Mercury

Mercury
a metal that exists in three forms:
Elemental (liquid at room temperature)
Inorganic salts
Component of organic compounds

Exposure: inhalation & ingestion
* Ingestion most common route of exposure
* Consumption of contaminated food major source of exposure
* Inhalation & accidental ingestion of inorganic and organic
compounds (industry) most common reason for toxic levels.
Mercury
Each form of mercury has different toxicologic
characteristics.
Elemental mercury (Hg
0
)
can be ingested without significant effects
Inhalation is insignificant because of its low vapor
pressure
largely not absorbed because of its viscous liquid
nature.
Cationic mercury (Hg
2+
)
Moderately toxic
Partially absorbed (inorganic Hg)


Mercury
Organic mercury
Methyl mercury (CH
3
Hg
+
) very toxic
Not significantly absorbed
has significant local toxicity in the
gastrointestinal tract
rapidly and efficiently absorbed by passive
diffusion
Mercury
Systemic organic mercury (hydrophobic
compartments)
Results in high concentrations in brain and
peripheral nerves.
Organic mercury is biotransformed to the divalent
state, allowing it to bind to neuronal proteins
Elimination: renal filtration of bound low molecular
weight species or free (ionized) state.
Elimination rate is slow; chronic exposure exerts a
cumulative effect
Mercury toxicity
a result of protein binding, which results in a change of
structure and function.
The most significant result of this interaction is the
inhibition of many enzymes.
Acute gastrointestinal disturbances
binding to intestinal proteins after ingestion of inorganic
mercury
Severe bloody diarrhea
Ingestion of moderate amount
Ulceration and necrosis of the GI tract
Shock / Death
Severe cases

Clinical Significance
Tachycardia
Tremors
Thyroiditis
Disruption of renal function most significant
Glomerular proteinemia
Loss of tubular fxn
Neurologic symptoms
Primary toxic effect of organic Hg.

Low levels of exposure
causes

Higher levels of exposure
result in
Tremors Hyporeflexia
Behavioral changes Hypotension
Mumbling speech Bradycardia
Loss of balance Renal dysfunction
Death
Atomic Absorption
Analysis of mercury
Uses whole blood or an aliquot of a 24-hr
urine specimen or anodal stripping volametry.
Requires special techniques as a result of the
volatility of elemental Hg.
Pesticides
are substances that have been intentionally
added in the environment to kill or harm
undesirable life form
Classified into several categories
insecticides, herbicides, etc.
Purpose:
been applied to the control of vector-borne
disease and urban pests
to improve agricultural productivity
Can be found in occupational settings and in
the home frequent opportunities for exposure
Contamination of food
major route of exposure to the general public
Inhalation common occupational
Transdermal adsorption and accidental routes
Ingestion of exposure
Pesticides
Action: target specific but (most) nonselective

toxic effects to many nontarget species
(inc. human)
Health effects:
1. Short-term, low-level exposure
Not yet ellucidated
2. Extended low-level exposure
may result to chronic disease states
3. High-level exposure
may result in acute disease states or death
Pesticides
People applying the pesticide
most common victims of acute poisoning
Ingestion by children also common
Pesticide ingestion
A common suicide vehicle
Pesticides
Wide variation in the chemical configuration
from simple salts of heavy metals to complex HMW-
organic compounds
INSECTICIDES are the most prevalent of
pesticides
most common insecticides based on chem
configuration
1. Organophosphate
most abundant pesticides
reponsible fo about 1/3 of all pesticide poisoning
2. Carbamates
3. Halogenated hydocarbons
Pesticides
Acetylcholinesterase inhibitor
action of organophosphates and carbamates
in mammals
acetylcholine is responsible for stimulation of
muscle cells and several endocrine and exocrine
glands
action is terminated by postsynaptic
acetylcholinesterase
inhibition of acetylcholinesterase

prolonged presence of acetylcholine on its receptor

Pesticides
Pesticides
Low-level of exposure
Salivation
Lacrimation
Involuntary urination and defecation
Higher-level of exposure
Bradycardia -Slurred speech
Muscular twitching -Behavioral changes
Cramps -Death may occur
Apathy

