TOXICOKINETICS

Toxicokinetics is defined as the rates of all metabolic processes related to the expression
of toxicological end points. It is the method of the uptake of possibly toxic substances by
the body, the biotransformations they go through, the distribution of the substances and
their metabolites in the tissues, and the elimination of the substances and their
metabolites from the body.
Pharmacokinetics or toxicokinetics involved in absorption, distribution, and elimination
processes is a highly specialized branch of toxicology. Toxicokinetics is the quantitative study of
the movement of an exogenous chemical from its entry into the body, through its distribution to
organs and tissues via the blood circulation, and to its final disposition by way of
biotransformation and excretion. Toxicokinetics represents extension of kinetic principles to the
study of toxicology and encompasses applications ranging from the study of adverse drug effects
to investigations on how disposition kinetics of exogenous chemicals derived from either natural
or environmental sources or xenobiotics govern their deleterious effects on organisms including
humans. The elementary kinetic concepts for the absorption, distribution, metabolism, and
excretion of chemicals in the body system initially came from the study of drug actions or
pharmacology. Toxicokinetics is defined as the rates of all metabolic processes related to the
expression of toxicological end points. The human body can be open to a range of toxicants that
may be existent in different environmental media such as air, soil, water, or food. However, just
merely being exposed to these dangerous chemicals does not certainly transform into a
toxicological response. As the toxicological response is often associated to the exposed dose,
relations between the toxicant and the body’s barriers and defense mechanisms will have an
effect on toxicant movement in the body, and eventually control the degree and magnitude of
toxicant absorption and distribution to the target tissue. The overall entry depends on both the
amount present and the saturability of the transport processes involved. Liver metabolism will
have the most significant effect on toxicant bioavailability following gastrointestinal absorption,
but microbial activity and various enzymes in the gastrointestinal tract and the skin can play a
significant role in oral and dermal absorption, respectively. Physicochemical features of the
toxicant such as the chemical form can be a valuable indicator of whether the toxicant will be
absorbed and distributed in the body. The understanding and interpretation of toxicological
findings require information on two key areas, firstly delivery of the compound to its site of
action (toxicokinetics) and secondly the mechanism of action and
potency of the chemical at the site of action (toxicodynamics).

Significance of toxicokinetic of T
Toxicokinetics is an extension of pharmacokinetics in that these studies are conducted at higher
doses than pharmacokinetic studies and the principles of pharmacokinetics are applied to
xenobiotics. In addition these studies are essential to provide information on the fate of the
xenobiotic following exposure by a define route. This information is essential if one is to
adequately interpret the dose-response relationship in the risk assessment process. The principles
of pharmacokinetics apply to any environmental xenobiotic, and many of the biological
processes involved in the absorption, distribution, and elimination, such as the metabolizing
enzymes, are nonspecific and shared by drugs and other low-molecular weight organic molecules
such as additives, pesticides, and contaminants. Toxicokinetic data have the potential to define:
1) The internal exposure in animals based on plasma or blood concentrations of the
parent compound or its active metabolite in relation to the dose given to the animals
2) The relationship between plasma or blood concentrations and those at the site of
toxicity
3) The information allowing quantitative interspecies comparisons derived from
appropriate blood/ plasma data after the administration of tracer doses to human
volunteers
The term toxicokinetics is now widely accepted to describe pharmacokinetic processes for
potentially toxic chemicals, which do not have a therapeutic effect. Toxicokinetics should
also be considered to confirm appropriate exposure levels in different treatment groups.

Toxicokinetic process includes following phases:

