Dose-response is a basic principle of toxicology that evaluates the clinical effects of substances based on the amount of exposure. It establishes a relationship between exposure levels and health effects, with higher doses generally causing more severe responses. Key aspects of dose-response include establishing causality, threshold effects, and the potency of a substance. Dose-response curves graphically depict the relationship, with a typical sigmoid curve showing little effect at low doses and increasing response rates as doses rise. Toxicology addresses various questions through subdisciplines like environmental, occupational, regulatory, and clinical toxicology. Common toxic agents studied include heavy metals, solvents and vapors, radiation, dioxins/furans, pesticides, and

1. Environmental Toxicology

2. What is the principle of toxicology?
“Evaluation of clinical effects of xenobiotics based on the amount of exposure is the basic toxicology
principle also called dose-response.”
What is dose-response?
Dose-response is a relationship between exposure and health effect, that can be established by measuring the
response relative to an increasing dose.
The dose-response relationship is an essential concept in toxicology. It correlates exposures with changes in body
functions or health. In general, the higher the dose, the more severe the response. The dose-response relationship is
based on observed data from experimental animal, human clinical, or cell studies.
Knowledge of the dose-response relationship establishes:
• Causality — that the chemical has induced the observed effects.
• The threshold effect — the lowest dose where an induced effect occurs.
• The slope for the dose response — the rate at which injury builds up.
Dose response is the meaning behind the Paracelus the father of toxicology statement “the dose makes the poison.”

3. Dose-Response Curves
When we graph the dose of a substance and the percentage of a
population that responds to that dose, the result is called the dose-
response curve. The x-axis is the dose, typically in a logarithmic scale.
This means units on the x-axis increase by a power of 10, allowing us to
compare a very wide range of doses on a single graph. The y-axis is the
response, or the percentage of subjects that show a response.
When plotting the response at various doses, the dose-response curve
normally takes the form of a sigmoid curve that is shaped like the letter
“S”, much like the example in Figure 1
• For most effects, small doses are not toxic.
• The point at which toxicity first appears is known as the threshold
dose level. From that point, the curve increases with higher dose
levels.
• The shape and slope of the dose-response curve for predicting the
toxicity of a substance at specific dose levels. The slope of the
curve indicates the change in the percent of the population
responding as the dose increases.
• Comparing dose-response curves among chemicals in this way can
help toxicologists understand more about them. A curve with a
steep slope indicates the chemical has a high potency, or toxic
strength, compared to other chemicals. The greater the slope, the
greater the potency.
Fig 1. Dose-Response Curves

4. FIELD/SCOPE of Toxicology
Toxicology addresses a variety of questions. For example, in
agriculture, toxicology determines the possible health effects from
exposure to pesticides or herbicides, or the effect of animal feed
additives, such as growth factors, on people.
Toxicology is also used in laboratory experiments on animals to
establish dose-response relationships.
Toxicology also deals with the way chemicals and waste products
affect the health of an individual.

5. The field of toxicology can be further divided into the following sub-disciplines or
subspecialities:
# Environmental Toxicology is concerned with the study of chemicals that
contaminate food, water, soil, or the atmosphere. It also deals with toxic
substances that enter bodies of waters such as lakes, streams, rivers, and oceans.
This sub-discipline addresses the question of how various plants, animals, and
humans are affected by exposure to toxic substances.
# Occupational (Industrial) Toxicology is concerned with health effects from
exposure to chemicals in the workplace. This field grew out of a need to protect
workers from toxic substances and to make their work environment safe.
Occupational diseases caused by industrial chemicals account for an estimated
50,000 to 70,000 deaths, and 350,000 new cases of illness each year in only
United States.
# Regulatory Toxicology gathers and evaluates existing toxicological information
to establish concentration-based standards of “safe” exposure. The standard is
the level of a chemical that a person can be exposed to without any harmful
health effects.

6. # Food Toxicology is involved in delivering a safe and edible supply of food to the
consumer. During processing, a number of substances may be added to food to make it
look, taste, or smell better. Fats, oils, sugars, starches and other substances may be
added to change the texture and taste of food. All of these additives are studied to
determine if and at what amount, they may produce adverse effects. A second area of
interest includes food allergies. Almost 30% of the American people have some food
allergy. For example, many people have trouble digesting milk, and are lactose
intolerant. In addition, toxic substances such as pesticides may be applied to a food crop
in the field, while lead, arsenic, and cadmium are naturally present in soil and water, and
may be absorbed by plants. Toxicologists must determine the acceptable daily intake
level for those substances.
# Clinical Toxicology is concerned with diseases and illnesses associated with short term
or long term exposure to toxic chemicals. Clinical toxicologists include emergency room
physicians who must be familiar with the symptoms associated with exposure to a wide
variety of toxic substances in order to administer the appropriate treatment.