Pesticides
Absorbed organoPO
4
bind with high affinity to
proteins (acetylcholinesterase)
Protein binding
prevents direct analysis = indirect measurement of
acetylcholinesterase inhibition
sensitive and specific for organoPO
4
exposure


acetylcholinesterase
membrane-bound enzyme = low serum activity
1. Erythrocytic enzyme
RBC that have high surface activity are commonly
used to increase analytic sensitivity of the assay
Not commonly performed

Pesticides: Lab Diagnosis
2. Serum pseudocholinesterase(SCHe)
alternative test
inhibited by organoPO
4
in a similar manner to the
RBC enzyme
changes in the serum activity of SCHe lack
sensitivity and specificity for organoPO
4
exposure
Pesticides: Lab Diagnosis
Pseudocholinesterase (SCHe)

found in liver, pancreas, brain, and serum
biologic fxn: not well defined
decrease level
Acute infxn
Pulmonary embolism
Hepatitis
Cirrhosis
several variants demo diminished activity

not specific for organoPO
4
poisoning

normal ref range: 4000-12000 U/L
intraindividual variation
degree of variance within an average individual
700 U/L
SCHe test is considered as screening test
Immediate antidotal therapy
initiated in cases of suspected organoPO
4

poisoning with decreased SCHe activity
Pseudocholinesterase (SCHe)

Toxicology of Therapeutic Drugs
Salicylates
Aspirin, Acetylsalicyclic acid
Analgesic, Antipyretic, Anti-inflammatory
Functions by decreasing thromboxane and
prostaglabin by inhibiting cyclooxygenase
Drawback: interferes with platelet aggregation
and GI function
Acidic in nature therefore excessive ingestion
is associated with metabolic acidosis

Treatment: neutralization and elimination of
excess acid
GC or liquid chromatography have the highest
analytic sensitivity and specificity
Trinder reaction- most common chromogenic
assay; reacts with salicyclate with ferric nitrate
to form a colored complex

Acetaminophen (Tylenol)

analgesic drugs
overdose is associated with a severe
hepatotoxicity
2 forms:
Solely
In combination with other compound


Process of elimination:
Hepatic uptake
Biotransformation
Conjugation
Excretion
Pathway of major concern: Hepatic mixed-
function oxidase system
Transformed into reactive intermediates
Conjugated with reduced glutathione


In overdose situation- glutathione becomes
depleted, reactive intermediate increases
Nomograms are available that predict
hepatotoxicity based on serum concentration

Toxicology of Drug Abuse
Drug Abuse
1.Drug Overdose- it is essential to identify the
responsible agent to ensure appropriate treatment.

2. Drug Abuse in non overdose situation-
provide rationale for treatment for addiction.

Testing for Drug Abuse
Involves screening of a single urine specimen
for many substances by qualitative screening
procedures.

This procedure detects only recent drug use.

With abstinence of relatively short duration-
abusing patient may not be identified

Testing for Drug Abuse
Evaluation of chronic abuse usually involves
several positive test results.

A positive drug screen cannot discriminate
between a single casual use and a chronic
abuse.

Drug Abuse or Overdose
Prescription
Over-the-counter
Illicit drugs
Recreational or Performance enhancement
Purposes-most common

Testing for Drug Abuse
Testing for drug abuse has become
commonplace in:
Professional
Industrial
Athletic setting.

The potential punitive measures associated
with the testing may involve or result in
criminal litigation .

Testing for Drug Abuse
Laboratories must ensure that data are legally
admissible and defendable.

Analytic methods are used(accurate and precise)

Documentation of specimen security.

Protocols and procedures must be established to
prevent and detect specimen adulteration.


Testing for Drug Abuse
Measurement of the ff.:
Urinary temperature
PH
Specific Gravity
Creatinine

*to ensure that specimen has not been diluted or
treated with substances that may interfere with
testing.



