormally refers to the use of filters to select the assay wavelength—used mainly for 
potassium, lithium, and sodium.
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344 I: GENERAL APPROACH TO THE POISONED PATIENT
Units of Measurement
In the United Kingdom and in other parts of Europe, some labora-
tories report analytical toxicology data in amount concentration
using what purport to be International System of Units (SI) molar
units (µmol/L, and so forth), whereas others continue to use mass
concentration [so-called “traditional units” (mg/L, and so forth or
even mg/dl)], which, in fact, have equal validity as regards SI. The
arguments in this debate have been reviewed (18). Reporting the
results of analytical toxicology measurements in mass concentra-
tion is logical while drugs are still dispensed and pesticides and
other chemicals are still quantified for use in mass units. Indeed,
mass concentration has to be used in the case of gentamicin and
other analytes with no fixed relative molecular mass (molecular
weight), and mass concentration should also be used if there is
uncertainty as to the entity being measured in a particular assay.
Most published analytical toxicology data are presented in SI
mass units per milliliter or per liter of the appropriate fluid, or
units that are numerically equivalent in the case of aqueous
solutions:
[parts per million] = µg/g = µg/cm3 = µg/ml = mg/L = 
mg/dm3 = g/m3
However, although the liter (= dm3) is a convenient volume for
laboratory and domestic use, it is not, in fact, an SI unit, and it can
be argued that the cubic meter or submultiples thereof should be
used instead. Clinical pharmacologists are, after all, quite accus-
tomed to calculating drug dosage per square meter body surface
area, and, thus, expressing drug concentrations per cubic meter of
plasma is consistent here. For measurements of concentrations in
solid tissues (hair, nails, liver, and so forth), then, SI mass units
should be used throughout (e.g., µg/g). Clearly the use of either
the solidus or the negative superscript convention to mean per or
divided by in conjunction with symbols in written reports is a mat-
ter for local decision taking into account SI guidelines (18). An
exception is when preparing written statements for a court of law
or other purpose outside the normal reporting channels. In such
cases, it is advisable to write out the whole unit of measurement
in full (e.g., milligrams per liter) on every occasion.
Conversion from mass concentration (ρ) to amount concen-
tration (c) (molar units) and vice versa is simple if the molar mass
(M) of the compound of interest is known. The following is an
example of a compound with a molar mass of 151.2 g/mol:
c = ρ/M [e.g., (1 mol/L) = (151.2 g/L)/(151.2 g/mol)]
ρ = c/M [e.g., (151.2 g/L) = (1 mol/L) × (151.2 g/mol)]
However, such conversions always carry a risk of error. Spe-
cial care is needed in choosing the correct molar mass if the drug
is supplied as a salt, hydrate, and so forth. This can cause great
discrepancies, especially if the contribution of the accompany-
ing anion or cation is high. Most analytical measurements are
expressed in terms of free acid or base and not salt. Relative
atomic or molecular masses (atomic or molecular weights) and
conversion factors (SI mass and amount concentration) for mea-
surements in blood and other fluids for some compounds of
interest are given in Appendices II and III.
GENERAL TOXICOLOGY
Many difficulties may be encountered when performing quali-
tative and quantitative analyses for poisons, especially if labora-
tory facilities are limited. The substances that may be present
include gases such as carbon monoxide, drugs, solvents, pesti-cides, metal salts, and naturally occurring toxins. Some poisons
may be pure chemicals and others complex mixtures. Plasma
concentrations associated with serious toxicity range from µg/L
in the case of cardiac glycosides such as digoxin to g/L in the
case of ethanol. New drugs, pesticides, and other compounds
continually present novel analytical challenges.
Diagnosis of Poisoning
Tests for poisons that a patient is thought to have taken and for
which specific therapy is available are often given priority. How-
ever, a defined series of tests (a screen) is needed in the absence of
clinical or other evidence to indicate the poisons involved. If pos-
sible, this screen should be tailored to the poisons commonly
encountered in a particular country—in Western Europe and
North America, for example, drugs have been taken by most poi-
soned patients admitted to the hospital. However, pesticides are
a major problem in many other countries. Screening for pesticides
is particularly difficult because such a wide variety of compounds
may be encountered. Before starting an analysis, it behoves the
analyst to obtain as much information about the patient as possi-
ble including medical and social history, especially any history of
alcohol or drug abuse; treatment in hospital including drug ther-
apy; and the results of laboratory and/or other investigations. It
is also important to be aware of the timing of the sample in rela-
tion to the time of the suspected ingestion or exposure because
this may influence the interpretation of results.