7. #Descriptive Toxicology is concerned with gathering toxicological information from animal
experimentation. These types of experiments are used to establish how much of a chemical would
cause illness or death. The United States Environmental Protection Agency (EPA), the Occupational
Safety and Health Administration (OSHA), and the Food and Drug Administration (FDA), use
information from these studies to set regulatory exposure limits.
# Forensic Toxicology is used to help establish cause and effect relationships between exposure to a
drug or chemical and the toxic or lethal effects that result from that exposure.
# Analytical toxicology identifies the toxicant through analysis of body fluids, stomach content,
excrement, or skin.
# Mechanistic Toxicology makes observations on how toxic substances cause their effects. The
effects of exposure can depend on a number of factors, including the size of the molecule, the
specific tissue type or cellular components affected, whether the substance is easily dissolved in
water or fatty tissues, all of which are important when trying to determine the way a toxic substance
causes harm, and whether effects seen in animals can be expected in humans.

9. General Classification of Toxic Agents is:
A. Heavy Metals
B. Solvents and Vapors
C. Radiation and Radioactive Materials
D. Dioxin/Furans
E. Pesticides
F. Plant Toxins
G. Animal Toxins
H. Subcategories of Toxic Substances
I. General Classifications of Interest to Communities

10. A. Heavy Metals
Heavy metals are different from other toxic substances in the way that they are
neither created nor destroyed by humans. Their use by humans plays an
important role in determining their potential for health effects. Their effect on
health could occur through at least two mechanisms:
• first, by increasing the presence of heavy metals in air, water, soil, and food
• second, by changing the structure of the chemical. For example, chromium III
can be converted to or from chromium VI, the more toxic form of the metal.
EXAMPLES
Arsenic
Cadmium
Lead
Beryllium
Hexavalent Chromium
Mercury

11. B. Solvents and Vapors
Nearly everyone is exposed to solvents. Occupational exposures can range from the use of “white-out” by
administrative personnel, to the use of chemicals by technicians in a nail salon. When a solvent evaporates, the
vapors may also pose a threat to the exposed population.
• SOLVENTS AND VAPOURS are liquid organic chemicals used to dissolve solid materials.
• Made up of natural sources such as turpentine and the citrus solvents, but most are derived from petroleum or
other synthetic sources.
• Used to dissolve materials like resins and plastics
• Disperse material which is in soluble in water
• Used in paints, varnishes, lacquers, inks, aerosol sprays, dyes, adhesives because they evaporate quickly and
cleanly.
EXAMPLES
PETROLEUM ETHER
• Used in laboratories, Solvent for oil, fats and Wax, As fuels in paints, varnishes and in photography.
• Chlorohydrocarbons replaced with petroleum ether in dry cleaning because its cheaper and lessflammable
• Toxic effect on Central Nervous System and dermatological system
• Inhalation cause CNS, Digestive system, Respiratory system

12. METHANOL
• Absorbed by Skin, Respiratory, GIT,
• Responsible Acidosis, Blindness, Death
• Severe human poisoning oral route(30min-60 min)
• Other effect by inhalation, Haemorrhages in to brain
DIETHYL ETHER
• Used in production of gum powder, primer for gasoline engines
• Extrapolated vapour pressure of 538mm Hg at 25 Celsius, present as vapour in atmosphere
• Degrade by reaction with photochemical producing hydroxyl radicals and nitrate radicals • General population come
contact by inhalation, contaminated water
BENZENE
• Used for production of ethyl benzene, cumin and cyclohexane
• Chronic inhalation leads Aplastic anaemia, leukaemia and multiple myeloma
• Acute exposure anaesthesia may develop at concentration above 3000ppm
• At 1000ppm cause giddiness, euphoria, nausea, headache, arrhythmias.
ACETONE
• Highly volatile, flammable, polar and aprotic solvent
• Used as cleaning agents in biomedical/pharmaceutical laboratory
• Repeated administration cause Increased white blood cell counts, increase eosinophil and decrease phagocytic activity of
neutrophils
• Shortening of menstrual cycle, premature menstrual periods, miscarriage and weakness of labor activity

