POISONS
• Cyanide
• Carbon monoxide
• Arsenic and other metals
• Organophosphates & Nerve Agents
• Inhalants (Toluene)
POISONS
Definitions
Therapeutic Index: The absolute difference between a tolerable (or
therapeutic) concentration and a toxic concentration
Poisons: Substances with little or no therapeutic index;
we’ll use…‘Toxic’ Index
Poisons in our environment
•Plant Alkaloids, e.g. Strychnine
•Venoms (Insect/Scorpion/Reptilian/Snake)
•Mushrooms
•amatoxin
•Microbial (Botulinus toxin)
•Chemical compounds (Cyanide CN)
•Metals
Cyanide CN
Poison in the environment-background levels
(sources/natural&industrial)
• Many natural sources of CN or CN
producing substances (cyanogenic)
• Peach pits, Cassava fruit, apple seeds
• Vitamin B12 (cyanocobalamin); many
metabolic processes produce CN of
cyanogenic chemicals; liver possesses
enzymatic pathways to detoxify CN
Cyanide CN
Poison in the environment-background levels
• Salts NaCN & KCN used widely (electroplating,
gold production and recovery)
• Many industrial uses
• Rodenticides/Pesticides - fumigants
• Nitroprusside used as an antihypertensive (action
through effect of NO on relaxing vascular muscle)
• CN (HCN) produced by burning synthetic
materials
Cyanide CN
Mechanism of poison’s action
• Reversibly binds to a critical component of
the respiratory chain (cytochrome c
oxidase) causing a reversible stop in
oxidative energy production
• Other enzyme systems are affected; oxidate
energy production is the most important
Cyanide CN
Mechanism of poison’s action
• Without oxidative energy production,
glucose and other sugar energy pathways
are the only source of energy
• Two tissues in particular are obligate
oxygen users: Brain and Heart
Cyanide CN
Onset of action
• Toxic effects depend upon “route of
administration” and concentration
• HCN gas when breathed is the fastest; death
can occur within minutes; individuals can
be incapacitated in HCN vapour within
seconds
• Swallowed CN salts or cyanogenic
substances take longer (absoprtion/ first
pass effect)
Cyanide CN
Course of toxic effect
•
•
•
•
CNS stimulation (counter effect) excitation
headache and stiff neck
giddiness
change in breathing pattern (dyspnea); can
be confused for hyperventilation
• nausea and vomiting
Cyanide CN
Course of toxic effect
•
•
•
•
*** asphyxia without cyanosis***
the oxygen remains in the blood and
individuals color looks good
convulsions and muscular contortion
breathing: short inhalation-long exhalation
heart races (tachycardia) then slows
(bradycardia)
Cyanide CN
Course of toxic effect
• Death due to asphyxia, cardiac and
respiratory arrest, with severe brain damage
(depending on time to death
Cyanide CN
Disease states with similar (masking) symptoms
• Heart attack
• Acute asthma
Cyanide CN
‘Toxic’ Index
• Relatively small
• 50 mg HCN 200-300 mg of NaCN or KCN
Response
PPM
• Immediately fatal
270
• Fatal in 10 min
181
• in 30 min
135
• 1 hr or dangerous to life
110-135
• slight symptoms (e.g. headache) 18-36
Cyanide CN
Routes of Absorption
• Primarily by breathing vapor or oral
administration
• Dermal and Occular
Cyanide CN
Pharmacokinetics – dynamics
• Bioavailability: up to 77% by inhalation/
50% orally/ also dermal (slow) and occular
absorption
• Vd 0.4 L/kg
• t ½ - approximately 1- 2 hr / converted to
thiocyante by rhodanase enzyme
Cyanide CN
Pharmacokinetics – dynamics
Blood concentrations
• No symptoms
• Flushing/tachycardia
• Toxicity-death
• Coma-Death
mg/100 mL
0.01-0.05
0.05-0.1
0.1-0.25
> 0.25
Cyanide CN
Pharmacokinetics – dynamics
Overdose Treatment/Antidote
• Lilly antidote kit (sodium bicarbonate, amyl
nitrate and sodium thiosulfate) with 100%
oxygen
Carbon Monoxide CO
Poison in the environment-background levels (sources/natural;industrial)
• Primary source is incomplete combustion
Carbon Monoxide CO
Mechanism of poison’s action
• Binds reversibly to hemoglobin - affinity of
hemoglobin for CO > O2
Carbon Monoxide CO
‘Toxic’ Index
• Based on saturation of whole blood
• Endogenous < 1 %
• Up to 12% environmental (smokers living
in high pollution areas) with no sequelae
• Toxicity 12-35%
• Fatal > 35% if acute/ >50% if gradual (i.e.
accumulation over time.)