The specialized nature of analytical toxicologic investiga-
tions dictates that facilities are concentrated in centers that are
often remote from the patient. The laboratory may undertake a
range of analyses in addition to emergency toxicology. Fre-
quently, routine clinical chemical tests are performed at one site,
whereas more complex toxicologic analysis is performed by a
different department or at a separate site. Despite this, the
importance of direct liaison between the physician treating the
patient and the analytical toxicologist cannot be overempha-
sized. Ideally, this liaison should commence before specimens
are collected, because some analytes, heavy metals for example,
require special precautions in specimen collection (Table 3). At
the other extreme, residues of samples held in a clinical chemis-
try laboratory or by other departments, for example, in the acci-
dent and emergency refrigerator, can be invaluable if the
possibility of poisoning is only raised in retrospect.
All relevant information about a patient gathered from a clini-
cian, nurse, or poisons information specialist should be recorded in
the laboratory using a suitably designed form. A note of a patient’s
occupation or hobbies can be valuable as this may indicate access
to particular poisons. Cyanide poisoning may result from accidents
in electroplating establishments, for example, whereas poisoning
with sodium barbitone is now encountered most frequently among
laboratory workers. Information on the drugs prescribed for the
patient, and indeed the patient’s relatives, is especially important
as this may not only reveal the poisons ingested but also warns that
a compound detected may be a drug prescribed for the patient.
Chlorpromazine metabolites, for example, may be detected in
urine for 18 months after cessation of chronic chlorpromazine ther-
apy as a result of enterohepatic recirculation. Even compounds
given inadvertently can cause serious toxicity in exceptional cir-
cumstances. Benzyl alcohol used as a preservative in intravenous
fluids has caused fatal poisoning in young children. Iodine used
intraabdominally after surgery has resulted in death.
The range of analyses that can be offered by specialized labora-
tories, some on an emergency basis, is shown in Table 11. General
toxicologic analyses (poisons screens) must use reasonable
amounts of commonly available samples (Table 2). If any tests are
to influence immediate patient management, the (preliminary)
results should be available within 2 to 3 hours of receiving the
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80: ROLE OF THE LABORATORY IN THE DIAGNOSIS AND MANAGEMENT OF POISONING 345
TABLE 11. Summary of drugs and other common poisons detected underivatized in blood and in urine by commonly available methods
Acidic and neutral drugs Cathine Drugs/drug groups detectable in urine/gastric con-
tents (gas-liquid chromatography)Barbiturates and anticonvulsants (blood, gas-
liquid chromatography)
Chloroquine
Chlorpheniramine Most of the drugs previously listed under the 
heading Detectable in blood after overdose, 
including:
Amylobarbitone Chlorpromazine
Butobarbitone Citalopram
Caffeine Cocaine β-Adrenoceptor blockers (but not atenolol, 
sotalol)Carbamazepine Codeine
Chlormethiazole Clomipramine Amphetamines (includes methylenedioxyam-
phetamine, methylenedioxyethylamphet-
amine, and methylenedioxymethamphetamine)
Chlorpropamide Clozapine
Ethosuximide Cyclizine
Glutethimide Desipramine Antidysrhythmics (includes disopyramide, 
flecainide, mexiletine)Ibuprofen Dextromoramide
Meprobamate Dextropropoxyphene (propoxyphene)b Antibiotics (includes chloramphenicol, metroni-
dazole, trimethoprim)Methaqualone Diethylpropion
Methocarbamol Dihydrocodeine Anticholinergics (includes dicyclomine, ben-
zhexol, procyclidine)Methohexitone Diltiazem
Methsuximide Dipipanone Antihistamines (includes chlorpheniramine, 
cyclizine, diphenhydramine, terfenadine)Methyprylone Disopyramide
Metronidazole Dothiepin (Prothiden) Local anesthetics (includes bupivacaine, lido-
caine, mepivacaine, prilocaine)Paracetamol Doxepin
Pentobarbitone Fenfluramine Narcotic analgesics (but not heroin/morphine)