Drug Abuse Testing
1. Screening Test
Simple
Rapid
Inexpensive
Capable of being automated
2.Confirmatory Test

Screening Test
Often referred to as SPOT TESTS

Have good analytical sensitivity with marginal
specificity.

Detect classes of drugs based on similarities in
chemical configuration.

Allow detection of parent compounds and
congeners which have similar effects.

Screening Test
Drawback
May also detect chemically related substances
that have no or low abuse potential .


*Interpretation of positive test results requires
integration of clinical context and further testing.
Confirmatory test
Uses methods with high specificity and
sensitivity.

Provide quantitative and qualitative
information.

GC-mass spectrophotometry (GC/MS)-
Reference method for confirmation of most
analytes.
General Analytic Procedures commonly
used for Analysis of Drug Abuse
1. Chromogenic Reactions- used as screening
procedures.
2. Immunoassay-based procedures-screening
and confirmatory assay. Offer a high degree
of sensitivity and are easily automated.
Chromatography Technique
1.Thin-layer Chromatography
Inexpensive method for the screening of many
drugs.

No instrumentation is required.

Qualitative identification and quantitation of
drugs.




AMPHETAMINES

a stimulant used for narcolepsy and
attention-deficit disorder

Initial effect: Increased mental and physical
capacity along with a perception of well-
being.

Followed by: Restlessness, irritability,
possibly psychosis
AMPHETAMINES
Overdose (rare in experienced users):
hypertension, cardiac arrhythmias,
convulsions, possibly death

OTC amphetamines: ephedrine,
pseudoephedrine, and phenylpropanolamine

amphetamine-like compounds are common
in allergy and cold medications





AMPHETAMINES

Screening: Immunoassay systems
(urine)

Confirmatory: Liquid or Gas
Chromatography



Usually administered orally in tablets (50-150
mg)

circulating half-life: 8-9 hours

eliminated by: hepatic metabolism
(20% unchanged in urine)

onset if effect: 30-60 minutes (up to 3.5 hours)

MDMA
ECSTASY
METHYLENEDIOXYMETHYLAMP
HETAMINE
METHYLENEDIOXYMETHYLAMPHET
AMINE
Desired effects:
hallucinations, euphoria,
emphatic and emotional responses,
and increased visual and tactile sensitivity


A screening test would usually not
test positive, thus a confirmatory test must be
performed.
ANABOLIC STEROIDS
Chemically related to testosterone

used as therapy for male hypogonadism

increases muscle mass and
improves athletic performance
ANABOLIC STEROIDS

ANABOLIC
STEROIDS

ANDROGENIC
ANABOLIC ANDROGENIC
STEROIDS
Chronic use of steroids:
toxic hepatitis
accelerated arthrosclerosis
abnormal aggregation of platelets (MI/stroke)
enlargement of the heart (death)

Males
testicular atrophy, sterility,
and impotence

Females
masculine traits, breast reduction
sterility


Screening Test:

Testosterone to Epitestosterone Ratio
(T/E)


high ratios associated with
exogenous testosterone testosterone



ANABOLIC ANDROGENIC
STEROIDS
Cannabinoids
Group of psychoactive compounds found in
marijuana.
THC (tetrahydrocannabinol)- most potent and
abundant
Marijuana or Hashish (processed product) can
be smoked or ingested.
Cannabinoids
Subjected effect of exposure:
Sense of well-being
Euphoria
Associated with:
Impairment of short-term memory
Intellectual function
Overdose has not been associated
With chronic use, Tolerance and mild
dependence may develop


