MODULE 3

3 Environmental effects of toxicants

3.1 Bioaccumulation- Health hazards due to 4
hexachlorobenzene, polychlorinated
biphenyls, Dioxins and DDT,
3.2 Environmental degradation of pesticides – 2
photolysis and microbial degradation

3.3 Bio-transformation, and bio-magnification: 2

Principles, receptor sites, absorption and
storage of xenobiotics, types of bio-
transformations, Influence of ecological
factors on the effects of toxicity
1
 HEALTH HAZARDS DUE TO
BIOACCUMULATION OF
HEXACHLOROBENZENE,
POLYCHLORINATED BIPHENYLS,
DIOXINS AND DDT

2
POLYCHLORINATED BIPHENYLS
(PCBS)
• Polychlorinated biphenyls (PCBs) are highly carcinogenic
chemical compounds, formerly used in industrial and
consumer products.

• They are organic chlorine compounds with the

formula C12H10−xClx

3
• Toxic, man-made, hazardous organic chemicals that have
dangerous effects on the environment and our health.

• PCBs persist in the environment for long periods and

can travel over great distances through air, water and
migratory species across international boundaries.
• They accumulate in fatty tissues and bio-magnify higher up
in the food chain, where they can be harmful to top
predators such as tuna, seals, polar bears and humans.

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 PROPERTIES
• Chemical stability over time
• Resistant to breakdown by light ,heat and air
• Fire resistant ,withstanding high temperature
• Not soluble in water
• Non flammable
• Electrical insulating properties
• No taste or smell,colourless to light yellow

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 COMMERCIAL AND INDUSTRIAL
USES
• Electrical insulating fluids in capacitors and transformers
• Plasticizers in paints, plastics and rubber products

• In pigments,dyes and carbonless paper

• Adhesives,protective surface coatings for wood

• Extenders for pesticides and flame retardants

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 BIOACCUMULATION
• PCBs entered air, water and soil during their
manufacture, use and disposal.

• Accidental spills and leaks during their transport, and from

leaks or fires in products containing PCBs
• In water , stick to organic particles and bottom sediments
,binds strongly to soil
• It consumed by small organisms and fish in water

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8
• PCBs persist in the environment ,concentrating upward in
food chain

• Adsorb strongly to soil and sediment

• Taken up by bottom feeding fish and other organisms

• Transferred through the food chain and biomagnified ,stored

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 HEALTH HAzARDS
• Liver disorders :elevation of serum triglycerides, induction
of mixed function oxidases

• Failure of reproduction: reduced sperm counts,

neurobehavioral deficits in newborns, reduced birth weights
• Risk of cancers: every commercial PCB mixture tested
caused cancer, increases rare liver cancers and malignant
melanoma

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• Hormone system: several PCB metabolites induce gene
mutations, chromosome breaks, chromosome loss

• Suppress immune system:decrease monocyte and

granulocyte counts.
• Decrease IgA and IgM antibody levels.

• Decrease in natural killer cell count.

• Carcinogenic effects: IARC classified PCBs as group 1 a
carcinogen for human

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Health effects due to PCBs
12
 HEXACHLOROBENZENE
• Hexachlorobenzene, or perchlorobenzene, is an
organochloride with the molecular formula C₆Cl₆.

• It is a fungicide formerly used as a seed treatment,

especially on wheat to control the fungal disease bunt.
• It has been banned globally .

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 PROPERTIES
• Highly stable, white, crystalline chlorinated hydrocarbon.

• Sparingly soluble in organic solvents such as benzene, diethyl

ether and alcohol, and insoluble in water.
• Resistance to biodegradation.
• When heated, it emits highly toxic fumes of hydrochloric acid,
other chlorinated compounds, CO, and carbon dioxide .

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 APPLICATION
• Used as a fungicide.
• Used directly in the manufacture of pyrotechnics, tracer
bullets and as a fluxing agent in the Al manufacture.

• Used as a starting material in the production of

pentachlorophenol, a porosity control agent in the
manufacture of graphite anodes, and as a peptizing agent in
the production of nitroso and styrene rubber.

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 BIOACCUMULATION
• Hexachlorobenzene can remain in the environment for a
long time, half-life up to 7.5 years.

• Slightly soluble in water, will remain in particles on the

bottom of lakes and rivers.
• Adsorbs strongly to soil.

• High levels can build up in fish, marine mammals, birds,

lichens, and animals that eat lichens or fish.
• Build up in wheat, grasses, some vegetables, and other
plants. 16
 HEALTH HAzARDS
• Causes liver, kidney (renal tubular tumours) and thyroid cancers
• Chronic oral exposure in humans has been shown to give rise to
liver disease, skin lesions with discoloration, ulceration,
photosensitivity, Thyroid effects, bone effects and loss of hair.
• Neurological changes.
• cause weakness, tremors, and convulsions; skin sores
• Long-term exposure can cause damage to the reproductive
system and can cause developmental effects

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Sample Footer Text

DIOXINS
• Dioxins and dioxin-like compounds (DLCs) are a group of chemical
compounds that are persistent organic pollutants (POPs) in
the environment. They are mostly by-products of burning or various
industrial processes.
• Once dioxins enter the body, they last a long time because of their
chemical stability and their ability to be absorbed by fat tissue, where
they are then stored in the body.