Phenazone Fluconazole Pesticides (includes some chlorinated pesticides, 
and some organophosphorus compounds 
and carbamates only)
Phenobarbitone Fluoxetine
Phenylbutazone Fluvoxamine
Phenytoin Haloperidol Phenothiazines (but not flupentixol and some 
other low-dose compounds)Primidone Hydroxyzine
Propofol Imipramine Tricyclic and related antidepressants (includes 
amitriptyline, clomipramine, desipramine, 
dothiepin, imipramine, nortriptyline)
Quinalbarbitone Lignocaine (lidocaine)c
Thiopentone Lofepramined
Tolbutamide Loxapine Atropine
Valproate Maprotiline Chlormethiazole
Barbiturates and anticonvulsants (urine, thin-
layer chromatography)
Methylenedioxyamphetamine Hyoscine (scopolamine)
Methylenedioxyethylamphetamine Ketamine
Amylobarbitone Methylenedioxymethamphetamine Nicotinee
Butobarbitone Methadone Propofol
Pentobarbitone Methylamphetamine Zopiclone
Phenobarbitone Metoclopramide Drugs detectable in urine/gastric contents (thin-
layer chromatography)Phenytoin Mianserin
Primidone Minaprine Those drugs previously listed under the heading 
Drugs/drug groups detectable in urine/gastric 
contents, β-adrenoceptor blockers, pheno-
thiazines, and also:
Quinalbarbitone Mirtazapine
Thiopentone Nefopam
Theophylline Nortriptyline
Analgesics (blood/urine, various methods) Olanzapine Cimetidine
Acetaminophen (paracetamol) Orphenadrine Heroin
Salicylatesa Pethidine (meperidine) Mefenamic acid
Nonsteroidal antiinflammatory drugs (blood, 
high-performance liquid chromatography)
Phentermine Morphine
Phenylpropanolamine Ranitidine
Diflunisal Procainamide Hypnotics/anxiolytics
Fenoprofen Procyclidine Volatile hypnotics (blood, gas-liquid chromatography)
Ibuprofen Propranolol Ethchlorvynol
Indomethacin Protriptyline Chlormethiazole
Ketoprofen (Pseudo)ephedrine 2,2,2-Trichloroethanolf
Mefenamic acid Pyrimethamine Benzodiazepines (blood, gas-liquid chromatogra-
phy–electron capture detection)Naproxen Quetipine
Piroxicam Quinine/quinidine Alprazolam
Antiasthmatics (blood, high-performance liq-
uid chromatography)
Remoxipride Bromazepam
RisperidoneChlordiazepoxide
Caffeine Sertraline Clobazam
Theophylline Strychnine Clonazepam
Basic drugs Sulpiride Diazepam
Detectable in blood after overdose (gas-liquid 
chromatography)
Terodiline Flunitrazepam
Thioridazine Flurazepam
Amisulpride Tranylcypromine Lorazepam
Amitriptyline Trazodone Lormetazepam
Amoxapine Trimethoprim Midazolam
Amphetamine Trimipramine Nitrazepam
Atracurium Venlafaxine Nordazepam
Benzhexol Verapamil Oxazepam
Brompheniramine Zopiclone Prazepam
Temazepam
Triazolam
(continued)
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346 I: GENERAL APPROACH TO THE POISONED PATIENT
specimens (1 hour in the case of acetaminophen and ethanol). In
some cases, the presence of more than one poison, for example,
may complicate the analysis, and examination of further speci-
mens from the patient may be required. A quantitative analysis
carried out on whole blood or plasma is usually needed to confirm
poisoning unequivocally, but this may not be possible if laboratory
facilities are limited or if the compound is particularly difficult to
measure. It is important to discuss the scope and limitations of the
tests performed with the clinician concerned and to maintain high
standards of laboratory practice, especially when performing tests
on an emergency basis. It may be better to offer no result rather
than misleading data based on an unreliable test.
Circumstantial evidence of poisoning is often ambiguous,
and thus, if an analysis is indicated, it is often advisable to per-
form a poisons screen routinely in all but the simplest cases. Sim-
ilarly, the analysis should not end after the first positive finding
because additional, hitherto unsuspected compounds may be
present (19). One exception is provided by sublethal carbon
monoxide poisoning, which can be difficult to diagnose even if
carboxyhemoglobin measurements are available—circumstan-
tial evidence of poisoning may here prove invaluable. Of course,
a positive result on a poisons screen does not of itself confirm poi-
soning, because such a result may arise from incidental or occu-
pational exposure or the use of drugs in treatment.
