Environmental

Toxicology

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Prepared By: Tesfahun Tesema (MSc.)

Hawassa University, 2021

 By:Tesfahun Tesema
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Nov, 2021
 CHAPTER ONE
1. Introduction to Environmental Toxicology
1.1. Definition of Key Terms in Environmental Toxicology

 Toxicology is the study of poisons

 Toxicology is the quantitative and qualitative study of the adverse

effects of toxicants/xenobiotics on biological organisms

 Environmental toxicology is the study of the impacts of pollutants

upon the structure and function of ecological systems.

 For the purposes of this text, the emphasis will be upon ecological

structures, from the molecular to the individual organism to the

community and to the ecosystem (Wayne& Landis, 2003).

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 It deals with the potentially deleterious impact of chemicals, present as

pollutants of the environment, to living organisms.

 Environmental toxicology: is concerned with the movement of toxicants and

their metabolites in the environment and in food chains and the effect of such
toxicants on populations of organisms. See also Ecotoxicology

 Ecotoxicology: "The field of study which integrates the ecological and

toxicological effects of chemical pollutants on populations, communities and

ecosystems with the fate (transport, transformation and breakdown) of such
pollutants in the environment"

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 Environment: can be defined as 'the external surroundings in which a plant

or animal lives, which tend to influence its development and behaviour'.

 More detailed view of the environment, is composed of both a living

component, or biota, which includes animals, plants, humans, etc., and a non-
living component, or abiota, such as air, water, soil, etc., and each component
interacts with the other in a variety of ways

 Toxicant is a chemical or physical agent that produces adverse effects on

biological organisms.

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 pollutant is that of a chemical that has exceeded normal background levels

and that has the potential to cause harm, always remembering that the
potential for harm increases with concentration.

 Xenobiotics (Greek xenos, a stranger; -biotic, pertaining to life) may include

substances, such as toxicants, that are not naturally produced within an

organism.

 Poison is a substance that can cause damage or disturbance to the function of

organisms or ecosystems

 Poisons are chemical/physical agents which produce adverse responses in

biological organisms

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 There are a variety of poisons, many of which occur naturally in plants and

animals or as minerals.

 There are also manmade poisons, which are the direct result of laboratory

synthesis.

 Toxins are poisonous substances produced by plants (phytotoxins), animals

(zootoxins), or bacteria (bacteriotoxins); a substance is toxic when it acts to

destroy or impair cellular function.

 Toxicity is the state of being poisonous, is also a general term used to indicate

adverse effects or symptoms produced by poisons or toxicants in organisms.

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1.2. History of Toxicology

 The prehistoric use of animal venoms and plant poisons is evident from

archaeological and cultural anthropological studies.

 Ancient cultures had a working knowledge of many naturally occurring

toxins that were used as medicinals, in hunting, and for war.

 Today, there are indigenous native peoples who still use naturally

occurring poisons and toxins for hunting and for medicinal purposes.

 One of the oldest written records of the early use of toxins is a series of

eight Egyptian papyri dating from 1900–1200 B.C.

 The use of plant and animal toxins by the Greeks was common.

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 The Greeks used poisons as the state method of execution.

 Socrates, Demosthenes, and Cleopatra were all victims of poisoning, albeit

for different reasons, including an execution and two suicides, respectively.

 Stories exist that the discovery of antidotes, which are agents to neutralize

the effects of a poison, was facilitated by giving known toxins to condemned

criminals followed by the administration of possible antidotes.

 The Romans (A.D. 50–400) made use of poisons for executions and

assassinations, political or otherwise.

 Throughout the Middle Ages, poisons were used to gain political and social,

as well as financial, advantage.

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 In general, the scholarship of the Middle Ages, from the ninth to fifteenth

centuries, was based more on dogma than on empirical evidence.

 The German physician Paracelsus (1493–1541), a product of the Renaissance,

brought the study of medicine and science to a new high.

 The role of experimentation, the relationship between dose and therapeutic, as

compared with toxic, responses to chemicals, and the specificity with which
different doses of chemical agents produce well-defined toxic or therapeutic
effects are included in his writings—“What is there that is not a poison? All
things are poison and nothing without poison. Solely the dose determines that
a thing is not a poison.”

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 These early contributions form the basis of what is now the science of

toxicology.

 Of particular interest to environmental toxicology are the writings of the

Italian physician Ramazzini. Diseases of Workers, published in 1713, deals

with ailments that result from exposure to toxic chemicals in the workplace.

 The beginnings of toxicology are usually traced to Orfila (1787–1853).

With his 1815 book, A General System of Toxicology, or, A Treatise on

Poisons, Drawn from the Mineral, Vegetable, and Animal Kingdoms,
Considered as to Their Relations with Physiology, Pathology, and Medical
Jurisprudence, this Spanish physician unknowingly established toxicology
as a separate and distinct scientific discipline and is generally regarded as
the father of modern toxicology.

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 Toxicology' traditionally known as the 'science of poisons' began with

early cave dwellers who recognized poisonous plants and animals and
used their extracts for hunting or warfare.

 Simultaneously, with time, to determine the effectiveness of a particular

compound the concept of toxicology was developed.

 Toxicology basically is defined as the study of the effects of chemical

agents on biological material with special emphasis on the harmful

effects.

 After gaining relevant information on the harmful effects of a compound

the levels for its safe usage or the degree of its safeness is established,
which is also known as its (compound) Biosafety level.

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 As a discipline, environmental toxicology is relatively new: As of 2002, the

26th annual symposium sponsored by the American Society for Testing and
Materials (ASTM) and the 23rd annual meeting sponsored by the Society for
Environmental Toxicology and Chemistry (SETAC) on environmental
toxicology had been held.

 In a rapidly evolving field, this text is only a snapshot of the directions and

research of the late 1980s until the early years of 2000.

 The science has evolved from the efficacy testing of pesticides in the 1940s to

the cleanup of burning rivers, polluted lakes, and wildlife kills of the 1960s.

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 The passage of the National Environmental Policy Act and the establishment

of the U.S. Environmental Protection Agency (EPA) forced the rapid

development of the field.

 The Clean Air and Clean Water standards were required by law to be

protective of human health and the environment.

 As the field of environmental toxicology has grown, so has its sophistication

and excitement.

 Environmental contamination is a fact of life, and scientists are continually

called upon to give expert advice, often with little data or time to develop the
necessary information.

 Public outcry can lead to short-term funding and yet a myopic view.

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 Often the concentration of the funding and research is upon the

immediate care of dying and sick animals, usually warm-blooded

vertebrates, without an appreciation of the damage done to the normal
development of the structure and function of an ecosystem.

 Solutions are required, yet the development of scientific knowledge and

management expertise does not always occur.

 Once the dying animals are buried and the smell goes away, the long-

term and irreversible changes within the ecosystem are often ignored.

 Likewise, overreaction and the implementation of treatment techniques

that are extraordinarily expensive and that do not provide a reasonable

return can drain funds and other resources from important societal needs.