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• Polychlorinated Dibenzo-p-Dioxins (PCDDs), Polychlorinated Dibenzofurans (PCDFs) and
(2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD). are collectively called dioxins.
• Co-planar Polychlorinated Biphenyls (co-planar PCBs or dioxin-like PCBs) possess
toxicity similar to that of dioxins and are called dioxin-like compounds.

• So that Dioxins include PCDDs, PCDFs and co-planar PCBs

• The general structure of a dioxin molecule is two rings of six carbon atoms (benzene
rings) bound by oxygen atoms with chlorine or hydrogen atoms attached.

• There are 75 kinds of PCDDs, 135 PCDFs and more than 10 co-planar PCBs, with the
shape of the molecule depending on the numbers and locations of the chlorine atoms

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Sample Footer Text

SOURCES
• Dioxins are mainly by-products of industrial processes but can also result from natural
processes, such as volcanic eruptions and forest fires.

• Dioxins are unwanted by-products of a wide range of manufacturing processes including

smelting, chlorine bleaching of paper pulp and the manufacturing of some herbicides and
pesticides.

• They can also be produced when garbage is burned.

• Extensive stores of PCB-based waste industrial oils, many with high levels of PCDFs, exist
throughout the world. Long-term storage and improper disposal of this material may result
in dioxin release into the environment and the contamination of human and animal food
supplies.

• Smoking: Cigarette smoke also contains small amounts of dioxins.

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 ACCUMULATION IN
Sample Footer Text

THE FOOD CHAIN

• Because of their lipophilic properties, the chemicals are readily absorbed into fatty tissue,
and thus they have a tendency to accumulate in animals—for example, in fish, as a result of
the chemicals presence in aquatic environments, and in cattle and other livestock, as a result
of the chemicals release into terrestrial environments.

• Consumption of potentially contaminated foods, such as beef and dairy products, is the
primary route for dioxin entry into the human body.

• Once in the human body, dioxins are absorbed into fat cells, where they persist for long
periods of time; the half-life of dioxin in humans has been estimated to be between 7 and 11
years.

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Sample Footer Text

HEALTH HAZARDS
• All types of cancer
• Additionally, dioxin exposure has been linked to a number of other diseases,
including type 2 diabetes, ischemic heart disease (reduced blood supply to the heart
muscle), and an acne-like skin disease called chloracne.

• Immune system suppression (when the body cannot fight off germs because of
reduced white blood cells or antibodies)

• Dioxins can cause developmental problems in children, lead to reproductive and

infertility problems in adults, result in miscarriages, damage the immune system,
and interfere with hormones.

• Exposure to dioxins has widespread effects in nearly every vertebrate species, at

nearly every stage of development, including in the womb.

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 DDT(Dichlorodiphenyltrichloroet
Sample Footer Text

hane)
• DDT is a persistent organic pollutant (POP). It is made by
humans and does not occur naturally in the
environment.

• Chemical formula for DDT is C14H9Cl5

• DDT is a colorless, tasteless, and almost
odorless crystalline chemical
compound, an organochloride. Originally developed as
an insecticide to prevent the spread of diseases and to
protect crops and it became famous for
its environmental impacts.

• It is created by the reaction of trichloromethanal with

chlorobenzene. 23
• First synthesized in 1874 by the Austrian chemist Othmar Zeidler. DDT's
insecticidal action was discovered by the Swiss chemist Paul Hermann Müller in
1939.

• It is highly hydrophobic and nearly insoluble in water but has good solubility in
most organic solvents, fats and oils

• It is a cheap chemical, highly toxic to insects but with extremely low toxicity to
mammals and humans. Thus it can be applied directly to human skin to kill
parasites without any harm to the people concerned

• Canada banned the use of DDT in the 1980s, but some countries (primarily in
Africa) still use it to prevent the spread of diseases, like malaria, that are carried
by insects. DDT is a mixture of several similar chemicals

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Sample Footer Text

DDT - THE BENEFITS

• Highly persistent so that it continues for months after application to kill insects such
as mosquitoes that carry disease

• Used to virtually eliminate malaria, dengue fever and filariasis

• Estimated to have saved about 50 million human lives and to have prevented more
than a thousand million human illnesses

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Sample Footer Text

DDT - THE PROBLEM

• DDT, and especially its derivative DDE (dichlorodiphenyldichloroethylene)
, are persistent molecules which are transferred from the point of
application through the air (following evaporation), through water (in
spite of very low water solubility) and through food webs following
bio- accumulation

• It can travel long distances in the air and settle in regions far away from
where it came. This process is called Long Range Atmospheric Transport.

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DDT BIO-ACCUMULATION
Bioaccumulation is a process of accumulation of chemicals in an organism that
takes place if the rate of intake exceeds the rate of excretion.
Bio-accumulation is the result of two things:
1. the fat solubility of DDT and derivatives enabling them to dissolve in cell
membranes and pass into cells to be stored in fatty tissue
2. the chemical resistance of DDT and derivatives to biotransformation to
water soluble metabolites which can be easily excreted

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 HEALTH HAZARDS
❖ Acute Health Effects
• The following acute (short-term) health effects may occur
immediately or shortly after exposure to DDT:
• DDT can cause nausea, vomiting, diarrhea and abdominal pain,
tingling sensation in the mouth, tongue, and lower face,
headache, dizziness, confusion, a sense of apprehension, and
tremors.
• Higher exposure can cause convulsions followed by death.