Selective test ordering based on clinical features (toxidromes) has
been advocated. This may be acceptable if there is no doubt about
the diagnosis and no other clinical indications for performing the
tests (20). However, the results of surveys performed to assess
the value of general toxicologic analyses are likely to be different if
the patient presents either a diagnostic or treatment problem.
Indeed, poisoning with certain compounds is not infrequently mis-
diagnosed, especially if the patient presents in the later stages of an
episode. Examples include cardiorespiratory arrest (cyanide), hep-
atitis (acetaminophen), diabetes (hypoglycemics, including ethanol
in young children), paresthesia (thallium), progressive pneumonitis
(paraquat), and renal failure (ethylene glycol).
The trend away from indiscriminate prescribing of barbitu-
rates and nonbarbiturate hypnotics such as glutethimide has led
to a reduction in the frequency with which such compounds are
encountered in acute poisoning in Western Europe and North
TABLE 11. (continued)
Benzodiazepines (urine, immunoassay) Substance abuse (various methods depend-
ing on circumstances; immunoassays 
often group specific for amphetamines 
and opiates)
Ioxynil
Group identification only Fenoprop
Solvents and related compounds 4-Chloro-2-methylphenoxyacetic acid
Volatile substances (blood/urine, gas chroma-
tography) (acetone, ethanol, isopropanol, 
and methanol commonly measured sepa-
rately by direct injection gas chromatogra-
phy; others measured by headspace gas 
chromatography. More details of the range 
of compounds that can be encountered 
are given in Table 20.)
4-Chloro-2-methylphenoxypropionic acid
Amphetamines (urine) 2,4,5-Trichlorophenoxyacetic acid
Amphetamine Bipyridilium herbicides (blood/urine, high-perfor-
mance liquid chromatography)Cathine
Diethylpropion Paraquat
Fenfluramine Diquat
Methylenedioxyamphetamine Chlorinated pesticides (blood, gas-liquid chroma-
tography)Methylenedioxyethylamphetamine
Acetone Methylenedioxymethamphetamine Chlordane
Bromochlorodifluoromethane Methylamphetamine 1,1,1-Trichloro-di-(4-chlorophenyl)ethane
Butane Phentermine Dieldrin
Butanone Phenylpropanolamine Heptachlor
Dichloromethane (Pseudo)ephedrine Lindane
Dimethyl ether Cannabis (urine, as cannabinoids) Pentachlorophenol
Ethanol Cocaine (urine, as benzoylecgonine) Organophosphorus compounds and carbamate insec-
ticides (blood/urine, gas-liquid chromatography)Halothane Lysergic acid diethylamide (urine)
Isobutane Opiates (urine) Carbaryl
Isoflurane Codeine Dimethoate
Isopropanol Dihydrocodeine Malathion
Methanol Heroin Pirimicarb
Nitrous oxide Morphine Pirimiphos methyl
Paraldehyde Pholcodine Toxic metals (see also Table 3)
Propane Diuretics (urine, thin-layer chromatography) Serum
Tetrachloroethylene Thiazides Iron
Toluene Spironolactone Blood
1,1,1-Trichloroethane Laxatives (urine, thin-layer chromatography) Antimony
Trichloroethylene Bisacodyl Arsenic
Xylene Danthron Cadmium
Glycols (blood/urine, gas-liquid chromatog-
raphy)
Phenolphthalein Lead
Rhein (from Senna, for example) Mercury
Ethylene glycol Pesticides Thallium
1,2-Propanediol Chlorophenoxy and hydroxybenzonitrile 
herbicides (blood/urine, high-perfor-
mance liquid chromatography)
Miscellaneous poisons
Essential oils (blood, gas-liquid chromatogra-
phy)
Bromide
Carbon monoxide
Camphor Bromoxynil Cyanide
Cineole 2,4-Dichlorophenoxyacetic acid Lithium
Eugenol 2,4-Dichlorophenoxypropionic acid Digoxin
aMay include aminosalicylate, aspirin, methyl salicylate, and salicylamide if Trinder’s test used (see Table 18).
bQuantitation by high-performance liquid chromatography recommended.
cCommon contaminant from catheter lubricant, and so forth.
dAs desipramine.
eCommonly from tobacco smoke.
fFrom chloral hydrate, dichloralphenazone, trichloroethylene, or triclofos (see Table 18).
gAs carboxyhemoglobin.