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1.3. Basic Principles and Scope of Toxicology

 Toxicology can be defined as that branch of science that deals with poisons,

and a poison can be defined as any substance that causes a harmful effect
when administered, either by accident or design, to a living organism.

 By convention, toxicology also includes the study of harmful effects caused

by physical phenomena, such as radiation of various kinds and noise.

 In practice, however, many complications exist beyond these simple

definitions, both in bringing more precise meaning to what constitutes a

poison and to the measurement of toxic effects.

 Broader definitions of toxicology, such as “the study of the detection,

occurrence, properties, effects, and regulation of toxic substances,” although

more descriptive, do not resolve the difficulties.

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 The study of toxicology serves society in many ways, not only to protect

humans and the environment from the deleterious effects of toxicants but also
to facilitate the development of more selective toxicants such as anticancer and
other clinical drugs and pesticides.

 Poison is a quantitative concept, almost any substance being harmful at some

doses but, at the same time, being without harmful effect at some lower dose.

 Between these two limits there is a range of possible effects, from subtle long-

term chronic toxicity to immediate lethality. Vinyl chloride may be taken as an

example.

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 It is a potent hepatotoxicant at high doses, a carcinogen with a long latent

period at lower doses, and apparently without effect at very low doses.

 Clinical drugs are even more poignant examples because, although

therapeutic and highly beneficial at some doses, they are not without
deleterious side effects and may be lethal at higher doses.

 The importance of dose is well illustrated by metals that are essential

in the diet but are toxic at higher doses.

 Thus iron, copper, magnesium, cobalt, manganese, and zinc can be

present in the diet at too low a level (deficiency), at an appropriate level

(maintenance), or at too high a level (toxic).

 The question of dose-response relationships is fundamental to toxicology

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 Compounds may be toxic under some circumstances but not others or,

perhaps, toxic in combination with another compound but nontoxic alone.

 The methylenedioxyphenyl insecticide synergists, such as piperonyl butoxide,

are of low toxicity to both insects and mammals when administered alone but
are, by virtue of their ability to inhibit xenobiotic-metabolizing enzymes,
capable of causing dramatic increases in the toxicity of other compounds.

 The measurement of toxicity is also complex. Toxicity may be acute or

chronic, and may vary from one organ to another as well as with age,
genetics, gender, diet, physiological condition, or the health status of the
organism.

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 Exposure of humans and other organisms to toxicants may result from many

activities: intentional ingestion, occupational exposure, environmental

exposure, as well as accidental and intentional (suicidal or homicidal)
poisoning.

 The toxicity of a particular compound may vary with the portal of entry into

the body, whether through the alimentary canal, the lungs, or the skin.

 Experimental methods of administration such as injection may also give

highly variable results; thus the toxicity from intravenous (IV), intraperitoneal
(IP), intramuscular (IM), or subcutaneous (SC) injection of a given compound
may be quite different.

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 Following exposure there are multiple possible routes of metabolism, both

detoxifying and activating, and multiple possible toxic endpoints

 Attempts to define the scope of toxicology, including that which follows,

must take into account that the various subdisciplines are not mutually
exclusive and are frequently interdependent.

 Due to overlapping of mechanisms as well as use and chemical classes of

toxicants, clear division into subjects of equal extent or importance is not

possible.

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 Environmental Toxicology is a young (1965) and interdisciplinary

science that uses both basic and applied scientific knowledge to

understand natural and anthropogenic pollutants life cycle and their
impacts upon structure and functions of biological and ecological
systems.

 Research in Environmental Toxicology includes both laboratory

experiments and field studies.

 Environmental Toxicology wants to answer two main questions.

 (1) How the release pollutant causes harmful effects?

 (2) What can we do to prevent or minimize risk to biological and ecological

system?

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1.4. Branches of Toxicology

 Modern toxicology is composed of three subdisciplines.

 The first, descriptive toxicology, involves toxicity testing of chemicals.

 Initially, the determination as to whether or not a chemical is toxic must be

made before safety and regulatory issues can be addressed.

 Toxicity testing usually takes place using experimental animals.

 Second, mechanistic toxicology examines the biochemical processes by

which identified toxicants have an impact on the organism.

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 Although descriptive toxicologists continue to identify agents of toxicity, the

exact mechanism by which many toxicants have their action on the organism
awaits continued study.

 Last, regulatory toxicology is concerned with assessing the data from

descriptive toxicology and mechanistic toxicology in an attempt to determine

the legal uses of specific chemicals, as well as the risk posed to the ecosystem
by the marketing of those chemicals.

 Many disciplines contribute to the understanding toxicology, clinical

toxicology examines the effects of toxicants on individuals and the efficacy of

treatment for symptoms related to intoxication.

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 Forensic toxicology is concerned with the medical and legal questions

relating to the harmful effects of known or suspected toxicants, and industrial

(or occupational) toxicology studies the disorders found in individuals who
have been exposed to harmful materials in their place of work.

 Environmental toxicology, which deals with the impact of known or

suspected toxicants on the ecosystem, including the human population…the

health hazards posed by the poisons around us.

 Although this text focuses on the effects of toxicants on the human species,

remember that our ecosystem is complex, and potentially all forms of life,
both plant and animal, may be affected by toxic substances (Williams, 1996).

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 Clearly, toxicology is pre-eminently an applied science, dedicated to the

enhancement of the quality of life and the protection of the environment.

 It is also much more.

 Frequently, the perturbation of normal life processes by toxic chemicals

enables us to learn more about the life processes themselves.

 Environmental toxicology is a multidisciplinary science involving many

widely diverse areas of study such as

 chemistry, the characterization of toxins;

 pharmacology, the mode of entry and distribution of toxins in the body;

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 biochemistry, the metabolism and interaction of toxins with cell components;

 physiology, the effect of toxins on body organs; . biology, the effect of toxins

on the environment;

 genetics, the effect toxins can have on the reproductive system and on future

generations by altering genetic codes;

 epidemiology, the effect on the population as a whole of chronic exposure to

small quantities of suspected agents;

 law, regulation of the use or release into the environment of toxic substances;

and

 economics, evaluation of the environmental cost vs. benefit of economic

development and the determination of trade-offs among economy, health, and

the environment.
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1.5. Applications of Toxicology

 This includes the various aspects of toxicology as they apply in the field

or the development of new methodology or new selective toxicants for

early application in the field setting.
 Clinical toxicology is the diagnosis and treatment of human poisoning.

 Veterinary toxicology is the diagnosis and treatment of poisoning in animals

other than humans, particularly livestock and companion animals, but not
excluding feral species.
 Other important concerns of veterinary toxicology are the possible transmission of

toxins to the human population in meat, fish, milk, and other foodstuffs, and the care
and ethical treatment of experimental animals.

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 Forensic toxicology concerns the medicolegal aspects, including

detection of poisons in clinical and other samples.

