TOXICOLOGY 2024. [email protected]
EMMANUELAKPABLI1
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Jul 23, 2024
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About This Presentation
TOXICOLOGY 2024.pdf
Slide Content
INTOXICATION
DR MRS SANDRA A N A CRABBE
MGCP, MBChB
DR MRS SANDRA A N A CRABBE
MGCP, MBChB
Objectives
Introduction
•Toxicology is a broad multidisciplinary science whose goal is to
determine the effects of chemical agents on living systems
•Toxins can range from pharmaceuticals , herbals, household products,
environmental agents, occupational chemicals, drugs of abuse and
chemical terrorism threats
•In the USA poisoning (both intentional and unintentional) is one of
the top 10 causes of injury-related death in all adult age groups
•Poisons have been with us from the beginning of written history and
Paracelsus rightly said “Everything is poison; there is nothing which is
not. The dose differentiates a poison”
•Toxicology is a broad multidisciplinary science whose goal is to
determine the effects of chemical agents on living systems
•Toxins can range from pharmaceuticals , herbals, household products,
environmental agents, occupational chemicals, drugs of abuse and
chemical terrorism threats
•In the USA poisoning (both intentional and unintentional) is one of
the top 10 causes of injury-related death in all adult age groups
•Poisons have been with us from the beginning of written history and
Paracelsus rightly said “Everything is poison; there is nothing which is
not. The dose differentiates a poison”
Introduction
•In practice, it is neither possible nor necessary to test for all of the
numerous clinical toxins that one may come across
•It is recognized that up to 24 agents account for 80% or more of cases
of intoxication treated in most emergency departments worldwide.
•Also the distribution of these agents is not uniform worldwide, some
more frequently in some locations than others.
•Thus the scope of clinical toxicology testing provided by the
laboratory will also depend on the pattern of local drug use and
available resources
•In practice, it is neither possible nor necessary to test for all of the
numerous clinical toxins that one may come across
•It is recognized that up to 24 agents account for 80% or more of cases
of intoxication treated in most emergency departments worldwide.
•Also the distribution of these agents is not uniform worldwide, some
more frequently in some locations than others.
•Thus the scope of clinical toxicology testing provided by the
laboratory will also depend on the pattern of local drug use and
available resources
Introduction
•There are some recognized situations in which drug/substance testing is
well established, whereas in many other instances of drug toxicity, the
value of drug screening is controversial
a)In the work place
b)For some athletic competitions
c)To monitor drug use during pregnancy
d)To evaluate drug exposure and or withdrawal in new borns
e)To monitor patients in pain management and drug abuse treatment
programs
f)To aid in prompt diagnosis of toxicity for some select drugs/agents for
which specific antidote or treatment modality is required
•There are some recognized situations in which drug/substance testing is
well established, whereas in many other instances of drug toxicity, the
value of drug screening is controversial
a)In the work place
b)For some athletic competitions
c)To monitor drug use during pregnancy
d)To evaluate drug exposure and or withdrawal in new borns
e)To monitor patients in pain management and drug abuse treatment
programs
f)To aid in prompt diagnosis of toxicity for some select drugs/agents for
which specific antidote or treatment modality is required
Introduction
•Drug testing approaches vary
1.Few specific tests (e.g. acetaminophen, salicylate, ethanol, digoxin, iron)
2.Testing for target groups of drugs (e.gstimulant panel, coma panel)
3.Comprehensive general drug screen that might include hundreds of
drugs/substances
•At a minimum, the laboratory should clearly identify and indicate limit of
detection for the drugs that it has the capability of detecting, else a report
of “negative” will be misleading
•Effective clinical toxicology requires close collaboration between the
laboratory and the healthcare team managing the patient
•Drug testing approaches vary
1.Few specific tests (e.g. acetaminophen, salicylate, ethanol, digoxin, iron)
2.Testing for target groups of drugs (e.gstimulant panel, coma panel)
3.Comprehensive general drug screen that might include hundreds of
drugs/substances
•At a minimum, the laboratory should clearly identify and indicate limit of
detection for the drugs that it has the capability of detecting, else a report
of “negative” will be misleading
•Effective clinical toxicology requires close collaboration between the
laboratory and the healthcare team managing the patient
Clinical considerations
•The following information is useful to guide test selection and
interpretation of results.
a)The time and date of the suspected exposure along with the time
and date of sample collection
b)History from the patient or witnesses that might aid in identification
of the toxin
c)Assessment of the physical state of the patient at the time of
presentation
•The following information is useful to guide test selection and
interpretation of results.
a)The time and date of the suspected exposure along with the time
and date of sample collection
b)History from the patient or witnesses that might aid in identification
of the toxin
c)Assessment of the physical state of the patient at the time of
presentation
Analytical consideration
•No single analytical technique is adequate for broad-spectrum drug
detection because of the wide range of drugs of interest. These include
1.Simple inexpensive and rapid tests spot tests
2.Immunoassays
3.Chromatographic and or mass spectrometric techniques
•Currently GC-MS is the most widely used for definitive confirmatory
procedure although LC-MS/MS is increasingly used in clinical and forensic
setting
•Confirmatory testing is mandatory for forensic drug testing (egwork place
test)
•No single analytical technique is adequate for broad-spectrum drug
detection because of the wide range of drugs of interest. These include
1.Simple inexpensive and rapid tests spot tests
2.Immunoassays
3.Chromatographic and or mass spectrometric techniques
•Currently GC-MS is the most widely used for definitive confirmatory
procedure although LC-MS/MS is increasingly used in clinical and forensic
setting
•Confirmatory testing is mandatory for forensic drug testing (egwork place
test)
Analytical considerations
•Critical issues in clinical toxicology include
1.Speed of analysis or turn around time
2.Availability
•Drug analysis that requires several hours to complete or not available
at all hours is of little value in clinical emergencies
•Rapid tests that produce false information can also result in
erroneous diagnostic and therapeutic decisions
•In quite a number of agents, quantitative determination is useful for
guiding management in clinical emergency situations
•In such clinical emergencies results should be ready within an hour
•Critical issues in clinical toxicology include
1.Speed of analysis or turn around time
2.Availability
•Drug analysis that requires several hours to complete or not available
at all hours is of little value in clinical emergencies
•Rapid tests that produce false information can also result in
erroneous diagnostic and therapeutic decisions
•In quite a number of agents, quantitative determination is useful for
guiding management in clinical emergency situations
•In such clinical emergencies results should be ready within an hour
Assignment
Question: Discuss the following as screening procedures for the
detection of drugs
Spot tests
Immunoassays
Point of Care Tests
Planar chromatography
Gas chromatography
High performance liquid chromatography
Question: Discuss the following as screening procedures for the
detection of drugs
Spot tests
Immunoassays
Point of Care Tests
Planar chromatography
Gas chromatography
High performance liquid chromatography
General considerations
•A diagnosis of poisoning is made more often on the basis of clinical than
laboratory findings (primary and secondary survey)
•In all cases of suspected poisoning the following biochemical tests may be
requested
a)Serum urea and electrolytes and liver function tests to assess kidney and
liver function
b)Blood glucose to exclude hypoglycaemia
c)Blood gases to assess acid-base status
•In a few specific poisoning additional biochemical tests may be of value
•A limited toxin screen in urine may be done in many labs but a positive
finding only indicates a toxin has been taken and not the severity of
overdose
•A diagnosis of poisoning is made more often on the basis of clinical than
laboratory findings (primary and secondary survey)
•In all cases of suspected poisoning the following biochemical tests may be
requested
a)Serum urea and electrolytes and liver function tests to assess kidney and
liver function
b)Blood glucose to exclude hypoglycaemia
c)Blood gases to assess acid-base status
•In a few specific poisoning additional biochemical tests may be of value
•A limited toxin screen in urine may be done in many labs but a positive
finding only indicates a toxin has been taken and not the severity of
overdose
Toxins for which biochemical tests are
potentially useful
TOXIN ADDITIONAL TEST
Amphetamine and Ecstasy Creatine kinase , AST
Carbon monoxide Carboxyhaemoglobin
Cocaine Creatine kinase, potassium
Digoxin/cardiac glycosides Potassium
Ethylene glycol Serum osmolality, calcium
Fluoride Calcium and magnesium
Insulin Glucose, C-peptide
Iron Iron, glucose
Lead(chronic) Lead, zinc protoporphyrin
Organophosphate Cholinesterase
Dapsone/oxidizing agents Methaemoglobin
Paracetamol Paracetamol
Salicylate Salicylate
Theophyline Glucose
potentially useful
TOXIN ADDITIONAL TEST
Amphetamine and Ecstasy Creatine kinase , AST
Carbon monoxide Carboxyhaemoglobin
Cocaine Creatine kinase, potassium
Digoxin/cardiac glycosides Potassium
Ethylene glycol Serum osmolality, calcium
Fluoride Calcium and magnesium
Insulin Glucose, C-peptide
Iron Iron, glucose
Lead(chronic) Lead, zinc protoporphyrin
Organophosphate Cholinesterase
Dapsone/oxidizing agents Methaemoglobin
Paracetamol Paracetamol
Salicylate Salicylate
Theophyline Glucose
Measurement of drug levels
•Usually knowledge of the plasma concentration of a toxin will not
alter the treatment of the patient
•Toxins for which measurement is useful include carbon monoxide,
iron, lithium, paracetamol, paraquat, phenobarbitone, phenytoin,
quinine, salicylate and theophylline
•Quantitative analysis will give an indication of the severity of the
poisoning
•Serial analysis provide a guide to the length of time that will elapse
before the effects begin to resolve
•Usually knowledge of the plasma concentration of a toxin will not
alter the treatment of the patient
•Toxins for which measurement is useful include carbon monoxide,
iron, lithium, paracetamol, paraquat, phenobarbitone, phenytoin,
quinine, salicylate and theophylline
•Quantitative analysis will give an indication of the severity of the
poisoning
•Serial analysis provide a guide to the length of time that will elapse
before the effects begin to resolve
General statements on treatment
•Most cases of poisoning are treated conservatively while the toxin is
eliminated by normal metabolism and excretion
•In situations where there is hepatic or renal insufficiency, haemodialysis
(for water soluble toxins) or oral activated charcoal may be used
•These measures are usually used for a small group of toxins including
salycilate, phenobarbitone, alcohols, lithium, carbamazepine and
theophylline
•When active measures are used, plasma toxin concentrations should be
measured
•For a few toxins, there are antidotes
•Most cases of poisoning are treated conservatively while the toxin is
eliminated by normal metabolism and excretion
•In situations where there is hepatic or renal insufficiency, haemodialysis
(for water soluble toxins) or oral activated charcoal may be used
•These measures are usually used for a small group of toxins including
salycilate, phenobarbitone, alcohols, lithium, carbamazepine and
theophylline
•When active measures are used, plasma toxin concentrations should be
measured
•For a few toxins, there are antidotes
Commonly used antidotes
Toxin Antidote
Atropine/hyoscyamine Physostigmine
Benzodiazepenes Flumezanil
Carbon monoxide Oxygen
Cyanide Dicobaltedetate
Digoxin/cardiac glycosides Neutralizing antibodies
Ethylene glycol/methanol Ethanol
Heavy metals Chelating agents
Nitrates/dapsone Methylene blue
Opiates Naloxone
Organophosphates Atropine/pralidoxime
Paracetamol N-acetylcysteine
Salicylate Sodium bicarbonate
Warfarin Vitamin K
Toxin Antidote
Atropine/hyoscyamine Physostigmine
Benzodiazepenes Flumezanil
Carbon monoxide Oxygen
Cyanide Dicobaltedetate
Digoxin/cardiac glycosides Neutralizing antibodies
Ethylene glycol/methanol Ethanol
Heavy metals Chelating agents
Nitrates/dapsone Methylene blue
Opiates Naloxone
Organophosphates Atropine/pralidoxime
Paracetamol N-acetylcysteine
Salicylate Sodium bicarbonate
Warfarin Vitamin K
Toxic syndromes (toxidromes)
•Are clinical syndromes that are essential for the successful recognition
of poisoning patterns. A toxidrome is the constellation of clinical signs
and symptoms that suggests a specific class of poisoning
•The most commonly encountered toxidromes are anticholinergic,
cholinergic, opioid, sympathomimetic, sedative-hypnotic.