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❖ Chronic Health Effects
❑ Cancer Hazard
• DDT may be a CARCINOGEN in humans since it has been shown
to cause liver cancer in animals.
❑ Reproductive Hazard
❖ DDT may damage the developing fetus.
❖ Other Long-Term Effects
• Prolonged and repeated exposure can irritate the eyes,
skin, nose and throat. DDT may damage the nervous
system causing numbness. "pins and needles." and/or
weakness in the hands and feet. DDT may affect the
liver and kidneys
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ENVIRONMENTAL DEGRADATION OF
PESTICIDES

1
 PESTICIDES
• A chemical used to control, repel, attract or kill pests, for
example, insects, weeds, birds, mammals, fish, or microbes
that are considered to be a nuisance
• Biologically active substances used for preventing,
destroying, or controlling pests by interfering with their
metabolic processes
• For decades, pesticides have been used for preventing
diseases transmitted by pests such as mosquitoes and fleas
in humans and animals, increasing food production by
destroying insects and other pests in agricultural areas, and
protecting the environment by controlling the growth of
molds, weeds, and algae
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 Problems
•In recent years, there have been continuing
concerns about the adverse impacts of pesticides
and their degradation products on public health and
the environment.
•The process of chemical crop protection is
profit-induced poisoning of the environment.
•Residues of pesticides increase in the environment
day by day due to their repeated and continuous
use
•Chronic exposure to small amount of residues lead
to suppression of immune system
•Cause carcinogenicity on long-term exposure

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 PESTICIDE MOVEMENT IN
ENVIRONMENT
• Pesticides are found in detectable levels in many parts of environment
• Once released into environment they built up in fat tissues of living organisms,
causing harm to health and loss of biodiversity
• Pesticides enter environment by direct and indirect sources
• Point sources like seed treatment, filling operations or cleaning of sprayers
• In addition to direct and indirect contact with agricultural pesticide products,
people may be exposed to pesticides in consumer products and pesticide
residues in exposure media (food, drinking water, air & soil).
• Contamination of food occur as a result of intentional use of pesticides.
• Once applied, pesticides disperse from the point of application and become
redistributed
• Organochlorine insecticides (DDT, etc.) are long lived and spread through the
atmosphere as spray drift, which adheres to dust and is transported thousands
of kilometers by global wind currents.
• Pesticide residues may return from the atmosphere to the surface of Earth by
way of rainout, fallout, or direct sorption.
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Overview of the fate and transport pathways of pesticides
in the environment

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 DEGRADATION OF PESTICIDES
• It is the breakdown of pesticides into benign substance that
is environmentally compatible
• Transformation or degradation is one of the key processes
that governs the envl fate and transport of a pesticide
• Comprises different processes including abiotic
degradation (e.g., oxidation, hydrolysis, and photolysis) and
biodegradation
• Transformed to a degradation product or completely
mineralized to carbon dioxide.
• The faster the degradation, the less time a pesticide stays
in the applied field, available for pesticidal activity.
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 .
•Although abiotic degradation plays a role in many cases,
biodegradation of pesticides by microorganisms is usually
the most important and dominant transformation process
•The two primary physical agents involved in the degradation
process are light and heat.
•Pesticide degradation or the breakdown of pesticides is
usually considered beneficial.
• Pesticide-destroying reactions change most pesticide
residues in the environment to nontoxic or harmless
compounds.
• However, degradation is detrimental when a pesticide is
destroyed before the target pest has been controlled.
• There are three types of pesticide degradation: (a) chemical
degradation, (b) photodegradation, and (c) microbial
degradation.

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 CHEMICAL DEGRADATION
• Chemical degradation is the breakdown of
pesticides by processes in which living
organisms are not involved.
• Hydrolysis,oxidation,reduction,substitution,
elimination and dehalogenation are processes
involved in chemical degradation.
• Hydrolysis is an important reaction that takes
place in water and soil for pesticide
degradation

37
 Factors Influencing Chemical
Degradation
• Organic matter content and clay content: organic matter content and clay content
provide larger surface area for enhancing hydrolytic degradation.
• pH: Soil pH or pH of the medium affects the hydrolytic process of pesticide
dissipation, which depends on the nature of pesticides, for example, some
pesticides are acid hydrolyzed and others are base hydrolyzed.
• Temperature: With the increasing temperature, the molecules in solution have
more energy, causing them to move and react faster
• Nature of substituents: The reactivity of pesticides depends on the substituents
present in the pesticides used.
• Effluent irrigation: Effluent irrigation enhances the chemical degradation of
pesticides by altering the pH of the soil solution and increasing dissolved organic
matter content