 Environmental toxicology is concerned with the movement of

toxicants and their metabolites and degradation products in the

environment and in food chains, and with the effect of such
contaminants on individuals and, especially, populations.
 Because of the large number of industrial chemicals and possibilities

for exposure, as well as the mosaic of overlapping laws that govern

such exposure, this area of applied toxicology is well developed.
 Industrial toxicology is a specific area of environmental toxicology

that deals with the work environment and constitutes a significant part
of industrial hygiene
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1.6. Classification of Toxic Agents

 there are two classes of toxic agents in general: Use Class and Exposure Class

toxicants

I. Use Class Toxicants

 This includes the toxicology aspects of the development of new chemicals for

commercial use.

 In some of these use classes, toxicity, at least to some organisms, is a desirable

trait; in others, it is an undesirable side effect.

 Use classes are not composed entirely of synthetic chemicals; many natural

products are isolated and are used for commercial and other purposes and must
be subjected to the same toxicity testing as that required for synthetic
chemicals.
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 Examples of such natural products include the insecticide, pyrethrin, the

clinical drug, digitalis, and the drug of abuse, cocaine.

 Agricultural chemicals include many compounds, such as insecticides,

herbicides, fungicides, and rodenticides, in which toxicity to the target organism is

a desired quality whereas toxicity to “ non-target species ” is to be avoided.
 Development of such selectively toxic chemicals is one of the applied roles of

comparative toxicology.

 Clinical drugs are properly the province of pharmaceutical chemistry and

pharmacology.
 However, toxic side effects and testing for them clearly fall within the science of

toxicology.

 Drugs of abuse are chemicals taken for psychological or other effects and may

cause dependence and toxicity. Many of these are illegal but some are of clinical
significance when used correctly.
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 Food additives are of concern to toxicologists only when they are toxic or being

tested for possible toxicity.

 Industrial chemicals are so numerous that testing them for toxicity or controlling

exposure to those known to be toxic is a large area of toxicological activity.

 Naturally occurring substances include many phytotoxins, mycotoxins, minerals,

and so on, all occurring in the environment.

 The recently expanded and now extensive use of herbal “ remedies” and dietary

supplements has become a cause of concern for toxicologists and regulators.

 Not only is their efficacy frequently dubious, but their potential toxicity is also largely

unknown.

 Combustion products are not properly a use class but are a large and important

class of toxicants, generated primarily from fuels and other industrial chemicals.

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II. Exposure Class Toxicants
 Air pollutants
 Water and Soil Pollutants

 Occupational Toxicants

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 Toxicokinetics and Toxicodynamics

 Toxicokinetics is the study of five time-dependent processes related to

toxicants as they interact with living organisms.

 These processes are: absorption, how toxicants enter the organism;

distribution, how toxicants travel within the organism; storage, how

some tissues preferentially harbor a toxicant; biotransformation, how
toxicants are altered (or detoxified) by chemical changes in the
organism; and elimination, how toxicants are removed from the
organism

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 An understanding of the time-dependent behavior of a toxicant as related

to its absorption, distribution, storage, biotransformation, and

elimination is necessary to explain how toxicants are capable of
producing local or systemic toxicity, acute or chronic toxicity, and
immediate or delayed toxicity.

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 Toxicodynamics examines the mechanisms by which toxicants produce

unique cellular effects within the organism

 As expected, if toxicants exert their influence at the level of the cell, the

mechanisms will involve cellular components.

 Included in the mechanisms of toxic action are alterations to the cell’s

plasma membrane, organelles, nucleus, cytoplasm, enzyme systems,

biosynthetic pathways, development, or reproduction.

 Whether reversible or irreversible cellular injury occurs will depend on

the duration of exposure as well as the specific toxicokinetic properties

of the toxicant.

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 CHAPTER TWO
2. Mechanisms of Chemical Reaction and Effects

2.1. Chemical Allergies

 Chemical allergy is an immunologically mediated adverse reaction to a

chemical resulting from previous sensitization or hypersensitivity:

 1) Low doses and repeated exposures of chemicals

 2) Chemicals combine with an endogenous protein to elicit and allergy

reaction called a hapten

 3) The formation of antibodies at least 1 or 2 weeks required

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 4) Skin ⇒ Acquired contact dermatitis (ACD), urticaria and itching
 5) Eyes ⇒ conjunctivitis
 6) Asphyxia ⇒ bronchiolar constriction

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 The four types of immunological hypersensitivity (allergic) reactions

include:
I. Type I Antibody-mediated reactions

II. Type II Antibody-mediated cytotoxic reactions

III. Type III Immune complex reactions

IV. Type IV Delayed-type hypersensitivity cell-mediated immunity

1. Type I antibody-mediated reactions occur in three phases.

 The initial or sensitization phase is triggered by contact with a previously

unrecognized antigen.

 This reaction entails binding of the antigen to the immunoglobulin E

(IgE) present on the surfaces of mast cells and basophils.

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 The second or activation phase follows after an additional dermal or

mucosal challenge with the same antigen.

 This phase is characterized by degranulation of mast cells and basophils, with

a subsequent release of histamine and other soluble mediators.

 The third stage, the effector phase, is characterized by accumulation of pre-

formed and newly synthesized chemical mediators that precipitate local and
systemic effects

 Degranulation of neutrophils and eosinophils completes the late-phase

cellular response.

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2. Type II antibody-mediated cytotoxic reactions differ from type I in the
nature of antigen, the cytotoxic character of the antigen–antibody reaction, and
the type of antibody formed (IgM, IgG).

 In general, antibodies are induced against target antigens that are altered cell

membrane determinants.

 A variety of therapeutic drugs are known to induce type II reactions,

particularly with continuous administration.

 Examples include antibiotics and cardiovascular agents, among others.

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3. Type III immune complex reactions are localized responses mediated
by antigen–antibody immune complexes.

 Type III reactions are stimulated by microorganisms and involve

activation of complement.

 Systemic (serum sickness) and localized (arthus reaction) immune

complex disease, infection-associated immune complex disease

(rheumatic fever), and occupational diseases (opportunistic pulmonary
fungal infections) induce complement–antibody–antigen complexes that
trigger the release of cytokines and recruitment of granulocytes,
resulting in increased vascular permeability and tissue necrosis.

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4. Type IV (delayed-type) hypersensitivity cell-mediated immunity involves
antigen-specific T cell activation.

 The reaction starts with an intradermal or mucosal challenge (sensitization

stage).

 The release of lysosomal enzymes from the phagocytes results in local tissue

necrosis.

 Contact hypersensitivity resulting from prolonged exposure to natural

products and metals, for example, is caused by the lipophilicity of the

chemicals in skin secretions, thus acting as a hapten.

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2.2. Idiosyncratic reaction

 Idiosyncratic reactions are abnormal responses to chemicals or drugs generally

resulting from uncommon genetic predisposition.

 An exaggerated response to the skeletal muscle relaxant properties of

succinylcholine, a depolarizing neuromuscular blocker, classifies as a typical

idiosyncratic reaction.

 In some subjects, a congenital deficiency in plasma cholinesterase results in a

reduction in the rate of succinylcholine deactivation.

 As succinylcholine accumulates, respiration fails to return to normal during the

postoperative period.