•Many may have several overlapping features
•Findings may also be affected by individual variability, comorbidities,
coingestants
•Are clinical syndromes that are essential for the successful recognition
of poisoning patterns. A toxidrome is the constellation of clinical signs
and symptoms that suggests a specific class of poisoning
•The most commonly encountered toxidromes are anticholinergic,
cholinergic, opioid, sympathomimetic, sedative-hypnotic.
•Many may have several overlapping features
•Findings may also be affected by individual variability, comorbidities,
coingestants
Assignment
•Explain broadly the mechanism by which the substances that produce
each of these effects act.
a.Anticholinergic syndrome
b.Cholinergic syndrome
c.Opioid
d.Sedative hypnotics
e.Sympathomimmetics
•Explain broadly the mechanism by which the substances that produce
each of these effects act.
a.Anticholinergic syndrome
b.Cholinergic syndrome
c.Opioid
d.Sedative hypnotics
e.Sympathomimmetics
Symptoms of important toxidromes
Toxidrome Symptom
Anticholinergic Agitation, blurred vision, decreased bowel sounds, dry
skin, fever, flushing, hallucinations, ileus,
lethargy/coma, mydriasis, myoclonus, psychosis,
seizures, tachycardia, urinary retention
Cholinergic Diarrhoea, urination, miosis, bradycardia,
bronchorrhoea, emesis, lacrimation, salivation
Opioid Bradycardia, decreased bowel sounds, hypotension,
hypothermia, lethargy/coma, miosis, shallow
respirations, slow respiratory rate
Sedative-hypnotic Ataxia, blurred vision, confusion, diplopia,
dysesthesias, hypotension, lethargy/coma, nystagmus,
respiratory depression, sedation, slurred speech
Sympathomimetic Agitation, diaphoresis, excessive motor activity,
excessive speech, hallucinations, hypertension,
hyperthermia, insomnia, restlessness, tachycardia,
tremor
Toxidrome Symptom
Anticholinergic Agitation, blurred vision, decreased bowel sounds, dry
skin, fever, flushing, hallucinations, ileus,
lethargy/coma, mydriasis, myoclonus, psychosis,
seizures, tachycardia, urinary retention
Cholinergic Diarrhoea, urination, miosis, bradycardia,
bronchorrhoea, emesis, lacrimation, salivation
Opioid Bradycardia, decreased bowel sounds, hypotension,
hypothermia, lethargy/coma, miosis, shallow
respirations, slow respiratory rate
Sedative-hypnotic Ataxia, blurred vision, confusion, diplopia,
dysesthesias, hypotension, lethargy/coma, nystagmus,
respiratory depression, sedation, slurred speech
Sympathomimetic Agitation, diaphoresis, excessive motor activity,
excessive speech, hallucinations, hypertension,
hyperthermia, insomnia, restlessness, tachycardia,
tremor
Examples of drugs under each toxidrome
•Anticholinergics: Tricyclic antidepressants, Antipsychotic drugs, Antihistamines,
Antimuscarinics
•Cholinergics: They act by producing uncontrolled acetylcholine transmission through
inactivation of cholinesterase enzymes or direct stimulation of acetylcholine receptors.
Organophosphate and carbamate compounds
•Opioid: Mainly used for their analgesic properties. Tendency to addiction due this
analgesic as well as euphoric effects. Morphine, codeine, methadone etc
•Sympathomimetics: Norepinephrine is the neurotransmitter for postganglionic
sympathetic fibres(adrenergic) which enervate skin, eyes, heart, lung, GIT, exocrine
glands and some neuronal tracts in CNS. The physiologic responses to activation of this
system depends on various receptors α1, α2, β1, β2 of which some are excitatory and
others opposing inhibitory responses. Drugs include amphetamines and cocaine
•Sedative-hypnotics: include alcohols, barbiturates and benzodiazepenes. They cause a
dose-dependent depression of the CNS. Used in treating insomnia, anxiety etc.
•Anticholinergics: Tricyclic antidepressants, Antipsychotic drugs, Antihistamines,
Antimuscarinics
•Cholinergics: They act by producing uncontrolled acetylcholine transmission through
inactivation of cholinesterase enzymes or direct stimulation of acetylcholine receptors.
Organophosphate and carbamate compounds
•Opioid: Mainly used for their analgesic properties. Tendency to addiction due this
analgesic as well as euphoric effects. Morphine, codeine, methadone etc
•Sympathomimetics: Norepinephrine is the neurotransmitter for postganglionic
sympathetic fibres(adrenergic) which enervate skin, eyes, heart, lung, GIT, exocrine
glands and some neuronal tracts in CNS. The physiologic responses to activation of this
system depends on various receptors α1, α2, β1, β2 of which some are excitatory and
others opposing inhibitory responses. Drugs include amphetamines and cocaine
•Sedative-hypnotics: include alcohols, barbiturates and benzodiazepenes. They cause a
dose-dependent depression of the CNS. Used in treating insomnia, anxiety etc.
Some common causes of
poisoning
poisoning
Agents that cause cellular hypoxia
•Carbon monoxide and methemoglobin-forming agents interfere with
oxygen transport, resulting in cellular hypoxia. Cyanide interferes with
oxygen use and therefore causes an apparent cellular hypoxia
•Carbon monoxide and methemoglobin-forming agents interfere with
oxygen transport, resulting in cellular hypoxia. Cyanide interferes with
oxygen use and therefore causes an apparent cellular hypoxia
Carbon monoxide (CO)
•Common exogenous sources of carbon monoxide include
1)cigarette smoke,
2)gasoline engines, and
3)improperly ventilated home heating units.
•Small amounts of CO are produced endogenously in the metabolic
conversion of haem to biliverdin. This endogenous production of CO
is accelerated in haemolytic anaemias
•Common exogenous sources of carbon monoxide include
1)cigarette smoke,
2)gasoline engines, and
3)improperly ventilated home heating units.
•Small amounts of CO are produced endogenously in the metabolic
conversion of haem to biliverdin. This endogenous production of CO
is accelerated in haemolytic anaemias
CO
•When inhaled, carbon monoxide binds tightly with the haem Fe
2+
of haemoglobin
to form carboxyhaemoglobin.
•The binding affinity of haemoglobin for CO is approximately 250 times greater
than that for oxygen. Therefore high concentrations of carboxyhaemoglobinlimit
the oxygen content of blood.
•The binding of carbon monoxide to a haemoglobin subunit also increases the
oxygen affinity for the remaining subunits in the haemoglobintetramer. Thus at a
given tissue PO2value, less oxygen dissociates from haemoglobin when CO is also
bound, shifting the haemoglobin-oxygen dissociation curve to the left.
•Consequently, CO
1)not only decreases the oxygen content of blood, but
2)also decreases oxygen availability to tissue, thereby producing a greater degree
of tissue hypoxia than would an equivalent reduction in oxyhaemoglobindue
to hypoxia alone.
•When inhaled, carbon monoxide binds tightly with the haem Fe
2+
of haemoglobin
to form carboxyhaemoglobin.
•The binding affinity of haemoglobin for CO is approximately 250 times greater
than that for oxygen. Therefore high concentrations of carboxyhaemoglobinlimit
the oxygen content of blood.
•The binding of carbon monoxide to a haemoglobin subunit also increases the
oxygen affinity for the remaining subunits in the haemoglobintetramer. Thus at a
given tissue PO2value, less oxygen dissociates from haemoglobin when CO is also
bound, shifting the haemoglobin-oxygen dissociation curve to the left.
•Consequently, CO
1)not only decreases the oxygen content of blood, but
2)also decreases oxygen availability to tissue, thereby producing a greater degree
of tissue hypoxia than would an equivalent reduction in oxyhaemoglobindue
to hypoxia alone.
CO
•Organs with high oxygen demand, such as the heart and brain, are most sensitive
to hypoxia and thus account for the major clinical sequelae of CO poisoning
•A general correlation between blood carboxyhaemoglobinconcentration and
clinical symptoms is given
•Factors other than carboxyhaemoglobinconcentration that contribute to the
toxicity include
1)length of exposure,
2)metabolic activity, and
3)underlying disease, especially cardiac or cerebrovascular disease
•Moreover, low carboxyhaemoglobinconcentrations relative to the severity of
poisoning may be observed if the patient was removed from the CO-
contaminated environment several hours before blood sampling
•Organs with high oxygen demand, such as the heart and brain, are most sensitive
to hypoxia and thus account for the major clinical sequelae of CO poisoning
•A general correlation between blood carboxyhaemoglobinconcentration and
clinical symptoms is given
•Factors other than carboxyhaemoglobinconcentration that contribute to the
toxicity include
1)length of exposure,
2)metabolic activity, and
3)underlying disease, especially cardiac or cerebrovascular disease
•Moreover, low carboxyhaemoglobinconcentrations relative to the severity of
poisoning may be observed if the patient was removed from the CO-
contaminated environment several hours before blood sampling
CO
•Treatment for carbon monoxide poisoning involves:
a)removal of the individual from the contaminated area and
b)the administration of oxygen.