Cannabinoids
THC a lipophilic substance, rapidly removed
from the circulation by passive distribution into
hydrophobic compartments, such as brain and
fat.
Results in slow elimination as a result of
redistribution of back into circulation and
subsequent hepatic metabolism
Half life:
1 day after a single use
3-5 days in chronic, heavy consumers
Hepatic metabolism products are eliminated in
urine.
Cannabinoids
Major urinary metabolite
11-nor- - tetrahydrocannabinol-9-carboxylic
acid(THC-COOH)
Can be detected in urine:
3-5 days after single use
4 weeks in chronic
Immunoassay for THC-COOH screening test
GC/MC confirmatory
Passive and Direct inhalation
Cocaine
An effective local anesthetic with a few
adverse effects at therapeutic concentrations
A potent CNS stimulator that elicits a sense of
excitement and euphoria
Administered directly
Insufflation or intravenous injection
Inhaled as a vapor when smoked in the free-base
form (crack)
Cocaine
It has high abuse potential
Half life: 0.5-1 hr
Due to its short half life, it requires repeated
dosages of increasing quantity
Acute cocaine toxicity is associated:
Hypertension
Arrhythmia
Seizure
MI
Cocaine
Primary factor that determines toxicity:
Dose
Route of administration
Intravenous administration-greatest hazard
followed by smoking
Cocaines short half-life is a result of rapid
hepatic hydrolysis to inactivate metabolites.
Major route of elimination.
Cocaine
Benzoylecgonine
Primary product of hepatic metablism
Eliminated in the urine
Half life: 4-7 hours
Sensitive and specific indicator of cocaine use
Detected in urine for up to 3 days after single use
and up to 20 days after the last dose for chronic
heavy abusers
Immunoassay (screening)
GC/MC (confirmatory)
Opiates
Class of substances capable of:
Analgesia
Sedation
Anesthesia
ALL derived from or chemically related to
substances derived from the opium poppy

Naturally occurring
substances
Opium
Morphine
Codein
Chemically modified
forms of naturally
occuring opiates
Heroin
hydromorphone
(Dilaudid)
oxycodone (Percodan)
Common synthetic
opiates
Meperidine
(Demerol)
methadone
(Dolophine)
propoxyphene
(Darvon)
pentazocine (Talwin)
fentanyl (Sublimaze)
Opiates
Have high level of overdose
Chronic use tolerance (physical and psychological dependence)
Acute overdose
presents with respiratory acidosis
possibly an increase in serum indicators of cardiac
damage
High-level opiate overdose
may lead to death
Tx: use of naloxone (opiate antagonist)
Opiates
Laboratory test:
1. Immunoassay
initial screening
most are primarilly designed to detect morphine
and codeine
Cross-reactivity
2. GC/MS
confirmatory method of choice
Opiates
Phencyclidine (PCP)
an illicit drug
properties
Stimulant
Depressant
Anesthetic
Hallucinogenic
has high-abuse potential
Adverse effects are commonly noted at doses
that produce the desired subjective effects
Overdose - assoc with coma and stupor
PCP can be
ingested
inhaled (by smoking PCP-laced tobacco or
marijuana)

Phencyclidine (PCP)
a lipophilic dug that rapidly distributes into fat
and brain
Elimination is slow
about 10-15%
administered dose that is eliminated unchanged
in the urine
Hepatic metabolism forms various products
Phencyclidine (PCP)
Detection of the parent drug in the urine
ID of PCP
In chronic heavy users
PCP can be detected 7-30 days after abstinence
Laboratory test:
1. Immunoassay screening procedure
2. GC/MS confirmatory method
Phencyclidine (PCP)
Sedative-Hypnotics
ALL members of this class are CNS depressants

High to low abuse potential
Most common type of sedative hypnotics
abused
Barbiturates - have higher abuse potential
Benzodiazipines -more commonly found in
abuse and overdose situations

Commonly abused
barbiturates:
Secobarbital
Pentobarbital
Phenobarbital




Commonly abused
benzodiazepines:
Diazepam (Valium)
Lorazepam (Ativan)
Chlordiazepoxide
(Librium)
Sedative-Hypnotics
Initial overdose lethargy
progress slurred speech
coma

Respiratory depression
most serious toxic effect
Hypotension can occur with barbiturates
Toxicity of these agents is potentiated by
ethanol
Sedative-Hypnotics
Laboratory tests:
1. Immunoassay
most common screening for both barbiturates and
benzodiazepines
Broad cross-reactivity
2. GC or Liquid chromatography
Confirmatory test
Sedative-Hypnotics