 Similarly, the cardiotoxic action of cocaine is exaggerated in cases of congenital

deficiency of plasma esterases, which are necessary for metabolism of the drug.
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 A paucity of circulating enzymes allows for uncontrolled, sympathetically

mediated effects in experimental animals and humans.

 Chemical idiosyncrasy refers to a genetically determined abnormal reactivity

to a chemical

 1) Individuals, extreme sensitive to low doses or extreme insensitive to high

doses

 2) Succinylcholine ⇒ Form pseudocholinesterase, less break down

succinylcholine

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2.3. Reversible Versus Irreversible Effects

 In general, the effects of most chemicals or drugs are reversible until a

critical point is reached — that is, when vital function is compromised or a

mutagenic, teratogenic, or carcinogenic effect develops.

 In fact, the carcinogenic effects of chemicals such as those present in

tobacco smoke may be delayed for decades until irreversible cellular

transformation occurs.

 Reversibility of the acute effects of chemicals is achieved through the

administration of antagonists, by enhancement of metabolism or

elimination, by delaying absorption, by intervening with another
toxicological procedure that decreases toxic blood concentrations, or by
terminating the exposure.
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2.4. Local Versus Systemic Effects

 As discussed below, local or systemic effects of a compound depend on site

of exposure.

 The integument (skin) and lungs are targets of chemical exposure because

they frequently serve as the first sites of contact with environmental

chemicals.

 Oral exposure requires absorption and distribution of an agent prior to the

development of systemic effects.

 Hypersensitivity reactions types I and IV are precipitated by local activation

of immune responses following a sensitization phase, while chemical-induced

type II reactions are elicited through oral or parenteral administration.

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2.5. Biochemical Properties
2.5.1 Chemical structure

 Important components of a toxicity testing protocol include the identification,

categorization, synthesis, and toxicity screening of chemicals according to their

classifications.

 Because chemical and drug development depends upon the availability of

parent compounds, the synthesis of structurally related compounds is an

important process.

 Thus, understanding the chemical structure of a compound allows for

reasonable prediction of many of its anticipated and adverse effects.

 Some examples of agents that are categorized according to their molecular

structures include organophosphorus insecticides, heavy metals,

benzodiazepines (sedative hypnotics), and imidazolines (tranquilizers). 49
 2.5.2 Mechanism of action

 Similarly, it is convenient to organize toxic agents according to their

physiologic or biochemical targets.

 Examples include mutagens, hepatotoxic compounds, methemoglobin-

producing agents, and acetylcholinesterase inhibitors.

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2.6. Exposure

 In the presence of specific circumstances, any chemical has the potential

for toxicity — i.e., the same dose of a chemical may be harmless if limited
to oral exposure but toxic if inhaled or administered parenterally.

 Thus the route and site of exposure exert significant influence in

determining the toxicity of a substance.

 More frequently, a therapeutic dose for an adult may be toxic for an infant

or child. Similarly, a substance may not exert adverse effects until a critical
threshold is achieved.

 Thus, in order to induce toxicity, it is necessary for the chemical to

accumulate in a physiological compartment at a concentration sufficiently

high to reach the threshold value.
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 Finally, repeated administration over a specified period of time also

determines the potential for toxicity.

 The following discussion details the circumstances for exposure and

dose of a chemical that favors oassociated lymphoid tissue (MALT) is

layered within this level, where prominent lymphatic nodules sustain the
presence of phagocytic macrophages and granulocytes.

 Salivary and intestinal glands contribute to the digestive process by

secreting saliva and digestive juices.

 The submucosa, muscularis, and serosa complete the strata that form the

anatomical envelope of the GI tract.

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 Enteroendocrine and exocrine cells in the GI tract secrete hormones and, in the

stomach, secrete acid and gastric lipase. r deters the potential for toxicity.

 The primary function of the stomach is mechanical and chemical digestion of

food, while absorption is secondary. Several factors influence the transit and
stability of a chemical in the stomach, thereby influencing gastric emptying
time (GET).

 The presence of food delays absorption and dilutes the contents of the

stomach, thus reducing subsequent chemical transit.

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 An increase in the relative pH of the stomach causes a negative feedback

inhibition of stomach churning and motility, which also results in delay of

gastric emptying.

 Any factor that slows stomach motility will increase the amount of time in the

stomach, prolonging the GET.

 Thus, the longer the GET, the greater the duration of a chemical presence

within the stomach, and the more susceptibility to gastric enzyme degradation
and acid hydrolysis.

 In addition, prolonged GET delays passage to and subsequent absorption in

the intestinal tract.

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2.6.1. Intranasal Administration

 Intranasal insufflation is a popular method for therapeutic administration

of corticosteroids and sympathomimetic amines and for the illicit use of

drugs of abuse such as cocaine and opioids.

 The dosage form in therapeutic use is usually aerosolized in a metered

nasal inhaler. In the case of illicit use, crude drugs are inhaled (snorted)
through the nares as fine or coarse powders.

 In both cases, absorption is rapid due to the extensive network of

capillaries in the lamina propria of the mucosal lining within the

nasopharynx.

 Thus the absorption rate rivals that of pulmonary inhalation.

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 2.6.2. Inhalation

 The vast surface area of the upper and lower respiratory tracts allows for wide

and immediate distribution of inhaled powders, particulates, aerosols, and

gases.

 Once a drug is ventilated to the alveoli, it is transported across the alveolar

epithelial lining to the capillaries, resulting in rapid absorption.

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2.6.3. Dermal and Parenteral Routes

 Parenteral administration includes epidermal, intradermal, transdermal,

subcutaneous, intramuscular, and intravenous injections.

 Parenteral routes, in general, are subject to minimal initial enzymatic

degradation or chemical neutralization, thus bypassing the hindrances

associated with passage through epithelial barriers.

 Epidermal and upper dermal injections have the poorest absorption

capabilities of the parenteral routes primarily because of limited circulation.

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 The deeper dermal and subcutaneous layers provide entrance to a richer

supply of venules and arterioles.

 A subcutaneous injection forms a depot within the residing adipose

tissue with subsequent leakage into the systemic circulation or the

majority of the injection can enter the arterioles and venules.

 Intramuscular injections ensure access to a more extensive vascular

network within skeletal muscle, accounting for more rapid exposure than
subcutaneous.

 Intravenous injection is the most rapid method of chemical exposure

because access to the circulation is direct and immediate.

 Thus, the route of exposure contributes as much to toxicity as the dose.

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2.7. Duration and Frequency

 2.7.1. Acute Exposure

 In general, any exposure shorter than or equal to 24-hr is regarded as acute.

 Exposure to most toxic gases (carbon monoxide, hydrogen cyanide)

requires less than 24 hr for toxicity.

 In most experimental settings, however, 72 hr may still be considered acute

exposure, such as in continuous low-dose exposure to hepatotoxic agents.

 In addition, a single intravenous injection of a chemical is certainly

classified as an acute exposure.

 Sub-acute exposure generally refers to continuous or repeated exposure to

a chemical for more than 72 hr but less than 1 month.

59
 2.7.2. Chronic Exposure

 Chronic exposure is any relative time period for which continuous or

repeated exposure beyond the acute phase is required for the same
chemical to induce a toxic response.