•The half-life of carboxyhaemoglobinis 5 to 6 hours when the patient
breathes room air; it is reduced to about 1.5 hours when the patient
breathes 100% oxygen
•Treatment for carbon monoxide poisoning involves:
a)removal of the individual from the contaminated area and
b)the administration of oxygen.
•The half-life of carboxyhaemoglobinis 5 to 6 hours when the patient
breathes room air; it is reduced to about 1.5 hours when the patient
breathes 100% oxygen
•READ ON CYANIDE AND OTHER METHAEMOGLOBIN FORMING
AGENTS
AGENTS
Ethanol
•There are various alcohols of toxicologic interest and these include ethanol,
methanol, isopropanol, acetone and ethylene glycol
•Most widely used and often abused chemical substance and its measurement is
one of the more frequently performed tests in the laboratory. Frequently, the
other alcohols listed above are included in a battery of test for alcohols for proper
evaluation of the intoxicated patient.
•The principal pharmacological action of ethanol is depression of the central
nervous system(CNS). The CNS effects vary, depending on the blood ethanol
concentration, from
1)euphoria and decreased inhibitions to
2)increased disorientation and loss of voluntary muscle control resulting in
irregular movement and then to
3)coma and death.
•There are various alcohols of toxicologic interest and these include ethanol,
methanol, isopropanol, acetone and ethylene glycol
•Most widely used and often abused chemical substance and its measurement is
one of the more frequently performed tests in the laboratory. Frequently, the
other alcohols listed above are included in a battery of test for alcohols for proper
evaluation of the intoxicated patient.
•The principal pharmacological action of ethanol is depression of the central
nervous system(CNS). The CNS effects vary, depending on the blood ethanol
concentration, from
1)euphoria and decreased inhibitions to
2)increased disorientation and loss of voluntary muscle control resulting in
irregular movement and then to
3)coma and death.
Ethanol
•A blood alcohol concentration of 80mg/dl(0.08%) is established as the
statutory limit for operation of a motor vehicle in most states in the United
States. Not all individuals experience the same degree of CNS dysfunction
at similar blood alcohol concentrations. Moreover, the CNS actions of
ethanol are more pronounced when the blood ethanol concentration is
increasing (absorptive phase) than when it is declining (elimination phase).
•When consumed with other CNS depressant drugs, ethanol exerts a
potentiation or synergistic depressant effect. This has been known to
occur at relatively low alcohol concentrations, and a number of deaths
have resulted from combined ethanol and drug ingestion
•A blood alcohol concentration of 80mg/dl(0.08%) is established as the
statutory limit for operation of a motor vehicle in most states in the United
States. Not all individuals experience the same degree of CNS dysfunction
at similar blood alcohol concentrations. Moreover, the CNS actions of
ethanol are more pronounced when the blood ethanol concentration is
increasing (absorptive phase) than when it is declining (elimination phase).
•When consumed with other CNS depressant drugs, ethanol exerts a
potentiation or synergistic depressant effect. This has been known to
occur at relatively low alcohol concentrations, and a number of deaths
have resulted from combined ethanol and drug ingestion
Ethanol (metabolism)
•Ethanol is metabolized principally by liver alcohol dehydrogenase to
acetaldehyde, which is subsequently oxidized to acetic acid by
aldehyde dehydrogenase.
•The rate of elimination of ethanol from blood varies among
individuals, averaging about 15mg/dL/h for males and 18mg/dL/h for
females.
•The elimination rate is also influenced by drinking practices (e.g.
alcoholics have increased elimination rates caused by enzyme
induction).
•Ethanol is metabolized principally by liver alcohol dehydrogenase to
acetaldehyde, which is subsequently oxidized to acetic acid by
aldehyde dehydrogenase.
•The rate of elimination of ethanol from blood varies among
individuals, averaging about 15mg/dL/h for males and 18mg/dL/h for
females.
•The elimination rate is also influenced by drinking practices (e.g.
alcoholics have increased elimination rates caused by enzyme
induction).
Ethanol
•Ethanol is a teratogen, and alcohol consumption during pregnancy has
been known to result in a baby being born with foetalalcohol spectrum
disorders (FASD).
•These effects may include physical, mental, behavioral, and/or learning
disabilities with possible lifelong implications.
•Other alcohol-related conditions include alcohol-related
neurodevelopmental disorders (ARND) and alcohol-related birth defects
(ARBD).
•In the USA, FASD, ARND, and ARBD affect more newborns every year than
Down syndrome, cystic fibrosis, spina bifida, and sudden infant death
syndrome combined (http://www.nofas.org).
•FASD, ARND, and ARBD are 100% preventable when a woman completely
abstains from alcohol during her pregnancy
•Ethanol is a teratogen, and alcohol consumption during pregnancy has
been known to result in a baby being born with foetalalcohol spectrum
disorders (FASD).
•These effects may include physical, mental, behavioral, and/or learning
disabilities with possible lifelong implications.
•Other alcohol-related conditions include alcohol-related
neurodevelopmental disorders (ARND) and alcohol-related birth defects
(ARBD).
•In the USA, FASD, ARND, and ARBD affect more newborns every year than
Down syndrome, cystic fibrosis, spina bifida, and sudden infant death
syndrome combined (http://www.nofas.org).
•FASD, ARND, and ARBD are 100% preventable when a woman completely
abstains from alcohol during her pregnancy
Laboratory findings characteristic of ingestion
of alcohols
Alcohol Serum osmolalgapMetabolic acidosis
with anion gap
Serum acetone Urine oxalate
Ethanol Pos Neg Neg Neg
Methanol Pos Pos Neg Neg
Isopropranol Pos Neg Pos Neg
Ethylene glycolPos Pos Neg Pos
of alcohols
Alcohol Serum osmolalgapMetabolic acidosis
with anion gap
Serum acetone Urine oxalate
Ethanol Pos Neg Neg Neg
Methanol Pos Pos Neg Neg
Isopropranol Pos Neg Pos Neg
Ethylene glycolPos Pos Neg Pos
ANALGESICS (Acetaminophen)
•In normal dosage, acetaminophen is safe and effective, but it may
cause severe hepatic toxicity or death when consumed in overdose
quantities. Less frequently, nephrotoxicity may also occur.
•The initial clinical findngsin acetaminophen toxicity are relatively mild
and nonspecific (nausea, vomiting, and abdominal discomfort) and
thus are not predictive of impending hepatic necrosis, which typically
begins 24 to 36 hours after a toxic ingestion and becomes most
severe by 72 to 96 hours.
•Although uncommon with severe overdose, coma and metabolic
acidosis may occur before development of hepatic necrosis.
•In normal dosage, acetaminophen is safe and effective, but it may
cause severe hepatic toxicity or death when consumed in overdose
quantities. Less frequently, nephrotoxicity may also occur.
•The initial clinical findngsin acetaminophen toxicity are relatively mild
and nonspecific (nausea, vomiting, and abdominal discomfort) and
thus are not predictive of impending hepatic necrosis, which typically
begins 24 to 36 hours after a toxic ingestion and becomes most
severe by 72 to 96 hours.
•Although uncommon with severe overdose, coma and metabolic
acidosis may occur before development of hepatic necrosis.
Acetaminophen
•Antidotal therapy with N-acetylcysteine (NAC) is most effective when
administered before hepatic injury occurs as signified by elevations of
aspartate aminotransferase (AST) and alanine aminotransferase (ALT).
•Thus the measurement of serum acetaminophen concentration
becomes vital for proper assessment of the severity of overdose and
for making appropriate decisions for antidotal therapy.
•A useful nomogram is available that relates serum acetaminophen
concentration and time following acute ingestion to the probability of
hepatic necrosis.
•Antidotal therapy with N-acetylcysteine (NAC) is most effective when
administered before hepatic injury occurs as signified by elevations of
aspartate aminotransferase (AST) and alanine aminotransferase (ALT).
•Thus the measurement of serum acetaminophen concentration
becomes vital for proper assessment of the severity of overdose and
for making appropriate decisions for antidotal therapy.
•A useful nomogram is available that relates serum acetaminophen
concentration and time following acute ingestion to the probability of
hepatic necrosis.
Acetaminophen (paracetamol)
•Blood samples not to be obtained earlier than 4 hours post ingestion to ensure
absorption is complete
•Applies only to acute and not chronic ingestion
•Not useful if time of ingestion is unknown or is considered unreliable
•If acetaminophen is ingested with another substance that may delay absorption
(e.g. an anticholinergic), patient should be clinically monitored for clinical effects
•Alcoholic patients, fasting or malnourished patients, and patients on long-term
therapy with microsomal enzyme-inducing drugs (anticonvulsants) may have
increased susceptibility to acetaminophen hepatotoxicity, presumably as a result
of induction of cytochrome P450 and, in the case of alcoholics or fasting patients,
depletion of glutathione. In these cases, it has been proposed that the decision
line in the nomogram should be lowered by 50% to 70%.
•Blood samples not to be obtained earlier than 4 hours post ingestion to ensure
absorption is complete
•Applies only to acute and not chronic ingestion
•Not useful if time of ingestion is unknown or is considered unreliable
•If acetaminophen is ingested with another substance that may delay absorption
(e.g. an anticholinergic), patient should be clinically monitored for clinical effects
•Alcoholic patients, fasting or malnourished patients, and patients on long-term
therapy with microsomal enzyme-inducing drugs (anticonvulsants) may have
increased susceptibility to acetaminophen hepatotoxicity, presumably as a result
of induction of cytochrome P450 and, in the case of alcoholics or fasting patients,
depletion of glutathione. In these cases, it has been proposed that the decision
line in the nomogram should be lowered by 50% to 70%.
Acetaminophen (metabolism)
•Acetaminophen is normally metabolized in the liver to glucuronide (50%-
60%) and sulfate (-30%) conjugates. A smaller amount (-10%) is
metabolized by a cytochrome P450 mixed-function oxidase pathway that is
thought to involve formation of a highly reactive intermediate (N-
acetylbenzoquinoneimine). This intermediate normally undergoes
electrophilic conjugation with glutathione and then subsequent
transformation to cysteine and mercapturic acid conjugates of
acetaminophen.