Carbon Monoxide CO
Onset of action
• Depends strictly with saturation levels
• e.g.
Response
PPM
Headache (20%)
60 min @ 200
20 min @ 500
Death (50%)
80 min @ 500
20 min @ 1500
In an area of high concentration - minutes to
incapacitation and death
Carbon Monoxide CO
Course of toxic effect
• Headache, drowsiness, dizziness, NV,
blurred vision, confusion, disorientation,
dementia, bradycardia-tachycardia,
hyperglycemia, seizures, coma, death
• Depends on concentration
Carbon Monoxide CO
Disease states with similar (masking) symptoms
• Severe headache often not recognized as a
symptom by victims
Carbon Monoxide CO
Pharmacokinetics – dynamics
• Inhalation
• Half-life 5-6 hrs.
• Binds to hemoglobin
carboxyhemoglobin
Carbon Monoxide CO
Overdose Treatment/Antidote
• Oxygen and Hyberbaric pressure chamber
• Half-life 5-6 hrs in std atmosphere
• 30-90 minutes with 100% oxygen
• 30 minutes in hyperbaric chamber
METALS
Poison in the environment-background levels (sources/natural;industrial)
• Most are relatively abundant in the
environment or vital ligands for
enzymes/co-enzymes and other
macromolecules
• Metals vital to Health
Iron, Copper, Selenium, Zinc
• Some Common Toxic Metals
Arsenic, Lead, Mercury, Thallium,
Nickel, Cadmium, Iron
METALS
Mechanism of poison’s action
• As- Multisystem disease due to inhibition of
oxidative energy pathway attacks SH
groups
• Pb - Same as As (SH groups)
• Tl - SH groups + subtitutes for K in ATPase
(energy) pump.
METALS
Mechanism of poison’s action
• Fe - Corrosive for GI tract -blood
coagulation & cardiovascular collapse
• Hg - Binds to thiol and sulfhydryl groups
METALS
‘Toxic’ Index
Metal Background
As
1 ng/mL
Fe
Hg
Pb
Tl
65 - 175 mcg/ 100 mL
< 2 mcg/100 mL
Tolerable intake
= 5 mcg/Kg
< 10 mcg/100 mL
US intake 1980 - 82
= 50 mcg/day
< 5 ng/ mL
Toxic
> 0.5 mg/ 100 mL
Fatal
> 1 mg/100
mL
> 350 mcg/ 100 mL > 1 gm
50 mcg/ 100 mL
> 50 mcg/ 100 mL
12-15 mg/Kg or
0.05 mg/100 mL
METALS
Onset of action
• As - 30 min - 2 hr; 200 mg Fatal 24 hr - 4
days
• Fe - 30 min - 6 hr; Fatal within 6 hrs or
longer
• Hg - usually long, slow build up
• Pb - usually long, slow build up
• Tl - GI symptoms within 12-24 hrs.
METALS
Course of toxic effect
Arsenic
•
•
•
•
•
Nausea &Vomiting,
bloody diarrhea,
abdominal pain,
burning on soles of feet,
sensory loss in extremities (lines in nail bed 4-6
weeks; Aldrich-Mees lines)
• death due to circulatory collapse
METALS
Course of toxic effect
Fe (Iron)
• Primarily GI- affects lining; NV, GI pain,
cardiovascular collapse
Hg (Mercury)
• CNS - tremor and loss of memory
Pb (Lead)
• CNS - difficulty concentrating, lead (blue-black)
line on gums
METALS
Course of toxic effect
Tl (Thallium)
•
•
•
•
•
•
Abdominal pain,
Nausea, Vomiting & Diarrhea,
peripheral neuropathy,
Aldrich-Mees lines,
*hair loss (2-4 weeks),
depressed respiration, delirium, seizure, coma, and
death
METALS
Disease states with similar (masking) symptoms
•
•
•
•
•
As -gastroenteritis, neurological disease
Fe - gastroenteritis, but easily detected
Hg - classic symptoms
Pb - classic symptoms
Tl - Viral disease; Guillain - Barre
syndrome (often misdiagnosed)
METALS
Routes of Absorption
• Mostly through industrial exposure or
surreptitious consumption (poisoning) or
suicide.
