Fundamentals of Toxicology

Sri Hainil,S.Si,M.farm,Apt
 What is Toxicology?

"the science of poisons"

The name toxicology is derived from the Greek

word "TOXIKON", which means an arrow.
 The harmful cerussa, that most noxious thing
Which foams like the milk in the earliest spring
With rough force it falls and the pail beneath fills
This fluid astringes and causes grave ills.
The mouth it inflames and makes cold from within
The gums dry and wrinkled, are parch'd like the skin
The rough tongue feels harsher, the neck muscles grip
He soon cannot swallow, foam runs from his lip
A feeble cough tries, it in vain to expel
He belches so much, and his belly does swell
His sluggish eyes sway, then he totters to bed
Phantastic forms flit now in front of his eyes
While deep from his breast there soon issue sad cries
Meanwhile there comes a stuporous chill
His feeble limbs drip and all motion is still
His strength is now spent and unless one soon aids
The sick man descends to the Stygian shades.
Nikander
 What is Toxicology?

Modern toxicology is defined as a study on the adverse

(toxic) effects of both chemical and physical agents on
biological systems. An important goal of toxicology is the
application of the discipline to safety evaluation and risk
assessment.
Areas of Toxicology
 What is toxic?

If exposure is great enough, all substances are toxic. This

includes water and oxygen.
“All substances are poisons, there is none which is not a
poison. The right dose differentiates a poison from a remedy.”
Paracelsus
Terms used in the classification of toxic substances

Toxin - Toxic substance of biological origin, e.g. botulism

toxin

Toxicant - Refers to a man-made substance

Xenobiotic - Foreign chemical to the body

Pollutant - Generally refers to substances generated or

concentrated by human activity and can be noxious or toxic
to living organisms
 Toxic agents are ubiquitous!

Toxicology deals with toxicity and mechanisms of toxicity

of chemicals used in:

- medicine for diagnostic, preventive, and therapeutic

purposes,
- in the food industry as direct and indirect additives,
- in agriculture as pesticides, growth regulators, artificial
pollinators
- in the chemical industry as solvents, components, and
intermediates of plastics and many other types of chemicals.
It is also concerned with the health effects of

- metals
- petroleum products
- wastes of paper and pulp industry
- air pollutants
- animal and plant toxins.

Risk assessment of deleterious of health effects induced

by chemicals is a major enterprise in toxicology.
Regulatory agencies try to determine the ADI
for toxicants: “Acceptable Daily Intake”

The daily intake of chemical, which during an entire

lifetime appears to be without appreciable risk on
the basis of all known facts at that time. WHO,
1962.

Incorporates uncertainty and modifying factors

(usually 10-fold for each uncertainty)
 Dose response relationship
80
70
60
50
40
Chemical
30
20
10
0
5 10 20 40 80
mg/kg
No observed effect level
(NOEL) Used to detect safety levels
 Classification of Toxic Substances
Lacks use of a conventional system

Origin - Microbial, fungal, plant, or animal toxin

Chemical Class - ie halogenated aromatic hydrocarbons,

heavy metals, organophosphate insecticides, solvents

Target organ - nephrotoxic, hepatotoxic, neurotoxic

Target Organism(s) – Pesticide – Rodenticide, Herbicide

Biological effect - Carcinogen, teratogen, mutagen,

 Biotoxins Plant toxins
mostly
Neurotoxins?
 Routs and exposure

Acute – dose occurs in less than 24 hour

• Ingestion
• Dermal
• Inhalation
• Intra-ocular
• Injection
Duration and frequency of exposure (2)
Sub-acute
– Less than one month by whatever route and
repetition
Sub-chronic
– Doses between one and three months
Chronic
– Exposure for more than three months to lifetime
 Toxicants in human exposure
Substance Frequency (%)
Cleaning substances 10.4
Analgesics 10.0
Cosmetics 8.3
Plants 6.1
Cough/cold preps 5.7
Bites/envenomations 4.2
Pesticides 3.8
Topicals 3.8
Chemicals 2.9
Alcohols 2.7
 Toxicant exposure may result in:

Immediate or delayed effects. NO by inhalation has effects

within seconds. Many carcinogens require 20+ years
before effects are observable

Reversible or irreversible effects. This is dose-dependent

for terminal effect toxicants but not for carcinogens.
The Intoxication Process: Mechanisms

Absorption

Distribution

Metabolism or biotransformation

Excretion
Variations in toxic response

Selective toxicity

Genetic polymorphism

Species differences
 How does body detoxify?
How are toxicants metabolized?
 As with therapeutic drugs, balance of
Phase I and Phase II enzymes is most
important
Not static or predictable
Variables include:
– Developmental age
– Pre-existing disease
– History of exposure
– Nutrition
– Interactions with other drugs and chemicals
– Lifestyle: smoking and ethanol
 Carcinogenesis

Carcinogenesis: Process by which chemicals cause cancer.

Many environmental chemicals/agents are known to cause human

cancer:
–Tobacco, cadmium, coal tar, cigarette smoke, UV light, X-rays etc
–A large number of chemicals are classified as carcinogens based
on their ability to induce tumors in animal models.

Chemicals can induce tumors by directly damaging or modifying

DNA (genotoxic) or indirectly by suppressing the immune system,
changing hormone balance etc
 Mutagenesis:

Mutagenesis: Toxicity on genetic material and its

inheritance.

Mutagens include ionizing radiation, alkylating agents,

most carcinogens
 Teratogenesis
Teratogenesis: Deleterious effects on developmental process.

Thalidomide is a well known teratogen for human species-was

introduced as a sedative. It was teratogenic even when taken once
during 3-7th week of pregnancy.

It caused shortening or
complete absence of limbs.

Methyl mercury
Alcohol
Diethyl stilbestrol (DES)-
a synthetic estrogen
 Reproductive toxicity

A large number of chemicals are toxic to the male or female

reproductive system.

•Can cause decreased sperm count.

•Some environmental chemicals such as

dichlorodiphenyltrichloroethane (DDT), DDE etc can mimic human
estrogen. They are called “environmental estrogens”.

•In wildlife they cause hermaphroditic fish and other reproductive

anomalies (sex reversal) in alligators.
 Organ toxicity

Neurotoxicity:

•Neurons can not normally regenerate. Thus toxic effects can

be permanent.

•Neurotoxic chemicals can cross blood brain barrier easily.

•Examples:

–Lead,

–Mercury: In Japan, in 1950s, a chemical plant released large

amounts of mercury into the bay. People who ate contaminated
fish suffered from severe neurotoxicity.
 Neurotoxicity
Pesticides: Organophosphorus (OP) and carbamate insecticides
inhibit acetyl choline esterase, an enzyme that breaks down acetyl
choline.
In humans, exposure to OP compounds causes muscle weakness,
paralysis of respiratory muscles and death.

Property of OP compounds used to develop “nerve gas”. •A

contaminant of “synthetic heroin”, MPTP (1-methyl-4-phenyl-
1,2,3,6-tetrahydropyridine), causes irreversible brain damage and
Parkinson’s-like symptoms.