•With acetaminophen overdose, the sulfationpathway becomes saturated,
and consequently a greater portion is metabolized by the P450 mixed
function oxidase pathway.
•When the tissue stores of glutathione become depleted, arylation of
cellular molecules by the benzoquinoneimineintermediate leads to hepatic
necrosis.
•Acetaminophen is normally metabolized in the liver to glucuronide (50%-
60%) and sulfate (-30%) conjugates. A smaller amount (-10%) is
metabolized by a cytochrome P450 mixed-function oxidase pathway that is
thought to involve formation of a highly reactive intermediate (N-
acetylbenzoquinoneimine). This intermediate normally undergoes
electrophilic conjugation with glutathione and then subsequent
transformation to cysteine and mercapturic acid conjugates of
acetaminophen.
•With acetaminophen overdose, the sulfationpathway becomes saturated,
and consequently a greater portion is metabolized by the P450 mixed
function oxidase pathway.
•When the tissue stores of glutathione become depleted, arylation of
cellular molecules by the benzoquinoneimineintermediate leads to hepatic
necrosis.
Pathways of acetaminophen metabolism
Acetaminophen
•Specific therapy for acetaminophen overdose is the administration of N-
acetylcysteine (NAC), which probably acts as a glutathione substitute. NAC may
also provide substrate to replenish hepatic glutathione or to enhance sulfate
conjugation or both.
•The time of administration of NAC is critical. Maximum efficacy is observed when
NAC is administered within 8 hours, but efficacy then declines sharply between
18 and 24 hours after ingestion.
•The antidote may have some beneficial effects even after liver injury has
occurred, presumably by its ability to improve tissue oxygen delivery and use.
•If the serum acetaminophen results are not available locally within 8 hours of
suspected ingestion, treatment with NAC should begin. This treatment may be
discontinued if belated assay results indicate that it is not warranted
•Specific therapy for acetaminophen overdose is the administration of N-
acetylcysteine (NAC), which probably acts as a glutathione substitute. NAC may
also provide substrate to replenish hepatic glutathione or to enhance sulfate
conjugation or both.
•The time of administration of NAC is critical. Maximum efficacy is observed when
NAC is administered within 8 hours, but efficacy then declines sharply between
18 and 24 hours after ingestion.
•The antidote may have some beneficial effects even after liver injury has
occurred, presumably by its ability to improve tissue oxygen delivery and use.
•If the serum acetaminophen results are not available locally within 8 hours of
suspected ingestion, treatment with NAC should begin. This treatment may be
discontinued if belated assay results indicate that it is not warranted
Acetaminophen (measurement)
•Many spectrophotometric methods are available for the determination of
acetaminophen. In general, these methods are relatively easy to perform
but are subject to various interferences such as bilirubin or bilirubin
byproducts absorbing at similar wavelengths.
•Some methods measure the nontoxic metabolites and the potentially toxic
parent acetaminophen, and thus may produce especially misleading
results. Therefore, only methods specific for parent acetaminophen should
be used.
•Immunoassaysare widely used for this purpose, as they are rapid, easily
performed, and accurate.
•Many spectrophotometric methods are available for the determination of
acetaminophen. In general, these methods are relatively easy to perform
but are subject to various interferences such as bilirubin or bilirubin
byproducts absorbing at similar wavelengths.
•Some methods measure the nontoxic metabolites and the potentially toxic
parent acetaminophen, and thus may produce especially misleading
results. Therefore, only methods specific for parent acetaminophen should
be used.
•Immunoassaysare widely used for this purpose, as they are rapid, easily
performed, and accurate.
Acetaminophen (measurement)
•A different spectrophotometric approach uses arylacylamide
amidohydrolase to hydrolyze acetaminophen (but not conjugates) to p-
aminophenol and acetate. Subsequent formation of the absorbing species
depends on the reaction of generated p-aminophenol with 8-
hydroxyquinoline or o-cresol.
•Arylacylamideamidohydrolase methods are susceptible to interference by
NAC, bilirubin, and immunoglobulin (Ig)M monoclonal immunoglobulins.
•Most chromatographic methods are very accurate and are considered
reference procedures.
•A qualitative, one-step lateral flow immunoassay (cutoff of 25µg/mL or
165µmol/L)may be suitable for point-of-care (POC) application, yet it has
a low positive predictive value.
•A different spectrophotometric approach uses arylacylamide
amidohydrolase to hydrolyze acetaminophen (but not conjugates) to p-
aminophenol and acetate. Subsequent formation of the absorbing species
depends on the reaction of generated p-aminophenol with 8-
hydroxyquinoline or o-cresol.
•Arylacylamideamidohydrolase methods are susceptible to interference by
NAC, bilirubin, and immunoglobulin (Ig)M monoclonal immunoglobulins.
•Most chromatographic methods are very accurate and are considered
reference procedures.
•A qualitative, one-step lateral flow immunoassay (cutoff of 25µg/mL or
165µmol/L)may be suitable for point-of-care (POC) application, yet it has
a low positive predictive value.
Salicylate (Read up)
•Salicylate poisoning can result in severe metabolic acidosis, from
which the patient may not recover. This common drug must be tested
for if there is any likelihood that it has been taken. The treatment for
salicylate poisoning is intravenous sodium bicarbonate, which both
enhances excretion and helps correct the acidosis
•Salicylate poisoning can result in severe metabolic acidosis, from
which the patient may not recover. This common drug must be tested
for if there is any likelihood that it has been taken. The treatment for
salicylate poisoning is intravenous sodium bicarbonate, which both
enhances excretion and helps correct the acidosis
METAL POISONING
Poisoning with metals is one of the oldest forms of toxicity known to
man. However, it is only recently that the mechanisms of toxicity have
become known. More importantly, the means of diagnosis and
treatment are now available. The symptoms of poisoning are related to
the amount ingested or absorbed and to the duration of exposure. In
general, the elemental metals are less toxic than their salts. Organic
compounds, where the metal is covalently bound to carbon
compounds such as methyl or ethyl groups, are highly toxic. Patients
with metal poisoning should be investigated and managed in specialist
units
Poisoning with metals is one of the oldest forms of toxicity known to
man. However, it is only recently that the mechanisms of toxicity have
become known. More importantly, the means of diagnosis and
treatment are now available. The symptoms of poisoning are related to
the amount ingested or absorbed and to the duration of exposure. In
general, the elemental metals are less toxic than their salts. Organic
compounds, where the metal is covalently bound to carbon
compounds such as methyl or ethyl groups, are highly toxic. Patients
with metal poisoning should be investigated and managed in specialist
units
Important questions relating to metal toxicity
1.Is the metal of concern toxic?
2.What is the prevalence associated with the metal of concern?
3.What are the signs and symptoms of exposure to that metal?
4.Is the degree of exposure known?
5.Are adequate analytical techniques available to analyze the metal?
6.Are appropriate body fluids and tissues and analytical techniques
available to identify and quantify the metal
1.Is the metal of concern toxic?
2.What is the prevalence associated with the metal of concern?
3.What are the signs and symptoms of exposure to that metal?
4.Is the degree of exposure known?
5.Are adequate analytical techniques available to analyze the metal?
6.Are appropriate body fluids and tissues and analytical techniques
available to identify and quantify the metal
General prevalence of metal based toxicity
•Mostly occur as a result of chronic low concentration exposure frequently
in individuals
•Of concern is the exposure to lead(Pb) and its consequence on mental
development in the young
•A significant number may be exposed due to a lack of knowledge of the
household products they are using
•Pbis found in many insecticides
•Cadmium is found in brightly colouredpaint pigments as well as tobacco
products
•Studies indicate that apoptotic pathways are initiated by metals such as As,
Cd, chromium (Cr), nickel (Ni), and beryllium (Be), and possibly lead (Pb),
antimony (Sb), and cobalt (Co)
•Mostly occur as a result of chronic low concentration exposure frequently
in individuals
•Of concern is the exposure to lead(Pb) and its consequence on mental
development in the young
•A significant number may be exposed due to a lack of knowledge of the
household products they are using
•Pbis found in many insecticides
•Cadmium is found in brightly colouredpaint pigments as well as tobacco
products
•Studies indicate that apoptotic pathways are initiated by metals such as As,
Cd, chromium (Cr), nickel (Ni), and beryllium (Be), and possibly lead (Pb),
antimony (Sb), and cobalt (Co)
Metal poisoning
•Apart from the occasional suicide or murder attempt, most
poisonings are due to environmental contamination or administration
of drugs, remedies or cosmetics that contain metal salts.
•In some type of situation, the Public Health Service is often called in
to identify the cause of an outbreak of unusual symptoms. The clinical
laboratory should be prepared to support these types of
investigations.
•Apart from the occasional suicide or murder attempt, most
poisonings are due to environmental contamination or administration
of drugs, remedies or cosmetics that contain metal salts.
•In some type of situation, the Public Health Service is often called in
to identify the cause of an outbreak of unusual symptoms. The clinical
laboratory should be prepared to support these types of
investigations.
Metal Poisoning
•There are three main clinical effects of exposure to toxic metals.
These are:
a)renal tubular damage,
b)gastrointestinal erosions and
c)neurological damage
•There are three main clinical effects of exposure to toxic metals.
These are:
a)renal tubular damage,
b)gastrointestinal erosions and
c)neurological damage
References and action limits for some toxic
metals
Metal Action limits/Indices of toxicityClinical sequeale
Arsenic >0.5ug/g of hair Diarrhoea, polyneuropathy,
gastrointestinal pain, vomiting,
shock, coma, renal failure
Aluminium >3umol/l in plasma-chronic
>10umol/l in plasma -acute
Encephalopathy, osteodystrophy
Cadmium >90nmol/l in blood or
>90nmol/24 hour in urine
Renal tubular damage, bone
disease, hepatocellular damage
Lead >50ug/100ml (0.24umol/l) adults
>25ug/100ml (0.12umol/l) females
in reproductive years
>40ug/100ml (0.19umol/l) under
18 years
Acute: colic, seizures and coma
Chronic: anaemia, encephalopathy
Mercury > 120nmol/mmol creatinine in
urine
Nausea and vomiting,
nephrotoxicity, neurological
dysfunction
metals
Metal Action limits/Indices of toxicityClinical sequeale
Arsenic >0.5ug/g of hair Diarrhoea, polyneuropathy,
gastrointestinal pain, vomiting,
shock, coma, renal failure
Aluminium >3umol/l in plasma-chronic
>10umol/l in plasma -acute
Encephalopathy, osteodystrophy
Cadmium >90nmol/l in blood or
>90nmol/24 hour in urine
Renal tubular damage, bone
disease, hepatocellular damage
Lead >50ug/100ml (0.24umol/l) adults
>25ug/100ml (0.12umol/l) females
in reproductive years
>40ug/100ml (0.19umol/l) under
18 years
Acute: colic, seizures and coma
Chronic: anaemia, encephalopathy
Mercury > 120nmol/mmol creatinine in
urine
Nausea and vomiting,
nephrotoxicity, neurological
dysfunction
Diagnosing toxicity
•Confirming the diagnosis of metal toxicity is difficult because signs
and symptoms are similar to those of a number of non–element-
dependent diseases.