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 PHOTODEGRADATION
• Photodegradation is the breakdown of pesticides by sunlight.
• An abiotic process in the dissipation of pesticides where molecular
excitation by absorption of light energy (by absorption of photons) results
in various organic reactions, or reactive oxygen species specifically or
nonspecifically oxidize the functional groups in a pesticide molecule.
• Photodegradation can destroy pesticides on foliage, on the surface of the
soil, in water, and even in the air.
• The photodegradation of pesticides is influenced by the intensity of
sunlight, properties of the application site, exposure time, properties of
the pesticides, pH of medium, water depth, salinity and presence of other
commonly occurring ions.
• Environmental degradation of pesticides that contain organic
chromophore or metal–organic complexes capable of absorbing light
energy directly.
• Photolysis was first proposed for the degradation of pesticide r (i.e.,
organochlorine insecticides) in fluid milk and butter oil by Li and Bradley.
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Direct Photolysis Indirect Photolysis
pesticides that absorb energy • sensitizers such as natural
from the UV light can trigger organic matters (NOM),
chemical reactions upon the absorbing photons would
irradiation of UV light: the result in the production of
chemical structure of a highly active species (i.e.,
pesticide can be transformed NOM*) through the
into an excited state and then excitement of UV light,
into a triple-state, which would which would react with
finally undergo via homolysis, pesticide residues.
heterolysis, and
photoionization.
 MICROBIAL DEGRADATION
• Microorganisms are known to play major roles in metabolizing
pesticides in the environment, mainly in water and soil.
• The process can take several steps to degrade pesticides into CO2 ,
H2O, and mineral salts.
• There are four types of microbes: bacteria, fungi, protozoa, and
algae.
• Bacteria and fungi are the most abundant in nature, so they are
the most important microorganisms for biological degradation.
• The degradation process follows different pathways depending on
the microbes present
• Pesticides are generally degraded by microbes along with material
excreted by the roots of plants.
• Bacterial degradation dominates in soils and water at pH > 5.5,
while in acidic medium, soil fungal degradation dominates.

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•
.
In the microbial degradation process, the pesticide is
absorbed into the cell membrane of the microbe.
• Enzymes present in the microbe breakdown the pesticide
into smaller fragments with minerals as the final
end-product.
• Microbial degradation is of two types, aerobic and
anaerobic, and depends on the surrounding conditions.
• The frequency of pesticide application influence microbial
degradation. Rapid microbial degradation is more likely
when the same pesticide is used repeatedly in a field.
Repeated applications can actually stimulate the buildup of
organisms that are effective in degrading the chemical. As
the population of these organisms increases, degradation
accelerates and the amount of pesticide available to
control the pest is reduced.

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Microbial degradation pathways

1. Mineralization
Numerous chemical pesticides are mimics of natural substances and
can be employed as a source of microbial nutrition. Through
microbial breakdown, the generation of inorganic compounds, CO2,
and water.
Mineralization is the optimal method of degradation, results
complete degradation of the pesticide into non-toxic inorganic
substances.
2. Co-metabolism
Some synthetic chemicals cannot be destroyed by microorganisms,
but in the presence of another carbon matrix and energy, they can be
partially decomposed; this phenomenon is known as co-metabolism.
[Link]: Under the influence of microorganisms, the ester bond
and the dialkylamine bond hydrolyze, resulting in the detoxification of
pesticides such as malathion, propanil, and others.
[Link]: Fecal hydrocarbon pesticides, in the role of the
enzyme, the halogen substituents by the H atom or carboxyl, to
replace the loss of toxicity, such as DDT degradation into DDE.
[Link]: Microorganisms, through the creation of oxidase, insert a
hydroxyl or produce an epoxide, such as carbendazim and 2,4- D
degradation, into organic compounds, especially those with an
aromatic ring.
[Link] reduction: N2O in the pesticide to NH2, such as
2,4-dinitrophenol, breakdown products of 2-amino-4-nitrophenol and
4-amino-2-nitrophenol; parathion to amino-phosphorus.
[Link]: To passivate methyl groups, add hazardous phenols
such as pentachlorophenol, tetrachlorophenol, and others.
[Link]: Containing methyl or other hydrocarbon groups,
related to N, O, and S, to remove these groups into non-toxic
chemicals, such as the removal of two N-methyl from dexamethasone
degradation.
Major enzymes applied for pesticide
biodegradation
1. Hydrolases
• Hydrolases are a large set of enzymes involved in the
biodegradation of pesticides.
Hydrolases accelerate the hydrolysis of several key biochemical
groups of pesticide (esters, peptide bonds, carbon-halide
bonds, ureas, thioesters, etc.) and often work without redox
cofactors, making them good candidates for all of the current
bioremediation techniques. [Link]
• These enzymes, which hydrolyze and detoxify
organophosphate insecticides, have been extracted from
several microorganisms (OPs).
3. Esterase
• Esterases are enzymes that catalyse hydrolysis reactions involving
carboxylic esters, amides, phosphate esters, etc.
• In the reaction catalysed by esterases, a wide variety of ester substrates
are hydrolyzed into their alcohol and acid components. R =
O-OCH3+ H2O↔R = O-OH + CH3OH
4. Oxidoreductases
Catalyzes transfer of electrons from one molecule to another. Microorganisms
play a crucial role in the removal of xenobiotics such as endosulfan from
contaminated locations due to their dynamic, complex, and intricate enzyme
systems that breakdown these compounds by removing their functional
groups of the parent substance
5. Mixed Function Oxidases (MFO)
In the MFO-catalyzed reaction, an oxygen atom is integrated into the
substrate while the other oxygen molecule is reduced to water.
In order to function, the MFO requires Nicotiamide-adenine dinucleotide
phosphate (NADPH) and oxygen.
6. Glutathione S-Transferase (GST)
The GSTs (EC [Link]) catalyse the conjugation of hydrophobic components
with glutathione tripeptide.
 Factors Influencing Microbial De
gradation
• Water depth: At lower depths, the rate of metabolism will be slower because
of the lower temperature.
• Mobility: If a pesticide is strongly bound to the soil, the biodegradation
process can not occur
• Temperature: High temperature increases the degradation rate, as with the rise
in temperature sorption decreases and metabolic activity of microbes’
increases.
• pH: The microbial degradation increases with pH.
• Soil moisture: Waterlogged conditions in combination with a high number of
nutrients promote growth of anaerobic microbial species. Bacteria, in general,
require a high level of moisture for degradation.
• Organic matter: In soils rich with organic matter, usually degradation of
pesticides increases due to cometabolism.
• Pesticide: The microbial degradation of pesticides depends on the structure of
the pesticide
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 ADVERSE EFFECTS
• Some pesticide degradation products show much more toxicity to animals and
humans than the parent compounds
• Pesticide degradation products may enhance or decrease microbial population,
inhibiting the growth of one or more specific microbes.
• Pesticide degradation products in water may block the action of hormones in
fish and amphibians, causing reproductive dysfunction and abnormal
development, which cause diminishing of productivity and fecundity