13. C. Radiation and Radioactive Materials
Radiation is the release and propagation of energy in space or through a material medium in
the form of waves, the transfer of heat or light by waves of energy, or the stream of particles
from a nuclear reactor
EXAMPLES
Alpha particles
consist of two protons and two neutrons, in the form of atomic nuclei.
• They are emitted from naturally occurring heavy elements such as uranium and radium, as
well as from some manmade elements.
• They have little penetrating power and can be stopped by the first layer of skin or a sheet of
paper.
• However, if alpha sources are taken into the body, for example by breathing or swallowing
radioactive dust, alpha particles can affect the body’s cells. Because they give up their
energy over a relatively short distance, alpha particles inside the body can inflict more
severe biological damage than other types of radiation.
Beta particles are fast-moving electrons ejected from the nuclei of many kinds of atoms.
• These particles are much smaller than alpha particles and can penetrate up to 1 to 2
centimetres of water or human flesh.
• They can be stopped by a sheet of aluminium a few millimetres thick.

14. GAMMA RAYS, AND X-RAYS
like light, represent energy transmitted in a wave without the movement of material, just as heat and
light from a fire or the sun travels through space.
• X-rays and gamma rays are virtually identical except that X-rays are generally produced artificially
rather than coming from the atomic nucleus.
• But unlike light, these rays have great penetrating power and can pass through the human body.
• It is more intense at higher altitudes than at sea level where the earth’s atmosphere is most dense
and gives the greatest protection.
Neutrons
are particles which are also very penetrating. On Earth they mostly come from the splitting, or
fissioning, of certain atoms inside a nuclear reactor.
• Water and concrete are the most commonly used shields against neutron radiation from the core of
the nuclear reactor.
It is important to understand that alpha, beta, gamma and X-radiation does not cause the body or any
other material to become radioactive. However, most materials in their natural state (including body
tissue) contain measurable amounts of radioactivity

15. Man-made Radiation
Ionising radiation is also generated in a range of medical, commercial and
industrial activities.
• The most familiar and, in national terms, the largest of these sources of
exposure is medical X-rays. A typical breakdown between natural background
and artificial sources of radiation is shown in the pie chart. Natural radiation
contributes about 88% of the annual dose to the population and medical
procedures most of the remaining 12%. Natural and most artificial radiations
are not different in kind or effect.

16. D. Dioxin/Furans
Dioxin, (or TCDD) was originally discovered as a contaminant in the herbicide Agent Orange. Dioxin is also a
by-product of chlorine processing in paper producing industries. They are a group of chemically-related
compounds that are persistent environmental pollutants (POPs). Tioxins are found throughout the world in
the environment and they accumulate in the food chain, mainly in the fatty tissue of animals.
EXAMPLES
• Polychlorinated dibenzo-p-dioxins (PCDDs), or simply dioxins
• Polychlorinated dibenzofurans (PCDFs), or furans
• Polychlorinated biphenyls (PCBs), derived from biphenyl
• Polybrominated compounds of the above classes may have similar effects.
Exposure to Dioxins
People can be exposed to these chemicals by eating high-fat foods such as milk products, eggs, meat, and
some fish. Workplace exposures can occur in industries that burn waste matter or that manufacture other
chemical products containing these substances.
Adverse Effects on human
Human health effects from low environmental exposures are unclear. People who have been unintentionally
exposed to large amounts of these chemicals have developed a skin condition called chloracne, liver
problems, and elevated blood lipids (fats). Laboratory animal studies have shown various effects, including
cancer and reproductive problems.

17. E. Pesticides
The EPA defines pesticide as any substance or mixture of substances intended to prevent, destroy, repel, or mitigate any pest. Pesticides may
also be described as any physical, chemical, or biological agent that will kill an undesirable plant or animal pest
Type Action
Algicides Control algae in lakes, canals, swimming pools, water tanks, and other sites
Antifouling agents Kill or repel organisms that attach to underwater surfaces, such as boat bottoms
Antimicrobials Kill microorganisms (such as bacteria and viruses)
Attractants
Attract pests (for example, to lure an insect or rodent to a trap). (However, food is not considered a pesticide when used as an
attractant.)
Biopesticides
Biopesticides are certain types of pesticides derived from such natural materials as animals, plants, bacteria, and certain
minerals
Biocides Kill microorganisms
Disinfectants and sanitizers Kill or inactivate disease-producing microorganisms on inanimate objects
Fungicides Kill fungi (including blights, mildews, molds, and rusts)
Fumigants Produce gas or vapor intended to destroy pests in buildings or soil
Herbicides Kill weeds and other plants that grow where they are not wanted
Insecticides Kill insects and other arthropods
Miticides Kill mites that feed on plants and animals
Microbial pesticides Microorganisms that kill, inhibit, or out compete pests, including insects or other microorganisms
Molluscicides Kill snails and slugs
Nematicides Kill nematodes (microscopic, worm-like organisms that feed on plant roots)
Ovicides Kill eggs of insects and mites
Pheromones Biochemicals used to disrupt the mating behavior of insects
Repellents Repel pests, including insects (such as mosquitoes) and birds
Rodenticides Control mice and other rodents
Slimicides Kill slime-producing microorganisms such as algae, bacteria, fungi, and slime molds