•Diagnosis of metal toxicity therefore requires demonstration of all of
the following factors:
1)a source of metal exposure must be evident,
2)the patient must demonstrate signs and symptoms typical of the
metal, and
3)abnormal metal concentration in the appropriate tissue or body
fluid must be evident
•Confirming the diagnosis of metal toxicity is difficult because signs
and symptoms are similar to those of a number of non–element-
dependent diseases.
•Diagnosis of metal toxicity therefore requires demonstration of all of
the following factors:
1)a source of metal exposure must be evident,
2)the patient must demonstrate signs and symptoms typical of the
metal, and
3)abnormal metal concentration in the appropriate tissue or body
fluid must be evident
Diagnosis
•Metal poisoning may be suspected in cases where it is not present
and missed in cases where it is the cause of the symptoms.
•Diagnosis may be made by measuring:
a.plasma or blood levels of the metal
b.urinary excretion of metals
c.an associated biochemical abnormality related to the toxicity.
•In some cases it may also be helpful to measure the metal
concentration in other tissuessuch as hair
•Metal poisoning may be suspected in cases where it is not present
and missed in cases where it is the cause of the symptoms.
•Diagnosis may be made by measuring:
a.plasma or blood levels of the metal
b.urinary excretion of metals
c.an associated biochemical abnormality related to the toxicity.
•In some cases it may also be helpful to measure the metal
concentration in other tissuessuch as hair
Diagnosing toxicity
•In clinical practice, analysis of toxic elements should always be
considered in the clinical work-up of the patient with
a.renal disease of unexplained origin,
b.bilateral peripheral neuropathy,
c.acute change in mental function,
d.acute inflammation of the nasal or laryngeal epithelium, or
e.a history of exposure
•In clinical practice, analysis of toxic elements should always be
considered in the clinical work-up of the patient with
a.renal disease of unexplained origin,
b.bilateral peripheral neuropathy,
c.acute change in mental function,
d.acute inflammation of the nasal or laryngeal epithelium, or
e.a history of exposure
Treatment
•As with most poisons, treatment consists of
a.removal of the source of the metal
b.increasing the elimination from the body,
c.correcting deranged physiological or biological mechanisms.
•Removal of the source may require that a person be removed from a
contaminated site or workplace or that the use of a medication or
cosmetic be discontinued.
•Elimination of heavy metals is achieved by treatment with chelating
agents that bind the ions and allow their excretion in the urine
•As with most poisons, treatment consists of
a.removal of the source of the metal
b.increasing the elimination from the body,
c.correcting deranged physiological or biological mechanisms.
•Removal of the source may require that a person be removed from a
contaminated site or workplace or that the use of a medication or
cosmetic be discontinued.
•Elimination of heavy metals is achieved by treatment with chelating
agents that bind the ions and allow their excretion in the urine
CLASSIFICATION OF METALS
•Some metals are essential for life, but if their concentration in one’s
body exceeds a certain threshold, toxicity may develop e.g. trace
elements
•Also, some nonessential metals are toxic even at low concentrations
•Review of the periodic table provides some insight into the
determination of a metal’s potential toxicity
•Some metals are essential for life, but if their concentration in one’s
body exceeds a certain threshold, toxicity may develop e.g. trace
elements
•Also, some nonessential metals are toxic even at low concentrations
•Review of the periodic table provides some insight into the
determination of a metal’s potential toxicity
Periodic table classification
•Elements in rows 3 and 4 of groups 1 and 2 of the periodic table are
essential elements. The gastrointestinal tract and the dermis are very
effective in regulating the body burden of these compounds. Consequently,
patients rarely experience toxicity from one of these elements unless the
element is injected directly into the vascular system.
•Elements in groups 6 through 12 in row 4 are essential for life but are
required at low concentrations; many are protein cofactors required for
enzymatic activity. The gastrointestinal tract and the dermis regulate intake
to some degree, but overload will induce passive diffusion that leads to
excessive concentrations and toxicity.
•Elements in rows 3 and 4 of groups 1 and 2 of the periodic table are
essential elements. The gastrointestinal tract and the dermis are very
effective in regulating the body burden of these compounds. Consequently,
patients rarely experience toxicity from one of these elements unless the
element is injected directly into the vascular system.
•Elements in groups 6 through 12 in row 4 are essential for life but are
required at low concentrations; many are protein cofactors required for
enzymatic activity. The gastrointestinal tract and the dermis regulate intake
to some degree, but overload will induce passive diffusion that leads to
excessive concentrations and toxicity.
Periodic table classification
•Elements in rows 5 and below are classifedas nonessential (or if
essential, are required at picomolarconcentrations or less). As one
moves from right to left across the periodic table, the elements
become more prevalent and therefore have greater potential to
induce toxicity.
•Elements in groups 13 through 16 in rows 4 through 6 are of
particular interest as toxins because they have electron configuration
that allows them to bond covalently with sulfur. This characteristic
has been identifedas a signicantfactor in the mechanism of action of
this group of metals. These metals include (1) As, (2) Cd, (3) Pb, (4)
Hg, and (5) thallium (Tl), which are toxins of considerable concern.
•Elements in rows 5 and below are classifedas nonessential (or if
essential, are required at picomolarconcentrations or less). As one
moves from right to left across the periodic table, the elements
become more prevalent and therefore have greater potential to
induce toxicity.
•Elements in groups 13 through 16 in rows 4 through 6 are of
particular interest as toxins because they have electron configuration
that allows them to bond covalently with sulfur. This characteristic
has been identifedas a signicantfactor in the mechanism of action of
this group of metals. These metals include (1) As, (2) Cd, (3) Pb, (4)
Hg, and (5) thallium (Tl), which are toxins of considerable concern.
Periodic table classification
•Elements in group 17 (halides) are essential for life but are toxic when
present in excess.
•The inert elements that constitute group 18 are toxic in the gas phase
because they can cause anoxia; their inert characteristic is the very
cause of their toxicity
•Elements in group 17 (halides) are essential for life but are toxic when
present in excess.
•The inert elements that constitute group 18 are toxic in the gas phase
because they can cause anoxia; their inert characteristic is the very
cause of their toxicity
Periodic Table
Occupational monitoring
•Employees are frequently monitored when working in an
environment where exposure to toxic metals is a possibility.
•The most common form of monitoring involves quantification of
airborne concentrations of metals in the production process
•Threshold limit value (TLV) : The maximum concentration of a
chemical allowable for repeated exposure without producing adverse
health effects
•TLV for airborne concentrations and time interval exposure
concentrations are specified by the U.S. National Institute for
Occupational Safety and Health (NIOSH).
•Employees are frequently monitored when working in an
environment where exposure to toxic metals is a possibility.
•The most common form of monitoring involves quantification of
airborne concentrations of metals in the production process
•Threshold limit value (TLV) : The maximum concentration of a
chemical allowable for repeated exposure without producing adverse
health effects
•TLV for airborne concentrations and time interval exposure
concentrations are specified by the U.S. National Institute for
Occupational Safety and Health (NIOSH).
Occupational monitoring
•Workers may also be monitored by quantification of biological samples.
•The most common sample used is a random urine sample, and results are
expressed in concentration units for the metal of interest per gram of
creatinine to normalize for excretion volume variances. Cd, Cr, and Pbhave
defined urine excretion concentrations set by a U.S. federal agency to
ensure worker safety
•The World Health Organization (WHO) has defined blood concentrations
for Pbthat are designed to warn employers when workers are
overexposed.
•Safety limits for other metals have been set by professional organizations.
•Workers may also be monitored by quantification of biological samples.
•The most common sample used is a random urine sample, and results are
expressed in concentration units for the metal of interest per gram of
creatinine to normalize for excretion volume variances. Cd, Cr, and Pbhave
defined urine excretion concentrations set by a U.S. federal agency to
ensure worker safety
•The World Health Organization (WHO) has defined blood concentrations
for Pbthat are designed to warn employers when workers are
overexposed.
•Safety limits for other metals have been set by professional organizations.
Analytical methods
•Analytical techniques used to measure metals in biological fluid include
1)atomic absorption spectrometry with flame (AA-F) or electrothermalatomization
furnace (AA-E A),
2)inductively coupled plasma emission spectroscopy (ICP-ES),
3)inductively coupled plasma mass spectrometry (ICP-MS), and
4)high-performance liquid chromatography–inductively coupled plasma mass
spectrometry (LC-ICP/MS).
•These techniques are specific and sensitive and provide the clinical laboratory with the
capability to measure a broad array of metals at clinically significant concentrations. For
e.g., ICP-MS and ICP-ES are used to measure several metals simultaneously.
•Photometric assays are available but require large volumes of sample and have limited
specificity.
•Spot tests are also available but should be considered obsolete because they are error
prone, often yielding false-positive results.
•Analytical techniques used to measure metals in biological fluid include
1)atomic absorption spectrometry with flame (AA-F) or electrothermalatomization
furnace (AA-E A),
2)inductively coupled plasma emission spectroscopy (ICP-ES),
3)inductively coupled plasma mass spectrometry (ICP-MS), and
4)high-performance liquid chromatography–inductively coupled plasma mass
spectrometry (LC-ICP/MS).
•These techniques are specific and sensitive and provide the clinical laboratory with the
capability to measure a broad array of metals at clinically significant concentrations. For
e.g., ICP-MS and ICP-ES are used to measure several metals simultaneously.
•Photometric assays are available but require large volumes of sample and have limited
specificity.
•Spot tests are also available but should be considered obsolete because they are error
prone, often yielding false-positive results.