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 Biotranformation
• Biotransformation refers to the chemical alteration of
substances by living organisms, particularly in the
context of xenobiotics or foreign compounds
entering the environment.
• It primarily occurs in the liver, although other organs
and tissues can also contribute to the process.
• Biotransformation plays a crucial role in the
elimination, detoxification, and activation of
compounds in the body.

51
 Principles of biotranformation
1. Phase I Reactions:
• Phase I reactions involve the introduction or exposure of
functional groups (e.g., hydroxyl, amino, or carboxyl groups)
on the parent compound.
• These reactions make the molecule more polar and often
generate more reactive intermediates.
• The most common phase I reactions include oxidation,
reduction, and hydrolysis.
• Oxidation reactions are catalyzed by enzymes known as
cytochrome P450 (CYP) enzymes, which add an oxygen
atom to the compound.
• Phase I reactions may also generate toxic intermediates,
which can be further processed in phase II reactions.

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 .
• 2. Phase II Reactions:
• Phase II reactions involve the conjugation of functional groups
introduced in phase I reactions with endogenous molecules,
such as glucuronic acid, sulfate, glutathione, or amino acids.
• These conjugation reactions further increase the water
solubility of the compound, facilitating its excretion from the
body.
• Phase II reactions include glucuronidation, sulfation,
methylation, acetylation, and conjugation with glutathione.

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.

54
• 3. Enzyme Systems:
• Biotransformation reactions are catalyzed by a variety of
enzymes.
• Cytochrome P450 enzymes (CYPs) are the most well-known
and diverse group of enzymes involved in phase I reactions.
• They are responsible for the oxidation of a wide range of
compounds. Other phase I enzymes include
flavin-containing monooxygenases (FMOs) and esterases.
• Phase II reactions are catalyzed by enzymes such as
UDP-glucuronosyl transferases (UGTs), sulfo-transferases
(SULTs), N-acetyl-transferases (NATs), and glutathione
S-transferases (GSTs).

55
.

56
 .
• 4. Drug-Drug Interactions:

• Biotransformation can be influenced by the presence of

other drugs.
• Some drugs can induce or inhibit the activity of
biotransformation enzymes, altering the metabolism of
co-administered drugs.
• For example, enzme inducers, such as rifampicin, can
increase the metabolism of other drugs, leading to reduced
efficacy.
• Conversely, enzyme inhibitors, like cimetidine, can inhibit
the metabolism of co-administered drugs, resulting in
increased drug concentrations and potential toxicity.

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 .
• 5. Genetic Variability:

• Genetic factors can significantly influence an individual's

ability to metabolize drugs.
• Genetic polymorphisms in biotransformation enzymes can
lead to variations in drug metabolism among individuals.
• Certain genetic variants may result in increased or
decreased enzyme activity, affecting drug efficacy and
safety.
• Examples of well-known genetic polymorphisms include
CYP2D6, which affects the metabolism of many drugs, and
UGT1A1, which affects the metabolism of bilirubin and
drugs like irinotecan.

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 Biomagnification
• Biomagnification refers to the
progressive increase in the
concentration of certain
substances, such as persistent
organic pollutants (POPs) or heavy
metals, in the tissues of organisms
at higher levels in the food chain
• This phenomenon occurs when
substances, such as toxic
pollutants or chemicals, are
ingested by organisms and are not
easily metabolized or excreted.
• Instead, these substances
accumulate in the tissues of
organisms over time, resulting in
higher concentrations in predators
at the top of the food chain.

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 Principles
1. Persistence:
• Biomagnification typically involves substances that are persistent,
meaning they do not easily break down or degrade in the
environment.
• Persistent substances can include certain pesticides, industrial
chemicals, heavy metals (like mercury and lead), and some
synthetic compds such as PCBs and certain types of dioxins.
• These substances can remain in the environment for long periods,
allowing them to enter and accumulate within food chains.
• 2. Low or no metabolic breakdown:
• Biomagnification occurs when substances are not efficiently
metabolized or broken down by organisms.
• Instead, they tend to accumulate in the fatty tissues or organs of
organisms.
• This is particularly evident in species higher up the food chain,
where the concentration of these substances can become
significantly magnified compared to their concentrations in lower
trophic levels.