 Sub-chronic exposure is understood to involve a duration between

acute and chronic.

 The traditional time of subchronic exposure is accepted as 1 to 3 month.

 In experimental and clinical toxicity, however, a subchronic exposure

may include repeated exposure for a period longer than 3 mo.

60
 Thus, the terms are flexible adaptations to define the onset of chemical

intoxication.

 In addition, considerable overlap in judgment is involved when labels are

assigned to exposure periods.

 Frequency of administration involves repeated doses of a drug or toxin

during the exposure period.

 Repeated administration of the same dose of a chemical within a time

period defined as acute or chronic establishes a greater potential for

adverse effects.

 Similarly, continuous repeated exposure to a toxin, especially during an

acute time period, has greater toxic potential.

61
 2.8. Accumulation

 Dose, duration, frequency, and route of exposure contribute to chemical

toxicity in part through accumulation of a compound in physiological

compartments.

 A normal dosage schedule is determined according to a chemical’s half-life (t

1/2) in plasma and its intended response — that is, the time required for plasma
levels to decrease to one-half of the measured or estimated concentration.

 Thus, if the frequency of administration occurs often within the t1/2 of a

chemical, its concentration in a compartment is likely to increase beyond the

desirable level.

 Accumulation results from overloading of a chemical within this compartment.

62
 2.8.1. According to Physiological Compartment

 Biological systems in their entirety are considered one-compartment

models.

 Ideally, a chemical capable of distributing uniformly throughout the

body would maintain steady-state levels for the exposure period.

 Blood levels* of a compound may also decrease uniformly, assuming a

constant rate of elimination.

 The body, however, is not a homogeneous chamber.

63
 A chemical, once absorbed, can distribute and/or bind to one or more of

many physiological sites.

 The distribution of a chemical depends largely on its physicochemical

characteristics.

 The compartments include whole blood, serum and serum proteins,

plasma and plasma proteins, adipose tissue, interstitial and extracellular

fluids, alveolar air space, and bone marrow.

 In addition, a chemical may preferentially accumulate in any tissue or

organ, thus acting as a discrete compartment.

64
 For instance, many therapeutic drugs such as warfarin (a vitamin K antagonist

anticoagulant) nonspecifically bind to circulating plasma proteins, resulting in

apparently lower blood concentrations than anticipated.

 Heavy metals preferentially accumulate in adipose tissue, kidney, and bone.

 Consequently their toxicity may be experienced for prolonged periods as the

compounds are slowly released from this compartment years after exposure
has ceased.

65
 Accumulation, therefore, is predicted based on a chemical’s apparent volume

of distribution (Vd), which is estimated as the total dose of chemical in the

body divided by the concentration of chemical in the plasma for a given
period.

 In general, the greater the Vd, the greater the potential for accumulation in

some physiological compartment.*

 2.8.2. According to Chemical Structure

 Accumulation is also determined by a chemical’s structure and its interaction

within the physiological compartment.

66
 This phenomenon is guided by the chemical’s predominant state of existence

in a physiological fluid — that is, it remains in the fluid compartment as an

ionic or non-ionic species.

 In general, at physiological pH, lipid soluble compounds will preferentially

remain in their non-ionic states, to bind to and accumulate in membranes of

tissues and organs.

 Conversely, water-soluble compounds remain as ionic species at the pH of

blood.

 Thus, because they are less prone to tissue binding, the ions are readily

available for renal secretion and elimination

67
 2.9. Chemical Interactions

 2.9.1 Potentiation

 Potentiation of toxicity occurs when the toxic effect of one chemical is

enhanced in the presence of a toxicologically unrelated agent.

 The situation can be described numerically as 0 + 2 > 2, where a relatively

non-toxic chemical alone has little or no effect (0) on a target organ, but may
enhance the toxicity of another co-administered chemical.

 The hepatotoxicity of carbon tetrachloride, for instance, is greatly enhanced in

the presence of isopropanol.

68
 2.9.2 Additive Effects

 Two or more chemicals whose combined effects are equal to the sum of the

individual effects is described as an additive interaction.

 This is the case with the additive effects of a combination of sedative

hypnotics and ethanol (drowsiness, respiratory depression).

 Numerically this is summarized as 2 + 2 = 4.

69
 2.9.3 Snergistic Effects

 By definition, a synergistic effect is indistinguishable from potentiation

except that, in some references, both chemicals must have some cytotoxic
activity.

 Numerically, synergism occurs when the sum of the effects of two chemicals

is greater than the additive effects, such as the effect experienced with a
combination of ethanol and antihistamines (1 + 2 > 3).

 The synergism and potentiation terms often are used synonymously.

70
 2.9.4 Antagonistic Effects

 The opposing actions of two or more chemical agents, not necessarily

administered simultaneously, are considered antagonistic interactions.

 Different types of antagonism include:

 Functional antagonism— The opposing physiological effects of chemicals,

such as with central nervous system stimulants versus depressants.

 Chemical antagonism— Drugs or chemicals that bind to, inactivate, or

neutralize target compounds such as the actions of chelators in metal

poisoning.

71
 Dispositional antagonism— The interference of one agent with the

absorption, distribution, metabolism, or excretion (ADME) of another;

examples of agents that interfere with absorption, metabolism, and excretion
include activated charcoal, phenobarbital, and diuretics, respectively.

 Receptor antagonism— The occupation of toxicological or pharmacological

receptors by competitive or non-competitive agents, such as the use of

tamoxifen in the prevention of estrogen-induced breast cancer.

72
 2.10. Dose–response Relationship

 2.10.1 General Assumptions

 A discussion of the effects of a chemical as a result of exposure to a particular

dose is necessarily followed by an explanation of the pathway by which that

dose elicited the response.

 This relationship has traditionally been known as the dose–response

relationship.* The result of exposure to the dose is any measurable, quantifiable,

or observable indicator.

 The response depends on the quantity and route of chemical exposure or

administration within a given period.

 Two types of dose–response relationships exist, depending on the numbers of

subjects and doses tested.

73
 2.10.2. Graded Dose–Response

 The graded dose–response describes the relationship of an individual test

subject or system to increasing and/or continuous doses of a chemical.

 The concentration of the chemical is inversely proportional to the

number of surviving cells in the cell culture system.

74
 2.10.3. Quantal Dose–Response

 Alternatively, the quantal dose–response is determined by the distribution of

responses to increasing doses in a population of test subjects or systems.

 This relationship is generally classified as an “all-or-none effect” in which the

test system or organisms are quantified as either responders or non-

responders.

 The LD50 is a statistically calculated dose of a chemical that causes death in

50% of the animals tested.

75
 The doses administered are also continuous or at different levels and the

response is generally mortality, gross injury, tumor formation, or some

other criterion by which a standard deviation or cut-off value can be
determined.

 In fact, other decisive factors such as therapeutic dose or toxic dose is

determined using quantal dose–response curves, from which are derived

the ED50 (effective dose 50%) and the TD50 (toxic dose 50%),
respectively.