•Certain metals are known to be toxic when humans are exposed to
elevated concentrations
•Five metals are listed in the top 20 of the 2007 CERCLA
(Comprehensive Environmental Response, Compensation, and
Liability Act) Priority List of Hazardous Substances They include As,
Pb, Hg, Cd, and Cr.
•Other metals of concern include aluminum (Al), Be, Co, copper (Cu),
gadolinium (Gd), iron (Fe), manganese (Mn), Ni, platinum (Pt),
selenium (Se), silicon (Si), silver (Ag), and Ti.
•Several of these metals are also considered essential trace elements
elevated concentrations
•Five metals are listed in the top 20 of the 2007 CERCLA
(Comprehensive Environmental Response, Compensation, and
Liability Act) Priority List of Hazardous Substances They include As,
Pb, Hg, Cd, and Cr.
•Other metals of concern include aluminum (Al), Be, Co, copper (Cu),
gadolinium (Gd), iron (Fe), manganese (Mn), Ni, platinum (Pt),
selenium (Se), silicon (Si), silver (Ag), and Ti.
•Several of these metals are also considered essential trace elements
SOME SPECIFIC METALS
LEAD (Pb)
•Exposure to Pbfrom any of these sources by (1) ingestion, (2) inhalation, or
(3) dermal contact has been known to cause significant toxicity.
•A typical diet in the United States contributes approximately 3 µg of Pbper
day of which 1-10% will be absorbed
•Most of the daily intake is excreted in the stool after direct passage through
the gastrointestinal tract.
•Although a significant fraction of the absorbed Pbis rapidly incorporated
into bone and erythrocytes, Pbis ultimately distributed among all tissues.
Lipid-dense tissues, such as the central nervous system, are particularly
sensitive to organic forms of Pb. Erythrocyte turnover of Pboccurs within
approximately 120 days.
•Lead is ultimately excreted in bile or urine
•Exposure to Pbfrom any of these sources by (1) ingestion, (2) inhalation, or
(3) dermal contact has been known to cause significant toxicity.
•A typical diet in the United States contributes approximately 3 µg of Pbper
day of which 1-10% will be absorbed
•Most of the daily intake is excreted in the stool after direct passage through
the gastrointestinal tract.
•Although a significant fraction of the absorbed Pbis rapidly incorporated
into bone and erythrocytes, Pbis ultimately distributed among all tissues.
Lipid-dense tissues, such as the central nervous system, are particularly
sensitive to organic forms of Pb. Erythrocyte turnover of Pboccurs within
approximately 120 days.
•Lead is ultimately excreted in bile or urine
Mechanisms of expression of Pbtoxicity
•Pbavidly inhibits amino levulinicacid dehydratase (ALAD),which is
an enzyme that catalyzes the synthesis of haem from porphyrin.
•Inhibition of ALAD causes accumulation of protoporphyrin in
erythrocytes, which is a signifcantmarker or Pbexposure.
•Anaemia caused by lack of haem is frequently observed in Pbtoxicity.
•Lead also is an electrophile that avidly forms covalent bonds with the
sulfydrylgroup of cysteinesin proteins. Thus proteins in all tissues
exposed to Pbwill have Pbbound to them. Keratin in hair contains a
high fraction of cysteine relative to other amino acids and actively
binds Pb. Consequently, hair analysis for Pbis a good marker for
exposure.
•Pbavidly inhibits amino levulinicacid dehydratase (ALAD),which is
an enzyme that catalyzes the synthesis of haem from porphyrin.
•Inhibition of ALAD causes accumulation of protoporphyrin in
erythrocytes, which is a signifcantmarker or Pbexposure.
•Anaemia caused by lack of haem is frequently observed in Pbtoxicity.
•Lead also is an electrophile that avidly forms covalent bonds with the
sulfydrylgroup of cysteinesin proteins. Thus proteins in all tissues
exposed to Pbwill have Pbbound to them. Keratin in hair contains a
high fraction of cysteine relative to other amino acids and actively
binds Pb. Consequently, hair analysis for Pbis a good marker for
exposure.
Mechanisms of Pbtoxicity
•Some proteins become labile as Pbbinds with them because Pb
causes the tertiary structure of the protein to change.
•Cells of the nervous system are particularly susceptible to this effect.
Some Pb-bound proteins change their tertiary configuration
sufficiently that they become antigenic.
•Renal tubular cells are particularly susceptible to this effect because
they are exposed to relatively high Pbconcentrations during
clearance
•Some proteins become labile as Pbbinds with them because Pb
causes the tertiary structure of the protein to change.
•Cells of the nervous system are particularly susceptible to this effect.
Some Pb-bound proteins change their tertiary configuration
sufficiently that they become antigenic.
•Renal tubular cells are particularly susceptible to this effect because
they are exposed to relatively high Pbconcentrations during
clearance
Lead (Pb)
•Inorganic lead has long been known to be toxic, but acute lead poisoning is
rare. Chronic toxicity is related to industrial exposure, lead leached from
water pipes, or the eating of lead-containing paints or dirt by children
(pica).
•Only 5–10% of lead is absorbed from the gastrointestinal tract in adults but
this proportion is higher in children (up to 50%).
•Lead poisoning causes anaemiaas well as hepatic, renal and neurological
sequelae.
•In general, the consequences of organic lead poisoning are neurological,
whereas inorganic lead poisoning results in constipation, abdominal colic,
anaemiaand peripheral and motor neuron deficiencies.
•Severe cases develop encephalopathy with seizures and coma
•Inorganic lead has long been known to be toxic, but acute lead poisoning is
rare. Chronic toxicity is related to industrial exposure, lead leached from
water pipes, or the eating of lead-containing paints or dirt by children
(pica).
•Only 5–10% of lead is absorbed from the gastrointestinal tract in adults but
this proportion is higher in children (up to 50%).
•Lead poisoning causes anaemiaas well as hepatic, renal and neurological
sequelae.
•In general, the consequences of organic lead poisoning are neurological,
whereas inorganic lead poisoning results in constipation, abdominal colic,
anaemiaand peripheral and motor neuron deficiencies.
•Severe cases develop encephalopathy with seizures and coma
Pb
•Biochemical evidence of lead poisoning is by the finding of raised
protoporphyrin levels in the erythrocytesdue to the inhibition of a
number of the synthetic enzymes of the haempathway by lead.
•A clinical sign is the appearance of a blue line on the gums.
•Lead is measured in whole blood or in urine.
•Excretion can be enhanced using chelating agents such as NaEDTA,
dimercaprol or N-acetyl-penicillamine.
•Because of their high toxicity the use and handling of organic lead
compounds, such as tetra-ethyl-lead, the anti-knocking agent in petrol, is
strictly regulated by law and they are being replaced by alternative
compounds
•Biochemical evidence of lead poisoning is by the finding of raised
protoporphyrin levels in the erythrocytesdue to the inhibition of a
number of the synthetic enzymes of the haempathway by lead.
•A clinical sign is the appearance of a blue line on the gums.
•Lead is measured in whole blood or in urine.
•Excretion can be enhanced using chelating agents such as NaEDTA,
dimercaprol or N-acetyl-penicillamine.
•Because of their high toxicity the use and handling of organic lead
compounds, such as tetra-ethyl-lead, the anti-knocking agent in petrol, is
strictly regulated by law and they are being replaced by alternative
compounds
•The definitive test for Pbtoxicity is measurement of blood Pb.
•Over the past 3 decades, studies have shown an inverse relationship
between blood Pbconcentrations and children’s IQ at increasingly lower Pb
concentrations.
•In response, the Centers or Disease Control and Prevention (CDC) has
continued to lower the upper limit of normal for children, which is now
stated at less than 10 µg/dL, with 5 per µg/dLthe reference concentration
at which the CDC recommends that public health actions be initiated
•The WHO has defined blood Pbconcentrations >30 µg/dLin adults as
indicative of significant exposure.
•Lead concentrations >60 µg/dLrequire chelation therapy (administration of
chelating agents to remove metals rom the body).
•Over the past 3 decades, studies have shown an inverse relationship
between blood Pbconcentrations and children’s IQ at increasingly lower Pb
concentrations.
•In response, the Centers or Disease Control and Prevention (CDC) has
continued to lower the upper limit of normal for children, which is now
stated at less than 10 µg/dL, with 5 per µg/dLthe reference concentration
at which the CDC recommends that public health actions be initiated
•The WHO has defined blood Pbconcentrations >30 µg/dLin adults as
indicative of significant exposure.
•Lead concentrations >60 µg/dLrequire chelation therapy (administration of
chelating agents to remove metals rom the body).
MERCURY (Hg)
•Hg is widely found in the environment and occurs both naturally and as the
result of industrial processes, with the single largest source of Hg being its
natural out-gassing from granite rock.
•In the past, Hg was extensively used in the manufacture of devices such as
(1) thermometers, (2) barometers, (3) manometers, and (4)
sphygmomanometers. However, concerns about its toxicity have resulted
in the phasing out of Hg-based instruments, which have been replaced by
(1) alcohol-filled, (2) digital, or (3) thermistor-based ones.
•It is still used as a dental amalgam and in lighting as mercury vapourlamps,
although these are being replaced by sodium vapourbulbs.
•Hg also is used (1) in the pulp and paper industry as a whitener, (2) as a
catalyst in the synthesis of plastics, and (3) as a potent fungicide in anti-
fouling and latex paints
•Hg is widely found in the environment and occurs both naturally and as the
result of industrial processes, with the single largest source of Hg being its
natural out-gassing from granite rock.
•In the past, Hg was extensively used in the manufacture of devices such as
(1) thermometers, (2) barometers, (3) manometers, and (4)
sphygmomanometers. However, concerns about its toxicity have resulted
in the phasing out of Hg-based instruments, which have been replaced by
(1) alcohol-filled, (2) digital, or (3) thermistor-based ones.
•It is still used as a dental amalgam and in lighting as mercury vapourlamps,
although these are being replaced by sodium vapourbulbs.
•Hg also is used (1) in the pulp and paper industry as a whitener, (2) as a
catalyst in the synthesis of plastics, and (3) as a potent fungicide in anti-
fouling and latex paints
Hg
•Mercury is essentially nontoxic in its elemental form (Hg
0
). In the absence
of any chemical or biological system that chemically alters Hg
0
, it is possible
to consume it orally with no significant side effects. However, once Hg
0
is
chemically modified to the ionized, inorganic species, Hg
2+
, it becomes
toxic. Further bioconversion to an alkyl Hg, such as methyl Hg (CH3Hg
+
),
yields a very toxic species of Hg that is highly selective for lipid-rich tissue,
such as the neuron.
