Introduction to toxicology

Study of effects of poison old

The study of adverse effect of chemical agents on biological system
Toxicology subdisciplines
A) Occupational toxicology
Occupational toxicology Deals with chemical found in the workplace
B) Environmental toxicology
Environmental toxicology deals with the potentially deleterious impact of chemicals, present
as pollutants of the environment, to living organisms. Ecotoxicology has evolved as an
extension of environmental toxicology. It is concerned with the toxic effects of chemical and
physical agents on living organisms, especially in populations and communities with defined
ecosystems.
C) Clinical toxicology
Clinical toxicology deals with diagnosis and treatment of the normal diseases or effects
caused by toxic substances of
exogenous origin
D) Forensic toxicology
Forensic toxicology closely related to clinical toxicology. It deals with the medical and legal
aspects of the harmful effects of chemicals on man, often in post mortem material, for
instance, where there is a suspicion of murder, attempted murder or suicide by poisoning
Pharmacological principles
Toxic response to frequency dose and tissue concentration
Dose= Actual mount that enters the body
Duration and frequency important contributors to DOSE
Toxicology is quantal response (all or none) rather than graded response
The dose makes the poison.
Exposure:
Acute Less than 24 hours
Subacute 30 days
Subchronic 30-90 days
Chronic Over 90days

Dose-response curve

Tissue concentration of drug is proportional to the response

Median lethal dose (LD50) is the dose which is expected to kill 50% of the population in
the particular group.
Median effective dose (ED50) is the dose that produces a desired response in 50% of the
test population when
pharmacological effects are plotted against dosage.
Median toxic dose (TD50) is the dose which is expected to bring toxic effect in 50% of the
population in the particular group.
Margin of safety= TD1/ED99

Mechanism of toxicology

Toxicodynamics is the mechanism of action of a toxic chemical to the body (what chemicals
do to the body). The targets for the toxicodynamic actions of toxic chemicals are
a) Enzymes
b) Membrane receptors
c) Intracellular receptors
d) Ion channel
Toxic effects generally result from adverse cellular, biochemical, or macromolecular changes
which attained by
a) Damage to an enzyme system
b) Disruption of protein synthesis
c) DNA damage
d) Modification of an essential biochemical function

Toxicity
Metals
Mercur
y

of heavy metals
General
Source
OrganicCNS effect (fish)
InorganicKidneys effect (dental amalgam)
Metal
Other exposure:
Occupation such as Miners thimerosal for vaccine storage
Adsorption
a) Pulmonary absorption of mercury vapour is high
b) Gastrointestinal absorption of Hg+1 or Hg+2 is on
the order of 15 %
c) Alkyl mercurial highly absorbed from the
gastrointestinal tract
d) Deposition mainly at kidney

Lead

Source
Manufacturing/Gasoline (organic)/Moonshine/Ayurveda
medication
Adsorption
a) Inorganic Lead via lungs and GIT
b) Organic lead can penetrate skin
c) First adsorbed into soft tissue then redistributed to:
i) Bone major deposit
ii) Others: teeth and hair
iii) Kidney elimination
Lead deposition if high Vit D and Phosphate
Mechanism
a) Bind to sulfhydryl groups Inhibit enymes such as
gamma-aminolevulinic acid dehydratase (ALA-D)
and ferrochelatase in heme synthesis Anemia
b) Inhibition of pyrimidine 5 nucleotidase
Basophilic stippling
c) Inhibit calcium dependent process Neurotoxicity

Toxicity
General symptoms
a) Intention tremor
b) Inflammation of the gums
with excessive salivation
c) Psychiatric symptoms, such
as excitability, insomnia,
irritation, and shyness
d) High pulmonary absorption
can lead to interstitial
pneumonitis

Treatment
Chelators:
a) Peniccilamine
b) Unithiol, DMPS
c) Succimer, DMSA
Calcium EDTA cannot be
used binds weakly
nephrotoxic

Nephrotoxicity symptoms
Nephrotic syndrome
Tubular dysfunction
Acute
a)
b)
c)
d)

exposure
Abdominal pain ("lead colic")
Joint/muscle aches
Short-term memory problems
Difficulty concentrating,
irritability
e) Anemia (sometimes
accompanied by basophilic
stippling on blood smear)
f) Nephropathy