 Graded and quantal curves are generated based on several assumptions.

76
 The time period at which the response is measured is chosen empirically or

selected according to accepted toxicological practices.

 For instance, empirical time determinations may be established using a

suspected toxic or lethal dose of a substance and the response is determined

over several hours or days.

 This time period is then set for all determinations of the LD50 or TD50 for

that period.*

 The frequency of administration is assumed to be a single dose administered

at the start of the time period when the test subjects are acclimated to the
environment.

77
 A dose-response relationship exists when a consistent mathematical

relationship describes the proportion of test organisms responding to a

specific dose for a given exposure period.

 Although a dose-response relationship may seem easy to establish, a number

of assumptions need consideration.

 The first assumption is that the observed response is caused by the substance

administered.

 A causal relationship must be established between the dose administered and

the observed response.

78
 It should be remembered that causal relationships are very different from

associative relationships.

 Direct cause-and-effect linkages involving single variables, rather than

associative linkages with two or more variables, are needed to establish

the dose-response relationship.

 Second, the magnitude of the response is assumed to be directly related

to the magnitude of the dose.

 This assumption goes beyond the first assumption that the observed

response is caused by the substance administered.

79
 The third dose-response relationship assumption states that it is possible

to correctly observe and measure a response.

 The ability to define and observe pathologies associated with toxicity is

dependent on the depth of understanding of cellular anatomy and

physiology.

 It is impossible to select and subsequently measure responses for which

related cellular structures and processes are unknown.

 This assumption stresses the value of the contributions from basic

science research.

80
 Dose-Response Graphs

 The graphic presentation of dose and response data permits an

environmental toxicologist to readily determine important dose-response

relationships.

 Furthermore, the graphs enable different toxicants to be compared. In a

dose-response graph the horizontal axis (X axis or abscissa) always

represents the dose in a logarithmic scale using mg/kg units (Figure 3–
2A and B).

 The vertical axis (Y axis or ordinate) represents the in vivo or in vitro

response.

81
 Proper labeling, which indicates

the response being measured

and the unit used for the series
of doses being tested, is
necessary for accurate
communication of the dose-
response relationship.

 To avoid errors associated with

misreading fractional doses,

decimal points should be
preceded by a zero (e.g., 0.1
mg/kg, instead of .1 mg/kg)
82
83
 Three features characterize the sigmoidal line on a cumulative dose-response

graph.

 First, there is a dose at which the first test organism will respond. This is

referred to as the threshold dose, which can be seen on the graph as the left-side

beginning of the sigmoidal line.

 The following are often used to refer to this beginning region of the cumulative

dose-response graphs: No Observable Effects Level (NOEL), NOAEL,

Suggested No Adverse Response Level (SNARL), Lowest Observable Effect

Limit (LOEL), and Threshold Limit Value (TLV).

84
 At progressively higher doses, the initially curved sigmoidal line begins to

straighten out .

 This second region of the graph represents the doses at which the majority of

test organisms were observed to exhibit the response. Of interest is the

cumulative 50% level, representing the dose at which the mean response
occurred.

 Third, the right side of the line on a cumulative dose-response graph may be

seen to once again curve and then become almost horizontal or flat.

 This region represents the higher doses at which the remaining few

test organisms finally exhibited the predetermined end effect.

 This region is said to exhibit the ceiling effect, since an increase in dose

produces little or no increase in response.

85
 Depending on the observable response selected for the toxicity test,

dosages may be characterized as being effective, toxic,

or lethal.

 An effective dose (ED) is evident when the desirable response is

observed at the dose tested.

 A toxic dose (TD) represents the dose at which toxicity is present in test

organisms.

 When lethality is the selected response, a lethal dose (LD) represents the

dose resulting in the death of the test organism.

86
 LD is always used when lethality is selected as the observable response, even

though lethality is in itself a response and could be referred to as ED.

 Note that therapeutic dose, although used in pharmacology, is

considered an effective dose and should be signified by ED, not TD.

 To facilitate the interpretation of data from a single dose-response study or

when comparing data from two or more dose response studies, it is useful to

examine the dose at which a specified cumulative percentage of test

organisms exhibit the ED, TD, or LD.

87
 2.10.4. Concentration

 It is assumed that at the conclusion of an experiment, the measured or

observed effect is, in fact, due to the presence of the chemical.

 The establishment of this causal relationship is critical if valid

conclusions are drawn from the dose–response curve.

 It is also presumed that the chemical in question is present at the

receptor site or cellular target responsible for the effect.

 Support for this assumption follows from measurement of concentrations

at the cellular or organ level.

88
 In fact, as the concentration of a chemical in the affected compartment

increases, the degree of response must increase proportionately if this

assumption is valid.

 For this reason, some references have suggested using the concentration

effect curve as an alternative label to dose–response.

 The former is purported to be a more ingenuous description of the causal

relationship and more accurately reflects the parameters measured.

 2.11. Criteria for Measurement

 Except for lethality, the selection of a measurable or observable

endpoint is crucial.

89
 A desirable biomarker accurately reflects the presence of a chemical at a cellular

or molecular site or suggests that a toxic effect originates from its action at the
target organ.

 Selection of a measurable endpoint thus depends on the suspected mechanism of

toxicity, if known, or on empirical determinations based on the chemical

formula.

 Some biomarkers are also subjective, such as reliance on histological grading,

calculation of the degree of anesthesia, pain, motor activity, or behavioral

change.

 Thus the standards for quantifying the endpoint are determined and established

prior to the experimental set-up.

90
 2.3.1 Route

 2.3.1.1 Oral Administration

 By far, oral administration of toxins is the most popular route of exposure.

 Oral administration involves the presence of several physiological barriers

that must be penetrated or circumvented if adequate blood concentrations of a

compound is achieved

 The mucosal layers of the oral cavity, pharynx, and esophagus consist of

stratified squamous epithelium that serves to protect the upper gastrointestinal

(GI) lining from the effects of contact with physical and chemical agents.

91
 Simple columnar epithelium lines the stomach and villi of the intestinal tract

that function in digestion, secretion, and absorption.

92
 ASSIGNMENT ONE (15%)
Instruction: Briefly Discuss the properties, sources, toxicity and effects of
toxicants and make a short note on:

1. Heavy Metals------------Group One

2. Major Air Pollutants-----Group Two

3. Pesticides-----------------Group Three

NB: Each group member must participate in doing the assignment

Presenter of the assignment will be randomly selected

Written Report (8%) and Presentation (7%).

93
 CHAPTER THREE
3. Effects of Ecotoxicants at different levels of biological
organization

94
95
96
 To understand the effect of chemicals the process can be broken down into

three stages:
 1. The chemical substance enters the environment and interacts with it. It spreads,

partition occurs between the different phases, it is transformed into other substances,
degrades etc. These processes define the environmental concentration of the substance
which reaches and affects the members of the biota.

 2. The chemical substance interacts with the living organism at an active space at

molecular level. This can be an important structural element or a molecule, for example
enzyme, nucleotide acid or membrane receptor of the organism.