•Chemically, it is possible to convert Hg from its elemental state to its
ionized state; in industry, this is accomplished by exposing Hg
0
to a strong
oxidant, such as chlorine.
•Elemental Hg is also bioconvertedto both Hg
2+
and alkyl Hg by
microorganisms that exist both in the normal human gut and in the bottom
sediment of lakes and rivers.
•Mercury is essentially nontoxic in its elemental form (Hg
0
). In the absence
of any chemical or biological system that chemically alters Hg
0
, it is possible
to consume it orally with no significant side effects. However, once Hg
0
is
chemically modified to the ionized, inorganic species, Hg
2+
, it becomes
toxic. Further bioconversion to an alkyl Hg, such as methyl Hg (CH3Hg
+
),
yields a very toxic species of Hg that is highly selective for lipid-rich tissue,
such as the neuron.
•Chemically, it is possible to convert Hg from its elemental state to its
ionized state; in industry, this is accomplished by exposing Hg
0
to a strong
oxidant, such as chlorine.
•Elemental Hg is also bioconvertedto both Hg
2+
and alkyl Hg by
microorganisms that exist both in the normal human gut and in the bottom
sediment of lakes and rivers.
Hg
•When Hg
0
enters bottom sediment, it is absorbed by bacteria, fungi,
and related microorganisms that metabolically convert it to Hg
2+
,
CH3Hg
+
, (CH3)
2Hg, and similar species. Consequently, the methyl
mercurialsare accumulated in the aquatic food chain and reach their
highest concentrations in predatory fish
•Consequent to accumulation of methylmercury in the aquatic food
chain, most human exposure to mercury happens through the eating
of contaminated fish, shell-fish, and sea mammals.
•When Hg
0
enters bottom sediment, it is absorbed by bacteria, fungi,
and related microorganisms that metabolically convert it to Hg
2+
,
CH3Hg
+
, (CH3)
2Hg, and similar species. Consequently, the methyl
mercurialsare accumulated in the aquatic food chain and reach their
highest concentrations in predatory fish
•Consequent to accumulation of methylmercury in the aquatic food
chain, most human exposure to mercury happens through the eating
of contaminated fish, shell-fish, and sea mammals.
•In adults, cases of methylmercury poisoning are characterized by the
focal degeneration of neurons in regions of the brain such as the
cerebral cortex and the cerebellum.
•Depending on the degree of in-utero exposure, methylmercury may
result in effects ranging from foetal death to subtle
neurodevelopmental delays.
•Since pregnant women, women of childbearing age, and young
children are particularly at risk, the FDA recommends that they avoid
eating shark, swordfish, mackerel, and tile-fish
focal degeneration of neurons in regions of the brain such as the
cerebral cortex and the cerebellum.
•Depending on the degree of in-utero exposure, methylmercury may
result in effects ranging from foetal death to subtle
neurodevelopmental delays.
•Since pregnant women, women of childbearing age, and young
children are particularly at risk, the FDA recommends that they avoid
eating shark, swordfish, mackerel, and tile-fish
Hg
•Mercury poisoning may be acute or chronic and is related to exposure to
elemental mercury vapour, inorganic salts or organic forms such as
methylmercury.
•Metallic mercury is relatively non-toxic if ingested, but mercury vapourcan
give rise to acute toxicity.
•The symptoms are respiratory distress and a metallic taste in the mouth.
•Mercurous salts, notably calomel, have been known to cause chronic
toxicity following skin absorption from powders and other forms, but are
less toxic than mercuric salts, notably mercuric chloride. This is highly toxic
when ingested.
•The symptoms are nausea and vomiting, muscular tremors, CNS symptoms
and renal damage..
•Mercury poisoning may be acute or chronic and is related to exposure to
elemental mercury vapour, inorganic salts or organic forms such as
methylmercury.
•Metallic mercury is relatively non-toxic if ingested, but mercury vapourcan
give rise to acute toxicity.
•The symptoms are respiratory distress and a metallic taste in the mouth.
•Mercurous salts, notably calomel, have been known to cause chronic
toxicity following skin absorption from powders and other forms, but are
less toxic than mercuric salts, notably mercuric chloride. This is highly toxic
when ingested.
•The symptoms are nausea and vomiting, muscular tremors, CNS symptoms
and renal damage..
Hg (ways of expressing toxicity)
•First, Hg
2+
avidly reacts with sulfydrylgroups of protein, causing a change in
the tertiary structure of the protein with subsequent loss of the biological
activity associated with that protein. As Hg
2+
becomes concentrated in the
kidney during regular clearance processes, this is the target organ that
experiences the greatest toxicity.
•Second, with the tertiary change noted previously, some proteins become
immunogenic, eliciting a proliferation of β-lymphocytes that generate
immunoglobulins to bind the new antigen (collagen tissues are particularly
sensitive to this).
•Third, alkyl Hg species, such as methylmercury, are particularly lipophilic
and actively bind to proteins in lipid-rich tissue, such as neurons; myelin is
particularly susceptible to disruption by this mechanism.
•Mercury has also been found to alter porphyrin excretion patterns
•First, Hg
2+
avidly reacts with sulfydrylgroups of protein, causing a change in
the tertiary structure of the protein with subsequent loss of the biological
activity associated with that protein. As Hg
2+
becomes concentrated in the
kidney during regular clearance processes, this is the target organ that
experiences the greatest toxicity.
•Second, with the tertiary change noted previously, some proteins become
immunogenic, eliciting a proliferation of β-lymphocytes that generate
immunoglobulins to bind the new antigen (collagen tissues are particularly
sensitive to this).
•Third, alkyl Hg species, such as methylmercury, are particularly lipophilic
and actively bind to proteins in lipid-rich tissue, such as neurons; myelin is
particularly susceptible to disruption by this mechanism.
•Mercury has also been found to alter porphyrin excretion patterns
MethylHgtoxicity symptoms
1.ataxia,
2.impaired speech,
3.visual field constriction,
4.hearing loss, and
5.somatosensory change,
•It is characterized histologically by cerebral cortex necrosis.
•Collectively, these symptoms have become known as Minamata
disease.
1.ataxia,
2.impaired speech,
3.visual field constriction,
4.hearing loss, and
5.somatosensory change,
•It is characterized histologically by cerebral cortex necrosis.
•Collectively, these symptoms have become known as Minamata
disease.
Hg
•In the late 1980s, the public became concerned about exposure to Hg
from dental amalgams
•In 2010, the FDA issued rules that classify dental amalgam, reclassify
dental mercury, and specify special controls for dental amalgam,
mercury, and amalgam alloy
•Concerns have been raised about the possible relationship between
Hg exposure from vaccines and autistic disorders (not very conclusive)
•In the late 1980s, the public became concerned about exposure to Hg
from dental amalgams
•In 2010, the FDA issued rules that classify dental amalgam, reclassify
dental mercury, and specify special controls for dental amalgam,
mercury, and amalgam alloy
•Concerns have been raised about the possible relationship between
Hg exposure from vaccines and autistic disorders (not very conclusive)
Hg (diagnosis)
•Analysis of blood, urine, and hair for Hg concentrations is used to
determine exposure.
•The quantity of Hg found in blood and urine correlates with the degree of
toxicity, and hair analysis has been used historically to document the time
of peak exposure.
•However, it should be noted that hair analysis for metals in general is
difficult because of contamination.
•Reference whole blood Hg concentration is usually lower than 10µg/L
•Individuals who have mild occupational exposure (e.g., dentists) may
routinely have whole blood Hg concentrations up to 15µg/L.
•Significant exposure is indicated when the whole blood Hg concentration is
greater than 50µg/L (if exposure is to methylmercury) or greater than 200
µg/L (if exposure is to Hg
2+
).
•Analysis of blood, urine, and hair for Hg concentrations is used to
determine exposure.
•The quantity of Hg found in blood and urine correlates with the degree of
toxicity, and hair analysis has been used historically to document the time
of peak exposure.
•However, it should be noted that hair analysis for metals in general is
difficult because of contamination.
•Reference whole blood Hg concentration is usually lower than 10µg/L
•Individuals who have mild occupational exposure (e.g., dentists) may
routinely have whole blood Hg concentrations up to 15µg/L.
•Significant exposure is indicated when the whole blood Hg concentration is
greater than 50µg/L (if exposure is to methylmercury) or greater than 200
µg/L (if exposure is to Hg
2+
).
Mercury
•Diagnosis is by estimation of blood and urine mercury concentrations
•Long-term monitoring of exposure, such as may be necessary with
those working with dental amalgam, may be carried out using hair or
nail clippings.
•Organic mercury compounds are very toxic. In the oceans, the
methyl-mercury concentration in the flesh of marine life increases as
you move up the food chain. Thus, in top predators such as tuna and
shark the concentration is such that organizations such as UK Food
Standards Agency have issued advice to pregnant women to limit
their intake
•Diagnosis is by estimation of blood and urine mercury concentrations
•Long-term monitoring of exposure, such as may be necessary with
those working with dental amalgam, may be carried out using hair or
nail clippings.
•Organic mercury compounds are very toxic. In the oceans, the
methyl-mercury concentration in the flesh of marine life increases as
you move up the food chain. Thus, in top predators such as tuna and
shark the concentration is such that organizations such as UK Food
Standards Agency have issued advice to pregnant women to limit
their intake
Hg
•The WHO safety standard for daily exposure to Hg is 45µg/d
•Daily urine excretion exceeding 50µg/d indicates significant exposure.
•Normally, hair contains less than 1µg/g of Hg; greater amounts
indicate increased exposure.
•Treatment with BAL or penicillaminewill mobilize Hg, allowing for its
excretion in the urine.
•Therapy is usually monitored by following urinary excretion of Hg
•Therapy may be terminated after the daily urine excretion rate falls
below 50µg/L.
•The WHO safety standard for daily exposure to Hg is 45µg/d
•Daily urine excretion exceeding 50µg/d indicates significant exposure.
•Normally, hair contains less than 1µg/g of Hg; greater amounts
indicate increased exposure.
•Treatment with BAL or penicillaminewill mobilize Hg, allowing for its
excretion in the urine.
•Therapy is usually monitored by following urinary excretion of Hg
•Therapy may be terminated after the daily urine excretion rate falls
below 50µg/L.
Copper (Cu) Toxicity
•Copper ingestion has been known to cause serious toxicity
•Exposure may be caused by common pesticides.