18. EXAMPLES
Chlorpyrifos
• is the most widely-used pesticide on crops, including corn, soybeans, broccoli,
and apples, and is also widely used in non-agricultural settings like golf courses.
Chlorpyrifos was invented as an alternative to the pesticide DDT
• Exposure to small amounts of chlorpyrifos can cause runny nose, tears, and increased
saliva or drooling. People may sweat, and develop headache, nausea, and dizziness.
More serious exposures can cause vomiting, abdominal muscle cramps, muscle
twitching, tremors and weakness, and loss of coordination.
Dichlorodiphenyltrichloroethane DDT
• People are most likely to be exposed to DDT from foods, including meat, fish, and dairy
products. DDT can be absorbed by eating, breathing, or touching products
contaminated with DDT.
• Human health effects from DDT at low environmental doses are unknown. Following
exposure to high doses, human symptoms can include vomiting, tremors or shakiness,
and seizures. Laboratory animal studies showed effects on the liver and reproduction.
DDT is considered as possible human carcinogen.

19. Methoxychlore
Lindane gamma-hexachlorocyclohexane (γ-HCH)
Vinclozolin etc
Some of the classical members of following groups are used in Pakistan:
Chlorinated Hydrocarbon Pesticide:
(1) Aldrin
(2) BHC benzene hexachloride (lindane/gammexane),
(3) Chlordane,
(4) DDT,
(5) Dieldrin,
(6) Endrin,
(7) Heptachlor,
(8) Thiodane.

20. F. Plant Toxins
Plant toxins are generally the metabolites produce through plants to protect themselves against
different threats like insects, predators and microorganisms These toxins found in food plants is due
to natural or new reproduction methods which enhance defensive mechanism.
EXAMPLES
Natural toxins
May be present inherently in plants. They are usually metabolites produced by plants to defend
themselves against various threats such as bacteria, fungi, insects and predators, which may be
species specific and give the plant its particular characteristics, e.g. colours and flavours. Common
examples of natural toxins in food plants include lectins in beans such as green beans, red kidney
beans and white kidney beans; cyanogenic glycosides in bitter apricot seed, bamboo shoots,
cassava, and flaxseeds
Glycoalkaloids
found in potatoes
4'-methoxypyridoxine
found in ginkgo seeds
colchicine
found in fresh lily flowers; and muscarine in some wild mushrooms.

21. Tannins
These substances have the capability to precipitate proteins. They make
the skin tough by deception of the proteins in the skin.
Proteins
A number of protein toxins produced by plants enter eukaryotic cells and
inhibit protein synthesis enzymatically. Examples of poisonous proteins
include ricin (castor plant), abrin (rosary pea) and white acacia.
All plant toxins could be neurotoxins and show cytotoxic effects.

22. G. Animal Toxins
These toxins can result from venomous or poisonous animal releases.Such as
snake, spider, lizard, scorpeans, sea snails and others. Venomous animals are
usually defined as those that are capable of producing a poison in a highly
developed gland or group of cells, and can deliver that toxin through biting
or stinging. Poisonous animals are generally regarded as those whose
tissues, either in part or in their whole, are toxic.

23. H. Subcategories of Toxic Substance
Classifications All of these substances may also be further
classified according to their:
# Effect on target organs (liver, kidney, hematopoietic system),
# Use (pesticide, solvent, food additive),
# Source of the agent (animal and plant toxins),
# Physical state (gas, dust, liquid),
# Labeling requirements (explosive, flammable, oxidizer),
# Chemistry (aromatic amine, halogenated hydrocarbon), or
# Poisoning potential (extremely toxic, very toxic, slightly toxic)

24. I. General Classifications of Interest to Communities
• Air pollutants
• Water pollutants
• Soil pollutants
• Occupation-related
• Acute and chronic poisons
All chemicals (or any chemical) may be poisonous at a given dose and through a particular
route. For example, breathing too much pure oxygen, drinking excessive amounts of water,
or eating too much salt can cause poisoning or death.