METALS
Pharmacokinetics – dynamics
Metal
As
Fe
Hg
Pb
Vd
t1/2
Elimination*
0.2 L/Kg
42-48 hrs
total body store 3-4 gm
hemosiderin in liver
? Elemental form poorly absorbed
Iron, Zinc, Ca deficiencies increase
absorption 50%; Widely distributed
Depends on body
burden
40-70 days
blood = 28-36 days;
bone = 20-30 years
renal detected in urine
for 30 hrs > 100 ng/mL
skin via desquamation;
~ 1 mg/day
1.5 L/Kg
*Most metals eliminated by the kidney
Tl
2-4 days
renal 24 hrs, then fecal
METALS
Overdose Treatment/Antidote
Specific chemicals sequester metals
• As - Dimercaprol, Penicillamine, Succimer
• Fe -Deferoxamine, Polyethylene glycol
• Hg - Dimercaprol, Succimer
• Pb - Dimercaprol, Penicillamine, Succimer
• Tl - Prussian blue (exchanges K for Tl) not FDA
approved; acetylcysteine investigational
Organophosphates &
Chemical Warfare Nerve Agents
Poison in the environment-background levels (sources/natural;industrial)
• Organophosphates were designed as
pesticides against eukaryotic pests (e.g. they
will also affect all pets and family
members)
• Most warfare nerve agents attack the same
metabolic pathways, but take minutes to kill
rather than hours - days.
• Organochlorines (DDT; 2,4 D) are generally
less toxic.
Parathion treated Cotton
Chemical Nerve Agents
Organophosphates &
Chemical Warfare Nerve Agents
Poison in the environment-background levels (sources/natural;industrial)
• Organophosphates:
e.g. Parathion, (phosphorothionic acid O,Odiethyl O-(4-nitrophenyl) ester), Diazinon
& Malathion
• Nerve agents:
Sarin (isopropyl Methylphosphonofluoridate),
Soman, Tabun,
VX (Methylphosphothionic acid S-(2-bis(1Methyl-Ethyl)Amino)Ethyl)O-Ethyl Ester)
Organophosphates &
Chemical Warfare Nerve Agents
Mechanism of poison’s action
•
•
•
•
•
Acetylcholinesterase inhibitors
Three stage action
Stage 1&2: Reversible for a period of time
Stage 3 : Becomes irreversible
Acetylcholinesterase has 2 binding sites for these
agents; the first can be reversed, the second can
not.
• Nerve agents may slao penetrate the brain &
disrupt GABA transmissions
Organophosphates &
Chemical Warfare Nerve Agents
‘Toxic’ Index
• Small to virtually non-existent
• Parathion
• Nerve agents: Sarin 4000x more potent than
parathion
• Lethal inhaled doses of sarin, tabun &
soman is 1mg
• VX - oily liquid absorbed dermally - 6 mg
is lethal
Organophosphates &
Chemical Warfare Nerve Agents
‘Toxic’ Index
• Maximum Control Limits (over 8 hrs)
Agent
PPM
Sarin & Tabun
1 x 10-5 (0.00001)
VX
1 x 10-4 (0.0001)
CN
36
5 to 6 orders of magnitude (100,000 to 1 M)
more potent than Cyanide.
Organophosphates &
Chemical Warfare Nerve Agents
Onset of action
• Organophosphates: depends on amount
consumed hours to days to weeks & months
• Nerve agents: within 5 minutes
• Aging of nerve agent-acetylcholinesterase
complex (stage 3):
Sarin
5 hours
Soman
2 minutes
Organophosphates &
Chemical Warfare Nerve Agents
Course of toxic effect
• Insomnia fatigue, memory loss, seizures,
ataxia, coma, salivation, sweating, tearing,
diarrhea, bradycardia, meiosis (pinpoint
pupils) muscle twitching, weakness or
paralysis.
• Death by respiratory arrest
Organophosphates &
Chemical Warfare Nerve Agents
Disease states with similar (masking) symptoms
Cholinergic symptoms:
–
–
–
–
–
–
salivation,
sweating, tearing,
diarrhea,
bradycardia,
meiosis (pinpoint pupils)
and memory loss/confusion
are classic symptoms for these agents
Organophosphates &
Chemical Warfare Nerve Agents
Routes of Absorption
• Readily absorpable by all routes
• Inhalation of gas and/or dust
• Dermal/Occular absorption (especially VX)
• Oral possible
Organophosphates &
Chemical Warfare Nerve Agents
Pharmacokinetics – dynamics
• Bioavailability not 100%
• hepatic conversion of organophosphates to weakly
active compounds
• onset of irreversible acetylcholinesterase binding
and extent of GABA inhibition
(pharmacodynamics) determine toxicity despite
kinetics
Organophosphates &
Chemical Warfare Nerve Agents
Pharmacokinetics – dynamics
• Organophosphates are cumulative
• Vd’s ?
• t 1/2 Malathion ~ 3hr others ?