•Copper arsenate is one of the active agents in marine antifouling paints and in
the wood preservative used with green “treated” wood. Copper arsenate wood
products have been taken off the market in the United States because of this
concern.
•Ingestion of copper produces
1.severe gastrointestinal pain with erosion of the epithelial layer of the
gastrointestinal tract,
2.haemolytic anaemia,
3.centrilobularhepatitis with jaundice, and
4.renal damage
•Copper ingestion has been known to cause serious toxicity
•Exposure may be caused by common pesticides.
•Copper arsenate is one of the active agents in marine antifouling paints and in
the wood preservative used with green “treated” wood. Copper arsenate wood
products have been taken off the market in the United States because of this
concern.
•Ingestion of copper produces
1.severe gastrointestinal pain with erosion of the epithelial layer of the
gastrointestinal tract,
2.haemolytic anaemia,
3.centrilobularhepatitis with jaundice, and
4.renal damage
•The classical presentation of Cu toxicosisis represented by the genetic disease of
Cu accumulation known as Wilson’s disease. T is disease is typified by
hepatocellular damage (increased transferases) and/or changes in mood and
behavior caused by accumulation of Cu in central neurons
•Evaluation of serum and urine copper concentration is useful in diagnosing
Wilson’s disease.
•Because most Cu circulating in blood is bound to caeruloplasmin, and
caeruloplasmin formation is decreased in Wilson’s disease, serum copper
concentration is less than the reference interval or serum (Cu, 0.7 to 1.4 µg/mL),
and urinary Cu concentrations are increased to 15 to 60 µg/L.
•Increased hepatic Cu >2.0 (adjusted for age and reported as the hepatic iron
index) is diagnostic for Wilson’s disease.
•Increased serum Cu is observed in patients prescribed oestrogen.
Cu accumulation known as Wilson’s disease. T is disease is typified by
hepatocellular damage (increased transferases) and/or changes in mood and
behavior caused by accumulation of Cu in central neurons
•Evaluation of serum and urine copper concentration is useful in diagnosing
Wilson’s disease.
•Because most Cu circulating in blood is bound to caeruloplasmin, and
caeruloplasmin formation is decreased in Wilson’s disease, serum copper
concentration is less than the reference interval or serum (Cu, 0.7 to 1.4 µg/mL),
and urinary Cu concentrations are increased to 15 to 60 µg/L.
•Increased hepatic Cu >2.0 (adjusted for age and reported as the hepatic iron
index) is diagnostic for Wilson’s disease.
•Increased serum Cu is observed in patients prescribed oestrogen.
IRON (Fe) toxicity
•Iron supplements are used frequently to maintain an adequate body
burden of Fe. Occasionally, ingestion exceeds the needed daily
requirement, resulting in Fe toxicity. For example, ingestion of more
than 0.5 g of Fe has been known to produce severe irritation of the
epithelial lining of the gastrointestinal tract, resulting in
haemosiderosis, which may develop into hepatic cirrhosis.
•The presence of Fe >350 µg/dLor transferrin >125 micromole/L in
serum corroborates this diagnosis
•Iron supplements are used frequently to maintain an adequate body
burden of Fe. Occasionally, ingestion exceeds the needed daily
requirement, resulting in Fe toxicity. For example, ingestion of more
than 0.5 g of Fe has been known to produce severe irritation of the
epithelial lining of the gastrointestinal tract, resulting in
haemosiderosis, which may develop into hepatic cirrhosis.
•The presence of Fe >350 µg/dLor transferrin >125 micromole/L in
serum corroborates this diagnosis
COBALT (Co)
•Co is widely distributed in the environment and is the essential
cofactor in vitamin B
12. Quantification of active vitamin B
12is the
usual way to assess nutritional status. Cobalt deficiency has not been
reported in humans
•Cobalt is found in metal alloys that are very hard, have high melting
points, and are resistant to oxidation.
•Cobalt is not highly toxic, but large exposures will produce pulmonary
oedema, allergy, nausea, vomiting, haemorrhage, renal failure, and
neurologic impairment
•Exposure to Co is of growing concern among patients with metallic
orthopaedicimplants
•Co is widely distributed in the environment and is the essential
cofactor in vitamin B
12. Quantification of active vitamin B
12is the
usual way to assess nutritional status. Cobalt deficiency has not been
reported in humans
•Cobalt is found in metal alloys that are very hard, have high melting
points, and are resistant to oxidation.
•Cobalt is not highly toxic, but large exposures will produce pulmonary
oedema, allergy, nausea, vomiting, haemorrhage, renal failure, and
neurologic impairment
•Exposure to Co is of growing concern among patients with metallic
orthopaedicimplants
Co
•Quantification of urinary Co is an effective means of identifying
individuals with excessive exposure
•Serum cobalt concentrations are increased above normal (>1 µg/L) in
patients with orthopaedicimplants made from cobalt alloys
•DeSmetand coworkers have provided data relating serum and joint
synovial fluid concentrations to orthopaedicimplant status.
•Joint fluid concentrations of metal ions were at least an order of
magnitude higher than those measured in the serum
•Quantification of urinary Co is an effective means of identifying
individuals with excessive exposure
•Serum cobalt concentrations are increased above normal (>1 µg/L) in
patients with orthopaedicimplants made from cobalt alloys
•DeSmetand coworkers have provided data relating serum and joint
synovial fluid concentrations to orthopaedicimplant status.
•Joint fluid concentrations of metal ions were at least an order of
magnitude higher than those measured in the serum
Chromium (Cr)
•Occupational exposure to Cr represents a significant health hazard.
•Chromium is used extensively in the manufacture of stainless steel, in
chrome plating, in the tanning of leather, as a dye for printing and textile
manufacture, as a cleaning solution, as an anticorrosive in cooling systems,
and in metallic orthopaedicimplants
•The toxic form of Cr is Cr
6+
[Cr(VI)], which is rare
•A strong oxidizing environment is required to convert the common form
Cr
3+
[Cr(III)] to Cr
6+
, as might be found when Cr
3+
is exposed to high
temperatures in the presence of oxygen or during high-voltage
electroplating.
•Inhalation of the vapoursof Cr
6+
causes erosion of the epithelium of the
nasal passages and produces squamous cell carcinomas of the lung.
•Occupational exposure to Cr represents a significant health hazard.
•Chromium is used extensively in the manufacture of stainless steel, in
chrome plating, in the tanning of leather, as a dye for printing and textile
manufacture, as a cleaning solution, as an anticorrosive in cooling systems,
and in metallic orthopaedicimplants
•The toxic form of Cr is Cr
6+
[Cr(VI)], which is rare
•A strong oxidizing environment is required to convert the common form
Cr
3+
[Cr(III)] to Cr
6+
, as might be found when Cr
3+
is exposed to high
temperatures in the presence of oxygen or during high-voltage
electroplating.
•Inhalation of the vapoursof Cr
6+
causes erosion of the epithelium of the
nasal passages and produces squamous cell carcinomas of the lung.
Cr
•Cr
6+
is highly lipid soluble and readily crosses cell membranes,
whereas Cr
3+
is rather insoluble and does not readily cross
membranes.
•Clinically, monitoring biological specimens for Cr
6+
is neither practical
nor clinically useful to detect Cr toxicity because the instant it enters a
cell, it is reduced to nontoxic Cr
3+
.
•Instead, monitoring the air at the manufacturing site for Cr
6+
is the
usual way to test or Cr
6+
exposure
•Quantification of total Cr in urine can be used to assess exposure to
total Cr
•Cr
6+
is highly lipid soluble and readily crosses cell membranes,
whereas Cr
3+
is rather insoluble and does not readily cross
membranes.
•Clinically, monitoring biological specimens for Cr
6+
is neither practical
nor clinically useful to detect Cr toxicity because the instant it enters a
cell, it is reduced to nontoxic Cr
3+
.
•Instead, monitoring the air at the manufacturing site for Cr
6+
is the
usual way to test or Cr
6+
exposure
•Quantification of total Cr in urine can be used to assess exposure to
total Cr
Cr
•The presence of chromium in erythrocytes is suggestive of exposure to Cr
6+
within the past 120 days, because Cr
6+
crosses biological membranes but
Cr
3+
does not.
•Increased serum chromium concentrations are observed in association
with orthopaedicimplants made from chromium alloys.
•ICP-MS is the preferred technology or quantification of Cr in body fluids
•Metal implants made up of various combinations of Al, Cr, Co, Fe, Mg, Mo,
Ni, and/or V, wear as the result of continuous motion at the metal on metal
surfaces, resulting in release of microparticlesinto the surrounding tissues,
which can corrode, resulting in the release of metal ions into the systemic
circulation
•The presence of chromium in erythrocytes is suggestive of exposure to Cr
6+
within the past 120 days, because Cr
6+
crosses biological membranes but
Cr
3+
does not.
•Increased serum chromium concentrations are observed in association
with orthopaedicimplants made from chromium alloys.
•ICP-MS is the preferred technology or quantification of Cr in body fluids
•Metal implants made up of various combinations of Al, Cr, Co, Fe, Mg, Mo,
Ni, and/or V, wear as the result of continuous motion at the metal on metal
surfaces, resulting in release of microparticlesinto the surrounding tissues,
which can corrode, resulting in the release of metal ions into the systemic
circulation
Cr
•Serum Cr analysis is useful for evaluation of implant wear. All patients with
an orthopedic implant will have Cr concentrations higher than individuals
without implants
•Preanalyticalhandling of the specimen for Cr analysis is critically
important.
•Many specimen collection products contain Cr in the rubber stopper or O-
rings to add plasticity to the rubber.
•Special rubber was created to manufacture evacuated blood collection
tubes suitable for use in trace metal testing.
•Attention to detail during specimen collection is essential for achieving
successful and clinically valid testing. Blood for Cr testing should be
collected in tubes that are approved by the Food and Drug Administration
(FDA) for trace metal testing
•Serum Cr analysis is useful for evaluation of implant wear. All patients with
an orthopedic implant will have Cr concentrations higher than individuals
without implants
•Preanalyticalhandling of the specimen for Cr analysis is critically
important.
•Many specimen collection products contain Cr in the rubber stopper or O-
rings to add plasticity to the rubber.
•Special rubber was created to manufacture evacuated blood collection
tubes suitable for use in trace metal testing.
•Attention to detail during specimen collection is essential for achieving
successful and clinically valid testing. Blood for Cr testing should be
collected in tubes that are approved by the Food and Drug Administration
(FDA) for trace metal testing
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