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 .
• 3. Higher trophic levels:
• Biomagnification is most pronounced in higher trophic levels of a
food chain.
• As organisms consume other organisms, the substances they
contain are accumulated and concentrated in their bodies.
• Predators at the top of the food chain, such as large fish, birds of
prey, or mammals, can experience the greatest magnification of
these substances due to their consumption of numerous lower
trophic level organisms throughout their lifetime.
• 4. Lipid solubility:
• Many substances that undergo biomagnification are lipophilic or
lipid-soluble, meaning they have an affinity for fats or lipids.
• Lipid-soluble substances can easily cross cell membranes and
accumulate in fatty tissues.
• This characteristic allows them to become stored in the fatty
tissues of organisms, leading to their increased concentration as
they move up the food chain.

61
 Receptors
• Receptor sites, also known as binding sites, are specific locations
on the surface or within cells where specific molecules, such as
neurotransmitters, hormones, or drugs, can bind and interact with
proteins or other molecules.
• These receptor sites are typically proteins or protein complexes
that are embedded in the cell membrane or located inside the cell.
• The binding of a molecule to its specific receptor site triggers a
series of cellular events and signals that can lead to various
physiological responses.
• The binding can be reversible or irreversible, depending on the
nature of the interaction between the molecule and the receptor.
• Receptor sites are highly specific, meaning that a particular
receptor site is designed to bind with a specific molecule or a
group of closely related molecules.
• This specificity is crucial for proper cell signaling and
communication, as it allows cells to selectively respond to certain
signals while ignoring others.

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 Types of Receptor sites
1. G protein-coupled receptors (GPCRs):
• These receptors span the cell membrane and are coupled to
intracellular signaling pathways through G proteins.
• They are involved in a wide range of physiological processes
and are the target of many drugs.

• 2. Ligand-gated ion channels:

• These receptors are ion channels that open or close in
response to binding of specific ligands, such as
neurotransmitters.
• They play a critical role in neuronal signaling and muscle
contraction.

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• 3. Enzyme-linked receptors: .
• These receptors have an intracellular enzymatic domain that
becomes activated upon ligand binding.
• They are involved in various signaling pathways, including
growth factor signaling.
• 4. Nuclear receptors:
• These receptors are located in the cell nucleus and regulate
gene expression in response to ligand binding.
• They play a crucial role in hormonal signaling and
transcriptional regulation.
• 5. Intracellular receptors:
• These receptors are located inside the cell, usually in the
cytoplasm or nucleus, and are involved in signaling
pathways that do not require membrane-bound receptors.
• Examples include receptors for steroids and certain
vitamins.

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 Xenobiotics
• Xenobiotics are foreign chemical substances that are not naturally
produced or expected to be found in an organism's body.
• These substances can include synthetic chemicals, drugs,
environmental pollutants, and other compounds that enter the
body through various routes such as ingestion, inhalation, or
absorption through the skin.
• Xenobiotics can have diverse effects on living organisms, and their
impact can vary depending on factors such as the specific
compound, dosage, duration of exposure, and the organism's
ability to metabolize and eliminate them.
• Some xenobiotics are relatively harmless, while others can be toxic
or have adverse effects on the health and well-being of organisms.
• In biological systems, xenobiotics are often metabolized by
enzymes in the liver or other organs through processes such as
biotransformation or detoxification.
• These metabolic processes aim to convert xenobiotics into more
water-soluble compounds that can be easily excreted from the
body, usually through urine or feces.
• When xenobiotics enter the body, they undergo processes of
absorption and storage.
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 Absorption
• Absorption is the process by which xenobiotics enter the body from their
external source, such as the gastrointestinal tract, lungs, or skin.
• The specific mechanisms of absorption depend on the route of entry:
• Gastrointestinal tract:
• Xenobiotics taken orally are typically absorbed in the gastrointestinal tract.
• They pass through the stomach and reach the small intestine, where most
absorption occurs.
• The intestinal epithelium contains various transporters and enzymes that
facilitate the absorption of xenobiotics into the bloodstream.
• Lungs:
• Inhalation is another common route of exposure to xenobiotics, such as
airborne pollutants or gases.
• The respiratory epithelium in the lungs provides a large surface area for
absorption.
• The xenobiotics can diffuse directly across the respiratory membrane into
the bloodstream.

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 • Distribution
• Once absorbed into the
bloodstream, xenobiotics
• Skin: are transported throughout
the body via the circulatory
• Xenobiotics can also be system.
absorbed through the skin,
although this route is • They can be carried by the
generally slower and less blood to various tissues and
efficient than oral or organs, including the liver,
inhalation absorption. kidneys, adipose tissue (fat),
and others.
• The rate of skin absorption
depends on factors like the • Distribution depends on
molecular size, lipophilicity factors like blood flow,
(ability to dissolve in lipids), tissue perfusion, and the
and the integrity of the skin chemical properties of the
barrier. xenobiotic (e.g., solubility,
binding to plasma proteins).