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80: ROLE OF THE LABORATORY IN THE DIAGNOSIS AND MANAGEMENT OF POISONING 347
America. However, these compounds still occur from time to
time. Benzodiazepines, tricyclic and related antidepressants,
anticonvulsants, narcotic and other analgesics, nonsteroidal
antiinflammatory drugs, and, of course, ethanol are all encoun-
tered regularly; multiple overdosage is frequent.
Blood is often the easiest specimen to obtain from an uncon-
scious patient and is needed for any quantitative measurements.
Urine is also a valuable specimen because drug or metabolite con-
centrations tend to be higher than in blood, and relatively large
volumes are usually available. Some compounds, such as many
benzodiazepines, however, are extensively metabolized before
excretion, and plasma is then the specimen of choice for detecting
the parent compound. Quantitative measurements in urine are
generally of little use. All poison screens have limitations (21)
(Table 12). Thus, of the drugs commonly used to treat depression,
lithium has to be looked for specifically, usually by use of an ion-
selective electrode, whereas monoamine oxidase inhibitors have
a prolonged action in the body, though plasma concentrations are
low even after overdosage. Any unbound drug is rapidly
excreted and may be difficult to detect except in a urine specimen
obtained soon after the event. Tricyclic antidepressants are lipo-
philic, and thus urinary concentrations even in fatal poisoning
may be below the limit of detection of the method used if death
has occurred relatively soon after the ingestion.
Treatment of Poisoning
Treatment of severely poisoned patients may include intravenous
administration of anticonvulsants, such as diazepam or chlorme-thiazole, or of antidysrhythmics, such as lidocaine, all of which
may be detected if a toxicologic analysis is subsequently per-
formed. Antidotes such as naloxone and antibiotics such as met-
ronidazole or trimethoprim may also be detected. Lidocaine gel
or spray is used as a topical anesthetic and is often an incidental
analytical finding after use, for example, during bladder catheter-
ization or endoscopy (22). Acute poisoning with oral or intrave-
nous lidocaine also occurs (23), and thus interpretation of the
finding of lidocaine must be undertaken cautiously. Drugs or
other compounds may also be given during first aid or investiga-
tive procedures such as lumbar puncture or computerized tomo-
graphic scans and may be detected on subsequent toxicologic
analysis. Iodinated hippuric acids are used as radiographic con-
trast media. The muscle relaxant atracurium, which gives rise to
laudanosine in vivo, is frequently given to facilitate mechanical
ventilation. Even emetine from syrup of ipecacuanha given to
induce vomiting may be detected on subsequent analysis. It is
therefore important that details of all drugs used in therapy are
notified to the laboratory at the time of the initial request.
Antidotes are available for some poisons, and their use is
often required before analytical confirmation of the diagnosis
can be obtained. Lack of response to a particular antidote, how-
ever, must not be used to indicate the absence of particular poi-
sons. Naloxone, for example, rapidly and completely reverses
coma due to opioids such as morphine and codeine without risk
to the patient, except that an acute withdrawal response may be
precipitated in dependent subjects. A lack of response, however,
may not mean that no opioids are present because another, non-
opioid, drug may be the cause of coma; too little naloxone may
have been given; or hypoxic brain damage may have followed a
cardiorespiratory arrest. In such cases, a toxicologic analysis is
needed to establish the nature of any poisons present.
The measurement of plasma concentrations of some poisons is
important because the decision to implement protective treat-
ment, chelation, or active elimination therapy may depend on the
result (Table 13). The decision to institute active elimination ther-
apy is not normally determined solely by plasma concentrations
but depends also on the clinical picture. The duration of such
therapy may again be influenced by plasma concentration mea-
surements. The analytical diagnosis of acetaminophen poisoning
is especially important because within the first 24 hours the clini-
cal features of potentially fatal poisoning are often unremarkable.