Absorption
Absorption is the acceptance of a constituent from the surroundings into the organism. The
mammalian body has a number of characteristic defense mechanisms and membrane barriers that
have a tendency to check the entry or absorption and distribution of these toxicants once an
exposure event has occurred. However, if the toxicant is freely absorbed into the body, there are
still other anatomical and physiological barriers that may prevent distribution to the target tissue
to elicit a toxic response. In order for a xenobiotic to reach its site of action, it must pass across
various body membranes, that is, cells of skin, cells of lung, gastrointestinal tract, erythrocyte
membrane, etc. As soon as the toxicant has been absorbed, the toxicant molecules can move
around the body in two ways:
i. By bulk flow transfer (i.e., in the blood stream)
ii. By diffusional transfer (i.e., molecule-by-molecule over short distances).
There are following types of absorptions:
1. Pulmonary absorption
The lungs are the primary route of deposition and absorption of small airborne particles, gases,
vapours and aerosols. For extremely water soluble gases and vapours a substantial part of the
uptake ensues in the nasal cavity and the respiratory branch, but for less soluble substances it
principally takes place in the lung alveoli.
2. Percutaneous absorption
The skin is a very efficient barrier. Apart from its thermoregulatory role, it is designed to protect
the organism from microorganisms, ultraviolet radiation and other deleterious agents, and also
against unnecessary water loss.
3. Gastrointestinal absorption
It occurs after accidental or intentional ingestion. Larger particles initially inhaled and deposited
in the respiratory tract may be absorbed after mucociliary transport to the pharynx. Almost all
soluble substances are well absorbed in the gastrointestinal tract. The low pH of the gut may
expedite absorption, for example, of metals.
4. Other routes
In toxicity testing and other experiments, exceptional routes of administration are often used for
accessibility, although these are uncommon and ordinarily unrelated in the occupational setting.
These routes include intravenous (IV), subcutaneous (SC), intraperitoneal (IP) and intramuscular
(IM) injections. Overall, substances are absorbed at a higher rate and more absolutely by these
routes, particularly after intra venous injection. This leads to short-lasting but high concentration
peaks that may increase the toxicity of a dose. Disposition is the term often used to describe the
simultaneous effects of distribution and elimination processes subsequent to absorption.
Distribution
Absorption of toxicants into the blood needs to be high enough so that it will have a
significant effect at the site of action in other areas of the body. The distribution process that
takes the absorbed drug to other tissues is dependent on various physiological factors and
physicochemical properties of the drug. This process is therefore a reversible movement of
the toxicant between blood and tissues or between extracellular and intracellular
compartments. There are, however, several complicating factors that can influence the
distribution of a toxicant. These include lipid solubility, pKa, and molecular weight. For
many toxicants, distribution from the blood to tissues is by simple diffusion down a
concentration gradient. The concentration gradient will be influenced by the partition
coefficient or rather the ratio of toxicant concentrations in blood and tissue. Tissue mass and
blood flow will also have a significant effect on distribution. For example, a large muscle
mass can result in increased distribution to muscle, while limited blood flow to fat or bone
tissue can limit distribution. There are unique anatomical barriers that can limit distribution of
toxicants. A classic example of such a unique barrier is the blood-brain barrier (BBB) which
can limit the distribution of toxicants into the CNS and cerebrospinal fluid. Generally after a
toxicant or drug is absorbed it can be distributed into different physiologic fluid
compartments. The obvious volume of distribution Vd is defined as the volume of fluid
necessary to contain the total amount A, of drug in the body at the equivalent concentration
as that present in plasma Cp.
Biotransformation
Biotransformation is a chemical alteration of chemicals such as nutrients, amino acids, toxins,
and drugs in the body. It is also needed to render non-polar compounds polar so that they are not
reabsorbed in renal tubules and are excreted. Vertebrates have advanced the ability to convert
many toxicants into other chemicals, often detoxifying the chemical and sometimes activating it.
The same or similar biochemical processes that hydrolyze, oxidize, and reduce toxicants in
vertebrates also take place in many lower organisms. Biotransformation is a process which leads
to a metabolic transformation of foreign compounds (xenobiotics) in the body. The process is
often mentioned as metabolism of xenobiotics. As a common rule metabolism converts lipid
soluble xenobiotics to large, water soluble metabolites that can be efficiently excreted. The liver
is the foremost place of biotransformation.

Xenobiotics, once inside the body, undergo a series of biotransformation. Biotransformation

follow a complex series of chemical reactions that are enzymatically facilitated and are
ordinarily irreversible reactions that are actively positive, resulting in a reduction in the Gibbs
free energy of the system. Thus the potential for biotransformation of a chemical depends on the
reduction in free energy that results from responding of the chemical with other chemicals in its
surroundings. Those reactions that introduce a new functional group into the molecule by
oxidation, reduction, or hydrolysis are designated Phase- I reactions, whereas the conjugation
reactions by which Phase- I metabolites are combined with endogenous substrates in the body
are denoted as Phase- II reactions. Chemicals may go through any one of these reactions or any
combination of them, either concurrently or sequentially. Because biotransformations are
catalysed by a large number of enzymes, it is to be expected that they will vary among species.
Qualitative differences imply the occurrence of different enzymes, whereas quantitative
differences imply variations in the rate of biotransformation along a common metabolic pathway,
the differences resulting from variances in enzyme levels, in the degree of competing reactions
or in the competence of enzymes capable of reversing the reaction. Most biotransformations are
detoxication reactions, many oxidative reactions produce reactive metabolite