 3. The effect of the interaction at molecular level appears at higher levels such as

biochemical and physiological levels, behaviour, population, community or the whole

ecosystem.

97
98
 Basically only three basic function need to be described by environmental

toxicology:
 1. Description of the fate and transport of chemicals in the biosphere and

the organism after the release to the environment.

 2. Description of the interaction of the material with the site of action.

 3. Description of the impact of this molecular interaction upon the

function of the ecosystem (Landis and Yu, 1999, 2003).

99
 The steps of the interaction of the chemicals with the ecosystem and

the parameters that can be measured at each step are the following:

 Chemical and physical-chemical characteristics of the xenobiotic

 The chemical structure of a specific molecule determines the impact of the

compound at molecular level.

 The contribution of the physical-chemical characteristics of a compound to

the observed toxicity is called QSAR – Quantitative Structure-Activity

Relationship.

100
1. Introduction of the xenobiotic into the environment –
biotransformation / biodegradation / bioaccumulation
 Enzyme induction

 Glutathione S transferases

 Mixed function oxidases

 Hydrolases

 DNA repair enzymes

101
2. Interaction with the site of action
 DNA/RNA

 Membrane receptors

 Key enzymes

 Biochemical integrity

102
3. Biochemical parameters (level of molecules)
 Stress proteins

 Metabolic indicators

 Acetylcholine-esterase inhibition

 Adenylate energy change

 Metallothionein production

 Immune-suppression

103
4. Physiological and behavioural characteristics (level of organisation)
 Chromosomal damage

 Lesion and necrosis

 Carcinogenic effects

 Teratogenic effects

 Reproductive success

 Behavioural alterations

 Mortality

 Compensatory behaviours

104
5. Population parameters
 Population density

 Productivity

 Mating success

 Alterations in genetic structure

 Competitive alterations

105
6. Community parameters
 Structure

 Diversity

 Energy transfer efficiency

 Stability

 Successional state

 Chemical parameters

7. Ecosystem parameters
 Diversity and distribution of species

 Metabolism

 Element cycle

 Landscape changes
106
3.1. LEVELS OF
ORGANIZATION
STUDIED IN
BIOLOGY

107
FROM THE SMALLEST LEVEL…
1. ATOMS
The smallest unit of matter that
cannot be broken down into
anything simpler by chemical
means.
3. Organelles
Specialized structures that perform
important cellular functions within
cells.
2. Molecules
The smallest units of most
compounds formed by the chemical
bonding of atoms.
4. Cell
The smallest unit of life –
collections of living matter
enclosed by a barrier that separates
them from their surroundings.
108
FROM THE SMALLEST LEVEL…
5. Tissues
Groups of similar cells that perform
a particular function.
7. Organ Systems
Groups of organs that work
together to perform closely related
functions.
6. Organs
Groups of tissues that work
together to perform closely related
functions.
8. Organisms
Living things composed cells
(multicellular organisms).
Species =a group of organisms so
similar to one another that they
can breed and produce FERTILE
OFFSPRING.
109
…TO THE LARGEST LEVEL.
9.Population 10. Community

Groups of individuals of the Groups different populations that live

same species that live in the together in a defined area.
same area.

12. Biome

Groups of ecosystems
11.Ecosystem
that have the same
climate and similar
Groups of all the organisms that
dominant communities
live in a particular place, together
with their nonliving environment.

13. Biosphere
Part of the Earth in which life exists including land,
water, air and atmosphere.
110
HOW IS LIFE CHARACTERIZED WITHIN THESE LEVELS…
WHAT IS LIFE DEFINED BY?

111
CHARACTERISTICS OF LIFE:

1. Composed of Cells
2. Reproduction
3. Growth & Development
4. Obtain & Use Energy…
METABOLISM
5. Respond to
Environment…
HOMEOSTASIS
6. DNA is the ‘Universal
Genetic Code
7. Evolution and
Adaptation
112
A CELL IS THE BASIC UNIT OF LIFE; ALL CELLS COME
FROM PREEXISTING CELLS

 Unicellular
 Organisms composed of
a single cell

 Multicellular
 Organisms composed of
many cells…diversity
and specialization of
function (over 85 types
of cells in the human
body) 113
 AHHH…REPRODUCTION

 Asexual Reproduction:
 Single parent copies its DNA and then
divides or ‘buds’ to produce
GENETICALLY IDENTICAL
OFFSPRING.
 This can mean ‘rapid-fire’ reproduction
of great numbers of identical organisms

 Sexual Reproduction:
 Two different parent cells unite
to produce the first cells of a
new organism.
 Offspring are GENETICALLY
UNIQUE leading to greater
genetic diversity and speciation
on Earth.

114
ALL ORGANISMS GROW AND DEVELOP

 Single celled organisms

(like bacteria) growth is
 Multicellular organisms
mostly a simple increase in
size undergo extensive development
from a single fertilized egg
dividing many, many times to
produce the multitude of cells
in mature organisms
 Differentiation is the changing
of shape and structure to
perform different functions.

115
OBTAIN AND USE ENERGY

 All living things obtain energy from their environment

or surroundings and use it for growth, development,
reproduction, and excretion – these processes occur at
different rates…
METABOLISM = Anabolism (synthesizing compounds – expends energy)
+ Catabolism (breaking compounds into simple components – releases energy)
= Combination of chemical reactions (total activity) that build
and break down materials as organisms carry out their life
processes.

116
LIVING ORGANISMS RESPOND TO THE
ENVIRONMENT

 Organisms detect and respond to a STIMULUS (signal) or anything in

the environment that causes a response whether internal or external.

*Internal stimuli are

*External
things like blood
stimuli include
glucose level (low
light, touch,
levels make you feel
sound, heat,
hungry, possibly weak,
smell, sight…
tired, head-achy, etc)

117
HOMEOSTASIS…’AUTOPILOT’
 The autonomic (self-controlled) processes by which organisms respond
to stimuli such that conditions in the body are kept suitable to sustain life

118
DNA IS THE ‘UNIVERSAL GENETIC
CODE’

 All life is based on a UNIVERSAL GENETIC

CODE…DNA (a 4 letter code) is common to
ALL life, determining the inherited traits of all
organisms!
 DNA is a type of biomolecule known
as a Nucleic Acid that had a three
dimensional shape called a double
helix. The shape of DNA allows for
duplication and ‘reading’ or
expressions of the genes it encodes.

119
ORGANISMS SHOW EVOLUTION AND ADAPTATION

 EVOLUTION is ability of a group of organisms to

change over time. This invaluable for survival in
constantly changing environments…
 An ADAPTATION is a trait of a living thing that helps
it compete and survive to reproduce in its
environment.

120
 3.2. Effects and Response at Molecular and Biochemical Levels

 Toxic effects are greatly variable in nature, potency, target organ, and

mechanism of action.

 A better understanding of their characteristics can improve assessment of the

associated health hazards.

 It can also facilitate the development of rational preventive and therapeutic

measures.

 All toxic effects result from biochemical interactions between the toxicants

(and/or their metabolites) and certain structures of the organism.