Treatment with N-acetylcysteine or methionine, however, must
TABLE 12. Some compounds not detected by commonly 
used overdose-screening procedures
Group Examples
Inorganic 
ions
Arsenic, barium, bismuth, borate, bromide, cadmium, 
copper, cyanide, fluoride, iron, lead, lithium, mer-
cury, sulfide, thallium
Organic 
chemicals
Camphor, carbon disulfide, carbon monoxide, carbon 
tetrachloride, dichloromethane, ethylene glycol, for-
mates, oxalates, petroleum distillates, phenols, tetra-
chloroethylene, toluene, 1,1,1-trichloroethane
Drugs Bretylium, cannabis, clonidine, colchicine, coumarin 
anticoagulants, dapsone, digoxin, glyceryl trinitrate, 
lysergic acid diethylamide, metformin, phenformin, 
salbutamol, tolbutamide
Pesticides Bromomethane, carbamate insecticides, chloralose, 
chlorophenoxy herbicides, dinitrophenol pesti-
cides, fluoroacetates, hydroxybenzonitrile herbi-
cides, organochlorine pesticides, organophosphorus 
insecticides, pentachlorophenol
TABLE 13. Emergency toxicologic analyses 
that may influence active treatment
Treatment Poison
Plasma concentration 
associated with 
serious toxicitya
Protective therapy
N-Acetylcysteine or 
methionine
Acetaminophen 200 mg/L at 4 h, 30 
mg/L at 16 h
Ethanol Ethylene glycol 0.5 g/L
Methanol 0.5 g/L
Antidigoxin Fab antibody 
fragments
Digoxin 6 µg/L
Chelation therapy
Desferrioxamine Aluminium 50–250 µg/L (serum)
Iron 8 mg/L (serum)
Ethylenediamine tetra-
acetate/dimercapto-
succinic acid
Lead 600 µg/L (whole blood)
Antimony 200 µg/L (whole blood)
Dimercaptopropane sul-
fonate
Arsenic 100 µg/L (whole blood)
Bismuth 100 µg/L (whole blood)
Mercury 100 µg/L (whole blood)
Active elimination therapy
Oral Prussian blueb Thallium 300 µg/L (urine)
Alkaline diuresis Chlorophenoxy 
herbicides
0.5 g/L
Barbitone 300 mg/L
Phenobarbitone 100 mg/L
Salicylates 500 mg/L
Hemodialysis/perito-
neal dialysis
Barbitone 300 mg/L
Ethanol 5 g/L
Ethylene glycol 0.5 g/L
Lithium 10 mg/L (1.5 mmol/L)
Methanol 0.5 g/L
Phenobarbitone 100 mg/L
2-Propanol 4 g/L
Salicylates 500 mg/L
aMany factors may modify response in a given patient.
bPotassium ferrihexacyanoferrate.
dart079_080(0282_0358).fm Page 347 Thursday, October 23, 2003 11:00 AM
348 I: GENERAL APPROACH TO THE POISONED PATIENT
be instituted promptly if it is to be effective (Chapter 64). Parace-
tamol poisoning is so common in the United Kingdom and in the
United States that an emergency assay should ideally be per-
formed on samples from all patients aged 10 years or older with
suspected intentional overdose (24). The severity of acute poison-
ing with ethylene glycol and with methanol is best assessed in the
early stages by measurement of plasma concentrations.
Interpretation of Results
Patients often respond differently to a given dose of a given
compound, especially so far as behavioral effects are concerned.
Some of the factors involved, which may include tolerance, age,
drug interactions, disease, and the formation of toxic metabo-
lites, are summarized in Tables 14 and 15. In particular, the
effects of short- and long-term ethanol consumption on drug
and metabolite pharmacokinetics have been reviewed (25).
Compilations of data to assist in the interpretation of analytical
results are available (26,27). The role of pharmacologically active
metabolites has been discussed (28–30).
It is important to bear in mind the time course of the episode
when providing interpretation. For example, results obtained
from samples taken before absorption or distribution are com-
TABLE 14. Some factors that may affect 
interpretation of toxicology results
Acidosis/alkalosis (water-solu-
ble ionizable poisons)
Age
Burns (state of hydration)
Disease
Drug therapy (long term and 
recent)
Duration of exposure
Ethanol consumption (short- 
and long-term)
Formulation (sustained release, 
racemate, and so forth)
Genetics
Hemolysis
Idiosyncrasy
Infection
More than one poison present
Nutrition
Occupation
Pregnancy
Route of exposure (especially if intra-
venous or inhalational rather than 
oral)
Shock
Site of sampling (especially important 
if patient undergoing an infusion 
and in postmortem cases)
Surgery
Time of sampling relative to expo-
sure and/or death
Tolerance
Trauma
See also, Flanagan RJ. Interpretation of analytical toxicology results and unit of mea-
surement conversion factors. Ann Clin Biochem 1998;35:261–267; and Drummer 
OH, Gerostamoulos J. Postmortem drug analysis: analytical and toxicological aspects. 
Ther Drug Monit 2002;24:199–209.