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 Storage
• The storage of xenobiotics occur in specific tissues or organs:
• Adipose tissue:
• Lipophilic xenobiotics, those that can dissolve in fats, have a
tendency to accumulate in adipose tissue due to its high lipid
content.
• This storage in adipose tissue can prolong the elimination half-life
of certain xenobiotics.
• Liver:
• The liver is a major site for the metabolism and detoxification of
xenobiotics.
• Some xenobiotics can be stored in the liver, particularly those that
are metabolized and transformed into more water-soluble
compounds for elimination.
• Bone:
• Certain xenobiotics, such as heavy metals like lead or cadmium,
can accumulate in bone tissue over time.
• These xenobiotics can be released back into the bloodstream
under certain conditions, potentially causing long-term toxic
effects.
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 Biotransformation
• Biotransformation, also known as biocatalysts or
enzyme-catalyzed transformation, uses biological
catalysts to modify chemical compounds.
• Microorganisms possess the capability to
enzymatically modify a wide range of organic
compounds.
• Bio-transformations broadly refer to the processes
in which microorganisms convert organic
compounds into structurally related products.

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 • Chemical alteration of the
drug in the body

POLAR
Compounds
NONPOLAR (lipid insoluble)
Compounds Not reabsorbed
(lipid soluble) in the renal
tubules and are
excreted

BIO TRANSFORMATION

3/14/2024 70
 Types of biotranformations
Biotransformation can be divided into two main categories: enzymatic and microbial.
1. Enzymatic Biotransformation
• Enzymatic biotransformation involves the use of purified enzymes to catalyze
chemical reactions. These enzymes can be isolated from a variety of sources,
including plants, animals, and microorganisms.
• One example of enzymatic biotransformation is the production of artemisinin, a drug
used to treat malaria. Artemisinin is derived from the sweet wormwood plant, but its
production is expensive and time-consuming.
• Key enzymes- HMGS, HMGR, DXS, DXR, FPS, ADS, DBR2, ALDH1, CYP71AV1

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 .
2. Microbial Biotransformation
• Microbial biotransformation involves the use of whole cells
or microorganisms to catalyze chemical reactions. These
microorganisms can be bacteria, yeast, fungi, or even algae.
• One example of microbial biotransformation is the
production of vanillin, a flavoring agent used in foods and
beverages. Traditionally, vanillin has been produced from
vanilla beans, which are expensive and difficult to grow.

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 Types of biotranformation reactions
2 TYPES
Phase I / Non-synthetic/Functionalization
• A functional group is generated
• Metabolite –active or inactive
Phase II / Synthetic /Conjugation
• An endogenous radical is conjugated
• Metabolite is usually inactive - some exceptions ie;
glucuronide conjugate of morphine, and sulphate
conjugate of minoxidil are active

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Biotransformation

74
Biotranformation

75
 Drug-metabolizing Enzymes
The drug-metabolizing enzymes are divided into two types:
A. Microsomal enzymes B. Non-microsomal enzymes
Microsomal enzymes
• These are located on the smooth endoplasmic reticulum (a system of
microtubules inside the cell), primarily in the liver, also the kidney,
intestinal mucosa, and lungs.
• The mono oxygenases, cytochrome P450, UGTs, epoxide hydrolases, etc.
are microsomal enzymes.
• They catalyze most of the oxidations, reductions, hydrolysis, and
glucuronide conjugation.
• Microsomal enzymes are inducible by drugs, diet, and other agencies.

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 .
Non-microsomal enzymes:
• These are present in the cytoplasm and mitochondria of hepatic
cells as well as in other tissues including plasma.
• The esterases, amidases, some flavoprotein oxidases and most
conjugases are non-microsomal.
• Reactions catalyzed are Some oxidations and reductions, many
hydrolytic reactions, and all conjugations except glucuronidation.
• The non-microsomal enzymes are not inducible but many show
genetic polymorphism
• Eg : Acetyltransferase, Pseudocholinesterase, Mono amino oxidase
(Dopamine), and N acetyl cysteine(Isoniazid)

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 Phase I Reactions
1. Oxidation
2. Reduction
3. Hydrolysis
4. Cyclization
5. Decyclization

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 Oxidation
• Addition of Oxygen / negatively
charged radical or removal of
Hydrogen / Positively charged radical
• Oxidation is the main process of
metabolism
• The simplest type of oxidation reaction
is dehydrogenation, which is the
removal of hydrogen from the
molecule.
• Eg. of drugs metabolized in this way
are Barbiturates, phenothiazines,
imipramine, etc.

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 Reduction
• Addition of Hydrogen / positively
charged radical or removal of Oxygen /
negatively charged radical
• Functional groups like Alcohols,
aldehydes, and quinones are reduced.
• Eg. of Drugs primarily reduced are
chloralhydrate, chloramphenicol,
halothane, and warfarin.
• Some reducing reactions include: Azo
reduction, Dehalogenation , Disulfide
reduction, Nitro reduction etc.

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 Hydrolysis
• Cleavage of drug molecules by taking up a
molecule of water.
• Esters, amides, and polypeptides are
hydrolyzed by esterase, amidases, and
peptidases respectively.
• Hydrolysis is a chemical reaction in which
the addition of water splits the toxicant into
two fragments or smaller molecules. The
hydroxyl group (OH-) is incorporated into
one fragment and the hydrogen atom is
incorporated into the other.
• Eg. of drug hydrolyses choline esters,
procaine, lidocaine, procainamide, aspirin,
pethidine, oxytocin etc.