Chronic exposure
a) Hypertension
b) Neuropsychiatric effects
c) Reproductive effects
d) Mortality
e) Kidney and accelerate agingrelated diseases related to
vision, hearing, and dental
health

Remove exposure
Chelators:
a) Succimer, DMSA
b) Ca EDTA
Mild Vitamin C dose

Arsenic

Cadmiu
m

d) Alters permeability of BBB Neurotoxicity

e) Affect DNA and RNA
f) Affect cell membrane, mitochondria Nephrotoxic,
anemia
g) Superoxide and hydrogen peroxide generation
Hypertension
Source
Metalic arsenic Non toxic
Organic As2O3 Badly absorbed
Inorganic usually low in food
Arsine gas (AsH3) Most toxic
Exposure: Soil, volcano, fish
* +3 and +5 arsenic consider most toxic
Adsorption
a) Well absorbed GIT and inhalation
b) Taken up by RBC and distributed to tissue
c) Deposit in skin, bone marrow, kidneys, and
peripheral nervous system
d) Excretion in kidney
Mechanism
a) Trivalent arsenic (+3)binds to sulfhydryl groups
(proteins, glutathione, cysteine) interfere enzyme
systems (eg: pyruvate dehydrogenase,
gluconeogenesis and glucose uptake, and
glutathione metabolism )
b) Pentavalent arsenic (+5) and arsine gas are
converted to trivalent arsenic in vivo, but they may
also have some direct effect on uncoupling oxidative
phosphorylation
c) The majority of trivalent arsenic is metabolized via
methylation to form monomethylarsonic acid (MMA)
followed by dimethylarsinic acid (DMA) and excreted
through the urine
Source
Exposure: Food, smoke, occupation, household products

f) Anemia

Acute poisoning
GITNausea, vomiting, abdominal
pain, and diarrhea dehydration,
hypotension, and QTc prolongation
cardiac arrhythmias, shock, acute
respiratory distress syndrome, and
sometimes death
Chronic poisoning
a) Skin lesions
b) Neurologic manifestations
c) Cancer
d) Cardiovascular
Hypertension
e) LiverJaundice
f) Endocrine
g) Respiratory
h) Mortality
i) Reproductive and
developmental

Nephrotoxicity symptoms
Tubular dysfunction

Acute
a)
b)
c)
d)

poisoning
Remove exposure
Nasogastric
Charcoal
Chelator: Dimercarprol/
succimer/ Unithiol

No cathartics as arsenic causes

diarrhoea
Chronic poisoning
Chelator: Dimercarprol/
succimer

No specific method

Adsorption
a) Ingestion or inhalation
b) Cadmium is transported to the liver where
metallothionein, a cadmium- and zinc-binding
protein, is synthesized
c) Metallothionein = detoxifying protein, transported to
the kidneys
d) Metallothionein enters the lysosomes where it is
degraded by lysozymes, releasing free cadmium
ions into the tubular cell cytoplasm.
Mechanism
Mainly hypothesis which involves accumulation of Cd in
tubules Reduce activation of calcitriol

Glomerular damage
Nephrolithiasis

Chelating agent may increase

nephrotoxicity

Bone disease

Vitamin D for bone disease

Lung toxicity and cancer

Obstructive lung disease,
emphysema

Venoms
Snake venom
Snake venom has combination of toxic and non-toxic compound.
Type of toxic compound:
a) Cholinesterases
b) Aminoacid oxidases
c) Hyaluronidases Dissolve intracellular and speed the spread of preys tissue
d) Proteinases break down of tissue
e) Phospholipases Harm muscle and nerve cell
f) Adenosine triphosphates
g) Phosphodiesterases
h) Neurotoxin Paralysis with nervous system
i) Cardiotoxin Irrerversible depolarisation of Cardiac muscle
j) Hemorrahagins
k) Haemotoxins
l) Myotoxins
Snake venom can affect presynaptic by inhibiting Ach release or postsynaptic by binding to AchR Neuromuscular blockade paralysis
Pufferfish
Selective block of Na channel in nerve cell
Antivenom
Injected into animals to stimulate antibody, the antivenom is used to treat animal bites

Research
ACE inhibitor from pit viper
Cobroxin (morphine like) from cobra
Nyloxin for arthritis pain from cobra