Organophosphates &
Chemical Warfare Nerve Agents
Overdose Treatment/Antidote
• Anticholinergic - 1o Atropine
• Specific competative inhibitor of stage 2
binding is Pralidoxone (PAM)
• PAM binds phosphotase (or related) portion
of the toxin and reactivates the ACH ase
INHALANTS
Poison in the environment-background levels (sources/natural;industrial)
•
•
•
•
•
Toluene, Benzene, Gasolene
Chloroform, trichloroethylene
CFC’s
Anaesthethics
Other volatile substances
• Most are industrial/medicinal
• Focus on Toluene
Toluene
Mechanism of poison’s action
• Toluene - solvent (causes CNS depression
and confusion) specific mechanism
unknown
• Similarities to alcohols
• May alter lipid structure of membranes
• May effect receptor sites/membrane bound
enzymes
• May affect cell proteins &/or RNA
Toluene
‘Toxic’ Index
• Tolerable limits are 50 PPM (188mg/m3 )
• Moderate
• Intoxicating - 0.1 to 0.25 mg/mL
...significant tolerance can develop!
• Fatal - 0.25 to 1.0 mg/mL
• Est. daily dose by inhalation 300 mcg
• Lethal oral dose 625 mg/kg
Toluene
Forensic Caution
• Volatile solvent
• Sample concentrations can decrease over
time
• Factors:
– storage temperature
– Type of cap/tube and tightness of seal
– Amount of head space in tube/container
Toluene
Onset of action
• Rapid as with all solvents/volatiles,
especially when inhaled, effects begin
within minutes
• “rapid in - rapid out”, but toluene is highly
lipophillic, therefore: “rapid in - delayed
out” and extended action
Toluene
Course of toxic effect
• Marked intoxication, mental confusion,
slurred speech, inability to concentrate,
memory loss, hallucinations, coma, death
Toluene
Disease states with similar (masking) symptoms
• Alcoholic
Toluene
Routes of Absorption
• Absorption via all routes:
• Inhalation is fastest (30 minutes, e.g. glue or
paint thinner sniffing)
• Oral - up to 2 hrs.
• Dermal - time?
Toluene
Pharmacokinetics – dynamics
• Vd: unkown but likely high…significantly
retained in body
• Half life 48-72 hrs, but at least bi-phasic
• Initial blood concentrations drop within
hours… then level out for days, especially
in overdose (e.g. industrial accident) cases.
• Eliminated by kidneys, conversion to
benzoic acid conjugated to form hippuric
acid…excreted for days.
Toluene
Overdose Treatment/Antidote
• Supportive therapy, oxygen if signifcant
respiratory depression develops
• Many standard treatments e.g. epinephrine
contra-indicated, due to combined
cardiotoxicity or other toxicities
POISONS
The Bitter End!
METALS
‘Toxic’ Index
• Metal Background
• As - 1 ng/mL; Toxic > 0.5 mg/ 100 mL; Fatal > 1
mg/100 mL
• Fe - 65 - 175 mcg/ 100 mL; Toxic > 350 mcg/ 100
mL
• Hg - Background < 2 mcg/100 mL; Toxic > 50
mcg/ 100 mL; Tolerable intake = 5 mcg/Kg
• Pb - Background < 10 mcg/100 mL; Toxic > 50
mcg/ 100 mL; US intake 1980-82 = 50 mcg/day
• Tl - Background < 5 ng/ mL 12-15 mg/Kg toxic;
0.05 mg/100 mL in blood
METALS
‘Toxic’ Index
Metal
Background
Toxic
Fatal
As
1 ng/mL
> 0.5 mg/100
mL
> 1 mg/100 mL
Fe
65 - 175
mcg/ 100 mL
< 2 mcg/100 mL
Tolerable intake
= 5 mcg/Kg
> 350 mcg/ 100 mL
> 1 gm
Pb
< 10 mcg/100 mL
US intake ‘80 - 82
= 50 mcg/day
> 50 mcg/ 100 mL
Tl
< 5 ng/ mL
12-15 mg/Kg or
0.05 mg/100 mL
Hg
50 mcg/ 100 mL
METALS
Pharmacokinetics – dynamics
• As - Vd = 0.2 L/Kg; t 1/2 = 42-48 hrs; Elimination - renal;
detected in urine for 30 hrs > 100 ng/mL
• Fe - total body store 3-4 gm; hemosiderin in liver;
Elimination - skin via desquamation; ~ 1 mg/day
• Hg - Elemental poorly absorbed; t 1/2 = 40-70 days;
• Pb - Iron, Zinc, Ca deficiencies increase absorption 50%;
Widely distributed; t 1/2 blood = 28-36 days; bone = 2030 years
• Tl - Vd = 1.5 L/Kg; t 1/2 = 2-4 days; Elimination - renal
24 hrs, then fecal
*Most metals eliminated by the kidney