TABLE 15. Some compounds decomposing in vivo or undergoing metabolism to give products of similar or greater toxicity
Compound Toxic decomposition product/metabolite Compound Toxic decomposition product/metabolite
Aldrin Dieldrin Hexane (also 2-hexanone) Hexane-2,5-dione
Alkyl nitriles Cyanide ion Hypochlorites Chlorine
Alkyl nitrites Nitrite ion Lofepramine Desipramine
Aloxiprin Salicylate Loxapine Amoxapine
α-Amanitin [Reactive intermediates] Metaldehyde Acetaldehyde (?)
Amoxapine 7-Hydroxyamoxapine, 8-hydroxyamoxapine Methanol Formaldehyde and formate
Aspirin Salicylate MethsuximideN-Desmethylmethsuximide
Benorylate Salicylate and acetaminophen (paracetamol) Methyl salicylate Salicylate
Benzene [Reactive intermediates] Minoxidil Minoxidil sulphate
Benzodiazepinesa N-Demethylated (and/or other) metabolites Morphine Morphine-6-glucuronide
Bopindolol Desbenzoylbopindololb Nitroprusside Cyanide ion
Bufuralol 1-Hydroxybufuralol Paracetamol [Reactive intermediates]
Bupropion Hydroxybupropion, threo- and erythro-
hydroxybupropion
Parathion Paraoxon
Pethidine Norpethidine
Buspirone 1-Pyrimidinylpiperazine Phalloidin [Reactive intermediates]
Camazepam Temazepam Phenacetin Paracetamolc
Carbamazepine Carbamazepine-10,11-epoxide Phenothiazinesa N-Demethylated (and/or other) metabolites
Carbon tetrachloride [Reactive intermediates] Phenylbutazone Oxyphenbutazone
Chloral 2,2,2-Trichloroethanol and trichloracetic acid Phenytoin [Reactive intermediates]
Chlordane Oxychlordane, heptachlor epoxide and others Phosphides Phosphine
Chloroform Phosgene Primidone Phenobarbitone
Clorazepate Nordazepam Procainamide N-Acetylprocainamide
Clozapine Norclozapine Prontosil Sulphanilamide
Cyanogenic glycosides Cyanide ion Rifampicin Desacetylrifampicin
Cyclophosphamide Acrolein, phosphoramide mustard Salicylamide Salicylate
Dichloralphenazone 2,2,2-Trichloroethanol and trichloracetic acid Spironolactone Canrenone
Dichloromethane Carbon monoxide Terfenadine Fexofenadine
Dichloropropane [Reactive intermediates] 1,1,2,2-Tetrachloroethane [Reactive intermediates]
3,4-Dihydroxyphenylalanine 3,4-Dihydroxyphenylethylamine (dopamine) Theophylline Caffeine (neonates only)
Ethylene glycol Glycolate and oxalate Thiocyanate insecticides Cyanide ion
Fenfluramine Norfenfluramine Trichloroethylene 2,2,2-Trichloroethanol and trichloracetic 
acidFluoxetine Norfluoxetine —
Flurazepam Desalkylflurazepam Triclofos 2,2,2-Trichloroethanol and trichloracetic 
acidHalothane [Reactive intermediates] —
Heptachlor Heptachlor epoxide Tricyclic antidepressants N-Demethylated (and/or other) metabolites
Heroin Morphine and morphine-6-glucuronide Trimethadione Dimethadione
Hexamethylmelamine Pentamethylmelamine, tetramethylmelamine
aSome compounds only.
bN-tertiary-Butyl-2-hydroxy-3-(2-methyl-1H-indol-4-yloxy)-1-propylamine.
cHepatorenal toxicity rare possibly because toxic metabolism of paracetamol inhibited by phenacetin.
dart079_080(0282_0358).fm Page 348 Thursday, October 23, 2003 11:00 AM
80: ROLE OF THE LABORATORY IN THE DIAGNOSIS AND MANAGEMENT OF POISONING 349
plete may be misleading, as in the case of acetaminophen and
with sustained release preparations such as those containing
theophylline. Aspects of the pharmacokinetics of drugs in over-
dose have been reviewed (31). Some compounds giving rise to
delayed or irreversible toxicity are listed in Table 16. Plasma
concentration measurements are especially valuable in assess-
ing the prognosis in paraquat poisoning (Chapter 239) (32).
There is much current interest in the role of chirality in drug
action (33). However, although it has been estimated that some
25% of drugs and pesticides are marketed as racemates, there is in
general little need for the enantiomers to be measured separately.