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 D)CYCLIZATION
• Formation of ring structure from a straight chain
compound. Eg: Proguanil

E)DECYCLIZATION

• Ring structure opened

• Eg; Phenytoin, Barbiturates

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 Phase II Reactions
1. Glucuronide conjugation
2. Acetylation
3. Sulfate conjugation
4. Glycine conjugation
5. Glutathione conjugation
6. Methylation
7. Ribonucleotide / Ribonucleoside synthesis

3/14/2024 Bio transformations 83

 1. Glucuronide Conjugation
• Carried out by a group of UDP-glucuronosyl transferases (UGTs).

• Compounds with a hydroxyl or carboxylic acid group are easily conjugated

with glucuronic acid
• Endogenous substrates like bilirubin, steroidal hormones, and thyroxine
utilize this pathway

• Glucuronidation takes up a molecule of water of the drug which favors its

excretion in bile.

• Eg: Chloramphenicol, Aspirin, Paracetamol, Lorazepam, Morphine,

Metronidazole

3/14/2024 Bio transformations 84

 2. ACETYLATION
• Drugs with Amino or Hydrazine
• Compounds having amino or hydrazine residues are
conjugated with the help of acetyl coenzyme-A
• Genetic polymorphism
• Acetylation-Rapid /Slow
• e.g. Sulfonamides, Isoniazid, PAS, Hydralazine,
Clonazepam, Procainamide.

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 3. Sulfate Conjugation
• Sulfation decreases the toxicity of xenobiotics. Unlike
glucuronic acid conjugates that are often eliminated in the bile,
the highly polar sulfate conjugates are readily secreted in the
urine.
• sulfation is a low-capacity pathway for xenobiotic conjugation.
Often glucuronidation or sulfation can conjugate the same
xenobiotics

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4. CONJUGATION WITH GLYCINE

• Glycine conjugation has generally been assumed to be a

detoxification mechanism, increasing the water solubility of
organic acids in order to facilitate urinary excretion.
• Drug group –Carboxylic acid ,Salicylic acid, Benzoic acid

5. CONJUGATION WITH GLUTATHIONE

• Augment water solubility and detoxify xenobiotics.
• Drug groups-Epoxide, Quinone

• Toxic metabolites of Paracetamol, Ethacrynic acid

• Cytoplasmic Enzyme -Glutathione S-Transferase

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6. METHYLATION

• Drugs with Amino & Phenol groups

• Histamine, Adrenaline, Nicotinic acid, Dopamine, Methyl dopa,

Captopril
• Enzyme-Methyl transferase
• Endogenous substance-Cysteine, Methionine
7. RIBONUCLEOTIDE /RIBONUCLEOSIDE SYNTHESIS

• This pathway is important for the Activation of many Purine &

Pyrimidine antimetabolites used in cancer chemotherapy.

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Advantages of Biotransformation
1. High Selectivity.

2. Biotransformation is more sustainable alternative to traditional

chemical methods.

3. Cost-Effective
4. Mild Reaction Conditions- such as low temperatures and
atmospheric pressure, which reduces energy consumption and
production costs.
5. Lower Environmental Impact

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 Disadvantages of Biotransformation
1. Limited Substrate Range- restrict type of compds produced

2. Sensitivity to Reaction Conditions- such as pH, temperature, and

substrate concentration, which can limit their effectiveness.

3. Product Inhibition

4. High Cost of Purification- more expensive and time-consuming,

which can limit the feasibility of large-scale production.
5. Stability Issues- limit the overall feasibility of large-scale
production

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 Applications of Biotransformation
1. Pharmaceutical Industry- produce a wide range of drugs.

2. Food Industry- produce flavors, fragrances, and other

additives

3. Environmental Applications- such as the treatment of

wastewater or the remediation of contaminated soil

4. Chemical Industry- produce a wide range of chemicals, such

as detergents, solvents, and biofuel.

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 Influence of Ecological factors on
Toxicity
1. Habitat and ecosystem type:
• The toxicity of a substance can vary depending on the
specific habitat or ecosystem in which it is found.
2. Biodegradability:
The ability of a substance to be broken down by
microorganisms can influence its toxicity. Substances that are
easily biodegradable tend to be less toxic, as they break down
into less harmful compounds.
3. Bioaccumulation:
Some substances can accumulate in the tissues of organisms as
they move up the food chain, leading to higher concentrations
and greater toxicity at higher trophic levels.

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4. Synergistic effects:
.
The toxicity of a substance can be enhanced when it is combined with other
substances in the environment. This can result in synergistic effects, where the
combined toxicity of two or more substances is greater than the sum of their
individual toxicities.
5. Exposure duration and concentration:
Length of time and concentration of exposure to a substance can influence its
toxicity. Short-term exposure to a high concentration of a substance can be
more toxic than long-term exposure to a lower concentration, and vice versa.
6. Species sensitivity:
Different species can have varying levels of sensitivity to toxic substances
7. Environmental stressors:
Environmental stressors such as changes in temperature, salinity, or pH can
affect the toxicity of substances.

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 .
8. Interactions with other environmental factors:
such as sunlight, oxygen levels, and the presence of other chemicals.
These factors can alter the chemical properties of a substance and
affect how it interacts with living organisms.
9. Genetic variability:
Genetic differences between individuals within a species can
affect their sensitivity to toxic substances.
10. Habitat quality:
Overall quality of the habitat can also influence the toxicity of
substances in the environment. For example, a degraded habitat with
poor water quality and reduced biodiversity may be more vulnerable
to the harmful effects of toxic substances than a healthy, thriving
ecosystem.

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