121
 The structure may be nonspecific, such as any tissue in direct contact with

corrosive chemicals.

 More often it is specific, involving a particular subcellular structure.

 A variety of structures may be affected.

 The toxic action of pollutants involves either compounds with intrinsic

toxicity or activated metabolites.

 These interact with cellular components at specific sites of action to cause toxic

effects, which may occur anywhere in the body.

 The consequences of such action may be reflected in changes in physiological

and biochemical processes within the exposed organism.

122
 The mechanisms involved in xenobiotic-induced toxicity are complex and

much remains to be elucidated.

 The ways in which xenobiotics can induce adverse effects in living

organisms include:
 disruption or destruction of cellular structure

 direct chemical combination with a cell constituent

 inhibition of enzymes

 initiation of a secondary action

 free-radical-mediated reactions

 disruption of reproductive function

123
 A toxicant may induce an injurious effect on plant or animal tissues by

disrupting or destroying the cellular structure.

 As mentioned previously, atmospheric pollutants, such as SO2,NO2, and O3, are

phytotoxic – they can cause plant injuries.

 Studies show that low concentrations of SO2 can injure epidermal and guard

cells, leading to enhanced stomatal conductance and greater entry of the pollutant
into leaves.

 In animals and humans, inhalation of sufficient quantities of NO2 and sulfuric

acid mists can damage surface layers of the respiratory system.

 Similarly, high levels of O3 can induce peroxidation of the polyunsaturated fatty

acids in the lipid portion of membranes, resulting in disruption of membrane

structure.

124
Chemical Combination with a Cell Constituent

 A pollutant may combine with a cell constituent, forming a complex and disrupting

cellular metabolism. For example, CO is widely known for its ability to bind to
hemoglobin (Hb). After its inhalation and diffusion into the blood, CO readily reacts
with Hb to form carboxyhemoglobin (COHb):
CO + Hb  COHb

 The presence of a large amount of COHb in the blood disrupts the vital system for

exchange of CO2 and O2 between the blood and the lungs and other body tissues.

 A number of toxicants or their metabolites are capable of binding to DNA to form

DNA adducts.

 Formation of such adducts results in structural changes in DNA, leading to

carcinogenesis.

125
Effect on Enzymes

 The most distinctive feature of reactions that occur in living cells is the

participation of enzymes as biological catalysts.

 Almost all enzymes are proteins with a globular structure, and many of them

carry out their catalytic function by relying solely on their structure.

 Many others require non-protein components, called cofactors.

 Cofactors may be metal ions or alternatively they may be organic molecules,

called coenzymes.

 Metal ions capable of acting as cofactors include K+, Na+, Cu2+, Fe2+ or Fe3+,

Mg2+, Mn2+, Ca2+, and Zn2+ ions

126
Secondary Action as a Result of the Presence of a Pollutant

 Allergic Response to Pollen

 In many individuals, allergic response occurs after inhalation of pollen, leading to

common symptoms of hay fever.

 These symptoms are due to the release of histamine, a substance formed from the

amino acid histidine through decarboxylation.

 The way in which carbon tetrachloride (CCl4) affects humans is another example.

 Once taken up into the body, CCl4 is known to cause a massive discharge of

epinephrine from sympathetic nerves, eventually resulting in liver damage.

 Epinephrine is a potent hormone, involved in many critical biological reactions in

animals and humans

127
 Chelation is a process wherein atoms of a metal in solution are sequestered by

ring-shaped molecules.

 The ring of atoms, usually with O, N, or S as an electron donor, has the metal as

an electron acceptor.

 The metal is more firmly gripped within this ring than if it were attached to

separate molecules.

 The formation of strain-free stable chelate rings requires at least two atoms that

can attach to a metal ion.

 The iron in a hemoglobin molecule and the magnesium in a chlorophyll

molecule are two such examples.

 Through chelation, some biologically active compounds are absorbed and

retained in the body, whereas others may be removed from it.

128
 The phenomenon called metal shift may account for some of the responses seen

in animals that are exposed to certain toxicants.

 Metal shift refers to movement of metals from one organ to another due to the

presence of a toxicant, and is among the earliest biological indicators of toxic

response.

 For example, rats exposed to F show an increase in serum Zn content, whereas

the levels of Se and Al in the rats’ whiskers were decreased.

 A similar change was observed with rats exposed to O3.

 When exposed to O3 for 4 hours, the rats showed increased levels of Cu, Mo,

and Zn in their lungs, while the levels of these metals in the liver were
decreased.

129
Free-radical-mediated Reactions

 A free radical is any molecule with an odd number of electrons, and can occur as

both organic and inorganic molecules.

 Free radicals are highly reactive and therefore highly unstable and short-lived.

 Free radicals are derived from both natural and anthropogenic sources.

 Anthropogenic sources of free radicals are found in such situations as when an

organism is exposed to ionizing radiation, certain drugs, or various xenobiotics.

 The free radicals thus produced can cause chain reactions and damage critical

cellular constituents, including proteins, lipids, and DNA.

 Certain atmospheric pollutants, such as O3, PAN, and NO2, can act as free radicals

themselves.

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Endocrine Disruption

 Estrogen, a steroid hormone, is produced in both males and females.

 It is produced in much large quantities in females and, therefore, is considered a

female hormone.

 In both humans and animals, a specific ratio of estrogen to androgens (male

hormones) is necessary for sexual differentiation in the developing fetus.

 If the ratio is perturbed, the offspring may be born with two sets of partially

developed sexual organs (intersex), or with a single set that is incompletely or

improperly developed.

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 Pollutants cause a wide variety of biochemical effects in organisms.

 Broadly, these can be divided into protective and non-protective responses.

 Protective responses include the induction of enzymes which have a

detoxifying function and the induction of proteins which can bind heavy

metals.

 Microsomal monooxygenases are examples of inducible enzymes which

usually have a detoxifying function.

 However, the situation is complicated by the fact that in a relatively small (yet

critically important) number of cases monooxygenases cause activation rather

than detoxication.

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Physiological effects of pollutants

 Physiology is defined as the branch of science concerned with the functioning

of organisms and the processes and functions of all or part of an organism.

 Thus, in ecotoxicology, we are concerned with describing the disruptive effects

of pollutants on ‘normal’ physiology, normal referring to the state of the

organism when not exposed to pollution although subject to other forms of
stress.

 Abnormal stresses may be completely novel and occur in response to man-

made chemicals that have appeared in the environment recently (on the
geological timescale), or they may simply be an increase in a response to a
substance to which the organism has evolved natural protection mechanisms
(e.g. metals).

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 It should also be emphasized that protective responses such as these bear an

energy cost which may have a detrimental effect on the organism

 Many responses, such as inhibition of cholinesterase, electrophysiological

changes caused by organochlorine insecticides, antagonism of vitamin K,

endocrine disruption and formation of DNA adducts, are non-protective and in
many instances are harmful to the organism.

 It is very important to elucidate the mechanisms by which chemicals express

toxicity.

 Understanding the mechanisms of toxicity can provide the basis for biomarker

assays and can lead to the development of antidotes

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