Some compounds that are unstable in whole blood or plasma are
listed in Table 17; special precautions are obviously needed if
these compounds are to be measured. Oxygen rapidly dissociates
carboxyhemoglobin and thus a blood sample should be obtained
as soon as practicable after carbon monoxide poisoning if mea-
surement of carboxyhemoglobin is to be attempted.
Reporting the Result
The results of urgent analyses must be communicated verbally
or electronically to the appropriate physician without delay, and
should be followed by a written report as soon as possible. Most
laboratories produce computer-generated reports. Ideally, con-
firmation from a second, independent method should be
obtained before reporting positive findings. However, this may
not always be practicable, especially if only simple methods
(e.g., colorimetric tests) are available. In such cases, it is vital that
the appropriate positive and negative controls have been ana-
lyzed together with the specimen.
Although it seems straightforward for the analyst to interpret
the results of analyses in which no compounds were detected,
such results are sometimes difficult to convey to physicians,
especially in writing. This is because it is important to give infor-
mation as to the poisons excluded by the tests performed with all
the attendant complications of the scope, limits of sensitivity,
and selectivity of the analyses and other factors such as sam-
pling variations. Because of the potential medicolegal and other
implications of any toxicologic analysis, it is important to avoid
jargon, such as negative, or sweeping statements, such as absent
or not present. The phrase not detected should convey precisely
the laboratory result, especially when accompanied by a state-
ment of the specimen analyzed and the limit of sensitivity of the
test (detection limit). However, it can still be difficult to convey
the scope of analyses such as that of gas-liquid chromatography
(GLC) for acidic and basic drugs as discussed previously. Even
with relatively simple tests such as Trinder’s test normally per-
formed on plasma or urine to detect aspirin ingestion, a number
of other salicylates, including methyl salicylate also react.
One way of giving at least some of this information in a written
report is to create a numbered list of the compounds or groups of
compounds normally detected by commonly used procedures. If
these groups are listed on the back of the report form, for example,
then it is a relatively simple matter to refer to the qualitative tests
performed by number and, thus, to convey at least some of the
information required. Problems may arise if a hospital or other
laboratory transcribes a report from a toxicology laboratory onto
its own report form that is then forwarded to the physician. The
units used for any measurement may be converted (sometimes
erroneously) from mass to amount concentration (molar units), and
any interpretation of the result may be discarded. Information on
the drugs looked for but not found may also be lost.
ANALYTICAL METHODS
Drugs and Pesticides
Specialized laboratories use a combination of solvent extraction
and thin-layer chromatography (TLC) together with GLC using
either flame-ionization or selective (nitrogen/phosphorus, elec-
tron capture and/or mass spectrometric) detectors as the basis
TABLE 16. Irreversible and delayed toxicity
Compound/group of compounds
Acetaminophen (hepatic, and sometimes renal toxicity)
Acetylcholinesterase inhibitors (organophosphorus insecticides, nerve gases)
Alkyl bromides (e.g., bromomethane)
α-Amanitin (hepatorenal toxicity)
Anticoagulants (e.g., warfarin and other coumarins/indanediones)
Antineoplastic agents (e.g., cyclophosphamide)
Aspirin
Carbon monoxide (neuropsychiatric sequelae)
Carbon tetrachloride (hepatorenal toxicity)
Chloroform (hepatorenal toxicity)
Chloroquine (retinal toxicity)
1,2-Dichloroethane (hepatorenal toxicity)
1,2-Dichloropropane (hepatorenal toxicity)
Ethylene glycol (renal and central nervous system toxicity)
Halothane (hepatic toxicity—rare)
Heavy metals (e.g., cadmium, lead, mercury, thallium)
Hexane and 2-hexanone (peripheral neuropathy)
Iron salts
Methanol (retinal and central nervous system toxicity)
Monoamine oxidase inhibitors
Paraquat (lung toxicity)
Phalloidin (hepatorenal toxicity)
Phenytoin (hepatic toxicity—rare)
Quinine (retinal toxicity)
Sustained-release preparations (e.g., theophylline)
TABLE 17. Some drugs, metabolites, and other 
poisons unstable in whole blood or plasma
Compound/group of compounds (examples)
Volatile compounds
All (aerosol propellants, anesthetic gases, carbon monoxide, etha-
nol, mercury, organic solvents, paraldehyde)
Nonvolatile