Elimination
The ability to efficiently eliminate toxic materials is critical to the survival of a species. The
complication of toxicant elimination processes has increased equal with the increased
complication associated with animal form. For unicellular organisms, passive diffusion can
suffice for the elimination of toxic metabolic wastes produced by the organism. Three main
routes of elimination culminate in the specialized organs of elimination, the liver, kidneys,
and lungs. The liver assists as a major organ at which lipophilic materials are collected from
the blood, biotransformed to generally less toxic and more polar derivatives, and then eliminated
into the bile. The kidneys balance the liver in that these organs accumulate wastes and other
chemicals in the blood through a filtration process and eliminate these wastes in the urine. The
respiratory membranes of the lungs are perfect for the removal of volatile materials from the
blood into expired air.

1. Renal Elimination

Kidneys are the spots of elimination of water-soluble chemicals that are removed from the blood
by the process of reverse filtration. Two characteristics are principally responsible for
determining whether a chemical will be eliminated by the kidneys or not, i.e., size and water
solubility.

2. Hepatic Elimination

The liver assists many vital purposes to the body. It has a large volume to hold blood and thus
helps as a blood storage site. The liver produces and secretes many constituents that are required
for typical biological function. It purifies the blood from several endogenous and foreign
molecules. It biotransform equally endogenous and exogenous materials, decreasing their
bioreactivity and assembling them for removal. It eliminates wastes and foreign chemicals
through biliary excretion. Three of these functions occur co-ordinately in a method that makes
the liver a chief organ of chemical elimination, chemical uptake from blood, chemical
biotransformation, and biliary elimination of chemicals.

3. Respiratory Elimination

The lungs are extremely specific organs that function in the uptake and elimination of volatile
materials (i.e., gasses). Consequently, the lungs can work as a major site for the elimination of
chemicals that have a high vapor pressure. The functional unit of the lung is the alveolus. These
small, highly vascularized, membranous sacs function to exchange oxygen from the air to the
blood (uptake), and equally, exchange carbon dioxide from the blood to the air (elimination).
This interchange occurs through passive diffusion. Chemicals that are adequately volatile also
may diffuse across the alveolar membrane, resulting in removal of the chemical from the blood
and elimination into the air. In addition to these major routes of elimination, several
quantitatively minor routes exist through which toxic materials can be eliminated from the body.
These include Skin, Mammary Glands, Hair and Sweat.

Bioavailability

Bioavailability: The fraction, or sometimes percentage, of the administered dose that enters the
general circulation as the parent compound. In the absence of pre-systemic clearance, or first
pass metabolism, the fraction is one. In oral exposure pre-systemic clearance may be due to
metabolism within the gastrointestinal content, gut wall or liver. A low bioavailability may be
due to poor absorption or first-order conditions and the state of being capable of being absorbed
and available to interact with the metabolic processes of an organism. Bioavailability is
characteristically a function of chemical properties, physical state of the material to which an
organism is exposed, and the capability of the individual organism to physiologically take up the
chemical. First-pass metabolism will reduce the systemic absorption of the substance and instead
increase the absorption of metabolites. This may lead to a diverse toxicity configuration. The
bioavailability must be understood with the purpose of determining what dose will prompt the
anticipated therapeutic effect. It will also clarify why the identical dose may cause a therapeutic
effect by one route but a toxic or no effect by another.

Toxicodynamics

Toxicodynamics is the study of the biochemical and physiological effects of toxicants and
regulates their mechanism of action. Toxicodynamics is the process of interaction of chemical
substances with target sites and the subsequent reactions leading to adverse effects. It states
about the molecular, biochemical, and physiological effects of toxicants or their metabolites in
biological systems. These effects are consequence of the interaction of the biologically effective
dose of the active form of the toxicant with a molecular target. Toxicodynamics can be used in
combination with toxicokinetics in environmental risk assessment to determine the potential
effects of releasing a toxicant into the environment.